Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase II Trial of Subcutaneous Methylnaltrexone in the Treatment of Severe Opioid-induced Constipation in Cancer Patients
Brief Summary: The purpose of this study is to evaluate the efficacy of methylnaltrexone in relieving opioid-induced constipation in cancer patients at various stages of disease.


Options:
A: 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).
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:

1. Male or female cancer patients 20 years of age or older
2. Cancer related pain that requires treatment with continuous around-the-clock strong opioid analgesic
3. Moderate to severe pain intensity(NRS pain score 4)
4. Opioid naïve patients or patients not treated with strong opioids(except PRN) within 4 weeks or patients who has been on weak opioids
5. Subject who provide signed and dated written voluntary informed consent

Exclusion Criteria:

1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are:

   * women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
   * women shoes partners have been sterilized by vasectomy or other means
   * two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive urine pregnancy test.
3. Have previously received treatment with Targin or Oxycontin within 4weeks(28days) of screening periods(including PRN)
4. If subjects started first cycle of chemotherapy during the 2 weeks before the screening visit or during the study, they should be excluded from the study.

   And If the chemotherapy regimen or dosage to be planned to change during the study, the subjects should be excluded from the study.
5. Patient who is administered laxatives with stable dose for more than 1 week
6. Patient with evidence of significant structural/functional abnormalities of GI tract which is not appropriate for oral medicine administration. Any history of hypersensitivity to Oxycodone and Naloxone
7. Patients with significant respiratory depression
8. Patients with acute or severe bronchial asthma or hypercarbia
9. Any patient who has or is suspected of having paralytic ileus
10. Severe Chronic obstructive pulmonary disease, pulmonary heart disease
11. Targin product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take
12. Patients with moderate and severe hepatic impairment
13. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (\>2.5 times the upper limit of normal, it is allowed \>5 times the upper limit of normal in case of transition in liver) or an abnormal total bilirubin and/or creatinine level(s) (greater than 1.5 times the upper limit of normal)
14. Any situation where opioids are contraindicated
15. Major surgery within 1 month prior to screening or planned surgery
16. Mainly pain originated other than cancer or cancer related conditions (eg. Musculoskeletal pain, inflammatory pain, diabetic polyneuropathy)
17. Patients with known or suspected unstable brain metastases or spinal cord compression that may require changes in steroid treatment throughout the duration of the study
18. Patients with uncontrolled seizures
19. Requiring interventional treatment for pain such as neurodestructive procedure or regional infusion
20. With a history of alcohol abuse within 6 months of screening
21. With a history of illicit drug abuse within 6 months of screening
22. Patients with increased intracranial pressure
23. 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
24. Patients with myxoedema, not adequately treated hypothyroidism or Addison's disease
25. Patients receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine)
26. Patients 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
27. Patients suffering from diarrhea and/or opioid withdrawal
28. With a disability that may prevent the patient from completing all study requirements and in particular, interfere with 24hrs pain intensity score
29. Clinically significant impairment of cardiovascular, respiratory and renal function
30. Patient who needs acute dose titration or whose pain intensity fluctuate significantly in a short period according to investigator's judgment
31. Having used other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
D: 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

Answer: D