Clinical trial NCT01955213: Methylnaltrexone for Opioid Induced Constipation
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
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Constipation
Keywords: constipation, methylnaltrexone, opoid
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: Stichting Nuts Ohra
First posted: 2013-10-07
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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.

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.


Eligibility 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.

Primary outcomes:
measure: Rescue-free laxation response
timeFrame: Within 4 hours after at least 2 of the first 4 doses (the first week of treatment).
Secondary outcomes:
measure: Time to first laxation
timeFrame: Between dosing and day 14
measure: Number of laxations
timeFrame: Between dosing and day 14
measure: Laxation within 4 hours
timeFrame: Between dosing and day 14
measure: laxation within 4 hours after each dose
timeFrame: Between dosing and day 14
measure: laxation within 24 hours after each dose
timeFrame: Between dosing and day 14
measure: laxation within 4 hours after 4 out of 7 doses
timeFrame: Between dosing and day 14
Other outcomes:
measure: Changes in leukocyte subsets
timeFrame: Day 0 to day 42
measure: Changes in serum cytokine levels
timeFrame: Day 0 to day 42
measure: Determination of the angiogenic profile.
timeFrame: Day 0 to day 42
measure: Determination of the angiogenic potential
timeFrame: Day 0 to day 42
Locations:
city: Alkmaar
country: Netherlands
facility: Medical Center Alkmaar
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: De Bilt
country: Netherlands
facility: Hospice Demeter
city: Hoofddorp
country: Netherlands
facility: Hospice Bardo
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekehuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Henk WM Verheul, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.