Here you will find a listing of projects that have been funded by a RIAT Support Center Grant.

2020 Competition Winners

Project Title Restoration of the FOURIER trial (evolocumab vs placebo in secondary cardiovascular prevention)
Investigators Juan Erviti, Leire Leache, Luis Carlos Saiz, Thomas L. Perry, and James M. Wright
Institution Collaboration between the University of British Columbia and the Cochrane Hypertension Group both in Vancouver and the National Health Service in Navarre, Spain
Project Dates September 1, 2020 – August 31, 2021
Grant Amount $132,000 USD
RIAT Call-to-Action https://www.bmj.com/content/346/bmj.f2865/rr-12
Project Description Evolocumab is a drug that lowers LDL-C levels. In 2017 the study FOURIER was published and the authors concluded that evolocumab was better than placebo in reducing the incidence of cardiovascular (CV) events in persons who had already suffered from a previous CV episode. However, serious and total CV adverse events were not reported. We gained access to European Medicines Agency documents and found preliminary evidence that evolocumab might not be better than placebo in reducing CV events. This would challenge the claims of better clinical results with evolocumab. Additionally, we identified some methodological limitations of the study that should have been described in the publication. The aim of this project is to restore the misreported FOURIER trial. Missing information on serious and total CV adverse events will be provided. Also the results, including all available information in regulatory documents, will be completely reassessed by blinded independent researchers. Finally, potential conflicts of interest of the authors and methodological limitations of the study will be more fully reported.  The team will ensure blinding to intervention and reassess all the EMA’s documents (over 20,000 pages). The principal researcher will identify potential cases which were misreported for independent validation by the research team. A new version of the trial results will be published. This is a highly relevant project that could challenge the claims of clinical benefits of evolocumab, and also provide important information on whether lowering cholesterol levels reduces CV disease and mortality.
Publications Erviti et al. https://doi.org/10.1136/bmjopen-2021-060172

 

Project Title Suicidal events and efficacy in two pivotal trials of fluoxetine in children with depression
Investigators Peter C. Gøtzsche, David Healy, Joanna Le Noury
Institution Institute for Scientific Freedom, Copenhagen, Denmark and School of Medical Sciences, Bangor University, Bangor, Wales
Project Dates July 1, 2020 – June 30, 2021
Grant Amount $146,999
RIAT Call-to-Action https://www.bmj.com/content/346/bmj.f2865/rr-13
Project Description Treatment of children and adolescents with antidepressants is controversial. The effect is of doubtful clinical relevance and the drugs increase the risk of suicide. It has been documented that published reports of depression trials cannot be trusted. There is widespread selective reporting, with underreporting of suicidal events, and other manipulations with the data are also common. Fluoxetine is approved in some countries for treatment of depression in children and adolescents. The basis for this approval is two placebo-controlled trials. The clinical study reports Eli Lilly submitted to drug regulators for marketing approval reveal that suicidal events and precursors to such events are missing in the published trial reports. In the publication of the first trial, there was no mention that two of the patients on fluoxetine attempted suicide versus none on placebo. The publication of the second trial also downplayed the harms of fluoxetine. The clinical study report reveals that several events that predispose to suicide and violence were more common on fluoxetine than on placebo (e.g. abnormal dreams, akathisia, hyperkinesia, delusions, emotional lability and hallucinations) and that one patient on fluoxetine discontinued the study because of suicidal ideation. Our project aims to restore the public record on these two trials. The primary outcomes will be suicidal events, precursors to suicidality or violence, and primary efficacy variables as defined in the original trial protocols.
Publications Gøtzsche PC, Healy D. Restoring the two pivotal fluoxetine trials in children and adolescents with depression. Int J Risk Saf Med. 2022;33(4):385-408. doi: 10.3233/JRS-210034. PMID: 35786661. (full text PDF)

2019 Competition Winners

Project Title RIAT reanalysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study
Investigators Ed Pigott,  Jay Amsterdam,  William Dubin,  Irving Kirsch,  Termeh Feinberg,  Colin Xu,  Thomas Kim
Institution Private practice
Project Dates September 1, 2019 – August 31, 2021
Grant Amount $150,000 USD
RIAT Call-to-Action https://www.bmj.com/content/346/bmj.f2865/rr-10
Project Description STAR*D is the largest and most consequential antidepressant study ever conducted with over 120 journal articles published by study investigators, innumerable citations of STAR*D’s findings by other researchers, and extensive coverage in the media, thereby giving it an oversized impact on the treatment of depression, worldwide. STAR*D provided up to 4 treatment steps per patient and was designed to give guidance in selecting the best next-step treatment option for the many patients who fail to gain sufficient relief from their first, and/or subsequent, antidepressant trial(s).

While STAR*D’s findings have been widely disseminated, its researchers evidenced multiple protocol violations with each violation having an inflationary effect on reported remission and response rates to antidepressants. Furthermore, 13 years after completing the study, STAR*D researchers have still not published steps 1-4 pre/post and follow-up findings for the 11 secondary outcome measures assessing health, work and social functioning, quality of life, side-effect burden, medical utilization and cost, and personal income.

Given the unreported deviations from STAR*D’s protocol and failure to report the findings from its secondary outcome measures, our aim is to restore the record for these trials by using the protocol-specified primary and secondary outcome measures and statistical analytic plan for treatment steps 1-4 and one-year follow-up. An accurate restoration is essential to understanding the true risks and benefits for each of STAR*D’s 11 pharmacologically distinct drug–drug combination treatments in five head-to-head comparisons. Our restoration therefore should have substantial public health and scientific significance to better inform the treatment of depression worldwide.

 

Project Title Misreported information about harms in trials of gabapentin for neuropathic pain
Investigators Evan Mayo-Wilson, Stephanie Dickinson, Tianjing Li
Institution Indiana University School of Public Health – Bloomington
Project Dates November 1, 2019 – July 30, 2021
Grant Amount $146,087 USD
RIAT Call-to-Action https://www.bmj.com/content/346/bmj.f2865/rr-14
Project Description The U.S. Food and Drug Administration (FDA) approved the drug gabapentin (brand name “Neurontin”) for the treatment of epilepsy. FDA later approved gabapentin for the pain condition “post herpetic neuralgia”. Doctors prescribe gabapentin for many health problems, including problems for which it has not been approved by FDA (“off label” use). It is used widely for nerve pain.

To promote the use of gabapentin for unapproved health problems, the manufacturer of gabapentin published studies in medical journals describing benefits observed in clinical trials. However, the manufacturer did not report the complete results of those trials. Instead, the manufacturer cherry-picked the best results. The manufacturer hid many harms by not reporting all of gabapentin’s potential side effects. Following multiple lawsuits, the manufacturer was fined by the U.S. Department of Justice and had to pay patients and providers who claimed that gabapentin was marketed illegally. In this study, we will reexamine 6 trials conducted by the manufacturer that were not published or not published completely. We will publish tables that include all harms observed in these trials of gabapentin for nerve pain, and we will publish a report summarizing the key findings for patients and clinicians.

2018 Competition Winner

Project Title TADSRIAT: Reanalysis of the most influential study of antidepressants in adolescents
Investigators Jon Jureidini (PI) Melissa Raven Catalin Tufanaru Sami Timimi
Institution  University of Adelaide
Project Dates  January 1, 2019 – June 30, 2020
Grant Amount $150,000 USD
RIAT Call-to-Action https://www.bmj.com/content/346/bmj.f2865/rr-3
Project Description More and more children and adolescents (and adults) are being prescribed antidepressants, despite uncertainty about their benefits and harms. Scientific research about mental health is important, but it is not always carried out and reported properly. Some problematic research and deceptive reporting has misled doctors and the public about the effectiveness and safety of antidepressants. Our project will carefully re-analyze an important US research study called ‘TADS: Treatment for Adolescents with Depression Study’. TADS investigated the effectiveness and safety of Prozac (fluoxetine) and counseling for depressed adolescents. The results were published 10-15 years ago, and there has been debate about them ever since. We will properly analyze the results, to clarify how well Prozac and counseling worked and how safe they were. Our project will provide valuable information about the benefits and harms of antidepressants for adolescents. It will help doctors and other health professionals and young people and their parents to make better decisions about how to deal with depression. Our project will also shed light on problems in mental health research and will help improve ways of checking how medical studies are reported, both of which will help to improve future research.