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
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 发起方
- 入组人数
- 7
- 试验地点
- 6
- 主要终点
- Rescue-free laxation response
研究概览
简要总结
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: methylnaltrexone (Drug)
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.
干预措施: methylnaltrexone (Drug)
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.
干预措施: methylnaltrexone (Drug)
结局指标
主要结局
Rescue-free laxation response
时间窗: Within 4 hours after at least 2 of the first 4 doses (the first week of treatment).
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).
次要结局
- laxation within 4 hours after each dose(Between dosing and day 14)
- laxation within 4 hours after 4 out of 7 doses(Between dosing and day 14)
- Number of laxations(Between dosing and day 14)
- Time to first laxation(Between dosing and day 14)
- Laxation within 4 hours(Between dosing and day 14)
- laxation within 24 hours after each dose(Between dosing and day 14)
研究者
H.M.W. Verheul
Prof. dr.
Amsterdam UMC, location VUmc