Constipation
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to evaluate the efficacy and safety of oral administration of 24 ug of lubiprostone twice daily (BID) for 4 weeks in participants with chronic idiopathic constipation (CIC) compared with placebo.
Detailed description
The drug being tested in this study is called lubiprostone. Lubiprostone is being tested to treat people who have chronic idiopathic constipation. This study will look at the frequency of spontaneous bowel movements (SBMs) in people who take lubiprostone compared to placebo. The study will enroll approximately 211 participants. Participants will be randomly assigned (by chance, like flipping a coin) equally to one of the two treatment groups, which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * Lubiprostone 24 μg * Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient All participants will be asked to take one capsule with breakfast and one capsule with dinner each day throughout the study. All participants will be asked to record each time they have a SBM and all details of each SBM (including the consistency of the stool and the difficulty they have in passing it) in a diary. This multi-center trial will be conducted in Mexico. The overall time to participate in this study is 8 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.
Interventions
DRUGLubiprostone
Lubiprostone capsules
DRUGPlacebo
Lubiprostone placebo-matching capsules
Sponsors
Takeda
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
1. In the opinion of the investigator, is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Has a history of constipation defined as having spontaneous bowel movement (SBM) frequency of less than 3 times per week on average for 6 months or longer and for whom the same SBM frequency is observed during the Screening Period. 4. Has had 1 or more of the symptoms associated with SBM (described below) for 6months or longer at the start of Screening: 1. Scybalum stool or hard feces in at least 1 out of every 4 bowel movements. 2. Sensation of incomplete evacuation in at least 1 out of every 4 bowel movements. 3. Straining in at least 1 out of every 4 bowel movements. 5. Rarely has loose stools without the use of laxatives. 6. Is willing and able to keep a diary on his/her own and willing and able to complete a questionnaire. 7. Is male or female and aged 18 years or older, at the time of signing an informed consent. 8. A female participant of childbearing potential who is sexually active agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and 14 days after the last dose of study drug.
Exclusion criteria
1. Has received any investigational compound within 30 days prior to Screening. 2. Has received lubiprostone in a previous clinical study or as a therapeutic agent. 3. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 4. Has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening. 5. Has a history or clinical manifestations of significant mechanical obstruction (intestinal obstruction due to tumor, hernia etc). 6. Has a history of hypersensitivity or allergies to lubiprostone or any of its excipients. 7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening Visit. 8. Is required to take excluded medications. 9. If female, is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period. 10. Participant whose constipation is considered to be due to drugs or to whom a prohibited concomitant medication has been administered. 11. Is having chronic constipation due to a secondary cause (medications, diabetes mellitus, hypothyroidism, depression, etc.) 12. Has sufficient criteria for irritable bowel syndrome (IBS) or functional defecation disorder. 13. SBM frequency is 3 or more per week. 14. SBM frequency has been less than 3 times per week for less than 6 months in duration or whose symptoms associated with SBM have been present for less than 6 months (hard feces, sensation of incomplete evacuation, or straining). 15. Has received treatment with a rescue medication within 24 hours prior to the first dose on the morning of Day1: bisacodyl suppository, which is a standard laxative, glycerin enema, or any other rescue medication. 16. Has megacolon/megarectum or has received a diagnosis of intestinal pseudo-obstruction. 17. Has confirmed or suspected organic disorders of the large intestine (obstruction, stenosis, carcinoma, or inflammatory bowel disease). Organic disorders of the large intestine can be confirmed or ruled out using the results of enema X-ray examination or total colonoscopy performed in the previous 2 years. If the participant has no history or shows no current evidence of weight loss, anemia, or rectal bleeding, organic disorders may be ruled out based on the results of such testing performed in the past 3 years. Any participant in whom total colonoscopy has detected a polyp requiring treatment is excluded from this study .Note: Participant should not be screened unless at least 7 days have passed since an enema X-ray examination, total colonoscopy or sigmoidoscopy have been performed. 18. Has been hospitalized for gastrointestinal or abdominal surgery within 3 months prior to Screening. 19. Has a significant cardiovascular, liver, lung, kidney, neurological, or mental disease (including existing alcohol or drug abuse problem) or a systemic disease. 20. Has significant clinical findings or in whom a significant abnormality has been found in hematology test, serum chemistry, or urinalysis. 21. Participant in whom noncompliance with the study protocol (administration schedule, visit schedule, diary completion or other study procedure) is expected. 22. Has a history of malignant disease (except basal cell carcinoma) within 5 years prior to Screening. 23. Has any screening abnormal laboratory value that suggests a clinically significant underlying disease or condition that may prevent the participant from entering the study; or the participant has: creatinine \>1.5 mg/dL, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>2 times the upper limit of normal (ULN), or total bilirubin \>2.0 mg/dL with AST/ALT elevated above the limits of normal values. 24. Participant who the investigator/subinvestigator has determined ineligible to participate in this study for any reason other than the above.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Spontaneous Bowel Movement (SBM) Frequency at Week 1 of Administration | Week 1 | A SBM is defined as any bowel movement (BM) that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SBM Frequency at Weeks 2, 3 and 4 | Weeks 2, 3 and 4 | A SBM is defined as any BM that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it. |
| Percentage of Participants Who Have a SBM Within 24 Hours After First Dose of Study Medication | Up to 24 hours after the first dose of study medication | A SBM is defined as any BM that does not occur within 24 hours after rescue medication use. Percentage of participants who have an SBM within 24 hours after the first dose was assessed and derived from the data on SBMs collected in the participant diary. |
| Mean Degree of Straining Score | Weeks 1, 2, 3 and 4 | For each participant, the mean degree of straining was averaged for all SBMs in a given week. The degree of straining for each SBM was collected in the participant diary. The degree of straining was scored on a 5-point scale where: 0=No straining, 1=Mild straining, 2=Moderate straining, 3=Strong straining or 4=Very strong straining with higher scores indicating more severe straining. |
| Mean Degree of Stool Consistency | Weeks 1, 2, 3 and 4 | For each participant, the mean stool consistency score was averaged for all SBMs in a given week. The mean degree of stool consistency for each SBM was collected in the participant diary based on the Bristol Stool Chart. The Bristol Stool Chart is a medical aid designed to classify the form of human feces into seven categories where: 1=Hard and round (difficult-to-pass), 2=Sausage-shaped but hard stool, 3=Sausage-shaped stool with cracks on the surface, 4=Sausage-shaped, soft stool with smooth surface, or coiled stool, 5=Soft, half-solid (and easy-to-pass) stool with clear crease, 6=Unshaped, loose stool with small, irregular-shaped pieces, or mushy stool or 7=Watery stool without solid pieces (entirely liquid). |
| Weekly Abdominal Symptoms Score | Weeks 1, 2, 3 and 4 | Weekly abdominal symptoms of bloating and discomfort upon waking in the morning was scored weekly on a 5-point scale where: 0=None, 1=Mild, 2=Moderate, 3=Severe or 4=Very severe, with a higher score indicating more severe symptoms. Assessment of weekly abdominal symptoms were recorded in the participant in the diary. |
Countries
Mexico
Participant flow
Recruitment details
Participants took part in the study at 10 investigative sites in Mexico from 11 May 2016 to 05 June 2017.
Pre-assignment details
Participants with a diagnosis of chronic idiopathic constipation were enrolled in a 1:1 ratio in one of two treatment groups to receive either lubiprostone 24 µg or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Lubiprostone 24 μg Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks. | 105 |
| Placebo Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks. | 106 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Significant Protocol Deviation | 0 | 2 |
| Overall Study | Voluntary Withdrawal | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Lubiprostone 24 μg | Total |
|---|---|---|---|
| Age, Continuous | 40.8 years | 43.3 years | 42.05 years |
| Body Mass Index (BMI) | 27.333 kg/m^2 STANDARD_DEVIATION 4.383 | 27.638 kg/m^2 STANDARD_DEVIATION 4.695 | 27.485 kg/m^2 STANDARD_DEVIATION 4.5326 |
| Height | 160.7 cm STANDARD_DEVIATION 7.42 | 161.9 cm STANDARD_DEVIATION 8.12 | 161.3 cm STANDARD_DEVIATION 7.78 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 67 Participants | 73 Participants | 140 Participants |
| Race/Ethnicity, Customized Multiracial | 9 Participants | 5 Participants | 14 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 27 Participants | 57 Participants |
| Region of Enrollment Mexico | 106 Participants | 105 Participants | 211 Participants |
| Sex: Female, Male Female | 90 Participants | 82 Participants | 172 Participants |
| Sex: Female, Male Male | 16 Participants | 23 Participants | 39 Participants |
| Smokers Participant had never smoked | 88 Participants | 78 Participants | 166 Participants |
| Smokers Participant was a current smoker | 13 Participants | 23 Participants | 36 Participants |
| Smokers Participant was an ex-smoker | 5 Participants | 4 Participants | 9 Participants |
| Weight | 70.67 kg STANDARD_DEVIATION 12.873 | 72.48 kg STANDARD_DEVIATION 13.916 | 71.57 kg STANDARD_DEVIATION 13.401 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 105 | 0 / 106 |
| other Total, other adverse events | 23 / 105 | 19 / 106 |
| serious Total, serious adverse events | 0 / 105 | 0 / 106 |
Outcome results
Primary
Spontaneous Bowel Movement (SBM) Frequency at Week 1 of Administration
A SBM is defined as any bowel movement (BM) that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it.
Time frame: Week 1
Population: Full Analysis Set (FAS) included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone 24 μg | Spontaneous Bowel Movement (SBM) Frequency at Week 1 of Administration | 6.7 number of SBM per week | Standard Deviation 4.55 |
| Placebo | Spontaneous Bowel Movement (SBM) Frequency at Week 1 of Administration | 5.2 number of SBM per week | Standard Deviation 2.82 |
p-value: 0.0295% CI: [0.1, 1.9]Van Elteren Test
Secondary
Mean Degree of Stool Consistency
For each participant, the mean stool consistency score was averaged for all SBMs in a given week. The mean degree of stool consistency for each SBM was collected in the participant diary based on the Bristol Stool Chart. The Bristol Stool Chart is a medical aid designed to classify the form of human feces into seven categories where: 1=Hard and round (difficult-to-pass), 2=Sausage-shaped but hard stool, 3=Sausage-shaped stool with cracks on the surface, 4=Sausage-shaped, soft stool with smooth surface, or coiled stool, 5=Soft, half-solid (and easy-to-pass) stool with clear crease, 6=Unshaped, loose stool with small, irregular-shaped pieces, or mushy stool or 7=Watery stool without solid pieces (entirely liquid).
Time frame: Weeks 1, 2, 3 and 4
Population: FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lubiprostone 24 μg | Mean Degree of Stool Consistency | Week 1 | 4.1 score on a scale | Standard Deviation 1.3 |
| Lubiprostone 24 μg | Mean Degree of Stool Consistency | Week 2 | 4.1 score on a scale | Standard Deviation 1.13 |
| Lubiprostone 24 μg | Mean Degree of Stool Consistency | Week 3 | 4.1 score on a scale | Standard Deviation 1.12 |
| Lubiprostone 24 μg | Mean Degree of Stool Consistency | Week 4 | 4.1 score on a scale | Standard Deviation 1.19 |
| Placebo | Mean Degree of Stool Consistency | Week 4 | 3.6 score on a scale | Standard Deviation 0.93 |
| Placebo | Mean Degree of Stool Consistency | Week 1 | 3.4 score on a scale | Standard Deviation 1.08 |
| Placebo | Mean Degree of Stool Consistency | Week 3 | 3.5 score on a scale | Standard Deviation 0.93 |
| Placebo | Mean Degree of Stool Consistency | Week 2 | 3.5 score on a scale | Standard Deviation 1.05 |
Comparison: Week 1p-value: <0.00195% CI: [0.4, 1]Van Elteren Test
Comparison: Week 2p-value: <0.00195% CI: [0.4, 0.9]Van Elteren Test
Comparison: Week 3p-value: <0.00195% CI: [0.4, 0.8]Van Elteren Test
Comparison: Week 4p-value: <0.00195% CI: [0.2, 0.7]Van Elteren Test
Secondary
Mean Degree of Straining Score
For each participant, the mean degree of straining was averaged for all SBMs in a given week. The degree of straining for each SBM was collected in the participant diary. The degree of straining was scored on a 5-point scale where: 0=No straining, 1=Mild straining, 2=Moderate straining, 3=Strong straining or 4=Very strong straining with higher scores indicating more severe straining.
Time frame: Weeks 1, 2, 3 and 4
Population: FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lubiprostone 24 μg | Mean Degree of Straining Score | Week 1 | 1.6 score on a scale | Standard Deviation 0.85 |
| Lubiprostone 24 μg | Mean Degree of Straining Score | Week 2 | 1.5 score on a scale | Standard Deviation 0.89 |
| Lubiprostone 24 μg | Mean Degree of Straining Score | Week 3 | 1.3 score on a scale | Standard Deviation 0.82 |
| Lubiprostone 24 μg | Mean Degree of Straining Score | Week 4 | 1.2 score on a scale | Standard Deviation 0.92 |
| Placebo | Mean Degree of Straining Score | Week 4 | 1.5 score on a scale | Standard Deviation 0.86 |
| Placebo | Mean Degree of Straining Score | Week 1 | 2.0 score on a scale | Standard Deviation 0.88 |
| Placebo | Mean Degree of Straining Score | Week 3 | 1.6 score on a scale | Standard Deviation 0.92 |
| Placebo | Mean Degree of Straining Score | Week 2 | 1.8 score on a scale | Standard Deviation 0.93 |
Comparison: Week 1p-value: 0.00195% CI: [-0.6, -0.2]Van Elteren Test
Comparison: Week 2p-value: 0.00495% CI: [-0.5, -0.1]Van Elteren Test
Comparison: Week 3p-value: 0.02495% CI: [-0.4, -0.1]Van Elteren Test
Comparison: Week 4p-value: 0.0195% CI: [-0.5, -0.1]Van Elteren Test
Secondary
Percentage of Participants Who Have a SBM Within 24 Hours After First Dose of Study Medication
A SBM is defined as any BM that does not occur within 24 hours after rescue medication use. Percentage of participants who have an SBM within 24 hours after the first dose was assessed and derived from the data on SBMs collected in the participant diary.
Time frame: Up to 24 hours after the first dose of study medication
Population: FAS included all participants randomized to receive study treatment whether or not they received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lubiprostone 24 μg | Percentage of Participants Who Have a SBM Within 24 Hours After First Dose of Study Medication | 60.0 percentage of participants |
| Placebo | Percentage of Participants Who Have a SBM Within 24 Hours After First Dose of Study Medication | 41.5 percentage of participants |
p-value: 0.00995% CI: [1.19, 3.62]Cochran-Mantel-Haenszel
Secondary
SBM Frequency at Weeks 2, 3 and 4
A SBM is defined as any BM that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it.
Time frame: Weeks 2, 3 and 4
Population: FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lubiprostone 24 μg | SBM Frequency at Weeks 2, 3 and 4 | Week 2 | 6.9 number of SBM per week | Standard Deviation 4.4 |
| Lubiprostone 24 μg | SBM Frequency at Weeks 2, 3 and 4 | Week 3 | 7.6 number of SBM per week | Standard Deviation 4.5 |
| Lubiprostone 24 μg | SBM Frequency at Weeks 2, 3 and 4 | Week 4 | 7.2 number of SBM per week | Standard Deviation 4.21 |
| Placebo | SBM Frequency at Weeks 2, 3 and 4 | Week 2 | 5.5 number of SBM per week | Standard Deviation 2.75 |
| Placebo | SBM Frequency at Weeks 2, 3 and 4 | Week 3 | 6.0 number of SBM per week | Standard Deviation 3.74 |
| Placebo | SBM Frequency at Weeks 2, 3 and 4 | Week 4 | 5.8 number of SBM per week | Standard Deviation 3.39 |
Comparison: Week 2p-value: 0.05195% CI: [0, 1.9]Van Elteren Test
Comparison: Week 3p-value: 0.00395% CI: [1, 2]Van Elteren Test
Comparison: Week 4p-value: 0.00995% CI: [0.1, 1.9]Van Elteren Test
Secondary
Weekly Abdominal Symptoms Score
Weekly abdominal symptoms of bloating and discomfort upon waking in the morning was scored weekly on a 5-point scale where: 0=None, 1=Mild, 2=Moderate, 3=Severe or 4=Very severe, with a higher score indicating more severe symptoms. Assessment of weekly abdominal symptoms were recorded in the participant in the diary.
Time frame: Weeks 1, 2, 3 and 4
Population: FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lubiprostone 24 μg | Weekly Abdominal Symptoms Score | Week 1 | 1.4 score on a scale | Standard Deviation 1.05 |
| Lubiprostone 24 μg | Weekly Abdominal Symptoms Score | Week 2 | 1.2 score on a scale | Standard Deviation 0.93 |
| Lubiprostone 24 μg | Weekly Abdominal Symptoms Score | Week 3 | 1.0 score on a scale | Standard Deviation 1.01 |
| Lubiprostone 24 μg | Weekly Abdominal Symptoms Score | Week 4 | 0.9 score on a scale | Standard Deviation 0.94 |
| Placebo | Weekly Abdominal Symptoms Score | Week 4 | 1.2 score on a scale | Standard Deviation 0.98 |
| Placebo | Weekly Abdominal Symptoms Score | Week 1 | 1.8 score on a scale | Standard Deviation 0.96 |
| Placebo | Weekly Abdominal Symptoms Score | Week 3 | 1.4 score on a scale | Standard Deviation 0.93 |
| Placebo | Weekly Abdominal Symptoms Score | Week 2 | 1.5 score on a scale | Standard Deviation 1.01 |
Comparison: Week 1p-value: 0.0295% CI: [-0.9, -0.1]Van Elteren Test
Comparison: Week 2p-value: 0.072Van Elteren Test
Comparison: Week 3p-value: <0.00195% CI: [-0.9, -0.1]Van Elteren Test
Comparison: Week 4p-value: 0.00495% CI: [-0.9, -0.1]Van Elteren Test