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Abstract
Objective To determine whether patients randomized to unapproved, disease-modifying interventions in neurodegenerative disease trials have better outcomes than patients randomized to placebo by performing a systematic review and meta-analysis of risk and benefit experienced by patients in randomized placebo-controlled trials testing investigational treatments for Alzheimer disease, Parkinson disease, Huntington disease, or amyotrophic lateral sclerosis (ALS).
Methods We searched MEDLINE, Embase, and ClinicalTrials.gov for results of randomized trials testing non–Food and Drug Administration–approved, putatively disease-modifying interventions from January 2005 to May 2018. Trial characteristics were double-extracted. Coprimary endpoints were the treatment advantage over placebo on efficacy (standardized mean difference in outcomes) and safety (risk ratios of serious adverse events and withdrawals due to adverse events), calculated with random effects meta-analyses. The study was registered on PROSPERO (CRD42018103798).
Results We included 113 trials (n = 39,875 patients). There was no significant efficacy advantage associated with assignment to putatively disease-modifying interventions compared to placebo for Alzheimer disease (standardized mean difference [SMD] −0.03, 95% confidence interval [CI] −0.07 to 0.01), Parkinson disease (SMD −0.09, 95% CI −0.32 to 0.15), ALS (SMD 0.02, 95% CI −0.25 to 0.30), or Huntington disease (0.02, 95% CI −0.27 to 0.31). Patients with Alzheimer disease assigned to active treatment were at higher risk of experiencing serious adverse events (risk ratio [RR] 1.15, 95% CI 1.04–1.27) and withdrawals due to adverse events (RR 1.44, 95% CI 1.21–1.70).
Conclusions Assignment to active treatment was not beneficial for any of the indications examined and may have been slightly disadvantageous for patients with Alzheimer disease. Our findings suggest that patients with neurodegenerative diseases are not, on the whole, harmed by assignment to placebo when participating in trials.
Glossary
- AD=
- Alzheimer disease;
- ADAS-Cog=
- Alzheimer's Disease Assessment Scale–Cognitive Subscale;
- ALS=
- amyotrophic lateral sclerosis;
- ALSFRS=
- ALS Functional Rating Scale;
- CI=
- confidence interval;
- FDA=
- Food and Drug Administration;
- HD=
- Huntington disease;
- NNTH=
- number needed to be treated for 1 additional patient to be harmed;
- PD=
- Parkinson disease;
- RCT=
- randomized placebo-controlled trial;
- RR=
- risk ratio;
- SAE=
- serious adverse events;
- SMD=
- standardized mean difference;
- UHDRS=
- Unified Huntington's Disease Rating Scale;
- UPDRS=
- Unified Parkinson's Disease Rating Scale;
- WAE=
- withdrawal due to adverse events
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Editorial, page 12
- Received May 15, 2019.
- Accepted in final form July 22, 2019.
- © 2019 American Academy of Neurology
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