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. 2020 Jan;13(1):88-97.
doi: 10.1111/cts.12682. Epub 2019 Sep 9.

An Innovative Disease-Drug-Trial Framework to Guide Binge Eating Disorder Drug Development: A Case Study for Topiramate

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Free PMC article

An Innovative Disease-Drug-Trial Framework to Guide Binge Eating Disorder Drug Development: A Case Study for Topiramate

Shamir N Kalaria et al. Clin Transl Sci. .
Free PMC article

Abstract

As with other psychiatric disorders, development of drugs to treat binge-eating disorder (BED) has been hampered by high placebo response and dropout rates in randomized controlled trials (RCTs). Although not approved for use in BED, several RCTs have suggested that topiramate is efficacious for BED in obese individuals. Using data from a positive investigator-initiated RCT of topiramate in 61 obese individuals with BED, the objective of the present study is (i) to develop a quantitative disease-drug-trial framework to inform future BED clinical trial designs, and (ii) to determine the optimal topiramate dose to achieve therapeutic efficacy. Disease-drug-trial models were developed separately for the two efficacy measures, namely, longitudinal normalized weekly binge-eating episode frequency (BEF) and binge day frequency (BDF). Model building consisted of (i) developing a placebo effect model that describes response from the placebo group, (ii) adding a drug effect to the placebo model to describe dose-response relationships, and (iii) developing a parametric time to event model to characterize patient dropout patterns. The placebo effect on normalized BEF and BDF over time demonstrated a maximum decrease of ~ 57% by 5 weeks. Participants had a higher dropout probability if no weight loss occurred during the trial period. The identified dose-response relationship demonstrated a daily dose of 125 mg was needed to exhibit a marked reduction in weekly BEF. The developed comprehensive disease-drug-trial model will be utilized to simulate different clinical trial designs to increase the success for future BED drug development programs.

Conflict of interest statement

The authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Kaplan‐Meier based visual predictive check for final dropout model (N = 500 simulations). Solid and dashed lines represent observed and predicted probabilities for dropout. Shaded regions represent the prediction interval for dropout probabilities in each category.
Figure 2
Figure 2
Visual predictive check plots. The final disease‐drug‐trial models characterizing longitudinal normalized weekly binge episodes in patients receiving topiramate and placebo (N = 500 simulations) (a) and binge day frequency (b). Solid and dashed lines represent the observed and model‐simulated 5th, 50th, and 95th percentiles. Colored bands demonstrate the 95% confidence interval for the simulated 5th, 50th, and 95th percentiles.
Figure 3
Figure 3
Categorical responder analysis comparing patients receiving placebo vs. topiramate. Response categories based on percent reduction in weekly binge episodes at study end point. Circle point and associated error bars represent model‐simulated (N = 500 simulations) mean and 95% confidence intervals. Square and triangle points represent observed percentage of patients in each responder category from two randomized controlled trials evaluating topiramate for binge‐eating disorder.18, 28 No response: < 50% reduction; moderate response: 50–74% reduction; marked response: 75–99% reduction; remission: cessation of binges.
Figure 4
Figure 4
Comparison of percentage of patients with 4‐week cessation of binges in patients receiving topiramate vs. placebo based on simulations of binge‐eating episode frequency. Dashed lines represent observed percentage of patients with 4‐week cessation of binges. The histogram displays the distribution of percentage of patients with 4‐week cessation of binges from model‐based simulations (N = 500 simulations).
Figure 5
Figure 5
Quantitative predictive check plots for the final weight submodel. (a) Longitudinal change from baseline in weight (kg) in patients taking topiramate and placebo. Solid and dashed lines represent the observed mean and model‐simulated 50% percentile respectively (N = 1,000 simulations). Shaded bands represent 95% confidence intervals. (b) Comparison of percentage of patients with clinically meaningful weight loss. Dashed lines represent observed percentage of patients with ≥ 5% weight loss. The histogram displays the distribution of percentage of patients with ≥ 5% weight loss from model‐based simulations (N = 500 simulations).
Figure 6
Figure 6
Dose‐response curves for assessing percent change from baseline in weekly binge episode frequency (BEF) and weekly binge day frequency (BDF). Dose‐response curves were developed using population mean parameter estimates from the final disease‐drug‐trial model. Dashed lines represent the corresponding dose to achieve a marked reduction (≥ 75%) in weekly binge episodes or BDF.

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