Assessment of Efficacy and Safety in Patients With Non-cancer-related Pain and Opioid-induced Constipation

• Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 12, for at least 9 out of 12 weeks and at least 3 out of the last 4 weeks. [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  Responder is defined as having at least 3 SBMs/week, with at least 1 SBM/week increase over baseline.
• Time (in hours) to first post-dose laxation without the use of rescue laxatives within the previous 24 hours. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Mean number of days per week with at least 1 SBM during Weeks 1 to 12. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

• Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 4, where a responder is defined as having at least 3 SBMs/week, with at least 1 SBM/week increase over baseline, for at least 3 out of the first 4 weeks. [ Time Frame: Up to 4 Weeks ] [ Designated as safety issue: No ]
• Response (responder/non-responder) to study drug over the entire 12 week treatment period, where a responder is defined as having at least 3 SBMs/week, with at least 1 SBM/week increase over baseline, for at least 75% of the weeks. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Regularity during the first 4 weeks of treatment, where regularity is measured as the mean number of days per week with at least 1 SBM during Weeks 1 to 4. [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]

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

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

• Experimental: 1
  Oral treatment
  Intervention: Drug: NKTR-118
• Experimental: 2
  Oral treatment
  Intervention: Drug: NKTR-118
• Placebo Comparator: 3
  Oral treatment
  Intervention: Drug: Placebo

Inclusion Criteria:

• Provision of written informed consent prior to any study-specific procedures.
• Men and women who are between the ages of ≥18 and <85 years.
• Self-reported active symptoms of OIC at screening (<3 SBMs/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 SBMs/week on average over the 2-week OIC confirmation period.
• Receiving a stable maintenance opioid regimen consisting of a total daily dose of 30 mg to 1000 mg of oral morphine, or equianalgesic amount(s) of 1 or more other opioid therapies for a minimum of 4 weeks prior to screening for non-cancer-related pain with no anticipated change in opioid dose requirement over the proposed study period as a result of disease progression.
• Willingness to stop all laxatives and other bowel regimens including prune juice and herbal products throughout the 2-week OIC confirmation period and the 12-week treatment period, and to use only bisacodyl as rescue medication if a BM has not occurred within at least 72 hours of the last recorded BM.

Exclusion Criteria:

• Patients receiving Opioid regimen for treatment of pain related to cancer.
• History of cancer within 5 years from first study visit with the exception of basal cell cancer and squamous cell skin cancer.
• Medical conditions and treatments associated with diarrhea, intermittent loose stools, or constipation.
• Other issues to the gastrointestinal tract that could impose a risk to the patient.
• Pregnancy or lactation.