Methylnaltrexone for Opioid Induced Constipation

NCT01955213 | Terminated

• 2 other identifiers: 2012/1692012-000850-75
• Study Type: observational
• Target: 7
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Constipation

Keywords

constipation, methylnaltrexone, opoid

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Time to first laxation

  Between dosing and day 14

• Number of laxations

  Between dosing and day 14

• Laxation within 4 hours

  Between dosing and day 14

• laxation within 4 hours after each dose

  Between dosing and day 14

• laxation within 24 hours after each dose

  Between dosing and day 14

Other Outcomes (4)

• Changes in leukocyte subsets

  Day 0 to day 42

• Changes in serum cytokine levels

  Day 0 to day 42

• Determination of the angiogenic profile.

  Day 0 to day 42

Study Arms (3)

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

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

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

Interventions

methylnaltrexone DRUG

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; Morphine Sulphate; Oxycodone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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. \~

You may not qualify if:

• 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

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Stichting Nuts Ohra: collaborator

Study Sites (6)

Medical Center Alkmaar

Alkmaar, Netherlands

Location

VU University Medical Center

Amsterdam, 1081HV, Netherlands

Location

Hospice Demeter

De Bilt, Netherlands

Location

Hospice Bardo

Hoofddorp, Netherlands

Location

Spaarne Ziekehuis

Hoofddorp, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 30922276 DERIVED

• 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.

  PMID: 25165428 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

From patients who also give informed consent for the second part of the study 50 ml of heparinized blood will be drawn before the first administration of methylnaltrexone (day 0), after 24 hours (day 1), at day 14 and approximately day 42 for immuno- and angiogenic measurements (see flow chart below). From this blood sample the size, phenotype and function of various leukocyte subsets, serum cytokine levels, VEGF levels, thrombocyte levels and circulating endothelial cell levels will be determined by means of fluorescence-activated cell sorting (FACS) or enzyme-linked immunosorbent assay (ELISA).

MeSH Terms

Conditions

Constipation

Interventions

methylnaltrexone

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Henk WM Verheul, MD, PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr.

Study Record Dates

• First Submitted: December 11, 2012
• First Posted: October 7, 2013
• Study Start: July 1, 2012
• Primary Completion: September 1, 2017
• Study Completion: September 1, 2017
• Last Updated: August 5, 2019

Record last verified: 2019-07

Locations

NL (6)