Opioid-Induced Constipation (OIC)
Conditions
Keywords
Non-Cancer-Related Pain, Opioid-Induced Constipation
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).
Interventions
DRUGNKTR-118
12.5 mg oral tablet once daily
DRUGPlacebo
Placebo to NKTR-118
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 84 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| 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. |
| 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. |
| 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 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. |
| 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. |
Countries
Belgium, Croatia, Czechia, Hungary, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This multicenter study was conducted in Belgium, Croatia, Czech Republic, Hungary, Spain, Sweden, United Kingdom, and the United States between 28 March 2011 and 20 September 2012.
Pre-assignment details
The study duration was up to 18 weeks, consisting of an initial screening period lasting up to 2 weeks, a 2-week OIC confirmation period, during which the diagnosis of OIC and stability of the opioid regimen were confirmed, a 12-week treatment period, and a follow-up visit 2 weeks after the last dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| NKTR-118 12.5 mg NKTR-118 12.5 QD, oral treatment | 232 |
| NKTR-118 25 mg NKTR-118 25 mg QD, oral treatment | 232 |
| Placebo Placebo QD, oral treatment | 232 |
| Total | 696 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 24 | 12 |
| Overall Study | Did Not Receive Treatment | 2 | 0 | 1 |
| Overall Study | Eligibility Criteria Not Fulfilled | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 3 | 0 | 3 |
| Overall Study | Lost to Follow-up | 11 | 9 | 9 |
| Overall Study | Other | 3 | 2 | 1 |
| Overall Study | Severe non-compliance with protocol | 2 | 2 | 2 |
| Overall Study | Study-Specific Withdrawal Criteria | 0 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 23 | 20 | 13 |
Baseline characteristics
| Characteristic | Total | NKTR-118 12.5 mg | NKTR-118 25 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 52.1 Years STANDARD_DEVIATION 11.58 | 52.0 Years STANDARD_DEVIATION 11.02 | 51.9 Years STANDARD_DEVIATION 12.11 | 52.3 Years STANDARD_DEVIATION 11.62 |
| Baseline laxative response status Laxative Adequate Response (LAR) | 14 Participants | 5 Participants | 5 Participants | 4 Participants |
| Baseline laxative response status Laxative Inadequate Response (LIR) | 370 Participants | 125 Participants | 124 Participants | 121 Participants |
| Baseline laxative response status Laxative Unknown Response (LUR) | 312 Participants | 102 Participants | 103 Participants | 107 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 125 Participants | 41 Participants | 40 Participants | 44 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 559 Participants | 187 Participants | 189 Participants | 183 Participants |
| Sex: Female, Male Female | 441 Participants | 149 Participants | 147 Participants | 145 Participants |
| Sex: Female, Male Male | 255 Participants | 83 Participants | 85 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 90 / 230 | 112 / 232 | 73 / 231 |
| serious Total, serious adverse events | 14 / 230 | 8 / 232 | 12 / 231 |
Outcome results
Primary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NKTR-118 12.5 mg | Response (Responder/Non-responder) to Study Drug During Weeks 1 to 12 | 81 Number of patients |
| NKTR-118 25 mg | Response (Responder/Non-responder) to Study Drug During Weeks 1 to 12 | 92 Number of patients |
| Placebo | Response (Responder/Non-responder) to Study Drug During Weeks 1 to 12 | 68 Number of patients |
Comparison: Analysis via Cochran Mantel-Haenszel test stratified by response to laxatives at baseline (LIR, LAR, LUR).p-value: 0.20295% CI: [0.911, 1.548]Cochran-Mantel-Haenszel
Comparison: Analysis via Cochran Mantel-Haenszel test stratified by response to laxatives at baseline (LIR, LAR, LUR).p-value: 0.02195% CI: [1.045, 1.739]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Degree of Straining | -0.67 units on a scale | Standard Error 0.06 |
| NKTR-118 25 mg | Change From Baseline in Degree of Straining | -0.80 units on a scale | Standard Error 0.06 |
| Placebo | Change From Baseline in Degree of Straining | -0.48 units on a scale | Standard Error 0.06 |
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.00595% CI: [-0.32, -0.06]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [-0.45, -0.18]Mixed Models Analysis
Secondary
Change From Baseline in Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12
Time frame: 12 weeks
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12 | 2.12 Number of Days | Standard Error 0.12 |
| NKTR-118 25 mg | Change From Baseline in Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12 | 2.41 Number of Days | Standard Error 0.13 |
| Placebo | Change From Baseline in Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12 | 1.73 Number of Days | Standard Error 0.12 |
Comparison: Analysis via Mixed Model Repeated Measures (MMRM) with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.0195% CI: [0.09, 0.69]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [0.37, 0.98]Mixed Models Analysis
Secondary
Change From Baseline in Mean Spontaneous Bowel Movements/Week
The number of spontaneous bowel movements/week was determined from the patient's eDiary.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Mean Spontaneous Bowel Movements/Week | 2.62 Number of SBMs/week | Standard Error 0.18 |
| NKTR-118 25 mg | Change From Baseline in Mean Spontaneous Bowel Movements/Week | 3.14 Number of SBMs/week | Standard Error 0.19 |
| Placebo | Change From Baseline in Mean Spontaneous Bowel Movements/Week | 2.10 Number of SBMs/week | Standard Error 0.18 |
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.02895% CI: [0.06, 0.98]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [0.58, 1.51]Mixed Models Analysis
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who randomized multiple times at different centers. MMRM analysis includes all patients with baseline and at least 1 post-baseline assessment, while the Ns at Week 12 reflect patients providing data at Week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain | -1.12 units on a scale | Standard Error 0.09 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain | -1.30 units on a scale | Standard Error 0.09 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain | -0.81 units on a scale | Standard Error 0.09 |
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.01195% CI: [-0.54, -0.07]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [-0.73, -0.25]Mixed Models Analysis
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who randomized multiple times at different centers. MMRM analysis includes all patients with baseline and at least 1 post-baseline assessment, while the Ns at Week 12 reflect patients providing data at Week 12.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Abdominal symptoms subscore | -0.67 units on a scale | Standard Error 0.06 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Stool symptoms subscore | -0.93 units on a scale | Standard Error 0.07 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Rectal symptoms subscore | -0.59 units on a scale | Standard Error 0.05 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Total score | -0.75 units on a scale | Standard Error 0.05 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Rectal symptoms subscore | -0.71 units on a scale | Standard Error 0.05 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Stool symptoms subscore | -1.04 units on a scale | Standard Error 0.07 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Abdominal symptoms subscore | -0.62 units on a scale | Standard Error 0.06 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Total score | -0.81 units on a scale | Standard Error 0.05 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Stool symptoms subscore | -0.66 units on a scale | Standard Error 0.07 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Total score | -0.63 units on a scale | Standard Error 0.05 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Rectal symptoms subscore | -0.47 units on a scale | Standard Error 0.05 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Abdominal symptoms subscore | -0.72 units on a scale | Standard Error 0.06 |
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.0895% CI: [-0.26, 0.01]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.01195% CI: [-0.32, -0.04]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.55295% CI: [-0.11, 0.2]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.23695% CI: [-0.06, 0.25]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.09595% CI: [-0.24, 0.02]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [-0.37, -0.1]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.00295% CI: [-0.44, -0.1]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [-0.56, -0.21]Mixed Models Analysis
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Percent Numbers of Days With a CSBM (Complete Spontaneous Bowel Movement) | 23.48 Percent days/week | Standard Error 1.88 |
| NKTR-118 25 mg | Change From Baseline in Percent Numbers of Days With a CSBM (Complete Spontaneous Bowel Movement) | 27.20 Percent days/week | Standard Error 1.93 |
| Placebo | Change From Baseline in Percent Numbers of Days With a CSBM (Complete Spontaneous Bowel Movement) | 16.76 Percent days/week | Standard Error 1.86 |
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.00295% CI: [2.37, 11.06]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [6.03, 14.84]Mixed Models Analysis
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Stool Consistency (Bristol Stool Scale) | 0.54 units on a scale | Standard Error 0.07 |
| NKTR-118 25 mg | Change From Baseline in Stool Consistency (Bristol Stool Scale) | 0.71 units on a scale | Standard Error 0.07 |
| Placebo | Change From Baseline in Stool Consistency (Bristol Stool Scale) | 0.26 units on a scale | Standard Error 0.06 |
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: 0.00195% CI: [0.12, 0.45]Mixed Models Analysis
Comparison: Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.p-value: <0.00195% CI: [0.29, 0.62]Mixed Models Analysis
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers. The LIR subgroup used 1 or more laxative classes for at least 4 days in the 2 weeks prior to entry and reported moderate to very severe symptoms.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NKTR-118 12.5 mg | Response (Responder/Non-responder) to Study Drug in the LIR Subgroup During Weeks 1 to 12 | 53 Number of patients |
| NKTR-118 25 mg | Response (Responder/Non-responder) to Study Drug in the LIR Subgroup During Weeks 1 to 12 | 58 Number of patients |
| Placebo | Response (Responder/Non-responder) to Study Drug in the LIR Subgroup During Weeks 1 to 12 | 38 Number of patients |
p-value: 0.07495% CI: [0.967, 1.884]Cochran-Mantel-Haenszel
p-value: 0.01495% CI: [1.078, 2.058]Cochran-Mantel-Haenszel
Secondary
Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours
Time frame: 12 weeks
Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NKTR-118 12.5 mg | Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours | 19.3 Hours |
| NKTR-118 25 mg | Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours | 12.0 Hours |
| Placebo | Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours | 37.2 Hours |
Secondary
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.
Time frame: Baseline (Week 1) to end of treatment (Week 12)
Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NKTR-118 12.5 mg | 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 | 12.8 hours |
| NKTR-118 25 mg | 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 | 18.1 hours |
| Placebo | 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 | 38.2 hours |