Trial Outcomes & Findings for Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial of Linaclotide Administered to Patients With Opioid-Induced Constipation Receiving Chronic Opioid Treatment for Non-Cancer Pain (NCT NCT02270983)

NCT ID: NCT02270983

Last Updated: 2019-04-08

Results Overview

Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 254 participants
• Primary outcome timeframe: Baseline (Week 0) to Week 8
• Results posted on: 2019-04-08

Participant Flow

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.

Participant milestones

Measure	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.	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.	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.
Overall Study STARTED	79	87	88
Overall Study COMPLETED	70	80	76
Overall Study NOT COMPLETED	9	7	12

Reasons for withdrawal

Measure	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.	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.	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.
Overall Study Adverse Event	3	2	6
Overall Study Lack of Efficacy	2	1	1
Overall Study Withdrawal by Subject	1	0	2
Overall Study Lost to Follow-up	1	1	2
Overall Study Protocol Violation	1	1	1
Overall Study family emergency	0	1	0
Overall Study study procedure non-compliance	1	0	0
Overall Study moved away from study site	0	1	0

Baseline Characteristics

Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial of Linaclotide Administered to Patients With Opioid-Induced Constipation Receiving Chronic Opioid Treatment for Non-Cancer Pain

Baseline characteristics by cohort

Measure	Placebo n=78 Participants 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.	Linaclotide 145 Micrograms n=87 Participants 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.	Linaclotide 290 Micrograms n=87 Participants 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.	Total n=252 Participants Total of all reporting groups
Age, Continuous	52.2 Years STANDARD_DEVIATION 10.6 • n=5 Participants	53.1 Years STANDARD_DEVIATION 9.2 • n=7 Participants	54.0 Years STANDARD_DEVIATION 10.5 • n=5 Participants	53.2 Years STANDARD_DEVIATION 10.1 • n=4 Participants
Age, Customized 18 to under 40	11 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	21 Participants n=4 Participants
Age, Customized 40 to under 65	56 Participants n=5 Participants	71 Participants n=7 Participants	67 Participants n=5 Participants	194 Participants n=4 Participants
Age, Customized 65 and over	11 Participants n=5 Participants	12 Participants n=7 Participants	14 Participants n=5 Participants	37 Participants n=4 Participants
Sex/Gender, Customized Male	31 Participants n=5 Participants	38 Participants n=7 Participants	32 Participants n=5 Participants	101 Participants n=4 Participants
Sex/Gender, Customized Female	47 Participants n=5 Participants	49 Participants n=7 Participants	55 Participants n=5 Participants	151 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	66 Participants n=5 Participants	71 Participants n=7 Participants	72 Participants n=5 Participants	209 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black or African American	9 Participants n=5 Participants	15 Participants n=7 Participants	10 Participants n=5 Participants	34 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Race · Multiple Races	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	4 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	11 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Not Hispanic or Latino	74 Participants n=5 Participants	82 Participants n=7 Participants	85 Participants n=5 Participants	241 Participants n=4 Participants
Weight	90.64 kg STANDARD_DEVIATION 24.56 • n=5 Participants	85.45 kg STANDARD_DEVIATION 22.78 • n=7 Participants	89.78 kg STANDARD_DEVIATION 22.61 • n=5 Participants	88.55 kg STANDARD_DEVIATION 23.31 • n=4 Participants
Height	168.05 cm STANDARD_DEVIATION 12.27 • n=5 Participants	170.70 cm STANDARD_DEVIATION 10.17 • n=7 Participants	168.00 cm STANDARD_DEVIATION 10.62 • n=5 Participants	168.95 cm STANDARD_DEVIATION 11.04 • n=4 Participants
Body Mass Index (BMI)	32.17 kg/m^2 STANDARD_DEVIATION 8.57 • n=5 Participants	29.09 kg/m^2 STANDARD_DEVIATION 6.32 • n=7 Participants	31.77 kg/m^2 STANDARD_DEVIATION 7.39 • n=5 Participants	30.97 kg/m^2 STANDARD_DEVIATION 7.54 • n=4 Participants
SBM Frequency Rate	1.05 SBMs per week STANDARD_DEVIATION 0.81 • n=5 Participants	1.01 SBMs per week STANDARD_DEVIATION 0.70 • n=7 Participants	1.14 SBMs per week STANDARD_DEVIATION 0.84 • n=5 Participants	1.07 SBMs per week STANDARD_DEVIATION 0.78 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline (Week 0) to Week 8

Population: 252 participants received at least one dose of study drug, comprising the ITT study population.

Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period.

Outcome measures

Measure	Placebo n=78 Participants 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.	Linaclotide 145 Micrograms n=87 Participants 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.	Linaclotide 290 Micrograms n=87 Participants 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.
Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week)	1.474 Number of SBMs per week Standard Error 0.361	2.799 Number of SBMs per week Standard Error 0.350	3.382 Number of SBMs per week Standard Error 0.353

SECONDARY outcome

Timeframe: Baseline (Day 0) up to 8 weeks

Population: 252 participants received at least one dose of study drug, comprising the ITT study population.

The median time to the first SBM after the first dose of investigational product

Outcome measures

Measure	Placebo n=78 Participants 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.	Linaclotide 145 Micrograms n=87 Participants 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.	Linaclotide 290 Micrograms n=87 Participants 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.
Time to First SBM After the First Dose of Investigational Product	47.1 hours Interval 25.0 to 71.8	26.5 hours Interval 21.8 to 45.0	28.7 hours Interval 23.5 to 47.0

SECONDARY outcome

Timeframe: 8-week treatment period

Population: 252 participants received at least one dose of study drug, comprising the ITT study population.

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.

Outcome measures

Measure	Placebo n=78 Participants 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.	Linaclotide 145 Micrograms n=87 Participants 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.	Linaclotide 290 Micrograms n=87 Participants 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.
Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria	33.3 Percentage of Responders	40.2 Percentage of Responders	47.1 Percentage of Responders

SECONDARY outcome

Timeframe: Baseline (Week 0) to Week 8

Population: Of the 252 participants in the ITT population, 200 participants had Stool Consistency data collected

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)

Outcome measures

Measure	Placebo n=59 Participants 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.	Linaclotide 145 Micrograms n=71 Participants 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.	Linaclotide 290 Micrograms n=70 Participants 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.
Change From Baseline in 8-Week Stool Consistency	0.911 Units on a scale Standard Error 0.172	1.662 Units on a scale Standard Error 0.165	1.898 Units on a scale Standard Error 0.168

SECONDARY outcome

Timeframe: Baseline (Week 0) to Week 8

Population: Of the 252 participants in the ITT population, 200 participants had 8-week straining data collected

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."

Outcome measures

Measure	Placebo n=59 Participants 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.	Linaclotide 145 Micrograms n=71 Participants 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.	Linaclotide 290 Micrograms n=70 Participants 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.
Change From Baseline in 8-Week Straining	-0.753 Units on a scale Standard Error 0.116	-1.212 Units on a scale Standard Error 0.111	-1.422 Units on a scale Standard Error 0.112

SECONDARY outcome

Timeframe: Baseline (Week 0) to Week 8

Population: 252 participants received at least one dose of study drug, comprising the ITT study population.

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.

Outcome measures

Measure	Placebo n=78 Participants 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.	Linaclotide 145 Micrograms n=87 Participants 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.	Linaclotide 290 Micrograms n=87 Participants 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.
Change From Baseline in 8-Week Abdominal Bloating	-0.983 Units on a scale Standard Error 0.164	-0.950 Units on a scale Standard Error 0.160	-1.590 Units on a scale Standard Error 0.160

Adverse Events

Placebo

Serious events: 5 serious events

Other events: 16 other events

Deaths: 1 deaths

Linaclotide 145 Micrograms

Serious events: 0 serious events

Other events: 24 other events

Deaths: 0 deaths

Linaclotide 290 Micrograms

Serious events: 1 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=78 participants at risk 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.	Linaclotide 145 Micrograms n=87 participants at risk 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.	Linaclotide 290 Micrograms n=87 participants at risk 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.
Nervous system disorders Seizure	1.3% 1/78	0.00% 0/87	0.00% 0/87
Injury, poisoning and procedural complications Ankle fracture	1.3% 1/78	0.00% 0/87	0.00% 0/87
Injury, poisoning and procedural complications Fall	1.3% 1/78	0.00% 0/87	0.00% 0/87
Cardiac disorders Transient Ischaemic Attack	0.00% 0/78	0.00% 0/87	1.1% 1/87
Cardiac disorders Cardiac arrest	1.3% 1/78	0.00% 0/87	0.00% 0/87
Renal and urinary disorders Calculus ureteric	1.3% 1/78	0.00% 0/87	0.00% 0/87
Injury, poisoning and procedural complications Periprosthetic fracture	1.3% 1/78	0.00% 0/87	0.00% 0/87

Other adverse events

Measure	Placebo n=78 participants at risk 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.	Linaclotide 145 Micrograms n=87 participants at risk 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.	Linaclotide 290 Micrograms n=87 participants at risk 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.
Gastrointestinal disorders Diarrhoea	16.7% 13/78	27.6% 24/87	36.8% 32/87
Gastrointestinal disorders Nausea	5.1% 4/78	0.00% 0/87	1.1% 1/87

Additional Information

Therapeutic Area Head

Forest Research Institute, Inc., an affiliate of Allergan

Phone: 862-261-7000

Email: IR-CTRegistration@allergan.com

Results disclosure agreements

• Principal investigator is a sponsor employee Publication of the results by the Investigator will be subject to mutual agreement between the Investigator, Forest Research Institute, Inc., an affiliate of Allergan, and Ironwood Pharmaceuticals Inc.
• Publication restrictions are in place

Restriction type: OTHER