Clinical Trial Design: Double-Blind Fixed Duration Trial with Long-term Double-Blind Various Treatment Duration

The randomized, double-blind, parallel-group design is the most common type of design for clinical trials (especially the confirmatory clinical trials). This type of design can be further classified into clinical trials with a fixed treatment duration or with various treatment durations. For clinical trials with a fixed duration, all patients are treated with study drugs for a fixed duration (for example, 16 weeks, 24 weeks, 52 weeks,...) and the primary efficacy endpoint will be estimated at the end of the fixed duration (for example, change from baseline in xxx measure at week 16, week 24, or week 52,...). For clinical trials with various durations such as event-driven study design, patients are treated with study drugs for various durations - the early enrolled patients may receive the study drugs for a much longer time than those later enrolled patients, and patients will stay in the study and receive the study drugs if no protocol-defined event occurs until the required number of events for the study has occurred and the entire study is closed. The event can be Clinical Worsening Event, MACE, Exacerbation, Hospitalization, Progression-free survival, Death,...

In the informed consent form, patients who participate in the clinical trial will be informed how long they may be treated with the experimental drug or placebo. The ethical issue arises if patients are randomly assigned to the placebo group and treated with placebo for a prolonged period of time.     

Lately, we saw several clinical trials with a hybrid approach containing a double-blind fixed duration and then followed by a double-blind various duration. The primary efficacy endpoint was measured at the end of the fixed duration (i.e., week 52 for INBUILD and ISABELLA trials and week 24 for STELLAR trial). The double-blind various duration was added to the trial to collect the information for secondary and exploratory endpoints that need a longer exposure time. The double-blind various duration depends on the enrollment speed and the timing of patients entering into the study. Early-enrolled patients will stay in the study much longer than the later-enrolled patients. The slower the enrollment speed is, the longer the double-blind various duration takes. 

INBUILD study: Nintedanib in Progressive Fibrosing Interstitial Lung Diseases 

For each patient, the trial consisted of two parts: Part A, which was conducted during the first 52 weeks, and Part B, which was a variable treatment period beyond week 52 during which patients continued to receive either nintedanib or placebo until all the patients had completed Part A. 

The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based on efficacy and safety data over 52 weeks.

The primary analysis of this study will therefore be performed once the last randomized patient reaches the Week 52 Visit (Visit 9 at the end of Part A). At that time, a database lock will occur and all the data will be unblinded. Efficacy and safety analyses will be performed on the data from Part A of the trial to assess the benefit-risk of nintedanib over 52 weeks. In addition, data collected in Part B of the trial (after 52 weeks) and available at the time of data cut-off for the primary analysis will be reported together with data from Part A (i.e. over the whole trial).

Once the benefit-risk assessment of nintedanib over 52 weeks is confirmed to be positive, all patients receiving trial medication in Part B will be offered open-label treatment with nintedanib in a separate study.

Trial 1199.247 i.e. Part B will continue until all patients have been switched to open-label nintedanib or completed the Follow-up Visit. A final database lock will then occur and Part B data collected between the data cut off for the primary analysis and the final database lock will be reported together with data from Part A i.e. over the whole trial.

ISABELLA Studies: GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis

See the paper: Rationale, design and objectives of two phase III, randomised, placebo controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2)

In each study, approximately 750 subjects will be randomized 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or matching placebo, once daily, in addition to local SOC. SOC is defined as either pirfenidone or nintedanib, or neither pirfenidone nor nintedanib (for any reason). Treatment will continue for at least 52 weeks (subjects will continue to receive randomized treatment until the last patient reaches 52 weeks in the study). A follow-up visit will be conducted 4 weeks after the end-of-study visit (figure 1 below).

STELLAR Study: Sotatercept in Pulmonary Arterial Hypertension

According to Acceleron's ATS 2021 INTERNATIONAL CONFERENCE ACCELERON INVESTOR AND ANALYST CALL, the STELLAR study was designed as the following:

The double-blind fixed duration is 24 weeks and the primary efficacy endpoint (6MWD) is measured at week 24. The double-blind various duration had a cap at 72 weeks, i.e., the maximum duration for the period is 72 weeks). Patients can be in the long-term double-blind treatment period for 0 (the last enrolled patient) to 72 weeks (early enrolled patients).