Adv Ther. 2022 Jul;39(7):3403-3422.doi: 10.1007/s12325-022-02168-4. Epub 2022 May 25.

Wayne J G Hellstrom ¹, Radboud J E M Dolhain ², Timothy E Ritter ³, Timothy R Watkins ⁴, Sarah J Arterburn ⁴, Goele Dekkers ⁵, Angi Gillen ⁴, Caroline Tonussi ⁴, Leen Gilles ⁵, Alessandra Oortwijn ⁶, Katrien Van Beneden ⁵, Dick E de Vries ⁶, Suresh C Sikka ⁷, Dirk Vanderschueren ⁸, Walter Reinisch ⁹

Author information

¹Tulane Health Sciences Center, New Orleans, LA, USA. whellst@tulane.edu.

²Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.

³GI Alliance, Southlake, TX, USA.

⁴Gilead Sciences, Inc., Foster City, CA, USA.

⁵Galapagos NV, Mechelen, Belgium.

⁶Galapagos BV, Leiden, Netherlands.

⁷Tulane University School of Medicine, New Orleans, LA, USA.

⁸Laboratory of Experimental and Clinical Endocrinology, KU Leuven, Leuven, Belgium.

⁹Medical University of Vienna, Vienna, Austria.

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.