Methylnaltrexone for Opioid Induced Constipation (RILAX)

Clinical Evaluation of the Efficacy of Methylnaltrexone in Resolving Constipation Induced by Different Opioid Subtypes, Combined With Laboratory Analysis of Immunomodulatory and Antiangiogenic Effects of Methylnaltrexone

Methylnaltrexone for the treatment of opioid-induced constipation in the setting of palliative or hospice care, is significantly more effective than placebo (1). However, in both the randomized and the open-label phase of the multi center trial showing this favorable outcome, the drug produced rescue-free laxation in only about half of the patients (2). There may be several reasons for this result, since constipation in palliative care patients often has multiple simultaneously occurring causes.

Assuming that constipation of the non-responders is still opioid-induced, one of the possible reasons for not responding to methylnaltrexone could be that central actions of opioids contribute to constipation by reducing motility of the intestines through direct actions in the spinal dorsal horn (2). However, as methylnaltrexone is a µ-receptor antagonist and not all opioids are solely µ-receptor agonists another reason may well be that successful laxation is determined by the receptor-profile of the specific opioid the patient is using.

Opioids do not only influence bowel functioning, but also immune system functioning and angiogenesis. Methylnaltrexone possibly antagonizes these changes, therefore this study will also investigate the influence of methylnaltrexone on immunologic and angiogenic parameters.

Study Overview

• Status: Terminated
• Conditions: Constipation
• Intervention / Treatment: Drug: methylnaltrexone

• Study Type: Observational
• Enrollment (Actual): 7

Contacts and Locations

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Medical Center Alkmaar
  • Amsterdam, Netherlands, 1081HV
    • VU University Medical Center
  • De Bilt, Netherlands
    • Hospice Demeter
  • Hoofddorp, Netherlands
    • Hospice Bardo
  • Hoofddorp, Netherlands
    • Spaarne Ziekehuis
  • Utrecht, Netherlands
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients receiving palliative care who are being treated with opioids for symptoms of pain or dyspnea, suffering from constipation, that is not relieved by first line oral laxatives.

Description

Inclusion Criteria:

• Age ≥ 18 years
• Receiving palliative care
• Life expectancy ≥ 2 weeks
• Able to give informed consent
• Receiving opioid treatment with either morphine sulphate, oxycodone or fentanyl

• Opioid treatment, both

  • On a regular schedule (not just as needed or rescue doses) for the control of pain or dyspnea for at least 2 weeks before the first dose of methylnaltrexone, and
  • On a stable opioid regimen for at least 3 days before the first dose of methylnaltrexone. This is defined as no dose reduction of ≥ 50%, dose increases are permitted. If rescue medication is prescribed of a different type of opioid than the regular dosed opioid, the rescue medication should be switched to the same type as the regular dosed opioid for at least 3 days before the first dose of methylnaltrexone.

• Has diagnosis of constipation, defined as either

  • < 3 bowel movements during the previous week by history and no clinically notable laxation* in the 24 hours before the first dose of methylnaltrexone, or
  • No clinically notable laxation* in the 48 hours before the first dose of methylnaltrexone.
• Constipation is defined as opioid induced, determined by investigator
• On stable laxative regimen for ≥ 3 days before the first dose of methylnaltrexone. This is defined as at least one type of laxative in an adequate dosing regimen, (e.g. macrogol 2 packets daily, magnesium(hydr)oxide 500 mg three times daily, bisacodyl 10 mg daily or sennoside A+B 10 ml daily) or at least two types of laxatives in a suboptimal dose with patient characteristics hampering optimal treatment.
• If the subject is a woman with presumed child bearing potential; negative urine pregnancy test at screening

• Surgically sterile or agrees to use a medically acceptable method of birth control or practice sexual abstinence for the duration of the methylnaltrexone treatment and the following 15 days. ~

  • including laxation after rescue laxative or enema ~ not necessary for postmenopausal women

Exclusion Criteria:

• Previous treatment with methylnaltrexone
• Known or suspected mechanical gastrointestinal obstruction
• Presence of an other cause of bowel dysfunction that is considered to be a major contribution to the constipation according to investigator
• Presence of a peritoneal catheter for intraperitoneal chemotherapy or dialysis
• Clinically relevant active diverticular disease
• History of bowel surgery within 10 days before first dose of methylnaltrexone
• Fecal ostomy
• Use of vinca alkaloids within previous 4 months
• Body weight <38 kg
• Renal failure defined as EGFR <30 ml/min per 1.73m2 or requires dialysis.
• Known or suspected allergy to methylnaltrexone or similar compounds (e.g. naltrexone or naloxone)
• Participation in a study with investigational products within 30 days before first dose of methylnaltrexone.
• Pregnant or nursing
• Clinically important abnormalities that may interfere with participation or compliance to the study, determined by investigator

Additional exclusion criteria for the immunologic and angiogenic analysis part of the study:

• Chemotherapy or treatment with tyrosine kinase inhibitor during 4 weeks before inclusion or treatment scheduled during participation in this study.
• Treatment with high dose corticosteroids during 2 weeks before inclusion in this study. This is defined as the equivalent of 30 mg of prednisone per day for ≥ 2 consecutive days.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Morphine Sulphate; Patient groups are defined by the type of opioid used, being either morphine sulphate, fentanyl or oxycodone.Patients will be treated with methylnaltrexone in a standard dosing regimen for their weight: 38-62kg:8 mg, 62-114kg:12 mg, >114 kg: 0.15 mg/kg) Methylnaltrexone will be administered subcutaneously every other day for up to 7 doses.	Drug: methylnaltrexone; Patients will be treated with methylnaltrexone in a standard dosing regimen for their weight: 38-62kg:8 mg, 62-114kg:12 mg, >114 kg: 0.15 mg/kg) Methylnaltrexone will be administered subcutaneously every other day for up to 7 doses.
Fentanyl; Patient groups are defined by the type of opioid used, being either morphine sulphate, fentanyl or oxycodone.Patients will be treated with methylnaltrexone in a standard dosing regimen for their weight: 38-62kg:8 mg, 62-114kg:12 mg, >114 kg: 0.15 mg/kg) Methylnaltrexone will be administered subcutaneously every other day for up to 7 doses.	Drug: methylnaltrexone; Patients will be treated with methylnaltrexone in a standard dosing regimen for their weight: 38-62kg:8 mg, 62-114kg:12 mg, >114 kg: 0.15 mg/kg) Methylnaltrexone will be administered subcutaneously every other day for up to 7 doses.
Oxycodone; Patient groups are defined by the type of opioid used, being either morphine sulphate, fentanyl or oxycodone.Patients will be treated with methylnaltrexone in a standard dosing regimen for their weight: 38-62kg:8 mg, 62-114kg:12 mg, >114 kg: 0.15 mg/kg) Methylnaltrexone will be administered subcutaneously every other day for up to 7 doses.	Drug: methylnaltrexone; Patients will be treated with methylnaltrexone in a standard dosing regimen for their weight: 38-62kg:8 mg, 62-114kg:12 mg, >114 kg: 0.15 mg/kg) Methylnaltrexone will be administered subcutaneously every other day for up to 7 doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rescue-free laxation response	The proportion of subjects that has a rescue-free laxation response within 4 hours after at least 2 of the first 4 doses (the first week of treatment).	Within 4 hours after at least 2 of the first 4 doses (the first week of treatment).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first laxation	Time to first laxation after initiation of treatment	Between dosing and day 14
Number of laxations	Number of laxations per week; Change in BFI score between day 0 and 14	Between dosing and day 14
Laxation within 4 hours	Presence of laxation within four hours after initiation of treatment	Between dosing and day 14
laxation within 4 hours after each dose	Number of doses after which laxation occured within four hours after treatment administration	Between dosing and day 14
laxation within 24 hours after each dose	Number of doses after which laxation occured within 24 hours after treatment administration	Between dosing and day 14
laxation within 4 hours after 4 out of 7 doses	Did laxation occur within 4 hours after at least 4 out of 7 treatment administrations?	Between dosing and day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in leukocyte subsets	The concentration of the following markers will be evaluated: T-, B-, NK-cells, monocytes/macrophages, DC subsets, neutrophilic granulocytes, and regulatory cell populations (invariant NKT cells, CD4+CD25+FOXP3+ regulatory T cells.	Day 0 to day 42
Changes in serum cytokine levels	Changes serum cytokine levels. The concentration of the following markers will be evaluated: IFN-γ, IL-2, IL-4, IL-10, IL-6 and TNF-α.	Day 0 to day 42
Determination of the angiogenic profile.	* Determination of the angiogenic profile by determination of angiogenic factor blood concentrations and the systemic levels of endothelial progenitor cells.	Day 0 to day 42
Determination of the angiogenic potential	* Determination of the angiogenic potential of blood on in vitro endothelial cell proliferation assays before and during treatment with methylnaltrexone (in a subgroup of patients, maximally n = 10 per group).	Day 0 to day 42

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Stichting Nuts Ohra
• Investigators: Principal Investigator: Henk WM Verheul, MD, PhD, Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Neefjes ECW, van der Wijngaart H, van der Vorst MJDL, Ten Oever D, van der Vliet HJ, Beeker A, Rhodius CA, van den Berg HP, Berkhof J, Verheul HMW. Optimal treatment of opioid induced constipation in daily clinical practice - an observational study. BMC Palliat Care. 2019 Mar 29;18(1):31. doi: 10.1186/s12904-019-0416-7.
• Neefjes EC, van der Vorst MJ, Boddaert MS, Zuurmond WW, van der Vliet HJ, Beeker A, van den Berg HP, van Groeningen CJ, Vrijaldenhoven S, Verheul HM. Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone. BMC Palliat Care. 2014 Aug 20;13:42. doi: 10.1186/1472-684X-13-42. eCollection 2014.

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ACTUAL): September 1, 2017
• Study Completion (ACTUAL): September 1, 2017

Study Registration Dates

• First Submitted: December 11, 2012
• First Submitted That Met QC Criteria: September 27, 2013
• First Posted (ESTIMATE): October 7, 2013

Study Record Updates

• Last Update Posted (ACTUAL): August 5, 2019
• Last Update Submitted That Met QC Criteria: July 31, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: constipation, methylnaltrexone, opoid
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Methylnaltrexone
• Other Study ID Numbers: 2012/169; 2012-000850-75 (EUDRACT_NUMBER)