- Fecal Incontinence
|MANTA and MANTA-RAy: Rationale and Design of Trials Evaluating Effects of Filgotinib on Semen Parameters in Patients with Inflammatory Diseases
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
1Tulane Health Sciences Center, New Orleans, LA, USA. firstname.lastname@example.org.
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.
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.