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

Study Overview
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Brief Summary
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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).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of NKTR-118 in Patients With Non-Cancer-Related Pain and Opioid-Induced Constipation (OIC)

Conditions
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Opioid-Induced Constipation (OIC)

Intervention / Treatment
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* Drug: NKTR-118
* Drug: NKTR-118
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent prior to any study-specific procedures. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Oral treatment | Drug: NKTR-118<br>* 12.5 mg oral tablet once daily<br>|
| Experimental: 2<br>Oral treatment | Drug: NKTR-118<br>* 25 mg oral tablet once daily<br>|
| Placebo Comparator: 3<br>Oral treatment | Drug: Placebo<br>* Placebo to NKTR-118<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (Responder/Non-responder) to Study Drug During Weeks 1 to 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. | Baseline (Week 1) to end of treatment (Week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (Responder/Non-responder) to Study Drug in the LIR Subgroup During Weeks 1 to 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. | Baseline (Week 1) to end of treatment (Week 12) | 
| 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 Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12 |  | 12 weeks | 
| Change From Baseline in Degree of Straining | 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. | Baseline (Week 1) to end of treatment (Week 12) | 
| Change From Baseline in Stool Consistency (Bristol Stool Scale) | 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. | Baseline (Week 1) to end of treatment (Week 12) | 
| Change From Baseline in Percent Numbers of Days With a CSBM (Complete Spontaneous Bowel Movement) | 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. | Baseline (Week 1) to end of treatment (Week 12) | 
| Change From Baseline in Mean Spontaneous Bowel Movements/Week | The number of spontaneous bowel movements/week was determined from the patient's eDiary. | Baseline (Week 1) to end of treatment (Week 12) | 
| 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 | 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. | Baseline (Week 1) to end of treatment (Week 12) | 
| Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | 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. | Baseline (Week 1) to end of treatment (Week 12) | 
| Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain | 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. | Baseline (Week 1) to end of treatment (Week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Cancer-Related Pain, Opioid-Induced Constipation