Risks and benefits of unapproved disease-modifying treatments for neurodegenerative disease

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.

Figure 1. PRISMA diagrams

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagrams for (A) Alzheimer disease, (B) Parkinson disease, (C) amyotrophic lateral sclerosis (ALS), and (D) Huntington disease. Diagrams include trial records in both the primary (long-duration) and secondary (short-duration) samples. ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognitive Subscale; ALSFRS = ALS Functional Rating Scale; FDA = Food and Drug Administration; RCT = randomized placebo-controlled trial; SAE = serious adverse events; UHDRS = Unified Huntington's Disease Rating Scale; UPDRS = Unified Parkinson's Disease Rating Scale; WAE = withdrawal due to adverse events.

Figure 2. Benefit associated with treatment assignment

Standardized mean difference between treatment and control groups on disease-specific efficacy scales (Alzheimer disease: Alzheimer's Disease Assessment Scale–Cognitive Subscale; Parkinson disease: Unified Parkinson's Disease Rating Scale; amyotrophic lateral sclerosis [ALS]: ALS Functional Rating Scale; Huntington disease: Unified Huntington's Disease Rating Scale–Total Motor Score) in long-duration trials (>24 weeks). Note that, for clarity, all the scales are represented such that a positive mean change represents a worsening, regardless of the original directionality of the scale. Letters following the e-reference number are used to differentiate between either multiple studies within the same publication or multiple publications from the same year. CI = confidence interval; SMD = standardized mean difference. e-References are available on FigShare, https://doi.org/10.6084/m9.figshare.10052426.v2.

Figure 3. Risk of SAEs associated with treatment assignment

Risk ratio (RR) of serious adverse events (SAEs) in long-duration trials (>24 weeks) of Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), and Huntington disease (n represents the number of SAEs; N represents the number of patients randomized). A correction factor of 0.5 was added for trials with no SAEs in either the treatment or placebo arm. Letters following the e-reference number are used to differentiate between either multiple studies within the same publication or multiple publications from the same year. CI = confidence interval. e-References are available on FigShare, https://doi.org/10.6084/m9.figshare.10052426.v2.

Figure 4. Risk of WAEs associated with treatment assignment

Risk ratio (RR) of withdrawals due to adverse events (WAEs) in long-duration trials (>24 weeks) (n represents the number of WAEs; N represents the number of patients randomized). A correction factor of 0.5 was added for trials with no WAEs in either the treatment or placebo arm. Letters following the e-reference number are used to differentiate between either multiple studies within the same publication or multiple publications from the same year. ALS = amyotrophic lateral sclerosis; CI = confidence interval. e-References are available on FigShare, https://doi.org/10.6084/m9.figshare.10052426.v2.

Figure 5. Correlation between efficacy and trial duration

Meta-regression of efficacy with covariate of trial duration. Effect size represents the standardized mean difference (SMD) between the treatment and placebo arms; a positive SMD indicates a trial that favored the placebo arm. The p values correspond to the slope of the regression line. The r² values were 4.96%, 0.27%, 0.14%, and 19.40% for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), and Huntington disease, respectively.