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Center for Global Research Data

Inferential reproducibility of therapeutic research: a registered report for a cross-sectional study of RCTs available on major data-sharing platforms

Lead Investigator: Florian Naudet, CHU Rennes
Title of Proposal Research: Inferential reproducibility of therapeutic research: a registered report for a cross-sectional study of RCTs available on major data-sharing platforms
Vivli Data Request: 7744, 6055
Funding Source: sponsored by the French National Research Agency; Code: ANR-17-CE-36-0010-01
Potential Conflicts of Interest: Florian Naudet has received support from the French National Research Agency for this project.
Number: ANR-17-CE-36-0010-01

Summary of the Proposed Research:

Randomized Controlled Trials (RCTs) are of major importance in providing information about health practices and policies. Ideally, the general public and scientists feel more confident when their methods and results can be reproduced. This registered report introduces a cross-sectional study aiming to explore inferential reproducibility (i.e. Individual Patient Data is available and qualitatively similar conclusions can be drawn from a re-analysis of the original trials) for RCTs, for which there is available data on major data-sharing platforms.

This study will include RCTs identified on 3 repositories (Clinical Study Data Request, VIVLI and Yale University Open Data Access). Eligible RCTs will be phase III studies conducted in the field of therapeutics. 62 of these studies will be randomly sampled, ensuring a precision of ± 7.5% to estimate our primary outcome, i.e. the proportion of studies where the conclusions are reproduced (we hypothesize that more than 90 % of studies could be reproduced). One researcher will then retrieve the Individual Patient Data for these studies and other necessary documents for re-analysis by contacting the platforms and the study sponsors. For each study he will prepare a dossier containing the Individual Patient Data (IPD), the protocol and information on the conduct of the study. A second researcher who will have no access to study reports (including publications) or analytical codes will use the dossier to run an independent reanalysis of each trial. All results from these re-analyses will be reported in terms of the conclusions, p-values, effect sizes and changes from the initial protocol in each study. Then a team of two researchers not involved in the re-analysis will compare results of the re-analysis with the published results of the trial. In case of conflicting results, a statistician will re-analyse the data independently before concluding to a lack of inferential reproducibility. Key issues that arose in the course of data requests and reanalysis will be qualitatively described.

This registered report is part of a wider project called “Reproducibility in Therapeutic Research”, funded by the Agence Nationale de la Recherche, and a complementary registered report aims to explore the reproducibility of trials used for decision-making on Marketing Authorizations for new medicines in the European Medicine Agency

Requested Studies:

An Eight-week Randomized, 4-arm, Double-blind Study to Compare the Efficacy and Safety of Combinations of Telmisartan 40mg + Amlodipine 5mg Versus Telmisartan 80mg + Amlodipine 5mg Versus Amlodipine 5mg Versus Amlodipine 10mg Monotherapy in Patients With Hypertension Who Fail to Respond Adequately to Treatment With Amlodipine 5mg Monotherapy
Data Contributor: Boehringer Ingelheim
Study ID: NCT00558428
Sponsor ID: 1235.5

A Randomised, Double-blind, Placebo-controled Parallel Group Efficacy and Safety Study of BI 1356 (5 mg Administered Orally Once Daily) Over 24 Weeks, in Drug Naive or Previously Treated (6 Weeks Washout) Type 2 Diabetic Patients With Insufficient Glycemic Control
Data Contributor: Boehringer Ingelheim
Study ID: NCT00621140
Sponsor ID: 1218.16

Efficacy {FEV1, COPD Exacerbations & HRQoL} & Safety of 5mcg Tiotropium Respimat in COPD
Data Contributor: Boehringer Ingelheim
Study ID: NCT00387088
Sponsor ID: 205.372

A Randomized Trial Of Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced Renal Cell Carcinoma Who Have Failed First-Line Sunitinib Therapy
Data Contributor: Pfizer Inc.
Study ID: NCT00474786
Sponsor ID: 3066K1-404

A 24-Week Study of the Efficacy and Safety of Teduglutide in Subjects With Parenteral Nutrition-Dependent Short Bowel Syndrome
Data Contributor: Takeda
Study ID: NCT00798967
Sponsor ID: CL0600-020

A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Placebo and Sitagliptin 100 mg When Used in Combination With Metformin in Subjects With Type 2 Diabetes
Data Contributor: Takeda
Study ID: NCT01549964
Sponsor ID: TAK-875_302

Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 mcg [2 Actuations of 2.5 mcg] and 10 mcg [2 Actuations of 5 mcg]) Delivered by the Respimat® Inhaler, in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Data Contributor: Boehringer Ingelheim
Study ID: NCT00782210
Sponsor ID: 1222.11

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of SYR110322 (SYR-322) Compared With Placebo in Subjects With Type 2 Diabetes
Data Contributor: Takeda
Study ID: NCT00286455
Sponsor ID: SYR-322-PLC-010

A Randomized, Double-Blind, Placebo-Controlled, Polysomnography Plus Outpatient Study to Determine the Safety and Efficacy of 4 mg Ramelteon in Adults With Chronic Insomnia
Data Contributor: Takeda
Study ID: NCT00756002
Sponsor ID: 01-06-TL-375-081

Comparison of Efficacy and Safety of Paricalcitol Injection With Maxacalcitol Injection in Adult Japanese Chronic Kidney Disease Subjects Receiving Hemodialysis With Secondary Hyperparathyroidism
Data Contributor: AbbVie
Study ID: NCT01341782
Sponsor ID: M11-517

A Phase III Randomised, Double-blind, Placebo-controlled Parallel Group Study to Compare the Efficacy and Safety of Twice Daily Administration of the Free Combination of BI 1356 2.5 mg + Metformin 500 mg, or of BI 1356 2.5 mg + Metformin 1000 mg, With the Individual Components of Metformin (500 mg or 1000 mg Twice Daily), and BI 1356 (5.0 mg Once Daily) Over 24 Weeks in Drug Naive or Previously Treated (4 Weeks Wash-out and 2 Weeks Placebo run-in) Type 2 Diabetic Patients With Insufficient Glycaemic Control
Data Contributor: Boehringer Ingelheim
Study ID: NCT00798161
Sponsor ID: 1218.46

A Phase III, Randomized Open-Label Study to Compare the Pharmacokinetics, Efficacy, and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)
Data Contributor: Roche
Study ID: NCT00950300
Sponsor ID: BO22227

A Randomized, Double-Blind, Parallel-Group, International Study to Evaluate the Safety and Efficacy of Ocrelizumab Given As a Single Infusion or Dual Infusion Compared With Placebo in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate Therapy
Data Contributor: Roche
Study ID: NCT00673920
Sponsor ID: ACT4394g

A Phase IIIb Multicenter, Double-blind, Placebo-controlled,Randomized Trial to Examine the Corticosteroid-sparing Effect of Certolizumab Pegol in Patients With Moderate to Severe Crohn’s Disease.
Data Contributor: UCB
Study ID: NCT00349752
Sponsor ID: C87059

A Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Assess the Efficacy and Safety of Tadalafil (LY450190) Once a Day in Subjects With Erectile Dysfunction Who Are Naïve to PDE5 Inhibitors
Data Contributor: Lilly
Study ID: NCT00836693
Sponsor ID: 12229

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Capecitabine and Cisplatin With or Without Ramucirumab as First-line Therapy in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (RAINFALL)
Data Contributor: Lilly
Study ID: NCT02314117
Sponsor ID: 15372

A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (2.5 mcg and 5 mcg) Delivered Via Respimat® Inhaler Once Daily in the Evening Over 48 Weeks in Children (6 to 11 Years Old) With Moderate Persistent Asthma
Data Contributor: Boehringer Ingelheim
Study ID: NCT01634139
Sponsor ID: 205.445

A Phase 3 Multicenter Study of the Safety and Efficacy of Adalimumab in Subjects With Moderate to Severe Hidradenitis Suppurativa – PIONEER II
Data Contributor: AbbVie
Study ID: NCT01468233
Sponsor ID: M11-810

A Prospective Randomised, Open Label, Blinded Endpoint (PROBE) Study to Evaluate DUAL Antithrombotic Therapy With Dabigatran Etexilate (110mg and 150mg b.i.d.) Plus Clopidogrel or Ticagrelor vs. Triple Therapy Strategy With Warfarin (INR 2.0 – 3.0) Plus Clopidogrel or Ticagrelor and Aspirin in Patients With Non Valvular Atrial Fibrillation (NVAF) That Have Undergone a Percutaneous Coronary Intervention (PCI) With Stenting
Data Contributor: Boehringer Ingelheim
Study ID: NCT02164864
Sponsor ID: 1160.186

Duloxetine Versus Placebo in the Prevention of Recurrence of Major Depressive Disorder
Data Contributor: Lilly
Study ID: NCT00105989
Sponsor ID: 8606

A Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Bevacizumab in Combination With Docetaxel in Comparison With Docetaxel Plus Placebo, as First Line Treatment for Patients With HER2 Negative Metastatic and Locally Recurrent Breast Cancer.
Data Contributor: Roche
Study ID: NCT00333775
Sponsor ID: BO17708

The Impact of LY2189265 Versus Metformin on Glycemic Control in Early Type 2 Diabetes Mellitus (AWARD-3: Assessment of Weekly AdministRation of LY2189265 in Diabetes-3)
Data Contributor: Lilly
Study ID: NCT01126580
Sponsor ID: 11375

A Randomized, Double-blind, Placebo-controlled Parallel Group Efficacy and Safety Study of BI 1356 Over 24 Weeks in T2D Patients With Insufficient Glycaemic Control Despite Metformin Therapy
Data Contributor: Boehringer Ingelheim
Study ID: NCT01215097
Sponsor ID: 1218.65

A Phase 3 Multi-Center, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study Comparing Adalimumab and Placebo in Adult Japanese Subjects With Rheumatoid Arthritis
Data Contributor: AbbVie
Study ID: NCT00870467
Sponsor ID: M06-859

A Randomized, Double-blind, Parallel Group Study of the Safety and Effect on Clinical Outcome of Tocilizumab SC Versus Tocilizumab IV, in Combination With Traditional Disease Modifying Anti-rheumatic Drugs (DMARDs), in Patients With Moderate to Severe Active Rheumatoid Arthritis
Data Contributor: Roche
Study ID: NCT01194414
Sponsor ID: WA22762

A Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Combination With Methotrexate for Inducing and Sustaining Clinical Response in the Treatment of DMARD-Naïve Adults With Early Active Rheumatoid Arthritis
Data Contributor: UCB
Study ID: NCT01519791
Sponsor ID: RA0055 Period 1

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of SYR110322 (SYR-322) When Used in Combination With Metformin in Subjects With Type 2 Diabetes
Data Contributor: Takeda
Study ID: NCT00286442
Sponsor ID: SYR-322-MET-008

A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT01120184
Sponsor ID: BO22589

(Note: Additional studies added as part of Data Request 7744)

A Randomized, 30-week, Active-controlled, Open Label, 2- Treatment Arm, Parallel-group, Multicenter Study Comparing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination to Insulin Glargine With or Without Metformin in Patients With Type 2 Diabetes Mellitus (T2DM)
Data Contributor: Sanofi
Study ID: NCT02058160
Sponsor ID: EFC12405

A Phase 3, Randomized, Multi-Center, Multi-National, Double-Blind Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Once Daily Versus Twice Daily Dosing of Genz-112638 in Patients With Gaucher Disease Type 1 Who Have Demonstrated Clinical Stability on a Twice Daily Dose of Genz-112638
Data Contributor: Sanofi
Study ID: NCT01074944
Sponsor ID: GZGD03109