MANTA and MANTA-RAy: Rationale and Design of Trials Evaluating Effects of Filgotinib on Semen Parameters in Patients with Inflammatory Diseases

Abstract

Introduction: The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies.

Methods and rationale: The MANTA and MANTA-RAy studies included men (aged 21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters).

Conclusions: Despite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters.

Trial registration: EudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195.

Keywords: Filgotinib; Inflammatory bowel disease; Janus kinase 1 preferential inhibitor; MANTA; MANTA-RAy; Randomized controlled trials; Reproductive health; Rheumatoid diseases; Semen parameters.

© 2022. The Author(s).

Figures

Fig. 1

MANTA and MANTA-RAy study designs. aStudy drug was discontinued upon entry into the monitoring phase (standard of care was initiated [or continued] in MANTA-RAy). Reversibility for a participant was defined as all semen parametersb that qualified the participant for entry into the monitoring phase returning to > 50% of baseline. bReduced semen parameters were defined as a ≥ 50% decrease in sperm concentration, and/or motility, and/or morphology compared with baseline. cDisease worsening for UC in MANTA was defined as an increase of ≥ 3 points in pMCS (to a score of ≥ 5) from week 13, on two consecutive visits, or an increase to a score of 9 (from a week 13 score of > 6) on two consecutive visits; disease worsening for CD in MANTA was defined as an increase of ≥ 100 points in CDAI score from the week 13 visit on two consecutive visits, and a score of ≥ 220 on two consecutive visits. dIn MANTA, participants who had disease worseningc between weeks 13 and 26 while on open-label filgotinib discontinued the study and completed an ET visit, and had a safety visit 30 days after the last dose of study drug. eResponse for UC in MANTA was defined as a reduction of ≥ 2 points in pMCS compared with the baseline visit. Response for CD in MANTA was defined as a reduction of ≥ 100 points in total CDAI score compared with the baseline visit; in patients with a total CDAI score of ≥ 220 (but ≤ 250) at the baseline visit, response was defined as a CDAI score of < 150. fIn MANTA, non-responderse at week 26 discontinued the study and had only a safety visit 30 days after the last dose of study drug. gIn MANTA, participants who had disease worseningc during the LTE (receiving open-label filgotinib or blinded study drug [filgotinib or placebo]) discontinued and completed an ET visit, followed by a safety follow-up visit 30 days after last study drug dose; participants receiving open-label filgotinib or blinded study drug who had reduced semen parametersb (assessed every 13 weeks) during the LTE entered the monitoring phase. hResponse for rheumatoid diseases in MANTA-RAy was defined as an improvement of ≥ 20% in PhGADA score compared with day 1. iIn MANTA-RAy, participants who were receiving open-label filgotinib or standard of care and required prohibited concomitant treatment discontinued the study and completed an ET visit. Safety visits occurred 30 days after the last study drug dose. CD Crohn’s disease, CDAI Crohn’s Disease Activity Index, ET early termination, FIL orally administered filgotinib, IBD inflammatory bowel disease, LTE long-term extension, PhGADA Physician's Global Assessment of Disease Activity, pMCS partial Mayo Clinic Score, QD once daily, UC ulcerative colitis