Evaluating the Impact of Stopping Chronic Therapies after Modulator Drug Therapy in Cystic Fibrosis: The SIMPLIFY Clinical Trial Study Design

Abstract

The care for individuals with cystic fibrosis (CF) with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple-combination CFTR (CF transmembrane regulator)-modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into the standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 years of age or older and stable on ETI therapy. The protocol is composed of two concurrent randomized controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is noninferior to continuing treatment after establishment of ETI, as measured by the 6-week absolute change in the percent-predicted forced expiratory volume in 1 second. Developing this study required a balance between ideal study-design principles and feasibility. SIMPLIFY will be the largest multicenter, randomized, controlled medication-withdrawal study in CF. This study is uniquely positioned to provide timely evidence on whether the daily treatment burden can be reduced among individuals on CFTR-modulator therapy. Clinical trial registered with www.clinicaltrials.gov (NCT04378153).

Keywords: CFTR modulators; noninferiority trial; treatment burden.

Figure 1.

SIMPLIFY study design schematic. Study A and study B are identical randomized, open-label, two-arm trials consisting of a 2-week screening period and randomization to either continue or discontinue hypertonic saline (HS) (study A) or dornase alfa (Dornase) (study B), followed by a 6-week study period. Study visits occur at Weeks −2 (screening), 0, 2, and 6. Only those who maintain adequate reported adherence to inhaled drug therapy between screening (Week −2) and Week 0 are eligible for randomization (Table 1). At Week 0, subjects currently being treated with only HS or Dornase will be enrolled in study A or study B (as applicable) and will be randomized 1:1 to either continue or discontinue their current prescribed therapy. At study entry, subjects who are currently being treated with both HS and Dornase will remain on both therapies during the screening period and then be randomized to study A (HS) or study B (Dornase) as well as being randomized (1:1) to continue versus discontinue the applicable therapy. The randomization to study A or study B among subjects on both therapies is not optional and is essential to reduce indication bias and ensure comparable populations across studies. After completion of the first study, these subjects may subsequently enroll in the alternative study if they meet eligibility criteria. Reenrolling subjects need not remain on the treatment regimen assigned in the first study but must meet all eligibility criteria regarding treatment stability before entry (Table 1). Within each study, randomization will be stratified by the Week 0 percent-predicted forced expiratory volume in 1 second (⩾90, <90), treatment combination at screening (single or concurrent use of HS and/or Dornase), prior study participation (yes/no), and age (⩾18 versus <18). For subjects randomly assigned to continue their therapy during a given study, this therapy is expected to be taken at least once daily according to each subject’s preexisting, clinically prescribed regimen. If one study completes enrollment faster than the other study, the protocol will be restricted to enrollment in only the open study.