Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients with Advanced Illness

Abstract

Purpose

We evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC).

Patients and Methods

This analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated.

Results

Overall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups.

Conclusion

Methylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients’ cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

Keywords:

• methylnaltrexone
• opioid-induced constipation
• µ-opioid receptor antagonist

Abbreviations

ECOG, Eastern Cooperative Oncology Group; OED, opioid equivalent dose; OIC, opioid-induced constipation; PAMORA, peripherally acting μ-opioid receptor antagonists; QOD, every other day; TEAE, treatment-emergent adverse event.

Study 302

Schulman Associates Institutional Review Board, Cincinnati, Ohio, USA

Research Ethics Board, McGill University Health Centre, Montreal, Quebec, Canada

University of British Columbia, British Columbia Cancer Agency Research Ethics Board, Vancouver, British Columbia, Canada

San Diego Hospice IRB, San Diego Hospice, San Diego, California, USA

University of Utah Institutional Review Board, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Henry Ford Health System Institutional Review Board, Henry Ford Health System, Detroit, Michigan, USA

Human Subjects Protection Office, The Penn State University/Milton S Hershey Medical Center, Hershey, Pennsylvania, USA

City of Hope IRB, City of Hope, Duarte, California, USA

Study 4000

Schulman Associates Institutional Review Board, Cincinnati, Ohio, USA

The University of Texas IRB, M.D. Anderson Cancer Center, Houston, Texas, USA

Division of Research Integrity & Compliance, Moffitt Cancer Center, Tampa, Florida, USA

Fox Chase Cancer Centre Institutional Review Board, Fox Chase Cancer Centre, Rockledge, Pennsylvania, USA

Regonala Etikprövningsnämnden i Linköping, Palliative Unit Vrinnevi Hospital, Linköping, Sweden

Ethics Committee CEIC, CSUB Ciutat Sanitaria Universitaria Bellvitge, Spain

Bellberry Limited, Dulwich, South Australia, Australia

Azienda Sanitaria Locale di Asti - ASL AT Sede, Asti, Italy

Comitato Etico Dell`Azienda Ospedaliera Guido Salvini di Garbagnate Milanese, Milan, Italy

Comitato Etico Indipendente Della Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

St Vincent’s Hospital Human Research Ethics Committee (HREC), St Vincent’s Hospital, Darlinghurst, New South Wales, Australia

Ethik-Kommission an der Medizinischen Fakultät Technischen Hochschule Aachen, University of Aachen, Aachen, Germany

Ethik-Kommission bei der Medizinischen Fakultät der Ludwig-Maximilians Universität München, Munich, Germany

The Peter Mac Ethics Committee, Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia

CIUSSS Research Ethics Board, The Jewish General Hospital, Montreal, Quebec, Canada

Bannatyne Campus Research Ethics Board, University of Manitoba, Winnipeg, Manitoba, Canada

Ethics Committee Research Leuven, UZ Leuven, Leuven, Belgium

Comité de Protection des Personnes – Sud Est V, Centre Hospitalier Universitaire de Grenoble, Grenoble, France

Hamilton Health Sciences, Hamilton, Ontario, Canada

London – Central MREC, London, United Kingdom

CHUQ Research Ethics Committee, Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada

Western Institutional Review Board, Olympia, Washington, USA

Comitê de ética em Pesquisa em seres Humanos da Fundação Antônio Prudente, A.C. Camargo Cancer Center, São Paulo, Brazil

University of Utah Institutional Review Board, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Alberta Cancer Research Ethics Committee, University of Alberta, Edmonton, Alberta, Canada

Comité Bioético para la Investigación Clínica, Mexico City, Mexico

VA New Jersey Healthcare System Institutional Review Board, VA New Jersey Healthcare System, East Orange, New Jersey, USA

Data Sharing Statement

The datasets generated and/or analyzed during the current study are not publicly available at this time due to the proprietary nature of this information. Requests for additional information should be made to the corresponding author.

Ethics Approval and Informed Consent

Patients or their legally acceptable representatives provided written informed consent to participate before any study specific procedures were conducted. The specific ethical review boards that provided approval and oversight are listed above for study 302 and study 4000.

Acknowledgment

This work was supported by Salix Pharmaceuticals, a division of Bausch Health US, LLC, Bridgewater, NJ, USA, which has licensed the rights to develop and commercialize Relistor^® from Progenics Pharmaceuticals, Inc., North Billerica, MA, USA, a wholly owned subsidiary of Lantheus Holdings, Inc., North Billerica, MA, USA. Progenics Pharmaceuticals had a role in the study design, implementation of the study, and data collection. Salix had a role in the data collection, data analysis, and the decision to publish. Technical editorial and medical writing assistance was provided under the direction of the authors by Drayton Hammond, PharmD, of Echelon Brand Communications, LLC, an OPEN Health company, Parsippany, NJ, USA. Funding for this assistance was provided by Salix Pharmaceuticals. The abstract of this paper was presented at the American College of Gastroenterology Annual Scientific Meeting in 2022 and the Society of Hospital Medicine Converge meeting in 2023 as a poster presentation. The poster’s abstract was published in The American Journal of Gastroenterology (https://journals.lww.com/ajg/Fulltext/2022/10002/S165_Impact_of_Patient_Subgroups_on_the_Efficacy.165.aspx) and in Journal of Hospital Medicine (https://shmpublications.onlinelibrary.wiley.com/toc/15535606/2023/18/S1).

Author Contributions

1. Made a significant contribution to the work reported: conception, study design, execution, acquisition of data, analysis, and interpretation. All authors

2. Have drafted or written, or substantially revised or critically reviewed the article. All authors

3. Have agreed on the journal to which the article will be submitted. All authors

4. Reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage. All authors

5. Agree to take responsibility and be accountable for the contents of the article. All authors

Disclosure

NM: Salix Pharmaceuticals – advisory boards. NES: Salix Pharmaceuticals – employee. RJI: Bausch Health US, LLC – employee. NS: Progenics Pharmaceuticals, Inc. – employee; Lantheus Holdings, Inc. – shareholder. EDS: Ardelyx, Mahana, Bausch Health/Salix, GI Supply/Laborie, Sanofi, Mylan – personal fees; Takeda and Neuraxis – non-financial supports, outside the submitted work.