Nick DeVito and Ben Goldacre

Background

The US FDA Amendments Act (FDAAA 2007) requires certain clinical trials to report their results onto ClinicalTrials.gov within one year of completion. Our FDAAA TrialsTracker shows all individual trials that breach this legal requirement. Once a week, we write about one unreported clinical trial: you can read more background here.

Trial NCT01922258

The week’s unreported trial is “A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Flexible Dosing of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer’s Type” (NCT01922258). This study enrolled 270 seniors (aged 55-90) with Alzheimer’s disease. The intervention group received brexpiprazole with flexible dosing between 0.5 and 2 mg/day for up to 12 weeks; the control group received placebo. The study was blinded for all participants and study personnel. The primary outcome was change in the Cohen-Mansfield Agitation Inventory (CMAI) total score. The secondary outcome was change in the Clinical Global Impression Severity of Illness (CGI-S) score, as related to symptoms of agitation. Eight additional measures were also listed as “other outcomes” covering changes in scores for a number of additional scales and sub-scales as well as safety outcomes. Brexpiprazole is currently approved under the trade name Rexulti for use in major depressive disorder and schizophrenia.

Clinical discussion

2010 estimates put the global prevalence of dementia at 24.3 million, with 4.6 million new cases each year. The authors predict that the global prevalence could reach 81.1 million by 2040. In the western world, Alzheimer’s type dementia makes up 60% of all dementia cases. A 2018 review of the literature on dementia found that agitation/aggression was the most commonly reported behavioural crisis. A recent study across 8 European countries reported total monthly mean societal cost differences in care due to agitation in dementia patients were €445 in home care settings and €561 in institutional long-term care settings. While some medications have shown promise in treating agitation in dementia patients, the US FDA has not approved any therapies for this indication; the EMA has only approved a single therapy (risperidone) for aggression in Alzheimer’s patients. Developing an effective treatment for agitation in dementia patients is important work with major implications for how we manage the disease in elderly patients.

Legislative discussion

We intend that this series should occasionally shed light on interesting issues around transparency rules, and how registry data is used. You can read some general background about the FDA Amendments Act 2007—and why a trial is considered “due”—here and here.

This unreported trial presents an interesting case-study as it touches a number of areas covered specifically by the FDAAA 2007, and subsequent final rule. The FDAAA 2007 requires results to be reported within 12 months; however it does allow sponsors to seek exemptions, for certain trials, in order to delay that timeline for reporting. For example, companies can seek a reporting delay of up to two additional years if the study investigates a new indication for an existing treatment.

The sponsors of this trial would have been eligible to seek such a reporting delay, because brexpiprazole is currently licensed for use in schizophrenia and depression, but not for agitation in Alzheimer’s type dementia patients; and because the trial was sponsored by the manufacturer. When a trial receives a certificate of delay, this is clearly noted on the trial’s results page, usually within a few days of the request being received.

However there is no certificate of delay for this trial, and it is nearly three months past its due date to report results. The final rule (§11.44) specifically notes that any requests for delay must be submitted “prior to the results information submission deadline” (our emphasis) which is one year from the primary completion date. Of note, another related study for the same treatment and condition, by the same sponsors (NCT01862640) did receive such a certificate two months before the reporting deadline. However, the sponsors of today’s Unreported Trial Of The Week have either not sought, or have not been granted, an exemption; therefore they can be expected to fully report their results within 12 months of trial completion, in accordance with the law.

As we have noted in previous UTOTW posts, under the FDAAA 2007, trials are required to report results directly onto ClinicalTrials.gov: publication of results elsewhere does not meet the legal reporting obligations. We note that previous research has shown that academic journal publications routinely permit misreporting of clinical trial methods and results; and that structured results reporting on ClinicalTrials.gov is more complete, especially with respect to adverse events. Nonetheless we also looked for company, journal, and conference publications giving full results for this trial. We found press releases and shareholder documents for this and one other related trial (NCT01862640): however, while topline primary and secondary results were discussed, there was no mention of the additional prespecified outcomes; and there was a notable lack of detail that would be expected for results on ClinicalTrials.gov. A brief overview of headline results in press or shareholder documents is certainly not compliant with the law on reporting results; it is also no substitute, ethically or scientifically, for a full report of methods and results.

Otsuka and Lundbeck, the sponsors of this trial, already have plans to initiate a third Phase 3 trial of brexpiprazole in agitation in Alzheimer’s type dementia patients this year following discussions with the FDA around their prior results. In our view, if these companies are to have further access to Alzheimer’s patients, they should be required to meet their legal requirements to fully report results of all previous trials, and honour the commitment made to those prior patients.

Conclusion

This unreported trial was sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. in collaboration with H. Lundbeck A/S. The study director was Dr. Eva Koheygi of Otsuka. We hope the investigators will share the results of this trial soon.

 

Ben Goldacre is a doctor, author, and director of the EBM DataLab at the University of Oxford. He co-founded the AllTrials campaign for trials transparency.

Competing interests: BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the Oxford Biomedical Research Centre, the NHS National Institute for Health Research School of Primary Care Research, the Health Foundation, and the World Health Organization; he also receives personal income from speaking and writing for lay audiences on the misuse of science.

Nicholas J DeVito is a researcher at the EBM Datalab at the University of Oxford.

Competing interests: ND is employed on BG’s LJAF grant.