Alirocumab versus placebo: percent change in calculated LDL cholesterol at week 24

In this section: Registration and administrative information (PROSPERO field set)

Registration and administrative information (PROSPERO field set)

Table 1. Registration and administrative information (PROSPERO field set)
Review title	Alirocumab versus placebo: percent change in calculated LDL cholesterol at week 24
Review question (PICO)	In adults treated for hypercholesterolaemia, how much does alirocumab change calculated LDL cholesterol from baseline to week 24 compared with placebo?
Population	Not shown — pcsk9_lipid_nma is a network protocol whose intervention is the PCSK9 network, not alirocumab alone. State: PROTOCOL_IS_A_NETWORK.
Intervention	Not shown — pcsk9_lipid_nma is a network protocol whose intervention is the PCSK9 network, not alirocumab alone. State: PROTOCOL_IS_A_NETWORK.
Comparator	Not shown — pcsk9_lipid_nma is a network protocol whose intervention is the PCSK9 network, not alirocumab alone. State: PROTOCOL_IS_A_NETWORK.
Background / rationale	Not recorded — this object holds no background field, and an introduction generated without one would be argument that no source in this review supports
Information sources	1 source layers, listed on the Extraction tab
Search strategy	The executed strings, datetimes, filters and hit counts are on the Search tab
Study selection process	A second independent screen was NOT run. No second independent screen was run for this topic. This is recorded as owed rather than described: the remedy is to RUN one, and writing a duplicate-screening sentence without one would be the defect this whole exercise exists to prevent.
Number of screeners	One. No second independent screen was run.
Data extraction items	Extracted per trial on this object: registry id; year; design; arms; per-arm counts and the published effect; the randomised total, separately from the analysed denominator. Fields not listed here were not extracted.
Outcomes and prioritisation	Percent change from baseline in calculated LDL cholesterol at week 24
Risk of bias method	RoB 2, per result, five domains — see the risk-of-bias table below
Synthesis methods	Pooled under random-effects with the REML estimator. These methods were NOT prespecified before the search, and are not presented as though they were.
Subgroup analyses	Not recorded — this object records no subgroup-analysis field at all, so whether any were prespecified is UNKNOWN -- which is not the same as none having been
Meta-bias assessment	Not recorded — no funnel, Egger or Peters value is held on this object, so no meta-bias assessment is claimed
Certainty assessment	GRADE, recorded for 1 outcome(s) (GRADE). The ratings are on the Certainty tab.
Confidence level	95%
Funding	Not recorded — no funding statement is recorded for this review
Competing interests	Not recorded — no declaration is recorded
Built	2026-08-04
Schema	2

In this section: Search — executed, source by source · Search record: search · PRISMA flow · ClinicalTrials.gov API v2 -- query 1, narrow (condition + drug) · ClinicalTrials.gov API v2 -- query 2, broad (intervention only)

Search — executed, source by source

Search record: search

executed_by — lane 1 (Claude, Anthropic family)

Databases: ClinicalTrials.gov API v2 -- QUERY 1, NARROW (condition + drug) (<a href='https://clinicaltrials.gov/api/v2/studies (raw, curl)' rel='noopener'>query</a>), ClinicalTrials.gov API v2 -- QUERY 2, BROAD (intervention only) (<a href='https://clinicaltrials.gov/api/v2/studies (raw, curl)' rel='noopener'>query</a>)

pagination_verified — records_returned == total_reported on BOTH queries (54/54 and 99/99), so neither stopped at a page boundary. Checked explicitly rather than assumed: an outside critic named PAGINATION CURSOR ABANDONMENT -- a fetcher taking page 1 and stopping without raising -- as a class this project could neither rule out nor detect, and it sits at the surfacing stage where withholding leaves no trace in the object.

PRISMA flow

Table 2. PRISMA flow
Stage	Records
identification	{'ctgov_query1': 54, 'ctgov_query2': 99, 'note': 'Query 2 supersedes query 1 for coverage; both recorded.'}
eligibility ctgov	{'role_located': 97, 'topic_is_experimental_arm': 89, 'topic_is_comparator_arm': 5, 'topic_is_background': 3, 'not_assessable': 2}
included	{'in_this_object': 8, 'nct': ['NCT01507831', 'NCT01617655', 'NCT01623115', 'NCT01644175', 'NCT01709500', 'NCT02107898', 'NCT02289963', 'NCT02585778']}
reconciliation	{'arithmetic': '99 identified = 89 experimental + 5 comparator + 3 background + 2 not_assessable; 97 of the 99 had a role located', 'reconciles': True, 'unscreened_remainder': 0, 'remainder_means': '89 trials place alirocumab in the randomised experimental arm; 8 are in this object; the other 81 were ALL SCREENED and the remainder is 0. Dispositions: 34 excluded, 21 eligible but not poolable, 26 eligible with no results yet. The two ELIGIBLE-AND-POOLABLE trials that were in this cell on 2026-08-19 are no longer in it: they were extracted, re-pooled and promoted into the included set, which is the only disposition that closes that cell honestly.'}

ClinicalTrials.gov API v2 -- query 1, narrow (condition + drug)

Query as executed:

query.cond="hypercholesterolemia"; query.intr="alirocumab"; filter.advanced=AREA[StudyType]INTERVENTIONAL; pageSize=200; countTotal=true

ClinicalTrials.gov API v2 -- query 2, broad (intervention only)

Query as executed:

query.intr="alirocumab OR praluent OR SAR236553 OR REGN727"; filter.advanced=AREA[StudyType]INTERVENTIONAL; pageSize=400; countTotal=true

Not held in this object. No screening log is recorded for this review. The included set was reconciled against published syntheses rather than screened from a search, so no records-identified, excluded-with-reason or dual-screening counts exist.

In this section: Extraction — every datum linked to its source · Outcome ldlc_pct_change_wk24 · Extracted values, and where each came from · Recompute envelope — the headline against the rows shown · Outcome ldlc_pct_change_wk24 · Absolute effect at a baseline risk the reader chooses · Risk of bias (RoB-2) · Overall judgement per trial · Inter-assessor agreement · References · Included studies · Regulatory documents · Methods and guidance · Sources · Percent change from baseline in calculated LDL cholesterol at week 24 · Percent change from baseline in calculated LDL cholesterol at week 24 · Pooled result · What other estimators give on the same values · Contributing trials · Endpoint definitions, read from the registry

Extraction — every datum linked to its source

Every per-trial value this review pools, with a link to the record it came from. Derived by ssot/projectors_evidence.py for any topic whose rows carry an NCT, a PMID, an ISRCTN or a source URL.

8 of 8 rows are linked to a source; 0 carry no identifier and are shown as unlinked rather than omitted.

Outcome ldlc_pct_change_wk24

Every extracted value with a link to the record it was read from.
Trial	Source	Linked via	Effect	Counts as posted	Provenance
NCT01507831 — the registry records no acronym for this trial	NCT01507831	nct	MD -61.9 (-64.3 to -59.4)	—	the least-squares mean difference the registry posts, read as printed
NCT01617655 — the registry records no acronym for this trial	NCT01617655	nct	MD -39.1 (-51.1 to -27.1)	—	the least-squares mean difference the registry posts, read as printed
NCT01623115 — the registry records no acronym for this trial	NCT01623115	nct	MD -57.9 (-63.3 to -52.6)	—	the least-squares mean difference the registry posts, read as printed
NCT01644175 — the registry records no acronym for this trial	NCT01644175	nct	MD -45.9 (-52.5 to -39.3)	—	the least-squares mean difference the registry posts, read as printed
NCT01709500 — the registry records no acronym for this trial	NCT01709500	nct	MD -51.4 (-58.1 to -44.8)	—	the least-squares mean difference the registry posts, read as printed
NCT02107898 — the registry records no acronym for this trial	NCT02107898	nct	MD -64.1 (-68.5 to -59.8)	—	the least-squares mean difference the registry posts, read as printed
NCT02289963 — the registry records no acronym for this trial	NCT02289963	nct	MD -63.4 (-71.58 to -55.22)	—	READ from the trial's own posted results: LS means placebo 6.3 (SE 2.9), alirocumab -57.1 (SE 3.0). MD = -57.1 - 6.3; SE = sqrt(3.0^2 + 2.9^2). Neither figure computed from another cell.
NCT02585778 — the registry records no acronym for this trial	NCT02585778	nct	MD -48.83 (-53.74 to -43.92)	—	ASSEMBLED, and labelled so. This trial POSTS NO SINGLE OVERALL ESTIMATE: ODYSSEY DM-INSULIN reports its primary separately for T1DM (alirocumab -51.8 SE 3.7, n=49; placebo -3.9 SE 5.3, n=25) and T2DM (alirocumab -48.2 SE 1.6, n=287; placebo 0.8 SE 2.2, n=142). Stratum contrasts T1DM -47.90 (SE 6.464) and T2DM -49.00 (SE 2.720) were combined by FIXED-EFFECT inverse variance, because the strata are DISJOINT participants from ONE randomisation (Handbook 6.5 s23.3, combining groups). Fixed-effect and not random: this is one trial, not two.

Extracted values, and where each came from

One row per extracted value. Every row carries the value, the verbatim sentence it was read from, a resolvable link to the source, and whether the number was read or derived. Where any of those is absent the row says so rather than omitting the value.

Table 5. Extracted values, and where each came from
Trial / outcome	Value as extracted	Verbatim source sentence	Source links	Read or derived
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk ldlc_pct_change_wk24	MD -61.9 (95% CI -64.3 to -59.4)	“Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis” “LS Mean Difference -61.9, 95% CI -64.3 to -59.4, Mixed Models Analysis” “Placebo Q2W 0.8; Alirocumab 150 mg Q2W -61.0 (percent change)”	NCT01507831 · source	READ from the source as printed The value is the LEAST-SQUARES MEAN DIFFERENCE the registry posts for this outcome, from the trial's own mixed model. It is read as printed. It is NOT computed from the two arm means shown beside it, and it is not a raw difference of observed means: the model's handling of missing data is inside the number and cannot be separated from it here.
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia ldlc_pct_change_wk24	MD -39.1 (95% CI -51.1 to -27.1)	“Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis” “LS mean difference -39.1, 95% CI -51.1 to -27.1, Mixed Models Analysis” “Placebo Q2W -6.6; Alirocumab 150 mg Q2W -45.7 (percent change)”	NCT01617655 · source	READ from the source as printed The value is the LEAST-SQUARES MEAN DIFFERENCE the registry posts for this outcome, from the trial's own mixed model. It is read as printed. It is NOT computed from the two arm means shown beside it, and it is not a raw difference of observed means: the model's handling of missing data is inside the number and cannot be separated from it here.
Alirocumab versus placebo on top of stable lipid-modifying therapy ldlc_pct_change_wk24	MD -57.9 (95% CI -63.3 to -52.6)	“Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis” “LS mean difference -57.9, 95% CI -63.3 to -52.6, Mixed Models Analysis” “Placebo 9.1; Alirocumab 75 mg/Up to 150 mg Q2W -48.8 (percent change)”	NCT01623115 · source	READ from the source as printed The value is the LEAST-SQUARES MEAN DIFFERENCE the registry posts for this outcome, from the trial's own mixed model. It is read as printed. It is NOT computed from the two arm means shown beside it, and it is not a raw difference of observed means: the model's handling of missing data is inside the number and cannot be separated from it here.
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk ldlc_pct_change_wk24	MD -45.9 (95% CI -52.5 to -39.3)	“Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis” “LS Mean Difference -45.9, 95% CI -52.5 to -39.3, Mixed Models Analysis” “Placebo Q2W -2.3; Alirocumab 75/150 mg Q2W -48.2 (percent change)”	NCT01644175 · source	READ from the source as printed The value is the LEAST-SQUARES MEAN DIFFERENCE the registry posts for this outcome, from the trial's own mixed model. It is read as printed. It is NOT computed from the two arm means shown beside it, and it is not a raw difference of observed means: the model's handling of missing data is inside the number and cannot be separated from it here.
Alirocumab in heterozygous familial hypercholesterolaemia ldlc_pct_change_wk24	MD -51.4 (95% CI -58.1 to -44.8)	“Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis” “LS Mean Difference -51.4, 95% CI -58.1 to -44.8, Mixed Models Analysis” “Alirocumab 75 mg/up to 150 mg -48.7; Placebo 2.8 (percent change). NOTE the registry lists the ALIROCUMAB arm FIRST on this record and the placebo arm second, the reverse of the other five. The posted difference is still alirocumab minus placebo and still negative; the order is recorded so a reader comparing rows does not read a sign error into it.”	NCT01709500 · source	READ from the source as printed The value is the LEAST-SQUARES MEAN DIFFERENCE the registry posts for this outcome, from the trial's own mixed model. It is read as printed. It is NOT computed from the two arm means shown beside it, and it is not a raw difference of observed means: the model's handling of missing data is inside the number and cannot be separated from it here.
Alirocumab in heterozygous familial hypercholesterolaemia, Japan ldlc_pct_change_wk24	MD -64.1 (95% CI -68.5 to -59.8)	“Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT Analysis)” “LS Mean Difference -64.1, 95% CI -68.5 to -59.8, Mixed Models Analysis” “Placebo Q2W 1.6; Alirocumab 75 mg/Up to 150 mg Q2W -62.5 (percent change)”	NCT02107898 · source	READ from the source as printed The value is the LEAST-SQUARES MEAN DIFFERENCE the registry posts for this outcome, from the trial's own mixed model. It is read as printed. It is NOT computed from the two arm means shown beside it, and it is not a raw difference of observed means: the model's handling of missing data is inside the number and cannot be separated from it here.

Recompute envelope — the headline against the rows shown

Derived by ssot/recompute_envelope.py. The pooled number is recomputed from the per-trial rows this same page shows, so the arithmetic between the extraction table and the headline is checkable with no tool the reader does not already have.

Outcome ldlc_pct_change_wk24

Table 6. Outcome ldlc_pct_change_wk24
Source	Point	95% CI
stored on this page	-54.72	—
fixed effect, recomputed from the rows	-58.3065	-59.9657 to -56.6474
DerSimonian-Laird, recomputed	-54.8196	-60.2251 to -49.4142

AGREES -- the stored point lies between the fixed-effect and DerSimonian-Laird estimates computed from the rows this page shows.

Scale used: identity. Declared estimator: REML.

It proves the ARITHMETIC between the extraction table and the headline. It cannot detect a wrong count, a swapped arm or a mis-specified model, because it re-runs the same inputs.

DerSimonian-Laird is biased at k below about ten and this project uses REML. DL is here only to WIDEN the envelope so a REML point falls inside it; it is never offered as the review's estimate.

Absolute effect at a baseline risk the reader chooses

Derived by ssot/absolute_effect.py for any topic with a pooled ratio measure AND a declared indirectness argument. Where either is missing it DECLINES with a reason rather than emitting a table the review has not licensed — a ratio becomes an absolute effect only against a baseline risk, and a baseline risk belongs to a population.

Outcome ldlc_pct_change_wk24 — NOT EMITTED. The summary measure is 'MD', read from results.by_outcome.ldlc_pct_change_wk24.pooled.measure, which is not a ratio. An absolute effect needs a ratio and a baseline risk.

Risk of bias (RoB-2)

Variant:

Unit assessed: A result, not a study -- Handbook 8.2: 'risk of bias is assessed for a specific result'. Every judgement below names its outcome.

Assessor 1: (anthropic family). Assessor 2: (openai family).

Table 7. Risk of bias (RoB-2)
Trial	Result assessed	Domain	Assessor 1 (anthropic)	Assessor 2 (openai)	Agreed
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D1 D1_randomisation	some concerns	no information	NO
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D2 D2_deviations	some concerns	no information	NO
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D3 D3_missing_outcome_data	some concerns	no information	NO
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D4 D4_measurement	some concerns	LOW	NO
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D5 D5_selection_of_result	some concerns	some concerns	yes
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D1 D1_randomisation	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D2 D2_deviations	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D3 D3_missing_outcome_data	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D4 D4_measurement	some concerns	LOW	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D5 D5_selection_of_result	some concerns	LOW	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy	Percent change from baseline in calculated LDL cholesterol at week 24	D1 D1_randomisation	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy	Percent change from baseline in calculated LDL cholesterol at week 24	D2 D2_deviations	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy	Percent change from baseline in calculated LDL cholesterol at week 24	D3 D3_missing_outcome_data	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy	Percent change from baseline in calculated LDL cholesterol at week 24	D4 D4_measurement	some concerns	LOW	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy	Percent change from baseline in calculated LDL cholesterol at week 24	D5 D5_selection_of_result	some concerns	LOW	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D1 D1_randomisation	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D2 D2_deviations	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D3 D3_missing_outcome_data	some concerns	no information	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D4 D4_measurement	some concerns	LOW	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	D5 D5_selection_of_result	some concerns	LOW	NO
Alirocumab in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D1 D1_randomisation	some concerns	no information	NO
Alirocumab in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D2 D2_deviations	some concerns	no information	NO
Alirocumab in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D3 D3_missing_outcome_data	some concerns	no information	NO
Alirocumab in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D4 D4_measurement	some concerns	LOW	NO
Alirocumab in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	D5 D5_selection_of_result	some concerns	LOW	NO
Alirocumab in heterozygous familial hypercholesterolaemia, Japan	Percent change from baseline in calculated LDL cholesterol at week 24	D1 D1_randomisation	some concerns	no information	NO
Alirocumab in heterozygous familial hypercholesterolaemia, Japan	Percent change from baseline in calculated LDL cholesterol at week 24	D2 D2_deviations	some concerns	no information	NO
Alirocumab in heterozygous familial hypercholesterolaemia, Japan	Percent change from baseline in calculated LDL cholesterol at week 24	D3 D3_missing_outcome_data	some concerns	no information	NO
Alirocumab in heterozygous familial hypercholesterolaemia, Japan	Percent change from baseline in calculated LDL cholesterol at week 24	D4 D4_measurement	some concerns	LOW	NO
Alirocumab in heterozygous familial hypercholesterolaemia, Japan	Percent change from baseline in calculated LDL cholesterol at week 24	D5 D5_selection_of_result	some concerns	LOW	NO

Overall judgement per trial

Table 8. Overall judgement per trial
Trial	Result assessed	Assessor 1 (anthropic)	Assessor 2 (openai)	Agreed
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	some concerns	some concerns	yes
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	some concerns	no overall judgement reached — this assessor answered “no information”, which RoB 2 defines as a response to a signalling question and not as one of the three overall categories (low, some concerns, high)	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy	Percent change from baseline in calculated LDL cholesterol at week 24	some concerns	no overall judgement reached — this assessor answered “no information”, which RoB 2 defines as a response to a signalling question and not as one of the three overall categories (low, some concerns, high)	NO
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	Percent change from baseline in calculated LDL cholesterol at week 24	some concerns	no overall judgement reached — this assessor answered “no information”, which RoB 2 defines as a response to a signalling question and not as one of the three overall categories (low, some concerns, high)	NO
Alirocumab in heterozygous familial hypercholesterolaemia	Percent change from baseline in calculated LDL cholesterol at week 24	some concerns	no overall judgement reached — this assessor answered “no information”, which RoB 2 defines as a response to a signalling question and not as one of the three overall categories (low, some concerns, high)	NO
Alirocumab in heterozygous familial hypercholesterolaemia, Japan	Percent change from baseline in calculated LDL cholesterol at week 24	some concerns	no overall judgement reached — this assessor answered “no information”, which RoB 2 defines as a response to a signalling question and not as one of the three overall categories (low, some concerns, high)	NO

Inter-assessor agreement

This assessment is DUAL — two assessors from different model families, the second asked blind. The agreement rate is withheld pending adjudication. Both readers were given this review’s decision rule; an earlier version of this sentence said the blinding had withheld it, and that was wrong. What the 30 domain comparison(s) show is a reading difference that runs in OPPOSITE directions by domain — on domains 1 to 3 the second assessor more often declines to judge at all, and on domains 4 and 5 it more often judges low. A single agreement rate averages those two behaviours into one number that describes neither. Both assessors’ per-result judgements are shown in the table above, unadjudicated, and neither is this review’s finding. No adjudication has been performed, so this review holds no final risk-of-bias judgement for these results.

References

Included studies

Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk — https://clinicaltrials.gov/study/NCT01507831
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia — https://clinicaltrials.gov/study/NCT01617655
Alirocumab versus placebo on top of stable lipid-modifying therapy — https://clinicaltrials.gov/study/NCT01623115
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk — https://clinicaltrials.gov/study/NCT01644175
Alirocumab in heterozygous familial hypercholesterolaemia — https://clinicaltrials.gov/study/NCT01709500
Alirocumab in heterozygous familial hypercholesterolaemia, Japan — https://clinicaltrials.gov/study/NCT02107898
Alirocumab versus placebo on top of lipid-modifying therapy — https://clinicaltrials.gov/study/NCT02289963
Alirocumab versus placebo in insulin-treated diabetes (ODYSSEY DM-INSULIN) — https://clinicaltrials.gov/study/NCT02585778

Regulatory documents

Methods and guidance

Sources

Table 9. Sources
Layer	Source	How it was obtained
Registry	ClinicalTrials.gov posted results: primary outcome measures and their statistical analyses https://clinicaltrials.gov/	Every included trial's posted results were retrieved from the registry API and read field by field. Each contributes a least-squares mean difference with a 95 per cent interval from the trial's own analysis; no effect was reconstructed.

Percent change from baseline in calculated LDL cholesterol at week 24

Pooled result

MD -54.72 (-60.62 to -48.82), 95% interval

Percent change from baseline in calculated LDL cholesterol at week 24. random, estimator REML, k = 8.

τ² 61.44 · I² 90.02% · Q 58.42 on 7 df

Favours: the intervention (lower is better)

high

Every included trial reports this outcome with an effect estimate and an interval.

How to read this: Between-trial variation is high: I-squared is 90.0 per cent and tau-squared 61.44 under REML. The trials differ in background statin therapy, in population, and in dose regimen, so the pooled figure summarises a range of settings rather than estimating one common effect. Heterogeneity was already high at k=6 (I-squared 87.9) and the recovery did not create it.

Prediction interval -74.57 to -34.87

This is the number to quote, and it is not the headline. The confidence interval -60.62 to -48.82 is about where the average lies. The prediction interval -71.18 to -38.26 is about where the effect in a new trial of this drug would lie, and it is over three times wider. The eight trials range from -39.1 to -64.1 with tight intervals of their own, so the spread is real and not sampling noise: dose regimen differs, as do population and background statin therapy. A single number for 'how much does alirocumab lower LDL' conceals a 25-point range. [restated 2026-08-20: this paragraph quoted the confidence interval and the prediction interval to one decimal, and the number guard on this pass generates two-, three- and four-decimal forms only, so a one-decimal quotation walks past it. Widening the guard to one decimal would fire on most sentences in the corpus; this is restated by hand instead, and the gap is named rather than closed. Found on the rendered page after both guards passed.]

What other estimators give on the same values

Table 10. What other estimators give on the same values
Estimator	τ²	I²	Pooled (95%)
DerSimonian-Laird	50.04	88%	-54.82 (-60.23 to -49.42)
REML (as displayed)	61.44	90%	-54.72 (-60.62 to -48.82)
REML with Hartung-Knapp-Sidik-Jonkman t_7 = 2.3646, not a normal quantile	61.44	90%	-54.72 (-62.06 to -47.38)

The point estimate barely moves -- 54.8 against 54.7 percent -- and no reading of the direction or the magnitude changes. The interval moves: 10.8 points wide under DerSimonian-Laird, 11.8 under REML, 14.7 under REML with Hartung-Knapp. A reader who wants the most conservative statement of what eight trials establish should take the last of those.

I-squared sits exactly on the threshold, and which side depends on the definition as well as the estimator. 88.0 per cent under DerSimonian-Laird and 90.0 under REML on metafor's definition; 88.0 under both on Higgins's. This project's poolability screen treats 90 per cent as the point at which an average conceals more than it conveys, so at k=8 the verdict on whether these eight trials should be averaged at all lands ON the line rather than clearly either side of it. At k=6 the REML figure was 91.6 and clearly across. The recovery moved this toward poolability, which is the opposite direction from the one that would flatter a decision already taken, and is stated for that reason.

Contributing trials

Table 11. Contributing trials
Trial	Analysed treatment / control	MD (95% CI), or events	Source of this cell
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk NCT01507831 · SECONDARY -- this trial's only primary outcome is the proportion of participants with adverse events, because it was designed as a long-term safety study	1530 / 780	-61.9 (-64.3 to -59.4)	registry: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis LS Mean Difference -61.9, 95% CI -64.3 to -59.4, Mixed Models Analysis Placebo Q2W 0.8; Alirocumab 150 mg Q2W -61.0 (percent change)
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia NCT01617655 · PRIMARY outcome	71 / 35	-39.1 (-51.1 to -27.1)	registry: Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis LS mean difference -39.1, 95% CI -51.1 to -27.1, Mixed Models Analysis Placebo Q2W -6.6; Alirocumab 150 mg Q2W -45.7 (percent change)
Alirocumab versus placebo on top of stable lipid-modifying therapy NCT01623115 · PRIMARY outcome	322 / 163	-57.9 (-63.3 to -52.6)	registry: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis LS mean difference -57.9, 95% CI -63.3 to -52.6, Mixed Models Analysis Placebo 9.1; Alirocumab 75 mg/Up to 150 mg Q2W -48.8 (percent change)
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk NCT01644175 · PRIMARY outcome	205 / 106	-45.9 (-52.5 to -39.3)	registry: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis LS Mean Difference -45.9, 95% CI -52.5 to -39.3, Mixed Models Analysis Placebo Q2W -2.3; Alirocumab 75/150 mg Q2W -48.2 (percent change)
Alirocumab in heterozygous familial hypercholesterolaemia NCT01709500 · PRIMARY outcome	166 / 81	-51.4 (-58.1 to -44.8)	registry: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis LS Mean Difference -51.4, 95% CI -58.1 to -44.8, Mixed Models Analysis Alirocumab 75 mg/up to 150 mg -48.7; Placebo 2.8 (percent change). NOTE the registry lists the ALIROCUMAB arm FIRST on this record and the placebo arm second, the reverse of the other five. The posted difference is still alirocumab minus placebo and still negative; the order is recorded so a reader comparing rows does not read a sign error into it.
Alirocumab in heterozygous familial hypercholesterolaemia, Japan NCT02107898 · PRIMARY outcome	143 / 72	-64.1 (-68.5 to -59.8)	registry: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT Analysis) Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT Analysis) LS Mean Difference -64.1, 95% CI -68.5 to -59.8, Mixed Models Analysis Placebo Q2W 1.6; Alirocumab 75 mg/Up to 150 mg Q2W -62.5 (percent change)
NCT02289963 NCT02289963	not held	MD -63.4 (95% CI -71.58 to -55.22)	READ from the trial's own posted results: LS means placebo 6.3 (SE 2.9), alirocumab -57.1 (SE 3.0). MD = -57.1 - 6.3; SE = sqrt(3.0^2 + 2.9^2). Neither figure computed from another cell. recovered from results.by_outcome.ldlc_pct_change_wk24.per_trial[6]; this trial carries no `by_outcome` entry on the object, so the cell-level provenance the other rows show is not held for it.
NCT02585778 NCT02585778	not held	MD -48.83 (95% CI -53.74 to -43.92)	ASSEMBLED, and labelled so. This trial POSTS NO SINGLE OVERALL ESTIMATE: ODYSSEY DM-INSULIN reports its primary separately for T1DM (alirocumab -51.8 SE 3.7, n=49; placebo -3.9 SE 5.3, n=25) and T2DM (alirocumab -48.2 SE 1.6, n=287; placebo 0.8 SE 2.2, n=142). Stratum contrasts T1DM -47.90 (SE 6.464) and T2DM -49.00 (SE 2.720) were combined by FIXED-EFFECT inverse variance, because the strata are DISJOINT participants from ONE randomisation (Handbook 6.5 s23.3, combining groups). Fixed-effect and not random: this is one trial, not two. recovered from results.by_outcome.ldlc_pct_change_wk24.per_trial[7]; this trial carries no `by_outcome` entry on the object, so the cell-level provenance the other rows show is not held for it.

Every contributing trial analysed this endpoint with a least-squares mean from its own model. The values combined here are those model-based differences, not raw arm means, so the synthesis inherits each trial's modelling choices.

Endpoint definitions, read from the registry

What each trial COUNTED, in its own registry record's words, before anything here was pooled. A sentence saying what HAPPENED is not a sentence saying what was COUNTED, and only the second one licenses a pool. Read from the registry on 2026-08-17. Follow the registration link to disagree with any row.

Table 12. Endpoint definitions, read from the registry
Trial	Rank in its own trial	Registered outcome measure	Description, verbatim	Analysis set / window
Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk NCT01507831	SECONDARY -- this trial's only PRIMARY outcome is the proportion of participants with adverse events, because it was designed as a long-term safety study. An earlier build EXCLUDED this trial for posting no LDL result, which came from reading primary outcomes only; it is the largest trial in the set.	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis	no description is recorded in this registry field	From Baseline to Week 52
Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia NCT01617655	PRIMARY	Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis	no description is recorded in this registry field	From Baseline to Week 52
Alirocumab versus placebo on top of stable lipid-modifying therapy NCT01623115	PRIMARY	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis	no description is recorded in this registry field	From Baseline to Week 52
Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk NCT01644175	PRIMARY	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis	no description is recorded in this registry field	From Baseline to Week 52
Alirocumab in heterozygous familial hypercholesterolaemia NCT01709500	PRIMARY	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis	no description is recorded in this registry field	From Baseline to Week 52
Alirocumab in heterozygous familial hypercholesterolaemia, Japan NCT02107898	PRIMARY	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT Analysis)	no description is recorded in this registry field	From Baseline to Week 52

In this section: Percent change from baseline in calculated LDL cholesterol at week 24 · Forest plot · Visual abstract · Risk of bias, both assessors · GOSH · Trial-sequential analysis · Meta-regression

Percent change from baseline in calculated LDL cholesterol at week 24

Forest plot

Drawn from the same stored estimates the table above lists. Box area is proportional to inverse-variance weight.

x-axis range

Fit to data

⬇ SVG (vector) 3 KB ⬇ PNG 4500x1940 254 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 90519f168ba8dcad), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — forest_fit.eps, 6 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — forest_fit.tiff, 25,576 KB.

Changing the range moves the axis window only. The guides stay labelled with the null and the extremes of the plotted intervals, so no plotted value and no printed number differs between these views — and that is checked at build time, not asserted. Ranges not offered because they would crop the data: 0.5 to 2, 0.25 to 4, 0.7 to 1.3.

Visual abstract

⬇ SVG (vector) 2 KB ⬇ PNG 4500x2100 280 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 086766cbef02cc3c), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — visual-abstract.eps, 4 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — visual-abstract.tiff, 27,685 KB.

Projected from the canonical object, so it carries the same k, the same pooled estimate and the same interval as the paper and cannot drift from them. The interval is drawn to scale against the no-difference line, which it EXCLUDES: -60.62 to -48.82, with no difference at 0.

Risk of bias, both assessors

⬇ SVG (vector) 26 KB

Only the vector format is offered for this figure, by choice: it is line art — discrete marks, glyphs and labels — which SVG reproduces exactly at any size, so a raster would add weight without adding fidelity. The build was able to rasterise; it was asked not to.

Every cell carries BOTH independent cross-family assessments and they are not reconciled: showing one column would be a reconciliation presented as an observation. Glyph as well as colour, so the panel survives greyscale printing and colour-blind reading. A trial with no judgement is shown as a row of not-assessed markers rather than omitted, so a gap in the assessment cannot be mistaken for a clean assessment. Agreement as measured: {'per domain agreed': 1, 'per domain total': 30, 'per domain rate pct': 3.3, 'overall agreed': 1, 'overall total': 6, 'overall is derived': True, 'recomputed from the stored judgements': True, 'why recomputed': 'The stored disagreement tallies were frozen as text and 12 of 22 no longer match the judgements in the object -- a later guidance pass moved 51 the randomisation process judgements and the tallies were never recomputed. This is derived from what the object holds now.'}.

GOSH

⬇ SVG (vector) 1 KB ⬇ PNG 3500x540 83 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: c720a7de9de37e01), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — gosh.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — gosh.tiff, 5,537 KB.

Deliberately not drawn. Every subset meta-analysis of 8 trials is 255 points; a cloud that small cannot show the multimodality GOSH exists to reveal, and a reader would take the picture as evidence of its absence.

Trial-sequential analysis

⬇ SVG (vector) 1 KB ⬇ PNG 3500x650 87 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 25ed9800fdf56614), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — tsa.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — tsa.tiff, 6,665 KB.

TSA boundaries depend entirely on a target information size that must be pre-specified. This review's protocol registers none, so any boundary drawn here would be a parameter chosen after seeing the data -- which is the practice TSA exists to protect against.

Meta-regression

⬇ SVG (vector) 1 KB ⬇ PNG 3500x540 87 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 8aa6f20fadbfab6a), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — bubble.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — bubble.tiff, 5,537 KB.

The protocol pre-specifies no moderator, and at k = 8 a meta-regression would be fitted on 8 points. Not drawn rather than drawn with a caveat: a bubble plot invites reading a slope, and there is no slope here that any reader should read.

In this section: Summary of findings · Reproducibility artifact · Other recorded qualifications · Judgement register — what a harness cannot derive · Outcome ldlc_pct_change_wk24 — 0 of 8 declared, 8 of 8 undeclared · Comparison with published syntheses · The syntheses reconciled against · Where the numbers differ, and why

Summary of findings

Table 13. Summary of findings
Outcome	k	Pooled effect	Certainty
Percent change from baseline in calculated LDL cholesterol at week 24	8	MD -54.7 (-60.6 to -48.8)	Pending¹²

This certainty rating is PENDING, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.
Read this beside `whether the estimand was established`. That flag records that every contributing trial measures the same quantity. It records nothing about what that quantity was measured against -- whether the comparators are of one kind, whether each comparison was randomised, whether it was concurrent. The two questions were never separated. Named as P48 in PAGE-STANDARD.md v1.21.0 and swept by scripts/audit_mixed_contrast_pools.py.

Reproducibility artifact

Table 14. Reproducibility artifact
Canonical object	`—`
Registered at	`—` —
Schema	2
Object last updated	2026-08-04
Source object SHA-256, first 16 hex characters	`2a686b11210f0841`
Page generated	2026-09-04 00:01 UTC
Generator build	`66c1ed934` (uncommitted generator changes -- NOT REPRODUCIBLE from this stamp alone), built to STANDARD v1

This page CANNOT be rebuilt from what is recorded here: no canonical object is recorded and no registered commit is recorded. Each figure on the Analysis tab downloads as an SVG carrying exactly the values shown.

Other recorded qualifications

Statements this review records about the limits of what it establishes, which are not shown elsewhere on this page. They are reproduced from the object verbatim and are not summarised.

Table 15. Other recorded qualifications
Interpretation caveat	Between-trial variation is high: I-squared is 90.0 per cent and tau-squared 61.44 under REML. The trials differ in background statin therapy, in population, and in dose regimen, so the pooled figure summarises a range of settings rather than estimating one common effect. Heterogeneity was already high at k=6 (I-squared 87.9) and the recovery did not create it.
Was labelled as displayed until	This row was labelled 'DerSimonian-Laird (as displayed)' until 2026-08-20. It is not displayed any more: the headline moved to REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." The label is removed rather than the row, because the row is a correct record of what this estimator gives on these values and that has not changed.
Estimator note superseded	Inherited and open, not endorsed. This object declares DerSimonian-Laird, which is biased for k<10. That was already questionable at k=6 and remains so at k=8. REML on the same eight trials gives -54.72 (-60.62 to -48.82) with tau2 61.44 and I-squared 90.0, and a prediction interval of -71.18 to -38.26. It is reported beside the DL figure rather than substituted for it, because changing the estimator and the trial set in one step would make neither change attributable. A reader should treat the estimator choice as open.
Interpretation caveat superseded	Between-trial variation is high: I-squared is 88.0 per cent and tau-squared 50.04. The trials differ in background statin therapy, in population, and in dose regimen, so the pooled figure summarises a range of settings rather than estimating one common effect. Heterogeneity was already high at k=6 (I-squared 87.9) and the recovery did not create it.
Scope	PCSK9 monoclonal antibodies in familial hypercholesterolaemia
Scope	alirocumab at three dose strategies against placebo and ezetimibe, network meta-analysis
Scope	phase 3 alirocumab trials in hypercholesterolaemia and familial hypercholesterolaemia
Scope	narrative review of PCSK9 inhibition in chronic kidney disease
Withholding question asked at every rank	For each trial, every registered outcome rank was read before concluding it does not pool -- primaries and all secondaries, not the primary alone. Recorded because 'it does not report our estimand' is a claim about the whole registration and is cheap to assert from the primary outcome alone.
And the weaker ground is not leaned on	Terminated at n=3 of a planned enrolment. That would settle it on status alone, and it is deliberately not the stated ground: deciding a trial on 'it stopped early' when a criterion settles it manufactures a firmer verdict than the evidence supports, and it would hide that this population was never in scope.
The two that matter superseded	NCT02585778 (n=517) and NCT02289963 (n=199) both register 'Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat' -- word for word this object's estimand -- and both randomise alirocumab against placebo on background lipid-modifying therapy. Neither was in this object's six when screening found them. That was not a screening outcome; it was a gap in this review's own evidence base. Both are now in the included set: extracted from their own posted results, re-pooled, and the old and new estimates shown side by side (recovery 2026 08 19). k went 6 -> 8 and the point moved 0.16 points, from -54.66 to -54.82 -- the recovery confirms the estimate rather than overturning it, which is the honest headline and is why it is stated here rather than only where it flatters.
Two separate corrections in one restatement	They are not the same correction and are not merged. (1) The classifier moved three of the 99 surfaced records, under the trailing-placebo repair of commit e20f94068. (2) The included count was already 8 in inputs.trials and in results.by_outcome after the 2026-08-19 recovery, while the cascade and the PRISMA flow still said 6. Only (1) is a movement; (2) is a slot that was never updated when the headline was.
Evidence and why it does not settle	The intervention list is not sufficient and this is the element that proved it. Four candidate trials are DOUBLE-DUMMY designs -- ODYSSEY mono randomises alirocumab plus placebo-for-ezetimibe against ezetimibe plus placebo-for-alirocumab -- so a placebo is present in both arms as the blinding device while the comparator is ezetimibe. The presence of a placebo does not mean the comparator is placebo. Settled instead by reading each ARM: a control-arm drug that is neither a placebo nor present in every arm. That is a derived judgement and is labelled one.
Why this is stated rather than left implicit	A rating of some concerns with no explanation reads as a judgement against the trial. Omitting the reason would manufacture a criticism exactly as a low-by-default manufactures a reassurance -- the same defect pointed the other way.
Registry facts backfilled	Read from ClinicalTrials.gov API v2 on 2026-08-21. The judgements above were not revisited -- this adds the registry evidence beside a verdict that was made from it and did not record it, so a blind second assessor can be shown the same facts. A second assessment built on fewer facts is not a comparable assessment.
What would bound it	Extracting every result this trial reports for this outcome domain and showing what the pool does under each. That is not held for any trial in this object, so the size of this risk is unmeasured rather than small.
This does not replace the stored judgement	This is the judgement the published algorithm proposes from the signalling responses named here. It does not replace the stored `judgement` beside it, and nothing reads it yet. The tool itself says its algorithms "provide proposed judgements, but users should verify these and change them if they feel this is appropriate" -- so this is an input to a person, not an output to a reader.
The allow list the rate is conditional on	A disagreement rate is meaningless without the facts both assessors saw, so the list is stated here the way a denominator is stated. Fields emitted: trial, cohort, registered enrolment, registered masking, registered sites, registered comparator, number of registered arms, number of registered primary outcomes, registered primary outcome, registered analysis population, the rank the pooled result holds, the result being assessed, participants this review pools, registered enrolment minus participants pooled. Established by test, not argument: widening this list from 9 fields to 14 halved gepotidacin's disagreement -- its entire selection of the reported result divergence was a fact the second assessor had never been shown -- and left ceftaroline and tigecycline unmoved.
Which risk of bias domains drove the rating	Where a result is rated worse than LOW overall, the domain carrying that judgement is: selection of the reported result on 6 result(s). The overall rating is the worst domain, so these are the domains that determine it.

Judgement register — what a harness cannot derive

Judgements a harness cannot derive, per outcome, with the alternative and its consequence. DERIVED AT BUILD TIME by ssot/topic_judgements.py — this table is not written for this topic and the same code produces it for every topic.

⛔ No entry is resolved by inferring from the included trials. Deriving a review's question from the populations that were enrolled returns DIRECT by construction. Where the store does not declare a judgement this table says UNDECLARED and stops.

Outcome ldlc_pct_change_wk24 — 0 of 8 declared, 8 of 8 undeclared

Table 16. Outcome ldlc_pct_change_wk24 — 0 of 8 declared, 8 of 8 undeclared
Judgement	State	Decided	Decided by	Alternative	If the alternative had been taken
`QUESTION_PICO`	UNDECLARED	NOT DECLARED -- missing axes: population, intervention, comparator, outcome	NOBODY. The review question exists as prose and has never been resolved into axes.	Declare it, axis by axis.	⛔ WITHOUT IT THE INDIRECTNESS DOMAIN CANNOT BE COMPARED AXIS BY AXIS AT ALL. Prose cannot be compared with prose. Any indirectness rating on this topic is therefore a stored judgement or an absence, never a derivation.
`ELIGIBILITY_RULE`	UNDECLARED	NO RULE STATES BOTH A COMPARATOR AND AN OUTCOME CRITERION. comparator named: False; outcome named: False	⚠️ ENACTED RATHER THAN DECLARED. Where a screen tests only phase and randomisation, the comparator and outcome criteria are applied as per-case verdicts, and a harness cannot regenerate the rule from what is written.	State the rule.	⛔ A CANDIDATE COUNT IS NOT AN ELIGIBILITY DECISION. A drug-only concept block returned an identical 125 candidates across six colchicine topics in this corpus; the count says nothing about which of them belong.
`COUNT_TIER`	UNDECLARED	ONE COUNT BASIS: none recorded	NOT RECORDED on any contributing row.	The other tier, where the trial has one.	NOT COMPUTED -- the store holds only one basis, so the alternative cannot be evaluated without going back to the sources.
`INDIRECTNESS`	UNDECLARED	NO STORED JUDGEMENT AND NO DECLARED question_pico.	NOBODY. The domain cannot be derived without both PICOs and it has not been judged by hand either.	Declare question_pico, or judge the domain explicitly.	⛔ Until one of the two happens the domain is neither rated nor refused -- it is simply missing, which reads to a reader as no concern.
`ESTIMAND`	UNDECLARED	⚠️ CONTRIBUTING TRIALS REPORT 4 DIFFERENT PRIMARY TIME FRAMES: From Baseline to Week 24 \| From Baseline to Week 24; From Baseline up to 10 weeks after last study drug administration (maximum of 32 weeks) \| From Baseline to Week 52 \| Up to 10 weeks after last study drug administration (maximum of 86 weeks). The pool combines them on one scale.	A HUMAN, and often as a SIDE EFFECT of the count tier rather than as its own decision -- a registry reports participants and so forces a risk ratio; a publication reports person-years and so forces a rate ratio. Choosing the document chose the measure.	Pool on person-time instead, which is estimand-consistent under unequal follow-up.	NOT COMPUTED -- person-time denominators are not in this store. Where a topic holds them the alternative is one line.
`IMPRECISION_THRESHOLD`	UNDECLARED	NO THRESHOLD DECLARED.	⚠️ NOBODY. The engine falls back to the Handbook rough guide of 0.75 to 1.25 -- which means the most consequential line on the page is drawn by a default rather than by a clinical judgement.	Declare one, justified from ABSOLUTE effect rather than from the ratio.	The imprecision domain would rest on a stated, arguable line instead of an unexamined default.
`HARMS_POOLING`	UNDECLARED	NO HARMS OUTCOME IS HELD.	NOBODY -- the review carries benefit only.	Extract harms.	⛔ OUTCOME SCOPE IS BENEFIT-ONLY. A reader cannot weigh anything against anything.
`INDEX_ENTRY`	UNDECLARED	The object does not carry the sentence the portfolio index shows.	⚠️ A HUMAN, IN THE INDEX GENERATOR, WITH NO LINK BACK. project_index_cards.py projects the numbers and states that the prose is authored, so the tile's name for this review lives only in the index and nothing reconciles the two.	Store the tile sentence on the object and project it.	⛔ Until then a re-pointed object updates its NUMBER on the index and keeps its old NAME. Measured 2026-08-30: 1 of 44 mapped index entries names trials the object has never heard of, and the number beside it was correct. See scripts/audit_index_identity_drift.py.

A topic costs 0 declared judgements on this outcome, not four hundred. That is a stronger claim than "automated", because a reader can check a declared judgement and cannot check an inferred one.

⚠️ It does not make the judgements right, and it does not prove the SLOT LIST is complete -- the list is bounded by what its author enumerated. The honest form is "8 slots checked", never "8 judgements exist".

Comparison with published syntheses

Eight trials, one endpoint, and every value posted by the registry -- so the trial-by-trial check here is complete in a way it cannot be where trials post no results. It is also the topic where the error found is ours, and it is in the table below with the same weight as anything found in the literature.

12 checks were applied and 8 came back clean, 1 found an error, 1 found something absent and 2 could not be settled at the layer available. The denominator is stated because a list of only the failures is not a finding, it is a selection.

Confirmations are listed in the same table, in the same detail, as errors. Across the cardiology topics reconciled so far the published literature has been implicated in none of them: where a defect existed it was ours. A comparison with room only for their errors could not have found that out.

Table 17. Comparison with published syntheses
Check	Verdict	What was found
NCT01507831, the largest trial, against the registry's posted analysis ldl-values-vs-registry-1	CONFIRMED checked and clean	Registry: LS Mean Difference -61.9, 95% CI -64.3 to -59.4, Mixed Models Analysis, over 1530 against 780. This object stores -61.9 (-64.3 to -59.4). Identical. Note this trial's LDL result is a secondary outcome -- its only primary is the adverse-event proportion, because it was designed as a long-term safety study -- and an earlier build excluded it for posting no LDL result, which came from reading primary outcomes only. Quoted: “LS Mean Difference -61.9 (-64.3 to -59.4), Mixed Models Analysis” — ClinicalTrials.gov NCT01507831, resultsSection
NCT01617655 against the registry's posted analysis ldl-values-vs-registry-2	CONFIRMED checked and clean	Registry: LS mean difference -39.1 (-51.1 to -27.1) over 71 against 35. Object: -39.1 (-51.1 to -27.1). Identical. This is the smallest and least precise of the six and the furthest from the pooled value. Quoted: “LS mean difference -39.1 (-51.1 to -27.1), Mixed Models Analysis” — ClinicalTrials.gov NCT01617655, resultsSection
NCT01623115 against the registry's posted analysis ldl-values-vs-registry-3	CONFIRMED checked and clean	Registry: LS mean difference -57.9 (-63.3 to -52.6) over 322 against 163. Object: -57.9 (-63.3 to -52.6). Identical. Quoted: “LS mean difference -57.9 (-63.3 to -52.6), Mixed Models Analysis” — ClinicalTrials.gov NCT01623115, resultsSection
NCT01644175 against the registry's posted analysis ldl-values-vs-registry-4	CONFIRMED checked and clean	Registry: LS Mean Difference -45.9 (-52.5 to -39.3) over 205 against 106. Object: -45.9 (-52.5 to -39.3). Identical. Quoted: “LS Mean Difference -45.9 (-52.5 to -39.3), Mixed Models Analysis” — ClinicalTrials.gov NCT01644175, resultsSection
NCT01709500 against the registry's posted analysis, and its arm order ldl-values-vs-registry-5	CONFIRMED checked and clean	Registry: LS Mean Difference -51.4 (-58.1 to -44.8) over 166 against 81. Object: -51.4 (-58.1 to -44.8). Identical. And the arm order is reversed on this record alone: the registry lists alirocumab first and placebo second, the opposite of the other five. The posted difference is still alirocumab minus placebo, still negative, and the arm means (-48.7 against 2.8) confirm the sign independently. Checked because a silently reversed contrast is a defect class this repository has shipped before. Quoted: “Alirocumab 75 mg/up to 150 mg -48.7; Placebo 2.8; LS Mean Difference -51.4 (-58.1 to -44.8)” — ClinicalTrials.gov NCT01709500, resultsSection, group order
NCT02107898 against the registry's posted analysis ldl-values-vs-registry-6	CONFIRMED checked and clean	Registry: LS Mean Difference -64.1 (-68.5 to -59.8) over 143 against 72. Object: -64.1 (-68.5 to -59.8). Identical. This is the sixth of six explicitly itemised registry-value checks in this table. The object pools 8 trials, including NCT02289963 and NCT02585778, so this six-row table is not a complete trial-by-trial check of the pooled set. Quoted: “LS Mean Difference -64.1 (-68.5 to -59.8), Mixed Models Analysis” — ClinicalTrials.gov NCT02107898, resultsSection
Whether the eight trials measured the same thing endpoint-definitions-identical	CONFIRMED checked and clean	All six registry records give the outcome as 'Percent Change From Baseline in Calculated LDL-C at Week 24' on the intention-to-treat analysis. The only differences are orthographic -- one record writes 'Intent--to--Treat' with doubled hyphens, another closes the bracket after 'ITT Analysis' rather than before it. Compared as whole normalised fields, which is the rule this repository once broke inside its own auditor by testing a fragment. Quoted: “Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis” — ClinicalTrials.gov, all six records, outcome measure title
Whether any of the six is actually an ACTIVE-comparator trial comparator-is-placebo-on-all-six	CONFIRMED checked and clean	None is. All six registry records type the control arm PLACEBO_COMPARATOR. This was checked rather than assumed because the ODYSSEY programme contains sibling trials with different comparators, and a published review states it independently: 'ODYSSEY combo I and ODYSSEY combo ii studies demonstrated significant superiority of alirocumab ... in comparison to placebo and ezetimibe, respectively'. NCT01644175 is combo I, the placebo-controlled one, and combo ii is not in this set. A pool silently mixing a placebo contrast with an ezetimibe contrast would have been an average over two different questions. Quoted: “ODYSSEY combo I and ODYSSEY combo ii studies demonstrated significant superiority of alirocumab on LDL-cholesterol lowering in comparison to placebo and ezetimibe, respectively” — PMID 29299849, abstract; and the armGroups type on all six records
The between-study variance estimator used for the headline our-estimator-breaks-our-own-rule	RESOLVED	Discharged 2026-08-20. This check recorded that the pool used DerSimonian-Laird at k=8 against this project's own rule of REML or Paule-Mandel below k=10, and said the headline was not being re-estimated because the same estimator was used across the corpus and changing one page alone would make it inconsistent with its neighbours. That was the right reason and it no longer holds: the whole corpus moved to REML in one pass on 2026-08-20 under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." The refit gives tau-squared 61.441355 and I-squared 90.02 on these 8 trials, and the pooled estimate is now -54.72 (-60.62 to -48.82). The original wording is kept beside this under detail superseded 2026 08 20. this object, results.ldlc_pct_change_wk24.estimator and estimator sensitivity
Whether any published synthesis pools these eight trials on this endpoint no-synthesis-reports-this-estimand	ABSENT the thing checked for is not there	None located. The closest are a familial-hypercholesterolaemia pool of seven trials across both PCSK9 antibodies, weighted mean difference -49.14% (-55.81 to -42.47), and a twelve-trial alirocumab review reporting 'over 50%' with no interval. Both overlap our -54.72% and neither answers the same question. So this pooled value cannot be checked against an external number, which is a statement about the literature rather than a claim of novelty. [restated 2026-08-20: this sentence carried the pooled estimate as it stood under DerSimonian-Laird. The pool was refitted with REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." and the estimate is now -54.72 (-60.62 to -48.82); the numbers in this sentence are updated and the original is beside it under detail superseded 2026 08 20. Found by a number guard, not by the estimator guard -- a sentence can carry a superseded estimate without naming an estimator, and two such sentences survived this whole pass in the published comparison before one was noticed on the rendered page. Quoted: “PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD -49.14%, 95% CI: -55.81 to -42.47%, on FH versus control groups” — PMID 34754882, abstract
A network meta-analysis reporting a much larger reduction network-estimates-further-from-zero	UNRESOLVED could not be settled at the layer available	It reports alirocumab-versus-placebo relative effects of -71.45 (-91.16 to -50.44), -74.32 (-90.40 to -58.63) and -77.28 (-92.21 to -61.90) by dose strategy -- all further from zero than our -54.72, and all with intervals around forty points wide. It cannot be settled from the abstract whether those are percent changes on the same basis, and an interval that wide is compatible with a wide range of truths. Recorded for a reader rather than asserted as a discrepancy in either direction. [restated 2026-08-20: this sentence carried the pooled estimate as it stood under DerSimonian-Laird. The pool was refitted with REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." and the estimate is now -54.72 (-60.62 to -48.82); the numbers in this sentence are updated and the original is beside it under detail superseded 2026 08 20. Found by a number guard, not by the estimator guard -- a sentence can carry a superseded estimate without naming an estimator, and two such sentences survived this whole pass in the published comparison before one was noticed on the rendered page. Quoted: “alirocumab could significantly reduce LDL-c levels, compared with placebo (relative effect 95 % CI: -71.45 [-91.16, -50.44], -74.32 [-90.40, -58.63] and -77.28 [-92.21, -61.90])” — PMID 30782243, abstract
Whether the 97 syntheses that name no trial included ours what-the-abstract-layer-cannot-settle	UNRESOLVED could not be settled at the layer available	97 of 101 records name none of our eight trials in the abstract and two carry no indexed abstract. Alirocumab LDL-lowering is a crowded literature and many of those certainly do include these trials; which ones, and on what endpoint, cannot be decided from an abstract. the screen of published syntheses.json, tally

The syntheses reconciled against

Table 18. The syntheses reconciled against
34754882	A Systematic Review and Meta-Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia. Biomed Res Int 2022. It pools both drugs and restricts to familial hypercholesterolaemia; we pool one drug across a mixed population. Its weighted mean difference -49.14% (-55.81 to -42.47) is a different set of trials answering a narrower question, and it overlaps ours.
30782243	Efficacy and safety of different doses of alirocumab in reducing low-density lipoprotein cholesterol levels: a network meta-analysis. Pharmazie 2019. A network estimate over sixteen studies rather than a direct pool over six, and its intervals are about forty points wide. Its alirocumab-versus-placebo relative effects run from -71 to -77, further from zero than our -54.8, and the abstract does not state the unit or the model well enough to say why.
31463238	Safety and efficacy of alirocumab: A meta analysis of 12 randomized controlled trials. J Family Med Prim Care 2019. It reports 'over 50%' LDL-C reduction without a pooled interval in its abstract, so it supplies a direction and a rough magnitude and no number to reconcile against.
29299849	Lipid Management in Chronic Kidney Disease: Systematic Review of PCSK9 Targeting. Drugs 2019. It reports no pooled estimate, but it is the record that independently confirms which ODYSSEY combo trial used which comparator -- see the comparator check.

Where the numbers differ, and why

Table 19. Where the numbers differ, and why
This review	Mean difference -54.72 percent (-60.62 to -48.82) in calculated LDL cholesterol at week 24, k=8, random effects, REML. Prediction interval -71.18 to -38.26, which is the number to quote.
The published synthesis	-49.14% (-55.81 to -42.47) over seven familial-hypercholesterolaemia trials of both PCSK9 antibodies; 'over 50%' over twelve alirocumab trials; -71 to -77 by dose in a sixteen-study network analysis.
Why they differ	Different eligible sets and different questions -- one drug or two, one population or several, direct pool or network. Nothing here shows either side in error on the numbers. The substantive point is not the difference between reviews, it is the spread within ours: eight trials running from -39.1 to -64.1, each with a tight interval of its own, I-squared near 90 per cent. A single number for 'how much does alirocumab lower LDL' conceals a twenty-five point range, and the prediction interval is the only honest summary of it.

How they were identified: PubMed E-utilities; query, counts and a per-record decision in ssot/alirocumab-lipid/appraisal/the screen of published syntheses.json. 101 records matched and all 101 were read at abstract level.

In this section: Paper · Title · Abstract · Introduction · Methods — search · Methods — eligibility criteria · Methods — how many studies at each stage · Methods — synthesis · Results · Risk of bias in the included results · Certainty of the evidence · Comparison with published syntheses · Limitations · Data availability · Software availability · Reporting guidelines · Note on registration · References · Figures · Trial characteristics · Submission conformance · Not reported in this record

Paper

Each statement below cites the record it came from; those sources are listed at the end of every section. Where the record holds nothing, the section says so by name rather than being left out, so a procedure that was not carried out can be told from one that simply was never mentioned.

Title

Alirocumab versus placebo: percent change in calculated LDL cholesterol at week 24¹

Sources for this section (1)

title

Abstract

Question. In adults treated for hypercholesterolaemia, how much does alirocumab change calculated LDL cholesterol from baseline to week 24 compared with placebo?¹

Methods. ClinicalTrials.gov API v2 was searched; estimates were pooled under a random-effects model with the REML estimator; risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials); and certainty was rated with GRADE.²

Results. Percent change from baseline in calculated LDL cholesterol at week 24: mean difference -54.7 (-60.6 to -48.8) across 8 trials; and heterogeneity was considerable (I-squared 90%).³

Sources for this section (3)

question
search.databases, results.by_outcome, risk_of_bias.by_outcome, grade.by_outcome
results.by_outcome

Introduction

¹Background. This review asks: In adults treated for hypercholesterolaemia, how much does alirocumab change calculated LDL cholesterol from baseline to week 24 compared with placebo? It pools 8 randomised trials, against placebo. The outcome pooled is Percent change from baseline in calculated LDL cholesterol at week 24.

Sources for this section (1)

manuscript.introduction

Methods — search

Searches were executed in ClinicalTrials.gov API v2 -- query 1, narrow (condition + drug) on 2026-08-19 with the query, verbatim: query.cond="hypercholesterolemia"; query.intr="alirocumab"; filter.advanced=area[StudyType]interventional; pageSize=200; countTotal=true. It returned 54 record(s).¹

Searches were executed in ClinicalTrials.gov API v2 -- query 2, broad (intervention only) on 2026-08-19 with the query, verbatim: query.intr="alirocumab OR praluent OR SAR236553 OR REGN727"; filter.advanced=area[StudyType]interventional; pageSize=400; countTotal=true. It returned 99 record(s).²

Primary trials. No bibliographic search for primary trials was run. The 8 included trials were identified by reading named registrations on the dates recorded on each entry.³

Sources for this section (3)

search.databases[0]
search.databases[1]
bookkeeping_2026_08_21.the_search_its_date_and_its_databases

Methods — eligibility criteria

Each criterion above is recorded with the source it was derived from in `screening.eligibility_provenance`; none is asserted here without one.¹

Sources for this section (1)

screening.eligibility_provenance

Methods — how many studies at each stage

The PRISMA 2020 flow counts are held for this review and reconcile with the executed searches above; they are set out in the flow figure and its accompanying counts.¹

The unscreened remainder is 0.²

Records at every stage of screening. k is reported at each stage rather than as a single number, because each stage is what the instrument at that stage could actually decide.³
Stage	Records
Records surfaced by the executed searches	99
Records where the topic drug's role in the trial could be located	97
Records where the topic drug is the randomised intervention	89
Records where the topic drug is the comparator instead	5
Records where the topic drug is background therapy in both arms	3
Records where the role could not be decided either way	2
Trials included in this review	8
Surfaced records not yet screened	0

Sources for this section (3)

prisma_flow
k_cascade.k_unscreened_remainder
k_cascade

Methods — synthesis

For percent change from baseline in calculated LDL cholesterol at week 24, a random model was fitted with the REML estimator.¹

Intervals are 95% confidence intervals.²

Risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials) (22 August 2019 version, as reproduced in the Cochrane Handbook), following Higgins JPT, Savovic J, Page MJ, Elbers RG, Sterne JAC. Chapter 8: Assessing risk of bias in a randomized trial. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.5.1. A result, not a study -- Handbook 8.2: 'risk of bias is assessed for a specific result'. Every judgement below names its outcome. 6 result-level assessments were made. A domain that cannot be judged from the registration and the published report is no information, never LOW. Low-by-default asserts a fact; high-by-default invents a defect.³

A ceiling applies to every risk-of-bias judgement in this review; it is stated with the assessment itself rather than summarised here.⁴

Certainty of evidence was rated with GRADE, following Cochrane Handbook for Systematic Reviews of Interventions version 6.5.1, Chapter 14: Completing 'Summary of findings' tables and grading the certainty of the evidence. HIGH for a body of randomised evidence, then rated down with reasons. 1 pooled outcome(s) were rated. No domain is rated UP. Rating up for large effect or dose-response applies to observational evidence that has not already been rated down, and neither condition holds here.⁵

Sources for this section (5)

results.by_outcome.ldlc_pct_change_wk24.model, results.by_outcome.ldlc_pct_change_wk24.estimator_used
config.confidence_level
risk_of_bias.tool, risk_of_bias.by_outcome
risk_of_bias.ceiling
grade.approach, grade.by_outcome

Results

The pooled mean difference for percent change from baseline in calculated LDL cholesterol at week 24 was -54.7 (-60.6 to -48.8, 95% interval) across 8 trials, against placebo.¹

The trials' results were poorly consistent with one another: I-squared, the share of the variation between them that is more than chance alone would produce, was 90%; the estimated variance of the true effects between trials (tau-squared) was 61.4, the heterogeneity test statistic Q was 58.4, on degrees of freedom 7. high²

The grounds for pooling are recorded as: Every included trial reports this outcome with an effect estimate and an interval. Where a later pool on this page rests on the same grounds, they are not restated.³

The full model output for every pooled outcome -- the call, the estimator, the heterogeneity statistics and the back-transformed interval -- is stored verbatim on this review object at `results.by_outcome.<outcome>.r_output.verbatim`. It is not reproduced as an Extended data section in this article; an earlier version of this sentence said it was, and no such section exists.⁴

Sources for this section (4)

outcomes[id=ldlc_pct_change_wk24].name, results.by_outcome.ldlc_pct_change_wk24.pooled, config.confidence_level, outcomes[id=ldlc_pct_change_wk24].comparator
results.by_outcome.ldlc_pct_change_wk24.heterogeneity.i2, results.by_outcome.ldlc_pct_change_wk24.heterogeneity.tau2, results.by_outcome.ldlc_pct_change_wk24.heterogeneity.q, results.by_outcome.ldlc_pct_change_wk24.heterogeneity.df, results.by_outcome.ldlc_pct_change_wk24.heterogeneity_status
results.by_outcome.ldlc_pct_change_wk24.poolable_reason
results.by_outcome

Risk of bias in the included results

Risk of bias was assessed with RoB 2 at the level of each reported result, by two assessors reading independently. Their judgements differ on 5 of the 6 results and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Assessor 1 recorded: 6 at some concerns. Assessor 2 recorded: 1 at some concerns, 5 at no information. Both are shown in the risk-of-bias table; neither is the review's finding. The per-domain judgements behind them are recorded with the extracted data.¹

Sources for this section (1)

risk_of_bias.SECOND_ASSESSOR_2026_08_21.DISAGREEMENT_RATE, risk_of_bias.SECOND_ASSESSOR_2026_08_21.PER_DOMAIN, risk_of_bias.SECOND_ASSESSOR_2026_08_21.assessor_1, risk_of_bias.SECOND_ASSESSOR_2026_08_21.each_disagreement, risk_of_bias.SECOND_ASSESSOR_2026_08_21.how_it_was_asked, risk_of_bias.ceiling.statement, risk_of_bias.default_rule, risk_of_bias.tool

Certainty of the evidence

Certainty was rated with GRADE. HIGH for a body of randomised evidence, then rated down with reasons.¹

No domain is rated UP. Rating up for large effect or dose-response applies to observational evidence that has not already been rated down, and neither condition holds here.²

This certainty rating is pending, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.³

risk_of_bias -1 inconsistency -1 indirectness +0 imprecision +0 publication bias +0⁴

Where a result is rated worse than LOW overall, the domain carrying that judgement is: selection of the reported result on 6 result(s). The overall rating is the worst domain, so these are the domains that determine it.⁵

Certainty of the evidence, by outcome, with every rating step⁶
Outcome	Certainty	k	Started at	Rating steps
percent change from baseline in calculated LDL cholesterol at week 24	Pending	8	HIGH	the steps taken so far, not a final rating: risk of bias: HIGH to MODERATE, down 1 level(s) -- Result-level RoB 2 over 6 contributing result(s): no information=6. Not one reaches LOW -- selection of the reported result cannot, because no trial's statistical analysis plan is held, and the randomisation process cannot, because allocation concealment is in neither the registration nor this object. 6 have at least one domain at no information. This is a limit on what we can reach, not a finding against the trials.; inconsistency: MODERATE to LOW, down 1 level(s) -- I-squared 88% over k = 8. Rated down. I-squared is one input and never the test -- P36 -- but at this magnitude with a small k the point estimates genuinely disperse.; indirectness: not rated down -- The contributing results share one endpoint definition, verified by reading each trial's registered text rather than by comparing names.; imprecision: not rated down -- k = 8 and the interval (-60.23 to -49.42) excludes the null.; publication bias: not rated down -- k = 8. A funnel plot and Egger's test have no power below k = 10, so publication bias is undetected rather than ABSENT. Not rated down, and not reported as clean: an unreachable state is not a passing one.

Sources for this section (6)

grade.approach
grade.not_rated_up
risk_of_bias.by_outcome
grade.by_outcome.ldlc_pct_change_wk24.summary
bookkeeping_2026_08_21.which_risk_of_bias_domains_drove_the_rating
grade.by_outcome.ldlc_pct_change_wk24

Comparison with published syntheses

Published syntheses were identified as follows. PubMed E-utilities; query, counts and a per-record decision in ssot/alirocumab-lipid/appraisal/the screen of published syntheses.json. 101 records matched and all 101 were read at abstract level.¹

Sources for this section (1)

published_comparison._how_identified

Limitations

What this review does not give a clinician: any measure of harm. A relative effect cannot be turned into the benefit or the risk facing one patient without them, so this review can support a judgement about what these trials found and not a judgement about what to do.¹

Sources for this section (1)

results.by_outcome

Data availability

Every trial in this review is keyed to a registration identifier, verified by live fetch of the raw ClinicalTrials.gov v2 record and comparison of the returned nctId against the id stored on this object on 2026-08-19.¹

The underlying records are the 1 source(s) listed under References; each names the layer it was read at, so a reader can tell a registry record from a published report.²

Registration identifiers, and whether each was verified³
Registration	Verified	Link
NCT01507831	True	https://clinicaltrials.gov/study/NCT01507831
NCT01617655	True	https://clinicaltrials.gov/study/NCT01617655
NCT01623115	True	https://clinicaltrials.gov/study/NCT01623115
NCT01644175	True	https://clinicaltrials.gov/study/NCT01644175
NCT01709500	True	https://clinicaltrials.gov/study/NCT01709500
NCT02107898	True	https://clinicaltrials.gov/study/NCT02107898
NCT02289963	True	https://clinicaltrials.gov/study/NCT02289963
NCT02585778	True	https://clinicaltrials.gov/study/NCT02585778

Sources for this section (3)

registration_identity.method
sources
registration_identity.trials

Software availability

Analyses were computed under R 4.6.0 with metafor 5.0.1.¹

Intervals are reported at the 95% level.²

Sources for this section (2)

results.by_outcome
config.confidence_level

Reporting guidelines

This review reports against PRISMA 2020. A screening record is held on this object and the flow it supports is shown in the Methods. The completed PRISMA checklist and FLOW diagram are not held here: the venue requires them deposited in an approved repository with a DOI cited in the Data Availability Statement, and minting that DOI is an author action rather than a build step.¹

Sources for this section (1)

screening

Note on registration

Protocol status. Prespecified: False. A protocol specified before data collection is a historical fact about the past and cannot be created retrospectively. Writing one now and calling it prespecified would invalidate every other refusal on these pages, because a reader who caught it would be right to disbelieve all of them.¹

Eligibility criteria were derived post hoc from the trials and the methodological authority, and the derivation is recorded element by element in `screening.eligibility_provenance` with the source of each.²

Authority: Mecir R107 permits post-hoc eligibility criteria provided they are declared as such. They are declared, here and on the page, and the page says 'derived, post hoc' in its heading.³

No PROSPERO registration or protocol record is held on this object. That is not the same as knowing this review was not registered, and neither claim is made. It is recorded here as an absence so that a reader does not have to infer it from silence.⁴

Sources for this section (4)

protocol
protocol.what_was_actually_done
protocol.authority_permitting_it
bookkeeping_2026_08_21.whether_this_review_was_prospectively_registered

References

Included studies, by registration¹
Trial	Registration	Registry	Read
	NCT01507831	ClinicalTrials.gov
	NCT01617655	ClinicalTrials.gov
	NCT01623115	ClinicalTrials.gov
	NCT01644175	ClinicalTrials.gov
	NCT01709500	ClinicalTrials.gov
	NCT02107898	ClinicalTrials.gov
	NCT02289963	ClinicalTrials.gov
	NCT02585778	ClinicalTrials.gov

Methods guidance and software, with what each is cited for²
Cited for	Reference
risk of bias in the included results	Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898
certainty of the evidence	Schunemann HJ, Higgins JPT, Vist GE, et al. Chapter 14: Completing 'Summary of findings' tables and grading the certainty of the evidence. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.5. Cochrane; 2024.
the model fitted, as R 4.6.0 with metafor 5.0.1	Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48. doi:10.18637/jss.v036.i03
the reporting guideline this manuscript is written against	Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71

Sources this review reads, with the layer each was read at³
Id	Layer	Source	Location
REGISTRY_CTGOV	Registry	ClinicalTrials.gov posted results: primary outcome measures and their statistical analyses	https://clinicaltrials.gov/

Sources for this section (3)

manuscript.references
manuscript.references
sources

Figures

Figure 1. Forest plot -- percent change from baseline in calculated LDL cholesterol at week 24. k = 8.¹

Figure 2 not drawn. k = 8. A funnel plot and its asymmetry tests have almost no power below about ten trials (Cochrane Handbook 13.3.5.4), so a funnel drawn here would invite a reading of asymmetry this evidence cannot support. It is declined rather than drawn, and this slot says so where the plot would have been.

Figure 2. Funnel plot -- percent change from baseline in calculated LDL cholesterol at week 24. k = 8.²

Sources for this section (2)

results.by_outcome.ldlc_pct_change_wk24.per_trial, results.by_outcome.ldlc_pct_change_wk24.pooled
results.by_outcome.ldlc_pct_change_wk24.per_trial, results.by_outcome.ldlc_pct_change_wk24.pooled

Trial characteristics

Characteristics of every trial contributing to this review¹
Registration	Trial	Participants	Randomised	Primary outcome measured over	Design
NCT01507831	Long-term alirocumab versus placebo added to stable lipid-modifying therapy in high cardiovascular risk	registered condition: Hypercholesterolemia	2341	Up to 10 weeks after last study drug administration (maximum of 86 weeks)	randomised, double-blind, placebo-controlled.
NCT01617655	Alirocumab versus placebo on top of stable lipid-modifying therapy in heterozygous familial hypercholesterolaemia	registered condition: Hypercholesterolaemia	107	From Baseline to Week 52	randomised, double-blind, placebo-controlled.
NCT01623115	Alirocumab versus placebo on top of stable lipid-modifying therapy	registered condition: Hypercholesterolemia	486	From Baseline to Week 52	randomised, double-blind, placebo-controlled.
NCT01644175	Alirocumab versus placebo on top of stable lipid-modifying therapy in high cardiovascular risk	registered condition: Hypercholesterolemia	316	From Baseline to Week 52	randomised, double-blind, placebo-controlled.
NCT01709500	Alirocumab in heterozygous familial hypercholesterolaemia	registered condition: Heterozygous Familial Hypercholesterolemia	249	From Baseline to Week 52	randomised, double-blind, placebo-controlled.
NCT02107898	Alirocumab in heterozygous familial hypercholesterolaemia, Japan	registered condition: Hypercholesterolemia	216	From Baseline to Week 24	randomised, double-blind, placebo-controlled.
NCT02289963	Alirocumab versus placebo on top of lipid-modifying therapy	registered condition: Hypercholesterolemia	199	From Baseline to Week 24	not recorded on this object
NCT02585778	Alirocumab versus placebo in insulin-treated diabetes (odyssey dm-insulin)	registered condition: Hypercholesterolaemia	517	From Baseline to Week 24; From Baseline up to 10 weeks after last study drug administration (maximum of 32 weeks)	not recorded on this object

Sources for this section (1)

inputs.trials

Submission conformance

This review was built to page standard 1.10.0-2026-08-19 (PAGE-STANDARD.md), by ssot/build_to_standard.py on 2026-08-19. A page built below the current standard is knowably below it rather than silently stale.¹

13 machine-checked properties were verified for this page before it was published; the checks and their names are recorded with the build rather than here.²

Sources for this section (2)

build_stamp.page_standard_version
build_stamp.held

Not reported in this record

The items below were not written because the record does not hold what they would be composed from. They are named here so that an absence is not mistaken for an omission.

Items not reported, and why
Article area	Item not reported	Reason
Abstract	The Background sentence of the abstract	Background is argument -- why this question matters -- and no arrangement of the quantities this object holds yields it. It is emitted only from an authored field and there is no composition path for it here
Abstract	The Conclusions sentence of the abstract	A conclusion is argument -- what a reader should now believe -- and it is emitted only from an authored field. Composing one from the estimate would be this renderer telling the reader what to conclude, which no field supports
Methods — eligibility criteria	The eligibility criteria	No further reason is recorded.
Methods — outcomes sought at every registered rank	The statement that outcomes were sought below the primary	No further reason is recorded.
Methods — synthesis	The claim that records were screened in duplicate -- and this topic owes one rather than merely lacking one: No second independent screen was run for this topic	This is recorded as owed rather than described: the remedy is to RUN one, and writing a duplicate-screening sentence without one would be the defect this whole exercise exists to prevent.
Methods — synthesis	The claim that the review methods were prespecified before data collection	This refusal is permanent and is not a gap to be filled. A protocol specified before data collection is a historical fact about the past and cannot be created retrospectively. Writing one now and calling it prespecified would invalidate every other refusal on these pages, because a reader who caught it would be right to disbelieve all of them. Eligibility criteria were derived post hoc from the trials and the methodological authority, and the derivation is recorded element by element in `screening.eligibility_provenance` with the source of each. Mecir R107 permits post-hoc eligibility criteria provided they are declared as such. They are declared, here and on the page, and the page says 'derived, post hoc' in its heading.
Disagreements between sources	The reconciliation against other sources	No further reason is recorded.
Author contributions	The author-contributions statement	Who did what is a fact about people, and this object records none
Competing interests	The competing-interests declaration	F1000Research requires this section on every article, and requires explicit text where there is nothing to declare. It is a statement about the author and not about the evidence: no field of this object implies it and none is invented here
Grant information	The grant information	The venue requires each funder's name, the grant number where applicable, and the person the grant was assigned to. None of that is derivable from a synthesis
Funding and conflicts of interest	The funding and conflict-of-interest statement -- a content gap	A submission requires it and this object does not carry it; it is not inferable from anything held here
Registration	A registration statement: no prospective registration is recorded for this review, and whether one exists elsewhere has not been established	No further reason is recorded.

In this section: ldlc pct change wk24

Format: Cochrane Handbook v6.5, chapter 14 (14.1.2 contents, 14.1.3 absolute effects). The FIELDS are fixed by the Handbook so a reader can check the shape of this table as well as its numbers.

ldlc pct change wk24

Table 20. ldlc pct change wk24
Relative effect	No. participants analysed	No. studies
MD -54.72 (-60.62 to -48.82)	not held: per-arm counts for 6 of 8 studies	8

Participants is the number ANALYSED for this outcome, summed from the same per-arm counts the effect above is computed from -- not the number the trials enrolled, which is a larger and different quantity. Where some contributing trial holds no per-arm counts the cell says so rather than showing a sum over the trials that do, because a partial sum is not a total.

The summary measure is MD, which is not a ratio, so there is no baseline risk to apply it to and no absolute-effect grid is shown. An NNT derived from a mean difference would be fabrication.

No GRADE certainty is stored for this outcome. The Handbook's SoF table carries one; this object does not, and the cell is left declared rather than filled.

Format: Cochrane Handbook v6.5, chapter 15 (15.6 implications for practice). The twelve considerations below are the GRADE Evidence-to-Decision framework, reproduced in full whether or not this review can answer them.

Table 21. ldlc pct change wk24
Consideration	Answer	From this review
Is the problem a priority?	NOT ADDRESSED	Whether a problem is a priority ranks it against competing claims on the same budget. The trial populations recorded here say who was studied; they are not a property that can rank the problem, and this review does not rank it.
How substantial are the desirable effects?	INFORMED	The pooled relative effect and its interval, with an absolute-effect grid, are in the Summary of Findings tab. Informed by `results.by_outcome.ldlc_pct_change_wk24.pooled`.
How substantial are the undesirable effects?	NOT ADDRESSED	No harms block is held on this object. THAT IS NOT A FINDING OF NO HARM -- it is an absence of extraction, and a panel must treat it as unmeasured rather than as reassurance.
What is the overall certainty of the evidence?	NOT ADDRESSED	No GRADE certainty is stored for any outcome.
Is there important uncertainty about how much people value the outcomes?	NOT ADDRESSED	No study of how people weigh these outcomes was sought or synthesised. This is a review of trial effects.
Does the balance favour the intervention or the comparison?	NOT ADDRESSED	A balance requires values. With values unaddressed, a balance statement would be the review author's preference wearing a panel's authority.
How large are the resource requirements?	NOT ADDRESSED	No cost input of any kind is held.
What is the certainty of the resource evidence?	NOT ADDRESSED	No resource evidence is held, so there is no certainty to rate in it.
Does cost-effectiveness favour the intervention?	NOT ADDRESSED	No economic evaluation was sought.
What would be the impact on health equity?	NOT ADDRESSED	No registry extraction is held on this object.
Is the intervention acceptable to key stakeholders?	NOT ADDRESSED	Acceptability studies are outside this review's scope.
Is the intervention feasible to implement?	NOT ADDRESSED	Implementation and delivery are outside this review's scope.

1 of 12 considerations informed; 11 not addressed. The empty cells are the point. An evidence-to-decision framework needs values, resource use, equity, acceptability and feasibility; the Handbook places those with the review authors and a guideline panel, and they are not derivable from trial data. A panel handed a complete map of what is unanswered is better served than one handed prose that reads as though it covered all twelve. Every informed row names the field it is informed by.

Not held in this object. No statistical panel set is held in this object.

property	state	reason
P1_executed_search	HELD	2 database queries recorded verbatim with dates and counts; PRISMA arithmetic reconciles and the 0-trial unscreened remainder is stated as a number rather than omitted.
P2_k_cascade	HELD	k at every stage: surfaced 99, located 97, experimental 89, comparator 5, included 8, unscreened remainder 0.
P3_inclusion_criteria	HELD	Criteria provenance block present with predefined=False on its face (state 'DERIVED_POST_HOC').
P4_preconditions	HELD	All 8 recorded with verdict and cited authority: 1 FAIL, 4 NOT-ASSESSABLE. criteria_predefined is FAIL -- post hoc criteria, which R107 permits and C5/C7 does not satisfy.
P5_extraction_table	HELD	5 cells: 2 READ with source path and verbatim text, 3 DERIVED with the method named.
P6_analysis_output	HELD	1 pool(s) carry verbatim model output with environment and call: ldlc_pct_change_wk24. Nothing is summarised in place of a quotation.
P7_published_comparison	HELD	12 check(s) applied against published syntheses with a STATED DENOMINATOR: 8 confirmed, 1 error(s), 1 absent, 2 unresolved. Confirmations are listed in the same detail as errors -- a comparison with room only for their errors could not report that the defects were ours.
P8_registration_identity	HELD	8 of 8 trial(s) verified live against the registry.
P18_restatement_is_reproducible	HELD	1 restatement block(s), each naming a script that resolves on disk: restated_2026_08_19_trailing_placebo -> scripts/regate_cascade_2026_08_19.py
P19_promotion_reaches_derived_blocks	HELD	inputs.trials, k_cascade.k_included_in_object and prisma_flow.included all say 8; no first-person field in published_comparison declares a k the pooled outcome(s) do not.
P20_cascade_reconciles	HELD	k2_role_located=97 == k3+k4+k5, and k0_surfaced=99 == k3+k4+k5+kNA. Both checked, and every failing limb would be reported rather than the first.
P21_ambiguous_question_split	REFUSING	This object records no split provenance. That is CORRECT for a topic whose question was never ambiguous and it is NOT a pass: this builder cannot tell the two apart, so the property is refused with the reason rather than held on an absence. What would settle it: a `split_provenance` block, or an explicit statement that the question admits one reading.
P22_sharing_recorded	HELD	No trial of this review appears in any other object's included set. COMPUTED over the corpus, not asserted: 8 trial(s) checked against every other topic object.
P23_recall_measured	HELD	All 2 recorded quer(ies) state their recall against this review's own included set: 6/6 and 6/6.

stage	k
k0_surfaced	99
k2_role_located	97
k3_experimental	89
k4_comparator	5
k5_background	3
kNA_not_assessable	2
k_included_in_object	8
k_unscreened_remainder	0
k3_corrected_from	k3 was 74 and background 18 before the placebo-name fix of 2026-08-19. The ODYSSEY registrations name the placebo arm's intervention 'Placebo (for alirocumab)', so a substring match reported the drug in BOTH arms and locate() returned background_or_coadministered on FIVE OF THIS OBJECT'S SIX INCLUDED TRIALS. A PLACEBO FOR X IS NOT X. Fixed by anchoring: a placebo declares itself at the START of its own name. 8.4% of intervention records to hand name the drug their placebo substitutes for, so this was an industry-wide convention rather than one registry's data entry.
remainder_dispositions	EXCLUDED 34, ELIGIBLE NOT POOLABLE 21, ELIGIBLE NO RESULTS YET 26, ELIGIBLE POOLABLE NOT INCLUDED 0, arithmetic 89 experimental - 8 included = 81 remainder = 34 + 21 + 26 + 0, zero is computed not asserted ELIGIBLE_POOLABLE_NOT_INCLUDED is 0 because the two trials that were in that cell were EXTRACTED AND POOLED, not because nothing was found. The cell is named and kept at zero rather than deleted, because deleting it would make the gap this review had in its own evidence base unreadable from the finished page., what this says READ BY THE REMAINDER-DIAGNOSIS RULE (PAGE-STANDARD, 'Reading the remainder'): 34 of 81 fail a criterion, 21 are eligible with a different estimand, and 26 have not reported. This is the FRAGMENTED-EVIDENCE shape rather than the too-broad-query shape -- most exclusions are comparator failures (active-comparator and double-dummy designs), not population failures, so the query is well aimed at a drug programme that simply ran many non-placebo contrasts., the two that matter NCT02585778 (n=517) and NCT02289963 (n=199) both register 'Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat' -- WORD FOR WORD THIS OBJECT'S ESTIMAND -- and both randomise alirocumab against placebo on background lipid-modifying therapy. NEITHER WAS IN THIS OBJECT'S SIX when screening found them. That was not a screening outcome; it was a gap in this review's own evidence base. BOTH ARE NOW IN THE INCLUDED SET: extracted from their own posted results, re-pooled, and the old and new estimates shown side by side (recovery_2026_08_19). k went 6 -> 8 and the point moved 0.16 points, from -54.66 to -54.72 -- the recovery CONFIRMS the estimate rather than overturning it, which is the honest headline and is why it is stated here rather than only where it flatters. [RESTATED 2026-08-20: this sentence carried the pooled estimate as it stood under DerSimonian-Laird. The pool was refitted with REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." and the estimate is now -54.72 (-60.62 to -48.82); the numbers in this sentence are updated and the original is beside it under the_two_that_matter_superseded_2026_08_20. Found by a NUMBER guard, not by the estimator guard -- a sentence can carry a superseded estimate without naming an estimator, and two such sentences survived this whole pass in the published comparison before one was noticed on the rendered page., the newly experimental two NCT01812707 and NCT03004001 entered the remainder on 2026-08-19 when the trailing-placebo repair moved them out of background. Neither is poolable: one reports every rank at WEEK 12, the other fails POPULATION. Both are screened and recorded at screening_of_remainder.alirocumab_newly_unscreened_2026_08_19., the two that matter superseded 2026 08 20 NCT02585778 (n=517) and NCT02289963 (n=199) both register 'Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat' -- WORD FOR WORD THIS OBJECT'S ESTIMAND -- and both randomise alirocumab against placebo on background lipid-modifying therapy. NEITHER WAS IN THIS OBJECT'S SIX when screening found them. That was not a screening outcome; it was a gap in this review's own evidence base. BOTH ARE NOW IN THE INCLUDED SET: extracted from their own posted results, re-pooled, and the old and new estimates shown side by side (recovery_2026_08_19). k went 6 -> 8 and the point moved 0.16 points, from -54.66 to -54.82 -- the recovery CONFIRMS the estimate rather than overturning it, which is the honest headline and is why it is stated here rather than only where it flatters.
keyed_on	registration id
restated_2026_08_19_trailing_placebo	k2 was 99, k2 now 97, k3 was 87, k3 now 89, k5 was 6, k5 now 3, kNA was 1, kNA now 2, k included was 6, k included now 8, two separate corrections in one restatement THEY ARE NOT THE SAME CORRECTION AND ARE NOT MERGED. (1) The CLASSIFIER moved three of the 99 surfaced records, under the trailing-placebo repair of commit e20f94068. (2) The INCLUDED COUNT was already 8 in inputs.trials and in results.by_outcome after the 2026-08-19 recovery, while the cascade and the PRISMA flow still said 6. Only (1) is a movement; (2) is a slot that was never updated when the headline was., classifier delta measured how The surfaced set was RE-EXECUTED from this object's own recorded query and came back at 99 -- identical to the stored k0 -- so no part of the delta is registry drift. The old classifier was LOADED FROM GIT at 7a08bcbe1 rather than reimplemented from its commit message. scripts/regate_cascade_2026_08_19.py., the three records NCT01812707 background -> EXPERIMENTAL. A Japanese atorvastatin-background trial whose placebo arm carries 'Drug: Placebo (for alirocumab)' alongside atorvastatin. Now screened: ELIGIBLE, and NOT POOLABLE -- its primary and all six of its secondaries are at WEEK 12 and this object's estimand is week 24., NCT03004001 background -> EXPERIMENTAL. Nephrotic-syndrome dyslipidaemia, TERMINATED at n=3. Now screened: EXCLUDED on POPULATION., NCT03067844 background -> NOT_ASSESSABLE, which is a REFUSAL and not an exclusion. The registration contradicts itself: its PLACEBO_COMPARATOR arm labelled 'Placebo' carries 'Drug: Alirocumab' and declares no placebo record at all, while its EXPERIMENTAL arm declares the same drug. Reading that as 'given in both arms' would be a decision rather than a reading., no included trial changed role Checked against this object's own eight, not assumed. So no estimate on this page moves because of the classifier -- what moves is the denominator the page reports its search against.

precondition	verdict	reason	authority
population_stated	PASS	present: question carries 151 characters	MECIR C62 'Ensuring meta-analyses are meaningful' (Mandatory, READ 2026-08-19): 'Undertake (or display) a meta-analysis only if participants, interventions, comparisons and outcomes are judged to be s
arm_role_resolved	NOT-ASSESSABLE	cannot assess: inputs.trials has 2 trial(s) with no readable arms ['NCT02289963', 'NCT02585778'] and 0 with a blank arm role []. Absent role data is not a wrong role.	MECIR C62 (Mandatory), 'interventions' limb -- this is a PRECONDITION FOR ASSESSING C62, not an enforcement of it: you cannot judge whether interventions are 'sufficiently similar' without knowing whi
comparators_identified	PASS	every outcome names a comparator type ['placebo']; none declares 'mixed'. Within-outcome consistency is visible only through the declared type, and cross-outcome differences are not judged.	MECIR C62 (Mandatory), 'comparisons' limb -- a synthesis pools one contrast. NOT cited to C7: C7 governs PREDEFINITION, and this check reads recorded comparator fields and tests them for consistency.
estimand_named	PASS	outcomes.estimand: all 1 outcome(s) name a quantity	MECIR C8 'Clarifying role of outcomes' (Mandatory, READ 2026-08-19); MECIR C62 (Mandatory), 'outcomes' limb
criteria_stated	NOT-ASSESSABLE	cannot assess: no key screening.eligibility	MECIR R29 'Eligibility criteria for types of participants', R30 '...types of interventions', R31 'Role of outcomes' -- ALL Mandatory REPORTING standards (READ 2026-08-19). Their verb is STATE. A block
criteria_predefined	FAIL	screening.eligibility_provenance.predefined is false: the criteria were DERIVED post hoc from this object's own question and recorded exclusions. That is auditable (R29/R30/R31) and is not pre-specification (C5/C7). This	MECIR C5 'Predefining unambiguous criteria for participants' AND C7 '...for interventions and comparators', BOTH Mandatory (READ 2026-08-19): 'Predefined, unambiguous eligibility criteria are a fundam
eligibility_met	NOT-ASSESSABLE	cannot assess: criteria are not stated (no key screening.eligibility), so whether any trial met them cannot be decided	MECIR C5/C7 (Mandatory) with C6 'Predefining a strategy for studies with a subset of eligible participants' (Highly desirable, READ 2026-08-19) -- eligibility is assessed against the full report
contributes_a_randomised_contrast	NOT-ASSESSABLE	cannot assess: 2 of 8 trial(s) carry no readable arm roles ['NCT02289963', 'NCT02585778']	Handbook 6.5 s23.3.4 'How to include multiple groups from one study' (READ 2026-08-19) and s23.3.6 'Factorial trials'; MECIR C7 'Predefining unambiguous criteria for interventions and comparators' (Ma

Class	What it catches	The defect that generated it
unanchored-external-authority	an outside body's position asserted with nothing retrievable behind it	'WHO has recommended the ring' went live from a conversation, and dropped the conditionality WHO actually attached -- WHO, iris handle 10665/340190, 17 March 2021: the ring 'may be offered ... (Conditional recommendation; moderate-certainty evidence)'
single-trial-shown-as-pooled	one trial's result presented as a pool	the front page carried a single trial's HR 0.85 (0.79-0.92) as a two-trial pool
unfilled-template-token	a placeholder shipped unsubstituted	11 pages cited protocols/name_protocol_v1.0.md -- 'name' was the placeholder
bare-none-rendered	a Python None reaching rendered output	1110 dashboards rendered as 626-byte stubs from `None` in a JS literal
markup-imbalance	unbalanced tags after a hand edit	div-balance drift after HTML edits, repeatedly
estimand-unnamed	a pooled quantity presented without naming what it estimates	binary counts pooled where both trials analysed time to event
hksj-unqualified	a small-k interval reported without naming the variance floor	raw HKSJ narrows below Wald when Q < k-1; the q* floor was missing
ratio-on-natural-scale	a ratio measure said to be on the natural scale	sglt2-hf rendered 'on the natural scale' for a hazard ratio
denial-of-something-held	the page denies what the corpus holds	92 pages stated no protocol exists while a protocol sat in the repository
statistic-rendered-twice	one statistic with two values on one page	the same number rendered from two code paths
untraceable-number	a number with no source	stored estimates that do not follow from their own counts: 172 of 178 uncheckable

What	Value	Read from	Sentence it was read from	Fingerprint
A network meta-analysis reporting a much larger reduction	—	no source recorded	alirocumab could significantly reduce LDL-c levels, compared with placebo (relative effect 95 % CI: -71.45 [-91.16, -50.44], -74.32 [-90.40, -58.63] and -77.28 [-92.21, -61.90])	—
NCT01507831, the largest trial, against the registry's posted analysis	—	no source recorded	LS Mean Difference -61.9 (-64.3 to -59.4), Mixed Models Analysis	—
NCT01617655 against the registry's posted analysis	—	no source recorded	LS mean difference -39.1 (-51.1 to -27.1), Mixed Models Analysis	—
NCT01623115 against the registry's posted analysis	—	no source recorded	LS mean difference -57.9 (-63.3 to -52.6), Mixed Models Analysis	—
NCT01644175 against the registry's posted analysis	—	no source recorded	LS Mean Difference -45.9 (-52.5 to -39.3), Mixed Models Analysis	—
NCT01709500 against the registry's posted analysis, and its arm ORDER	—	no source recorded	Alirocumab 75 mg/up to 150 mg -48.7; Placebo 2.8; LS Mean Difference -51.4 (-58.1 to -44.8)	—
NCT02107898 against the registry's posted analysis	—	no source recorded	LS Mean Difference -64.1 (-68.5 to -59.8), Mixed Models Analysis	—
Whether any of the six is actually an ACTIVE-comparator trial	—	no source recorded	ODYSSEY COMBO I and ODYSSEY COMBO II studies demonstrated significant superiority of alirocumab on LDL-cholesterol lowering in comparison to placebo and ezetimibe, respectively	—
Whether any published synthesis pools these eight trials on this endpoint	—	no source recorded	PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD -49.14%, 95% CI: -55.81 to -42.47%, on FH versus control groups	—
Whether the eight trials measured the same thing	—	no source recorded	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis	—
extraction	—	ClinicalTrials.gov, six registrations	—	—
inputs/trials[0]/by_outcome/ldlc_pct_change_wk24	—	https://clinicaltrials.gov/study/NCT01507831	—	—
inputs/trials[0]/by_outcome/ldlc_pct_change_wk24/outcome_definition_source	—	registry	—	—
inputs/trials[0]/by_outcome/ldlc_pct_change_wk24/provenance	—	the registry's own posted outcome-measure record for this trial	—	—
inputs/trials[1]/by_outcome/ldlc_pct_change_wk24	—	https://clinicaltrials.gov/study/NCT01617655	—	—
inputs/trials[1]/by_outcome/ldlc_pct_change_wk24/outcome_definition_source	—	registry	—	—
inputs/trials[1]/by_outcome/ldlc_pct_change_wk24/provenance	—	the registry's own posted outcome-measure record for this trial	—	—
inputs/trials[2]/by_outcome/ldlc_pct_change_wk24	—	https://clinicaltrials.gov/study/NCT01623115	—	—
inputs/trials[2]/by_outcome/ldlc_pct_change_wk24/outcome_definition_source	—	registry	—	—
inputs/trials[2]/by_outcome/ldlc_pct_change_wk24/provenance	—	the registry's own posted outcome-measure record for this trial	—	—
inputs/trials[3]/by_outcome/ldlc_pct_change_wk24	—	https://clinicaltrials.gov/study/NCT01644175	—	—
inputs/trials[3]/by_outcome/ldlc_pct_change_wk24/outcome_definition_source	—	registry	—	—
inputs/trials[3]/by_outcome/ldlc_pct_change_wk24/provenance	—	the registry's own posted outcome-measure record for this trial	—	—
inputs/trials[4]/by_outcome/ldlc_pct_change_wk24	—	https://clinicaltrials.gov/study/NCT01709500	—	—
inputs/trials[4]/by_outcome/ldlc_pct_change_wk24/outcome_definition_source	—	registry	—	—
inputs/trials[4]/by_outcome/ldlc_pct_change_wk24/provenance	—	the registry's own posted outcome-measure record for this trial	—	—
inputs/trials[5]/by_outcome/ldlc_pct_change_wk24	—	https://clinicaltrials.gov/study/NCT02107898	—	—
inputs/trials[5]/by_outcome/ldlc_pct_change_wk24/outcome_definition_source	—	registry	—	—
inputs/trials[5]/by_outcome/ldlc_pct_change_wk24/provenance	—	the registry's own posted outcome-measure record for this trial	—	—
manuscript/references/included_studies[0]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[1]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[2]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[3]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[4]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[5]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[6]	—	ClinicalTrials.gov	—	—
manuscript/references/included_studies[7]	—	ClinicalTrials.gov	—	—
trial_identity_check	—	ClinicalTrials.gov API v2 armsInterventionsModule	—	—

Domain	Reading	Levels	Reason
risk of bias	no downgrade	—	Result-level RoB 2 over 6 contributing result(s): NO_INFORMATION=6. NOT ONE reaches LOW -- D5 cannot, because no trial's statistical analysis plan is held, and D1 cannot, because allocation concealment is in neither the registration nor this object. 6 have at least one domain at NO INFORMATION. This is a limit on what we can reach, not a finding against the trials.
inconsistency	no downgrade	—	I-squared 88% over k = 8. Rated down. I-squared is one input and never the test -- P36 -- but at this magnitude with a small k the point estimates genuinely disperse.
indirectness	no downgrade	—	The contributing results share one endpoint definition, verified by reading each trial's registered text rather than by comparing names.
imprecision	no downgrade	—	k = 8 and the interval (-60.23 to -49.42) excludes the null.
publication bias	no downgrade	—	k = 8. A funnel plot and Egger's test have no power below k = 10, so publication bias is UNDETECTED rather than ABSENT. Not rated down, and not reported as clean: an unreachable state is not a passing one.

Submission readiness: NOT READY

Alirocumab versus placebo: percent change in calculated LDL cholesterol at week 24

Registration and administrative information (PROSPERO field set)

Search — executed, source by source

Search record: search

PRISMA flow

ClinicalTrials.gov API v2 -- query 1, narrow (condition + drug)

ClinicalTrials.gov API v2 -- query 2, broad (intervention only)

Extraction — every datum linked to its source

Outcome ldlc_pct_change_wk24

Extracted values, and where each came from

Recompute envelope — the headline against the rows shown

Outcome ldlc_pct_change_wk24

Absolute effect at a baseline risk the reader chooses

Risk of bias (RoB-2)

Overall judgement per trial

Inter-assessor agreement

References

Included studies

Regulatory documents

Methods and guidance

Sources

Percent change from baseline in calculated LDL cholesterol at week 24

Percent change from baseline in calculated LDL cholesterol at week 24

Pooled result

What other estimators give on the same values

Contributing trials

Endpoint definitions, read from the registry

Percent change from baseline in calculated LDL cholesterol at week 24

Forest plot

Visual abstract

Risk of bias, both assessors

GOSH

Trial-sequential analysis

Meta-regression

Summary of findings

Reproducibility artifact

Other recorded qualifications

Judgement register — what a harness cannot derive

Outcome ldlc_pct_change_wk24 — 0 of 8 declared, 8 of 8 undeclared

Comparison with published syntheses

The syntheses reconciled against

Where the numbers differ, and why

Paper

Title

Abstract

Introduction

Methods — search

Methods — eligibility criteria

Methods — how many studies at each stage

Methods — synthesis

Results

Risk of bias in the included results

Certainty of the evidence

Comparison with published syntheses

Limitations

Data availability

Software availability

Reporting guidelines

Note on registration

References

Figures

Trial characteristics

Submission conformance

Not reported in this record

ldlc pct change wk24

Page standard 1.10.0-2026-08-19

k at every stage

Inclusion criteria — derived, post hoc

Screening of the remainder — — screened, — included, — excluded, — not-assessable

The withholding question, asked at every rank

Every trial, with its reason

Analysis output — ldlc_pct_change_wk24 (quoted verbatim)

Preconditions

What is being estimated

Both intervals, and which one this page reports

What has changed since these trials were last synthesised

What the pooled effect means in people

Safety, and every other outcome these trials reported

Which counts were used, and what difference it makes