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 over a 6-month period.
Interventions
DRUGNKTR-118
12.5 mg oral tablet once daily
DRUGPlacebo
Oral tablet intake once daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 84 Years
Healthy volunteers
No
Inclusion criteria
* Must have completed the 12-week study D3820C00004 through Visit 8. * Provision of written informed consent prior to any study-specific procedures. * Men and women who were between the ages of \>18 and \<85 years at the time of the screening visit for study D3820C00004. * Continuing to receive 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. * Willingness to continue abstinence from all laxatives and other bowel regimens including prune juice and herbal products throughout this additional 12-week treatment period, and to use only bisacodyl as rescue medication if a bowel movement (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 the screening visit of study D3820C00004 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 related to the gastrointestinal tract that could impose risk to the patient. * Pregnancy or lactation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Patients Experiencing at Least One Adverse Event (AE) | Baseline (Week 0) to end of the follow-up period (Week 14) | The incidence of patients experiencing at least one AE during the randomized treatment and follow-up periods was calculated. |
| Incidence of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | Baseline (Week 0) to end of the follow-up period (Week 14) | The incidence of patients experiencing AEs that resulted in discontinuation of IP during the randomized treatment or follow-up periods was calculated. |
| Incidence of Patients Experiencing Severe Adverse Events (SAEs) | Baseline (Week 0) to end of the follow-up period (Week 14) | The incidence of patients experiencing SAEs during the randomized treatment and follow-up periods was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Baseline (prior to treatment) to last on-treatment assessment (up to 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) | Baseline (prior to treatment) to last on-treatment assessment (up to 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. |
Countries
Australia, Germany, Slovakia, United States
Participant flow
Recruitment details
This multicenter study was conducted in the United States between 07 July 2011 and 13 September 2012.
Pre-assignment details
Study D380C00007 is an extension study of D3820C00004. Of the patients randomized in D3820C00004, n=302 continued and enrolled into D380C00007. The study duration was up to 14 weeks, consisting of 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 mg QD, oral treatment | 95 |
| NKTR-118 25 mg NKTR-118 25 mg QD, oral treatment | 98 |
| Placebo Placebo QD, oral treatment | 103 |
| Total | 296 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 | 3 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Did not receive treatment | 1 | 1 | 3 |
| Overall Study | Eligibility Criteria Not Fulfilled | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 1 |
| Overall Study | Non-compliance with study schedule | 1 | 0 | 1 |
| Overall Study | Severe noncompliance with protocol | 1 | 0 | 0 |
| Overall Study | Study-Specific Withdrawal Criteria | 1 | 2 | 0 |
| Overall Study | Subject had spinal surgery | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 8 | 8 |
Baseline characteristics
| Characteristic | Placebo | Total | NKTR-118 12.5 mg | NKTR-118 25 mg |
|---|---|---|---|---|
| Age, Continuous | 52.6 Years STANDARD_DEVIATION 10 | 52.3 Years STANDARD_DEVIATION 9.89 | 51.8 Years STANDARD_DEVIATION 9.51 | 52.6 Years STANDARD_DEVIATION 10.19 |
| Gender Female | 61 Participants | 180 Participants | 62 Participants | 57 Participants |
| Gender Male | 42 Participants | 116 Participants | 33 Participants | 41 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 23 Participants | 69 Participants | 24 Participants | 22 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 4 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 76 Participants | 221 Participants | 71 Participants | 74 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 | 15 / 94 | 27 / 97 | 11 / 100 |
| serious Total, serious adverse events | 6 / 94 | 6 / 97 | 5 / 100 |
Outcome results
Primary
Incidence of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP)
The incidence of patients experiencing AEs that resulted in discontinuation of IP during the randomized treatment or follow-up periods was calculated.
Time frame: Baseline (Week 0) to end of the follow-up period (Week 14)
Population: The Safety analysis set included all patients who participated in Study D3820C00004 and received at least 1 dose of study drug in Study D3820C00007, 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 | Incidence of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | 4 Participants |
| NKTR-118 25 mg | Incidence of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | 4 Participants |
| Placebo | Incidence of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | 3 Participants |
Primary
Incidence of Patients Experiencing at Least One Adverse Event (AE)
The incidence of patients experiencing at least one AE during the randomized treatment and follow-up periods was calculated.
Time frame: Baseline (Week 0) to end of the follow-up period (Week 14)
Population: The Safety analysis set included all patients who participated in Study D3820C00004 and received at least 1 dose of study drug in Study D3820C00007, 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 | Incidence of Patients Experiencing at Least One Adverse Event (AE) | 32 Participants |
| NKTR-118 25 mg | Incidence of Patients Experiencing at Least One Adverse Event (AE) | 40 Participants |
| Placebo | Incidence of Patients Experiencing at Least One Adverse Event (AE) | 33 Participants |
Primary
Incidence of Patients Experiencing Severe Adverse Events (SAEs)
The incidence of patients experiencing SAEs during the randomized treatment and follow-up periods was calculated.
Time frame: Baseline (Week 0) to end of the follow-up period (Week 14)
Population: The Safety analysis set included all patients who participated in Study D3820C00004 and received at least 1 dose of study drug in Study D3820C00007, 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 | Incidence of Patients Experiencing Severe Adverse Events (SAEs) | 6 Participants |
| NKTR-118 25 mg | Incidence of Patients Experiencing Severe Adverse Events (SAEs) | 6 Participants |
| Placebo | Incidence of Patients Experiencing Severe Adverse Events (SAEs) | 5 Participants |
Secondary
Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL)
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 (prior to treatment) to last on-treatment assessment (up to Week 12)
Population: The modified intent-to-treat (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 N denotes the number of patients with a baseline and last on-treatment value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Worries/concerns | -1.0 units on a scale | Standard Deviation 1.09 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Psychosocial discomfort | -0.8 units on a scale | Standard Deviation 0.97 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Total score | -1.0 units on a scale | Standard Deviation 0.89 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Physical discomfort | -1.0 units on a scale | Standard Deviation 0.97 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Satisfaction | -1.2 units on a scale | Standard Deviation 1.14 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Psychosocial discomfort | -0.7 units on a scale | Standard Deviation 0.86 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Total score | -0.9 units on a scale | Standard Deviation 0.82 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Physical discomfort | -1.1 units on a scale | Standard Deviation 0.97 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Worries/concerns | -0.9 units on a scale | Standard Deviation 0.91 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Satisfaction | -1.3 units on a scale | Standard Deviation 1.22 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Satisfaction | -1.1 units on a scale | Standard Deviation 1.21 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Worries/concerns | -0.7 units on a scale | Standard Deviation 0.86 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Total score | -0.8 units on a scale | Standard Deviation 0.74 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Psychosocial discomfort | -0.6 units on a scale | Standard Deviation 0.81 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) | Physical discomfort | -1.0 units on a scale | Standard Deviation 0.96 |
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 (prior to treatment) to last on-treatment assessment (up to Week 12)
Population: The modified intent-to-treat(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 N denotes the number of patients with a baseline and last on-treatment value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Total score | -0.9 units on a scale | Standard Deviation 0.71 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Abdominal symptoms subscore | -0.8 units on a scale | Standard Deviation 0.85 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Rectal symptoms subscore | -0.7 units on a scale | Standard Deviation 0.84 |
| NKTR-118 12.5 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Stool symptoms subscore | -1.2 units on a scale | Standard Deviation 0.9 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Stool symptoms subscore | -1.1 units on a scale | Standard Deviation 1.04 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Total score | -0.9 units on a scale | Standard Deviation 0.85 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Rectal symptoms subscore | -0.7 units on a scale | Standard Deviation 0.84 |
| NKTR-118 25 mg | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Abdominal symptoms subscore | -0.7 units on a scale | Standard Deviation 0.97 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Stool symptoms subscore | -0.9 units on a scale | Standard Deviation 1.04 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Abdominal symptoms subscore | -0.7 units on a scale | Standard Deviation 0.82 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Rectal symptoms subscore | -0.6 units on a scale | Standard Deviation 0.9 |
| Placebo | Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) | Total score | -0.8 units on a scale | Standard Deviation 0.84 |