Chronic Idiopathic Constipation
Conditions
Keywords
Chronic Idiopathic Constipation, Constipation, Irritable Bowel Syndrome
Brief summary
This is a Phase 2a, randomized, double-blind, placebo-controlled, 14-day repeat oral, dose ranging study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) effects of SP-304 in patients with chronic idiopathic constipation.
Detailed description
This is a Phase 2a, randomized, double-blind, placebo-controlled, 14-day repeat oral, dose ranging study to determine the safety, PK and PD effects of SP-304 in patients with chronic idiopathic constipation. Patients diagnosed with chronic idiopathic constipation (CIC) will be screened for the anticipated 4 cohorts, to yield 80 randomized patients for enrollment. Four dose cohorts are planned (0.3 mg, 1.0 mg, 3.0mg, and 9.0 mg) with 20 patients per dose cohort \[randomization ratio 3:1 (15 receive SP-304:5 receive placebo)\]. Patients who continue to meet all the entry criteria and complete the pre-treatment bowel movement (BM) diary will receive, in a double-blind, randomized fashion, SP-304 or matching placebo. It is expected that each patient will complete all 14 days of dosing (including making accurate BM diary entries for all 14 days in the treatment period). All patients receiving at least one dose of SP-304 or matching placebo will be considered evaluable for the safety endpoints. If a patient receives at least 5 doses per treatment week (1 dose per day for 7 days) and has completed BM diary entries for those 5 dosing days in each corresponding treatment week, he/she will be considered evaluable.
Interventions
DRUGSP-304 0.3 mg
SP-304 0.3 mg
DRUGSP-304 1.0 mg
SP-304 1.0 mg
DRUGSP-304 3.0 mg
SP-304 3.0 mg
DRUGSP-304 9.0 mg
SP-304 9.0 mg
DRUGPlacebo
Placebo
Sponsors
Bausch Health Americas, Inc.
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Subject is able to understand and willing to sign the Informed Consent Form (ICF) and capable of providing written authorization for use and disclosure of protected health information per requirements of 45 CFR 164.508 (Health Insurance Portability and Accountability Act \[HIPAA\]). * Subject is male or non-pregnant, non-breastfeeding female, between 18 and 75 years of age (inclusive) at the time of first dose. * Subject has a body mass index (BMI) between 18 and 35 kg/m2. * Subject meets the Rome III Diagnostic Criteria for constipation (Drossman, 2006) for the past 3 months with symptom onset \> 6 months prior to diagnosis.
Exclusion criteria
* Subject reports loose stool (fluffy pieces with ragged edges, a mushy stool) or watery stool (no solid pieces, entirely liquid; BSFS score of 6 or 7, respectively) in the absence of any laxative, enema, suppository or prohibited medicine for \> 25% of BMs during the 3 months prior to the Screening visit and during the 14 day pre-treatment period. * Subjects who meet the Rome III criteria for IBS. * Subject has failed to complete the pre-treatment bowel movement diary accurately and completely during the pre-treatment period prior to Day 1 dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 21 days: Baseline through Follow-up (Treatment Days 14, 7 days post treatment) | Incidences of adverse events from Baseline through the end of the Follow-up period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM) | Study days 1 through 14 | Using a Daily Diary, patients recorded the number of spontaneous bowel movements having the sensation of complete evacuation (Complete Spontaneous Bowel Movement - CSBM). The total number of spontaneous bowel movements associated with a feeling of complete evacuation were summed and divided by 2 (the number of weeks in treatment). Change was calculated as the difference between the number of the CSBMs at the completion of the 2-week treatment period, versus the 14-day pretreatment baseline. |
| Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM) | Study Days 1 through 14 | Using a Daily Diary, patients recorded the number of spontaneous bowel movements (SBM). The overall weekly frequency was calculated as the total number of SBMs divided by 2 (the number weeks of treatment). Change was calculated as the difference between the number of the SBMs at the completion of the 2-week treatment period, versus the 14-day pretreatment baseline. |
| Changes From Baseline Overall in Bristol Stool Form Scale (BSFS) | Study day 1 through 14 | Using a Daily Diary, patients recorded Stool Consistency using the 7-point Bristol Stool Form Scale (BSFS) (1 = separate hard lumps, like nuts; 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; 6 = fluffy pieces with ragged edges, a mushy stool; 7 = watery, no solid pieces, entirely liquid). Changes in mean BSFS were assessed from the average 14-day pretreatment baseline to the average during the 2-week treatment period. |
| Changes From Baseline Overall in Ease of Passage (Straining) | Study Days 1 through 14 | Using a Daily Diary, patients recorded Ease of Passage (Straining) using the 7-point Ease-of-Passage Scale (1 = manual disimpaction/enema needed, 2 = severe straining, 3 = moderate straining, 4 = mild straining, 5 = no straining, 6 = urgency, 7 = incontinent). Changes in overall ease of passage (Straining) were assessed from the average 14-day pretreatment baseline to average during the 2-week treatment period |
Countries
United States
Participant flow
Recruitment details
This study was conducted between 3 March 2010 and 26 August 2010 at 14 study centers in the United States. Four dose cohorts were planned (0.3 mg, 1.0 mg, 3.0 mg, and 9.0 mg with 20 patients per dose cohort randomized in a 3:1 ratio \[15 pts receive SP-304, 5 pts receive placebo\].
Pre-assignment details
During the pre-treatment period (Study Days -14 though -1), 84 eligible patients completed daily bowel movement diaries to obtain baseline data. Of these, 78 patients (58 and 20 patients for the SP-304 and placebo treatment groups, respectively) received at least one dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| SP-304 1.0 mg Subjects receiving SP-304 1.0 mg for 14 consecutive days | 14 |
| SP-304 3.0 mg Subjects receiving SP-304 3.0 mg for 14 consecutive days | 15 |
| SP-304 9.0 mg Subjects receiving SP-304 9.0 mg for 14 consecutive days | 15 |
| Placebo Subjects receiving Placebo for 14 consecutive days | 20 |
| SP-304 0.3 mg Subjects receiving SP-304 0.3 mg for 14 consecutive days. | 14 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Pretreatment Period | Abnormal Lab values Exl 16 | 0 | 0 | 0 | 1 | 0 |
| Pretreatment Period | Failed Urine drug screen Day 1 | 0 | 1 | 0 | 0 | 0 |
| Pretreatment Period | Venipuncture Failure | 0 | 0 | 1 | 0 | 0 |
| Pretreatment Period | Withdrew Consent (Patient/PI) | 0 | 0 | 0 | 1 | 2 |
| Treatment Period | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 |
| Treatment Period | Noncompliance with protocol | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | SP-304 3.0 mg | SP-304 1.0 mg | SP-304 9.0 mg | Placebo | SP-304 0.3 mg | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 12 Participants | 14 Participants | 17 Participants | 11 Participants | 65 Participants |
| Age, Continuous | 48.5 years STANDARD_DEVIATION 16.17 | 50.5 years STANDARD_DEVIATION 10.6 | 47.3 years STANDARD_DEVIATION 12.71 | 47.7 years STANDARD_DEVIATION 14.64 | 51.1 years STANDARD_DEVIATION 11.95 | 48.9 years STANDARD_DEVIATION 13.24 |
| Complete Spontaneous Bowel Movement Frequency | 0.5 CSBMs per week STANDARD_DEVIATION 0.92 | 0.6 CSBMs per week STANDARD_DEVIATION 0.74 | 0.4 CSBMs per week STANDARD_DEVIATION 0.54 | 0.3 CSBMs per week STANDARD_DEVIATION 0.53 | 0.4 CSBMs per week STANDARD_DEVIATION 0.53 | 0.4 CSBMs per week STANDARD_DEVIATION 0.66 |
| Ease of Passage (Straining) | 2.7 units on a scale STANDARD_DEVIATION 0.61 | 2.8 units on a scale STANDARD_DEVIATION 0.79 | 3.0 units on a scale STANDARD_DEVIATION 0.89 | 3.0 units on a scale STANDARD_DEVIATION 0.67 | 3.1 units on a scale STANDARD_DEVIATION 0.64 | 2.9 units on a scale STANDARD_DEVIATION 0.72 |
| Region of Enrollment United States | 15 participants | 14 participants | 15 participants | 20 participants | 14 participants | 78 participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 12 Participants | 18 Participants | 12 Participants | 69 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 3 Participants | 2 Participants | 2 Participants | 9 Participants |
| Spontaneous Bowel Movement Frequency | 2.1 events per week STANDARD_DEVIATION 0.93 | 2.2 events per week STANDARD_DEVIATION 0.99 | 1.9 events per week STANDARD_DEVIATION 0.75 | 2.0 events per week STANDARD_DEVIATION 1.01 | 2.2 events per week STANDARD_DEVIATION 1.12 | 2.1 events per week STANDARD_DEVIATION 0.95 |
| Stool Consistency (Bristol Stool Form Scale) | 1.8 units on a scale STANDARD_DEVIATION 0.69 | 2.6 units on a scale STANDARD_DEVIATION 0.84 | 2.7 units on a scale STANDARD_DEVIATION 1.56 | 2.6 units on a scale STANDARD_DEVIATION 1.28 | 2.5 units on a scale STANDARD_DEVIATION 0.81 | 2.4 units on a scale STANDARD_DEVIATION 1.13 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 14 | 6 / 14 | 2 / 15 | 6 / 15 | 4 / 20 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 15 | 0 / 15 | 1 / 20 |
Outcome results
Primary
Number of Participants With Adverse Events
Incidences of adverse events from Baseline through the end of the Follow-up period.
Time frame: 21 days: Baseline through Follow-up (Treatment Days 14, 7 days post treatment)
Population: Safety Population: all patients who received at least one dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP-304 0.3 mg | Number of Participants With Adverse Events | 3 Participants |
| SP-304 1.0 mg | Number of Participants With Adverse Events | 6 Participants |
| SP-304 3.0 mg | Number of Participants With Adverse Events | 2 Participants |
| SP-304 9.0 mg | Number of Participants With Adverse Events | 6 Participants |
| Placebo | Number of Participants With Adverse Events | 4 Participants |
Secondary
Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM)
Using a Daily Diary, patients recorded the number of spontaneous bowel movements having the sensation of complete evacuation (Complete Spontaneous Bowel Movement - CSBM). The total number of spontaneous bowel movements associated with a feeling of complete evacuation were summed and divided by 2 (the number of weeks in treatment). Change was calculated as the difference between the number of the CSBMs at the completion of the 2-week treatment period, versus the 14-day pretreatment baseline.
Time frame: Study days 1 through 14
Population: Modified-Intent-to-Treat population: All patients who received at least one dose of study medication and had at least one post-baseline diary assessment. One participant in the SP-304 0.3 mg group did not have information about complete evacuation post-baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SP-304 0.3 mg | Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM) | 1.7 CSBMs per week | Standard Deviation 2.3 |
| SP-304 1.0 mg | Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM) | 3.3 CSBMs per week | Standard Deviation 2.85 |
| SP-304 3.0 mg | Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM) | 1.8 CSBMs per week | Standard Deviation 3.75 |
| SP-304 9.0 mg | Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM) | 2.7 CSBMs per week | Standard Deviation 2.89 |
| Placebo | Change From Baseline Overall in Number of Complete Spontaneous Bowel Movements (CSBM) | 2.0 CSBMs per week | Standard Deviation 3.02 |
Secondary
Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM)
Using a Daily Diary, patients recorded the number of spontaneous bowel movements (SBM). The overall weekly frequency was calculated as the total number of SBMs divided by 2 (the number weeks of treatment). Change was calculated as the difference between the number of the SBMs at the completion of the 2-week treatment period, versus the 14-day pretreatment baseline.
Time frame: Study Days 1 through 14
Population: Modified-Intent-to-Treat population: All patients who received at least one dose of study medication and had at least one post-baseline diary assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SP-304 0.3 mg | Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM) | 2.4 SBMs per week | Standard Deviation 2.21 |
| SP-304 1.0 mg | Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM) | 4.1 SBMs per week | Standard Deviation 4.1 |
| SP-304 3.0 mg | Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM) | 2.4 SBMs per week | Standard Deviation 3.39 |
| SP-304 9.0 mg | Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM) | 4.2 SBMs per week | Standard Deviation 2.88 |
| Placebo | Change From Baseline Overall in Number of Spontaneous Bowel Movements (SBM) | 2.4 SBMs per week | Standard Deviation 2.67 |
Secondary
Changes From Baseline Overall in Bristol Stool Form Scale (BSFS)
Using a Daily Diary, patients recorded Stool Consistency using the 7-point Bristol Stool Form Scale (BSFS) (1 = separate hard lumps, like nuts; 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; 6 = fluffy pieces with ragged edges, a mushy stool; 7 = watery, no solid pieces, entirely liquid). Changes in mean BSFS were assessed from the average 14-day pretreatment baseline to the average during the 2-week treatment period.
Time frame: Study day 1 through 14
Population: Modified-Intent-to-Treat population: All patients who received at least one dose of study medication and had at least one post-baseline diary assessment. One participant in the SP-304 0.3 mg group did not have post-baseline results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SP-304 0.3 mg | Changes From Baseline Overall in Bristol Stool Form Scale (BSFS) | 1.1 units on a scale | Standard Deviation 1.23 |
| SP-304 1.0 mg | Changes From Baseline Overall in Bristol Stool Form Scale (BSFS) | 1.8 units on a scale | Standard Deviation 1.18 |
| SP-304 3.0 mg | Changes From Baseline Overall in Bristol Stool Form Scale (BSFS) | 1.6 units on a scale | Standard Deviation 1.53 |
| SP-304 9.0 mg | Changes From Baseline Overall in Bristol Stool Form Scale (BSFS) | 1.8 units on a scale | Standard Deviation 1.56 |
| Placebo | Changes From Baseline Overall in Bristol Stool Form Scale (BSFS) | 0.9 units on a scale | Standard Deviation 1.23 |
Secondary
Changes From Baseline Overall in Ease of Passage (Straining)
Using a Daily Diary, patients recorded Ease of Passage (Straining) using the 7-point Ease-of-Passage Scale (1 = manual disimpaction/enema needed, 2 = severe straining, 3 = moderate straining, 4 = mild straining, 5 = no straining, 6 = urgency, 7 = incontinent). Changes in overall ease of passage (Straining) were assessed from the average 14-day pretreatment baseline to average during the 2-week treatment period
Time frame: Study Days 1 through 14
Population: Modified-Intent-to-Treat population: All patients who received at least one dose of study medication and had at least one post-baseline diary assessment. One participant in the SP-304 0.3 mg group did not have post-baseline results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SP-304 0.3 mg | Changes From Baseline Overall in Ease of Passage (Straining) | 0.9 units on a scale | Standard Deviation 1.05 |
| SP-304 1.0 mg | Changes From Baseline Overall in Ease of Passage (Straining) | 1.6 units on a scale | Standard Deviation 1.04 |
| SP-304 3.0 mg | Changes From Baseline Overall in Ease of Passage (Straining) | 1.3 units on a scale | Standard Deviation 1.17 |
| SP-304 9.0 mg | Changes From Baseline Overall in Ease of Passage (Straining) | 1.2 units on a scale | Standard Deviation 1.06 |
| Placebo | Changes From Baseline Overall in Ease of Passage (Straining) | 0.5 units on a scale | Standard Deviation 1.12 |