Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-Blind Placebo-Controlled Study of Methylnaltrexone (MNTX) for the Relief of Constipation Due to Chronic Opioid Therapy in Patients With Advanced Medical Illness
Brief Summary: To test the effectiveness of MNTX in advanced illness subjects.


Options:
A: 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.
B: Inclusion Criteria:

1. Advanced medical illness with a life expectancy of 1 to 6 months
2. No clinically significant laxation within 48 hours prior to the first dose of study drug
3. On stable opioid and laxative regimen for a least 3 days prior to treatment
4. Age greater than 18years
5. Females of child-bearing age must have a negative pregnancy test.

Exclusion Criteria:

1. Females who are pregnant or nursing.
2. Previous treatment with MNTX or prior treatment with naltrexone or naloxone for treatment of OIC
3. Any disease process suggestive of gastrointestinal obstruction
4. Fecal ostomy.
C: Inclusion Criteria:

* Histologically or cytologically confirmed neoplasm
* 18 years of age or older
* Have received opioids for analgesia for at least 2 weeks and been on a stable regimen of opioids and laxatives for 3 or more days before study entry
* Fewer than three laxation during the preceding week and no laxation within 24 hours before study entry, or no laxation within 48 hours before study entry
* Life expectancy of at least 6 months
* World Health Organization Performance Status 0-3
* Women of childbearing potential must have a negative pregnancy test
* Breastfeeding should be discontinued prior to study entry
* Ability to understand and the willingness to sign a written informed consent document.
* Laboratory values within a week of study entry:

Absolute neutrophil count \> 1,500/microliter Hemoglobin \> 7 g/dL Platelet count \> 100,000/microliter Calculated calcium \< 10.5 mg/dL Calculated creatinine clearance \> 30 mg.min Alanine aminotransferase \< 3 x upper limit of normal (ULN) Aspartate aminotransferase \< 3 x ULN Alkaline phosphatase \< 2.5 x ULN Bilirubin \< 1.5 x ULN

Exclusion Criteria:

* Constipation not primarily caused by opioids, such as mechanical gastrointestinal obstruction or ongoing vinca alkaloid administration
* Indwelling peritoneal catheter
* Clinically active diverticular disease
* Fecal impaction
* Acute surgical abdomen
* Fecal ostomy
* Peritoneal carcinomatosis
* Known hypersensitivity to methylnaltrexone, naltrexone, or naloxone
* Administration of any investigational drug or experimental product within the previous 30 days
* Initiation of a new bowel regimen or prokinetic agents within a week of study entry
D: Inclusion Criteria:

1. Male or female subjects at least 18 years or older with a diagnosis of cancer.
2. Females less than one year post-menopausal must have a negative urine pregnancy test recorded at the screening visit, be non-lactating, and willing to use adequate and highly effective method of contraception throughout the study. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilization, implants, injectables, combined oral contraceptives, some IUDs (hormonal), sexual abstinence or vasectomised partner.
3. Subjects who are receiving WHO step II or Step III analgesic medication who have constipation induced, or worsened by their opioid medication, as shown by

   1. the subject's medical need of regular intake of laxatives to have at least 3 bowel evacuations per week, or having less than 3 bowel evacuations when not taking a laxative, respectively.
   2. the subject's self-assessment that their constipation was induced or worsened by their current pre-study opioid medication.
4. Documented history of moderate to severe, chronic cancer pain that requires around-the-clock opioid therapy (starting dose at the beginning of the double-blind phase of oxycodone PR between 20 - 80 mg/day) and are likely to benefit from WHO step III opioid therapy for the duration of the study. Subjects must be willing to discontinue their current opioid analgesic routine.
5. Subjects are willing to discontinue pre-study laxative medication and take study specific laxative medication.
6. Subjects taking daily fibre supplementation or bulking agents are eligible if they can be maintained on a stable dose and regimen throughout the study, and in the investigators opinion are willing and able to maintain adequate hydration.
7. Subjects willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent.
8. Subjects already taking non-opioid analgesics and all other concomitant medications (including those for the treatment of depression) are eligible to take part in the study. However, all concomitant medications that are considered necessary for the subject's welfare should be continued at a stable dose throughout the double-blind phase of the study and under the supervision of the investigator. Regarding cyclic chemotherapy please see exclusion criteria list.

Exclusion Criteria:

1. Subjects that require a dose \>80 mg/day oxycodone PR at the start of the double-blind phase.
2. Any history of hypersensitivity to oxycodone, naloxone, bisacodyl, related products, and other ingredients.
3. Subjects with any situation in which opioids are contra-indicated, severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive pulmonary disease, cor pulmonale, severe bronchial asthma, paralytic ileus.
4. Evidence of clinically significant cardiovascular, renal, hepatic or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results, and physical examination, that would place the subject at risk upon exposure to the study medication or that may confound the analysis and/or interpretation of the study results.
5. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (\>3 times the upper limit of normal) or an abnormal total bilirubin and/or creatinine level(s) (greater than 1.5 times the upper limit of normal).
6. Subjects with known or suspected unstable brain metastases or spinal cord compression that may require changes in steroid treatment throughout the duration of the study.
7. Subjects with uncontrolled seizures.
8. Subjects with increased intracranial pressure.
9. In the investigator's opinion, subjects who are receiving hypnotics or other central nervous system (CNS) depressants that may pose a risk of additional CNS depression with opioid study medication.
10. Subjects with myxodema, not adequately treated hypothyroidism or Addisons disease.
11. Active alcohol or drug abuse and/or history of opioid abuse.
12. Subjects receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine).
13. Subjects with evidence of clinically significant gastrointestinal disease (e.g. paralytic ileus, peritoneal carcinosis), significant structural abnormalities of the gastrointestinal tract (e.g. scarring, obstruction etc) either related or not related to the underlying cancer or disease progression.
14. Subjects who have a confirmed diagnosis of ongoing irritable bowel syndrome.
15. Subjects suffering from diarrhea and/or opioid withdrawal.
16. Surgery completed prior to the start of the Screening Period, or planned surgery during the study that would influence pain or bowel function during the study or preclude completion of the study.
17. Cyclic chemotherapy in the two weeks before the screening visit or planned during the core study that has shown in the past to influence bowel function. If subjects are having their first cycle of chemotherapy during the 2 weeks before the screening visit or during the double-blind phase of the study they should be excluded from the study.
18. Radiotherapy that, in the investigators opinion, would influence bowel function or pain during the double-blind phase of the study.
19. Subjects presently taking, or who have taken, naloxone 30 days prior to the start of the Screening Period.
20. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period).

Answer: B