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

Wayne J.G. Hellstrom*, Radboud J.E.M. Dolhain, 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

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)3403-3422
Number of pages20
JournalAdvances in Therapy
Volume39
Issue number7
Early online date25 May 2022
DOIs
Publication statusPublished - Jul 2022

Bibliographical note

Funding Information:
The authors thank Michael Molloy-Bland, PhD, of Oxford PharmaGenesis for providing medical writing support, funded by Galapagos NV, Mechelen, Belgium, in accordance with Good Publication Practice guidelines.

Funding Information:
The authors would like to acknowledge Robin Besuyen of Galapagos BV, Leiden, Netherlands, for his contributions to the design and methodology of the MANTA and MANTA-RAy studies and his interpretation of the data. Publication coordination was provided by Jessica Naddafy-Clark of Galapagos NV. The MANTA study was sponsored by Gilead Science Inc. and conducted in collaboration with Galapagos NV. The MANTA-RAy study was sponsored by Galapagos NV and conducted in collaboration with Gilead Science Inc. Funding for medical writing support, and for the journal’s Rapid Service and Open Access Fees, was provided by Galapagos NV. The authors thank Michael Molloy-Bland, PhD, of Oxford PharmaGenesis for providing medical writing support, funded by Galapagos NV, Mechelen, Belgium, in accordance with Good Publication Practice guidelines. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. WH, SS and DV contributed to the concept or design of the work and endorsed the trial design. RD, WR and TER were members of the study advisory board. DV, TW, CT, GD and AG contributed to the concept or design of the work. LG and SA contributed to the acquisition or analysis of the data. All authors contributed to the interpretation of the data and critically reviewed the manuscript for important intellectual content, and approved the final version of the manuscript for submission. Wayne Hellstrom has been a consultant or advisor for Boston Scientific, Coloplast and Endo; an investigator for Coloplast and Endo; a lecturer for Endo; on advisory boards for Gilead, Maximus and Promescent; and is a board member, officer and trustee for Theralogix. Radboud J. E. M. Dolhain has received unrestricted research grants from Dutch Arthritis Association, UCB Pharma and Galapagos; consulting fees from Galapagos; and speaking fees from UCB Pharma, Roche, Abbvie, Genzyme, Novartis and Lilly. Timothy E. Ritter has received personal fees from AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gilead, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda. Dirk Vanderschueren received consultancy fees from Galapagos for the design and set-up of the studies. Suresh Sikka declares no competing interests. Walter Reinisch has served as a speaker for Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult; as a consultant for Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Quell Therapeutics, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; as an advisory board member for Abbvie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC; and has received research funding from Abbvie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, Janssen, MSD, Sandoz, Takeda. Tim Watkins, Sarah Arterburn, Angi Gillen and Caroline Tonussi are employees and shareholders of Gilead Sciences, Inc. Goele Dekkers, Leen Gilles, Alessandra Oortwijn, Katrien Van Beneden and Dick de Vries are employees of Galapagos. The MANTA and MANTA-RAy studies were conducted in accordance with the principles of the Declaration of Helsinki, International Council for Harmonisation guidelines, or with the laws and regulations of the country in which the research was conducted, whichever afforded the greatest protection to study participants. Trial protocols and subsequent amendments were approved by the relevant institutional review board at each participating site. All patients provided written informed consent before enrolment. Data sharing is not applicable to this article as no data sets were generated or analysed for the information presented in this article.

Funding Information:
Wayne Hellstrom has been a consultant or advisor for Boston Scientific, Coloplast and Endo; an investigator for Coloplast and Endo; a lecturer for Endo; on advisory boards for Gilead, Maximus and Promescent; and is a board member, officer and trustee for Theralogix. Radboud J. E. M. Dolhain has received unrestricted research grants from Dutch Arthritis Association, UCB Pharma and Galapagos; consulting fees from Galapagos; and speaking fees from UCB Pharma, Roche, Abbvie, Genzyme, Novartis and Lilly. Timothy E. Ritter has received personal fees from AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gilead, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda. Dirk Vanderschueren received consultancy fees from Galapagos for the design and set-up of the studies. Suresh Sikka declares no competing interests. Walter Reinisch has served as a speaker for Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult; as a consultant for Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Quell Therapeutics, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; as an advisory board member for Abbvie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC; and has received research funding from Abbvie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, Janssen, MSD, Sandoz, Takeda. Tim Watkins, Sarah Arterburn, Angi Gillen and Caroline Tonussi are employees and shareholders of Gilead Sciences, Inc. Goele Dekkers, Leen Gilles, Alessandra Oortwijn, Katrien Van Beneden and Dick de Vries are employees of Galapagos.

Funding Information:
The MANTA study was sponsored by Gilead Science Inc. and conducted in collaboration with Galapagos NV. The MANTA-RAy study was sponsored by Galapagos NV and conducted in collaboration with Gilead Science Inc. Funding for medical writing support, and for the journal’s Rapid Service and Open Access Fees, was provided by Galapagos NV.

Publisher Copyright:
© 2022, The Author(s).

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