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

• DOI: 10.1007/s12325-022-02168-4
• Publication Date: 2022-05-25T17:02:51Z
• Authors: Wayne J. G. Hells...; Radboud J. E. M. ...; Timothy E. Ritter; Timothy R. Watkins; Sarah J. Arterburn; Goele Dekkers; Angi Gillen; Caroline Tonussi; Leen Gilles; Alessandra Oortwijn; Katrien Van Beneden; Dick E. de Vries; Suresh C. Sikka; Dirk Vanderschueren; Walter Reinisch
• Keywords: Male; Pyridines; Janus kinase 1 preferential inhibitor; MANTA-RAy; Filgotinib; Triazoles; Inflammatory Bowel Diseases; 16. Peace & justice; Inflammatory bowel disease; 3. Good health; Study Protocol; 03 medical and health sciences; 0302 clinical medicine; Rheumatoid diseases; Semen; MANTA; Randomized controlled trials; Reproductive health; Sperm Motility; Humans; Janus Kinase Inhibitors; Semen parameters

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