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

Phase 3

Completed

Conditions: Opioid-Induced Constipation (OIC)

Interventions: Drug: Placebo
Drug: NKTR-118

Registration Number: NCT01309841

Lead Sponsor: AstraZeneca

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 652

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3	Placebo	Oral treatment
2	NKTR-118	Oral treatment
1	NKTR-118	Oral treatment

Primary Outcome Measures

Name	Time	Method
Response (Responder/Non-responder) to Study Drug During Weeks 1 to 12	Baseline (Week 1) to end of treatment (Week 12)	Responder was defined as having at least 3 spontaneous bowel movements (SBMs)/week with at least 1 SBM/week increase over baseline for at least 9 out of the 12 treatment weeks and 3 out of the last 4 treatment weeks during the double-blind treatment period. An SBM is a bowel movement occurring 24 hours or more since the last use of rescue medication.

Secondary Outcome Measures

Name	Time	Method
Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours in the Laxative Inadequate Response (LIR) Subgroup	Baseline (Week 1) to end of treatment (Week 12)	Time to first post-dose laxation without the use of rescue laxatives within the last 24 hours was calculated in hours as: Date/Time of first post-dose laxation without rescue - First dose date/time.
Change From Baseline in Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12	12 weeks
Response (Responder/Non-responder) to Study Drug in the LIR Subgroup During Weeks 1 to 12	Baseline (Week 1) to end of treatment (Week 12)	Responder is defined as having at least 3 SBMs/week, with at least 1 SBM/week increase over baseline for at least 9 out of 12 weeks and at least 3 out of the last 4 weeks.
Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours	12 weeks
Change From Baseline in Degree of Straining	Baseline (Week 1) to end of treatment (Week 12)	A single-item straining question was asked via the eDiary: "How much did you strain during your bowel movement?" Patients responded on a 5 point Likert scale: 1=Not at all; 2=A little bit; 3=A moderate amount; 4=A great deal; 5=An extreme amount. A negative change from baseline indicates improvement.
Change From Baseline in Stool Consistency (Bristol Stool Scale)	Baseline (Week 1) to end of treatment (Week 12)	Patients rated stool consistency through completion of the BSS after each BM. The 7 stool types are: 1. Separate hard lumps, like nuts (hard to pass); 2. Sausage-shaped, but lumpy; 3. Like sausage, but with cracks on its surface; 4. Like a sausage or snake, smooth and soft; 5. Soft blobs with clear cut edges (passed easily); 6. Fluffy pieces with ragged edges, a mushy stool; 7. Watery, no solid pieces. A positive change from baseline indicates improvement.
Change From Baseline in Percent Numbers of Days With a CSBM (Complete Spontaneous Bowel Movement)	Baseline (Week 1) to end of treatment (Week 12)	A single-item question on the completeness of evacuation, developed and validated through 1:1 interviews with OIC patients, was asked via the eDiary: "Did you feel like your bowels were completely empty after the bowel movement?" Patients provided a yes or a no response. A positive change from baseline indicates improvement.
Change From Baseline in Mean Spontaneous Bowel Movements/Week	Baseline (Week 1) to end of treatment (Week 12)	The number of spontaneous bowel movements/week was determined from the patient's eDiary.
Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM)	Baseline (Week 1) to end of treatment (Week 12)	The PAC-SYM questionnaire is a 12-item questionnaire that evaluates the severity of symptoms of constipation in 3 domains (stool, rectal, and abdominal symptoms) on a 5-point Likert scale ranging from 0 (absent) to 4 (very severe) in the 2 weeks (14 days) prior to assessment. Each domain score is the mean of the non-missing items for that domain. The total score is the mean of all non-missing items (ie, symptoms). The range of the domain or total score is 0 (response is 'absent' for each item) to 4 (response is 'very severe' for each item). A negative change from baseline indicates improvement.
Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain	Baseline (Week 1) to end of treatment (Week 12)	The PAC-QOL scale is a 28-item self-report instrument designed to evaluate the burden of constipation on patients' everyday functioning and well-being in the 2 weeks (14 days) prior to assessment. Each item is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (extremely). The instrument can be used to generate an overall score, but is also reported to assess 4 specific constipation-related domains including: 1) Worries and concerns (11 items), 2) Physical discomfort (4 items), 3) Psychosocial discomfort (8 items), and 4) Satisfaction (5 items). Each domain score is the mean of the non-missing items for that domain. The total score is the mean of all non-missing items. The range of the domain or total score is 0 (response is 'not at all' for each item) to 4 (response is 'extremely' for each item). A negative change from baseline indicates improvement.