Opioid-Induced Constipation
Conditions
Keywords
Opioid-Induced Constipation, Linaclotide, Linzess
Brief summary
The purpose of this study was to evaluate the safety and efficacy of linaclotide for the treatment of opioid-induced constipation (OIC), in adults receiving stable opioid treatment for chronic non-cancer pain that has been present for a minimum of 3 months. This study included up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients meeting the entry criteria were randomized to 1 of 2 doses of linaclotide or placebo once per day for 8 weeks. This 8-week study assessed the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of OIC.
Interventions
Sponsors
Ironwood Pharmaceuticals, Inc.
Forest Laboratories
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has chronic non-cancer pain that has been present for a minimum of 3 months * Patient has been receiving a stable oral dose of a full-opioid agonist for at least 4 days per week during the 8 consecutive weeks * Patient meets protocol criteria for Opioid-Induced Constipation (OIC): \< 3 spontaneous bowel movements (SBMs) per week and reports one of the following symptoms for at least 4 weeks: 1. Straining during \> 25% of BMs 2. Lumpy or hard stools during \> 25% of BMs 3. Sensation of incomplete evacuation during \> 25% of BMs * Patient meets the colonoscopy requirements defined by the American Gastroenterological Association guidelines * Patient has successfully completed protocol procedures (with no clinically significant findings) * Patient is compliant with Interactive Voice Response System (IVRS) for daily diary reporting * Patient has a total of \< 6 SBMs in IVRS during the 14 days before and up to the time of Randomization * Patient has adequate relief and well-controlled pain with current dose of opioid
Exclusion criteria
* Patient has been using opioids for abdominal pain * Patient has symptoms of or been diagnosed with chronic constipation or chronic idiopathic constipation prior to initiation of opioid treatment * Patient has symptoms of or been diagnosed with Irritable Bowel Syndrome (IBS) prior to initiation of opioid treatment * Patient has a history of loose or watery stools for \> 25% of BMs during the 3 months before the Screening in the absence of laxatives, suppositories, or enemas * Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility * Patient has any protocol-excluded or clinically significant medical or surgical history that would limit the patient's ability to complete or participate in this clinical trial or could confound the study assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | Baseline (Week 0) to Week 8 | Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First SBM After the First Dose of Investigational Product | Baseline (Day 0) up to 8 weeks | The median time to the first SBM after the first dose of investigational product |
| Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria | 8-week treatment period | A 6/8 Week SBM 3 + 1 responder was a participant who met the weekly SBM 3 + 1 responder criteria for at least 6 out of the 8 weeks of the Treatment Period. For each week in the Treatment Period, a weekly SBM 3 + 1 responder was a patient who had an SBM weekly rate ≥ 3 and an increase ≥ 1 in the SBM weekly rate from baseline for that week. |
| Change From Baseline in 8-Week Stool Consistency | Baseline (Week 0) to Week 8 | Stool Consistency was assessed using the 7-Point Bristol Stool Form Scale: 1. = separate hard lumps like nuts (difficult to pass) 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on 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 7. = watery, no solid pieces (entirely liquid) |
| Change From Baseline in 8-Week Straining | Baseline (Week 0) to Week 8 | Straining was measured on a 5-point ordinal scale where a value of 1 is not at all and a value of 5 is an extreme amount. |
| Change From Baseline in 8-Week Abdominal Bloating | Baseline (Week 0) to Week 8 | Abdominal bloating was collected daily via IVRS calls and measured using an 11-point numerical rating scale, where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating. |
Countries
United States
Participant flow
Pre-assignment details
14 calendar days (minimum) to 21 calendar days (maximum) before randomization, participants had to provide information about bowel habits, symptom severity, and rescue medication use through daily IVRS calls. A total of 254 patients were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | 78 |
| Linaclotide 145 Micrograms Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | 87 |
| Linaclotide 290 Micrograms Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | 87 |
| Total | 252 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 6 |
| Overall Study | family emergency | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 2 |
| Overall Study | moved away from study site | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 1 |
| Overall Study | study procedure non-compliance | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Linaclotide 145 Micrograms | Linaclotide 290 Micrograms | Total |
|---|---|---|---|---|
| Age, Continuous | 52.2 Years STANDARD_DEVIATION 10.6 | 53.1 Years STANDARD_DEVIATION 9.2 | 54.0 Years STANDARD_DEVIATION 10.5 | 53.2 Years STANDARD_DEVIATION 10.1 |
| Age, Customized 18 to under 40 | 11 Participants | 4 Participants | 6 Participants | 21 Participants |
| Age, Customized 40 to under 65 | 56 Participants | 71 Participants | 67 Participants | 194 Participants |
| Age, Customized 65 and over | 11 Participants | 12 Participants | 14 Participants | 37 Participants |
| Body Mass Index (BMI) | 32.17 kg/m^2 STANDARD_DEVIATION 8.57 | 29.09 kg/m^2 STANDARD_DEVIATION 6.32 | 31.77 kg/m^2 STANDARD_DEVIATION 7.39 | 30.97 kg/m^2 STANDARD_DEVIATION 7.54 |
| Height | 168.05 cm STANDARD_DEVIATION 12.27 | 170.70 cm STANDARD_DEVIATION 10.17 | 168.00 cm STANDARD_DEVIATION 10.62 | 168.95 cm STANDARD_DEVIATION 11.04 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 4 Participants | 5 Participants | 2 Participants | 11 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 74 Participants | 82 Participants | 85 Participants | 241 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 1 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Black or African American | 9 Participants | 15 Participants | 10 Participants | 34 Participants |
| Race/Ethnicity, Customized Race Multiple Races | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 66 Participants | 71 Participants | 72 Participants | 209 Participants |
| SBM Frequency Rate | 1.05 SBMs per week STANDARD_DEVIATION 0.81 | 1.01 SBMs per week STANDARD_DEVIATION 0.7 | 1.14 SBMs per week STANDARD_DEVIATION 0.84 | 1.07 SBMs per week STANDARD_DEVIATION 0.78 |
| Sex/Gender, Customized Female | 47 Participants | 49 Participants | 55 Participants | 151 Participants |
| Sex/Gender, Customized Male | 31 Participants | 38 Participants | 32 Participants | 101 Participants |
| Weight | 90.64 kg STANDARD_DEVIATION 24.56 | 85.45 kg STANDARD_DEVIATION 22.78 | 89.78 kg STANDARD_DEVIATION 22.61 | 88.55 kg STANDARD_DEVIATION 23.31 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 78 | 0 / 87 | 0 / 87 |
| other Total, other adverse events | 16 / 78 | 24 / 87 | 33 / 87 |
| serious Total, serious adverse events | 5 / 78 | 0 / 87 | 1 / 87 |
Outcome results
Primary
Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week)
Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period.
Time frame: Baseline (Week 0) to Week 8
Population: 252 participants received at least one dose of study drug, comprising the ITT study population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | 1.474 Number of SBMs per week | Standard Error 0.361 |
| Linaclotide 145 Micrograms | Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | 2.799 Number of SBMs per week | Standard Error 0.35 |
| Linaclotide 290 Micrograms | Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | 3.382 Number of SBMs per week | Standard Error 0.353 |
p-value: 0.003595% CI: [0.439, 2.211]ANCOVA
p-value: <0.000195% CI: [1.021, 2.796]ANCOVA
Secondary
Change From Baseline in 8-Week Abdominal Bloating
Abdominal bloating was collected daily via IVRS calls and measured using an 11-point numerical rating scale, where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating.
Time frame: Baseline (Week 0) to Week 8
Population: 252 participants received at least one dose of study drug, comprising the ITT study population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 8-Week Abdominal Bloating | -0.983 Units on a scale | Standard Error 0.164 |
| Linaclotide 145 Micrograms | Change From Baseline in 8-Week Abdominal Bloating | -0.950 Units on a scale | Standard Error 0.16 |
| Linaclotide 290 Micrograms | Change From Baseline in 8-Week Abdominal Bloating | -1.590 Units on a scale | Standard Error 0.16 |
p-value: 0.87295% CI: [-0.371, 0.437]ANCOVA
p-value: 0.003495% CI: [-1.011, -0.203]ANCOVA
Secondary
Change From Baseline in 8-Week Stool Consistency
Stool Consistency was assessed using the 7-Point Bristol Stool Form Scale: 1. = separate hard lumps like nuts (difficult to pass) 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on 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 7. = watery, no solid pieces (entirely liquid)
Time frame: Baseline (Week 0) to Week 8
Population: Of the 252 participants in the ITT population, 200 participants had Stool Consistency data collected
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 8-Week Stool Consistency | 0.911 Units on a scale | Standard Error 0.172 |
| Linaclotide 145 Micrograms | Change From Baseline in 8-Week Stool Consistency | 1.662 Units on a scale | Standard Error 0.165 |
| Linaclotide 290 Micrograms | Change From Baseline in 8-Week Stool Consistency | 1.898 Units on a scale | Standard Error 0.168 |
p-value: 0.000795% CI: [0.324, 1.178]ANCOVA
p-value: <0.000195% CI: [0.558, 1.416]ANCOVA
Secondary
Change From Baseline in 8-Week Straining
Straining was measured on a 5-point ordinal scale where a value of 1 is not at all and a value of 5 is an extreme amount.
Time frame: Baseline (Week 0) to Week 8
Population: Of the 252 participants in the ITT population, 200 participants had 8-week straining data collected
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 8-Week Straining | -0.753 Units on a scale | Standard Error 0.116 |
| Linaclotide 145 Micrograms | Change From Baseline in 8-Week Straining | -1.212 Units on a scale | Standard Error 0.111 |
| Linaclotide 290 Micrograms | Change From Baseline in 8-Week Straining | -1.422 Units on a scale | Standard Error 0.112 |
p-value: 0.001795% CI: [-0.746, -0.174]ANCOVA
p-value: <0.000195% CI: [-0.957, -0.382]ANCOVA
Secondary
Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria
A 6/8 Week SBM 3 + 1 responder was a participant who met the weekly SBM 3 + 1 responder criteria for at least 6 out of the 8 weeks of the Treatment Period. For each week in the Treatment Period, a weekly SBM 3 + 1 responder was a patient who had an SBM weekly rate ≥ 3 and an increase ≥ 1 in the SBM weekly rate from baseline for that week.
Time frame: 8-week treatment period
Population: 252 participants received at least one dose of study drug, comprising the ITT study population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria | 33.3 Percentage of Responders |
| Linaclotide 145 Micrograms | Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria | 40.2 Percentage of Responders |
| Linaclotide 290 Micrograms | Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria | 47.1 Percentage of Responders |
p-value: 0.333295% CI: [0.73, 2.58]Cochran-Mantel-Haenszel
p-value: 0.050695% CI: [1, 3.68]Cochran-Mantel-Haenszel
Secondary
Time to First SBM After the First Dose of Investigational Product
The median time to the first SBM after the first dose of investigational product
Time frame: Baseline (Day 0) up to 8 weeks
Population: 252 participants received at least one dose of study drug, comprising the ITT study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First SBM After the First Dose of Investigational Product | 47.1 hours |
| Linaclotide 145 Micrograms | Time to First SBM After the First Dose of Investigational Product | 26.5 hours |
| Linaclotide 290 Micrograms | Time to First SBM After the First Dose of Investigational Product | 28.7 hours |
p-value: 0.142995% CI: [0.92, 1.77]Log Rank
p-value: 0.028795% CI: [1.04, 1.97]Log Rank