Methylnaltrexone for Opioid Induced Constipation (RILAX)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by VU University Medical Center
Sponsor:
Collaborator:
Fonds Nuts Ohra
Information provided by (Responsible Party):
H.M.W. Verheul, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01955213
First received: December 11, 2012
Last updated: April 11, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention
Constipation
Drug: methylnaltrexone

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: 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

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • Rescue-free laxation response [ Time Frame: Within 4 hours after at least 2 of the first 4 doses (the first week of treatment). ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Time to first laxation [ Time Frame: Between dosing and day 14 ] [ Designated as safety issue: No ]
    Time to first laxation after initiation of treatment

  • Number of laxations [ Time Frame: Between dosing and day 14 ] [ Designated as safety issue: No ]
    • Number of laxations per week
    • Change in BFI score between day 0 and 14

  • Laxation within 4 hours [ Time Frame: Between dosing and day 14 ] [ Designated as safety issue: No ]
    Presence of laxation within four hours after initiation of treatment

  • laxation within 4 hours after each dose [ Time Frame: Between dosing and day 14 ] [ Designated as safety issue: No ]
    Number of doses after which laxation occured within four hours after treatment administration

  • laxation within 24 hours after each dose [ Time Frame: Between dosing and day 14 ] [ Designated as safety issue: No ]
    Number of doses after which laxation occured within 24 hours after treatment administration

  • laxation within 4 hours after 4 out of 7 doses [ Time Frame: Between dosing and day 14 ] [ Designated as safety issue: No ]
    Did laxation occur within 4 hours after at least 4 out of 7 treatment administrations?


Other Outcome Measures:
  • Changes in leukocyte subsets [ Time Frame: Day 0 to day 42 ] [ Designated as safety issue: No ]
    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.

  • Changes in serum cytokine levels [ Time Frame: Day 0 to day 42 ] [ Designated as safety issue: No ]
    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.

  • Determination of the angiogenic profile. [ Time Frame: Day 0 to day 42 ] [ Designated as safety issue: No ]
    * Determination of the angiogenic profile by determination of angiogenic factor blood concentrations and the systemic levels of endothelial progenitor cells.

  • Determination of the angiogenic potential [ Time Frame: Day 0 to day 42 ] [ Designated as safety issue: No ]
    * 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).


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).


Estimated Enrollment: 195
Study Start Date: July 2012
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01955213

Contacts
Contact: Henk MW Verheul, MD, PhD +31-20- 4444321 h.verheul@vumc.nl
Contact: Liesbeth Neefjes, MD +31-20-4444321 e.neefjes2@vumc.nl

Locations
Netherlands
Medical Center Alkmaar Not yet recruiting
Alkmaar, Netherlands
VU University Medical Center Recruiting
Amsterdam, Netherlands, 1081HV
Contact: Henk MW Verheul, MD, PhD    +31-20-4444321    h.verheul@vumc.nl   
Sub-Investigator: Liesbeth Neefjes, MD         
Hospice Demeter Not yet recruiting
De Bilt, Netherlands
Spaarne Ziekehuis Not yet recruiting
Hoofddorp, Netherlands
Hospice Bardo Not yet recruiting
Hoofddorp, Netherlands
University Medical Center Utrecht Not yet recruiting
Utrecht, Netherlands
Sponsors and Collaborators
VU University Medical Center
Fonds Nuts Ohra
Investigators
Principal Investigator: Henk WM Verheul, MD, PhD VU University Medical Center
  More Information

No publications provided

Responsible Party: H.M.W. Verheul, Prof. dr., VU University Medical Center
ClinicalTrials.gov Identifier: NCT01955213     History of Changes
Other Study ID Numbers: 2012/169, 2012-000850-75
Study First Received: December 11, 2012
Last Updated: April 11, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by VU University Medical Center:
constipation, methylnaltrexone, opoid

Additional relevant MeSH terms:
Constipation
Signs and Symptoms, Digestive
Signs and Symptoms
Morphine
Analgesics, Opioid
Methylnaltrexone
Naltrexone
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Narcotic Antagonists

ClinicalTrials.gov processed this record on September 14, 2014