Abstract

Objective Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome.

Methods We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model.

Results Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group.

Conclusions For rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This data presented here was collected with support from the NIH (HD070855), The Snow Foundation and the ADA.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Data were from the Washington University Wolfram Research Clinic (https://wolframsyndrome.wustl.edu/items/research-clinic/; ClinicalTrials.gov Identifier NCT03951298). The study protocol was approved by the Human Research and Protection Office (HRPO) at Washington University in St. Louis.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The raw data used in the analyses described in this manuscript cannot be made available in the manuscript, supplemental files, or a public repository due to the small sample size and rarity of Wolfram syndrome, which could lead to the identification of individuals even after data de-identification. The corresponding author may be contacted to request data. According to the Human Research Protection Office (HRPO) at Washington University, a preface to a data sharing agreement and a data sharing agreement reviewed by the research office will be employed prior to data sharing. HRPO regulations permit access to potentially identifiable data only to research personnel on our study protocol and approved through the University.

List of AbbreviationsERendoplasmic reticulumWURSWolfram Unified Rating ScaleMRImagnetic resonance imaginglogMARlogarithm of the minimum angle of resolutioneTIVestimated total intracranial volumeLMElinear mixed effects.