Assessment of Efficacy and Safety in Relieving Opioid-induced Constipation in Patients With Cancer-related Pain

• Part A and Part B: Change from baseline in RFBMs/week [ Time Frame: Will be collected daily through the 4-week treatment period as well as the 12 week extension ] [ Designated as safety issue: No ]
• Part A and Part B: mean number of days per week with at least 1 RFBM. [ Time Frame: Will be collected daily through the 4-week treatment period as well as athe 12 week extension ] [ Designated as safety issue: No ]
• Part A: Time (in hours) to first post-dose RFBM [ Time Frame: Will be collected daily through the 4-week treatment period part A only. ] [ Designated as safety issue: No ]
• Part A: Change from baseline in the degree of straining associated with RFBMs during the 4-week placebo-controlled treatment period. [ Time Frame: Will be collected daily through the 4-week treatment period part A only. ] [ Designated as safety issue: No ]
• Part A: Change from baseline in stool consistency (BSS) during the 4-week placebo-controlled treatment period. [ Time Frame: Will be collected daily through the 4-week treatment period .part A only. ] [ Designated as safety issue: No ]
• Part A: Percentage of days with complete evacuation during the 4-week placebo-controlled treatment period. [ Time Frame: Will be collected daily through the 4-week treatment period part A only. ] [ Designated as safety issue: No ]
• Part A and B: Change from baseline in Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) total score and each domain score for Weeks 2 and 4. [ Time Frame: Part A: Will be evaluated at Visits 3, 5 and 6. Part B: will be evaluated at Visits 4 and 6. ] [ Designated as safety issue: No ]

• Regularity during the 4-week treatment period, where regularity is measured as the mean number of days per week with at least 1 RFBM. [ Time Frame: Will be collected daily through the 4-week treatment period. ] [ Designated as safety issue: No ]
• Time (in hours) to first post-dose RFBM. [ Time Frame: Will be collected daily through the 4-week treatment period. ] [ Designated as safety issue: No ]
• Change from baseline in the degree of straining associated with RFBMs during the 4-week treatment period. [ Time Frame: Will be collected daily through the 4-week treatment period. ] [ Designated as safety issue: No ]
• Change from baseline in stool consistency (BSS) during the 4-week treatment period. [ Time Frame: Will be collected daily through the 4-week treatment period. ] [ Designated as safety issue: No ]
• Percentage of days with complete evacuation during the 4-week treatment period. [ Time Frame: Will be collected daily through the 4-week treatment period. ] [ Designated as safety issue: No ]
• Change from baseline in Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) total score and each domain score for Weeks 2 and 4. [ Time Frame: Will be evaluated at Visits 3, 5 and 6. ] [ Designated as safety issue: No ]

The purpose of this study is to compare the effect of NKTR-118 with placebo in the treatment of opioid-induced constipation (OIC) in patients with cancer-related pain, including those patients that have inadequate response to laxative therapy (LIR).

The study consists of 2 parts; A initial 4-week treatment period (part A) and then a 12 week extension with active treatment (part B).

• Drug: NKTR-118
  12.5 mg oral tablet once daily
• Drug: NKTR-118
  25 mg oral tablet once daily
• Drug: Placebo
  Oral treatment

• Experimental: 1 (part A and B)
  Oral treatment
  Intervention: Drug: NKTR-118
• Experimental: 2 (part A and B)
  Oral treatment
  Intervention: Drug: NKTR-118
• Placebo Comparator: 3 (part A only)
  Oral treatment
  Intervention: Drug: Placebo

Inclusion Criteria:

• Provision of written informed consent prior to any study-specific procedures.
• Men and women aged 18 or older.
• Histologically or cytologically confirmed neoplasm causing pain and requiring management with opioids.
• Self-reported active symptoms of OIC at screening (<3 RFBMs/week and experiencing >1 reported symptom of hard/lumpy stools, straining, or sensation of incomplete evacuation/anorectal obstruction in at least 25% of BMs over the previous 4 weeks); and Documented confirmed OIC (<3 RFBMs/week on average aver the 2-week OIC confirmation period.
• Receiving a stable maintenance opioid regimen consisting of a total daily dose of >30 mg of oral morphine, or equianalgesic amount(s) of 1 or more opioid therapies for a minimum of 4 weeks prior to screening for cancer-related pain with no anticipated change in opioid dose requirement over the proposed study period as a result of disease progression.

Exclusion Criteria:

• Patients receiving Opioid regimen for treatment of pain other than related to cancer.
• Any condition that may have affected the permeability of the blood-brain barrier, eg, known brain metastases, meningeal metastases, brain injury, multiple sclerosis, recent brain injury, uncontrolled epilepsy.
• Patients with cancer-related pain due to ovarian cancer, leukaemia, or lymphoma are excluded. Patients with multiple myeloma will be allowed.
• Patients requiring radiation therapy between the diaphragm and pelvis 4 weeks prior to Visit 1 (screening) and/or during Part A of the study are excluded. Any patients with suspected clinically relevant radiation-induced injury of small or large intestine are excluded.
• Pregnancy or lactation.