Functional Constipation
Conditions
Keywords
Linaclotide, pediatric functional constipation, Linzess
Brief summary
Functional constipation (FC) is a common healthcare problem in children of all ages, potentially due to genetic predisposition, inadequate fiber and fluid intake, and immobility. Currently, there are no pharmacological therapies approved for the treatment of FC. This study will assess adverse events and change in disease activity with linaclotide therapy in participants with FC. Linaclotide is an approved drug being developed for the treatment of FC in pediatric patients who meet modified Rome IV criteria for childhood FC. In Part 1 of this study, participants are placed in 3 groups, which occur consecutively. Each group receives a different dosage of linaclotide. In Part 2 of the study, participants will be randomly assigned to receive either linaclotide or placebo. There is a 1 in 2 chance that participants will be assigned to placebo. Up to 30 and at least 18 pediatric participants 6 months to less than 2 years of age with FC will be enrolled in the study at approximately 38 sites worldwide. Participants will receive oral solution of linaclotide prepared from capsule by parent/guardian once daily for 4 weeks. There may be higher treatment burden for participants in this trial compared to their standard of care (due to study procedures). Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.
Interventions
DRUGLinaclotide
Capsule; oral
DRUGPlacebo
Capsule; oral
Sponsors
Ironwood Pharmaceuticals, Inc.
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 23 Months
Healthy volunteers
No
Inclusion criteria
* Individuals must be 6 months to less than 1 year and 11 months old, at the time the legally authorized representative (LAR)/parent/guardian signs the informed consent in alignment with local requirements. * The LAR/parent/guardian who will be completing the electronic diary (eDiary) is able to read and understand the assessments in the eDiary device and must undergo training. * Participant meets Rome IV criteria for functional constipation (FC): for at least 1 month before Screening (Visit 1), the participant must meet 2 or more of the following: * 2 or fewer defecations per week (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) * History of excessive stool retention * History of painful or hard bowel movements (BMs) * History of large-diameter stools * Presence of a large fecal mass in the rectum * LAR/Parent/Guardian is willing to discontinue any laxatives used before the Preintervention Visit in favor of the protocol-permitted rescue medicine.
Exclusion criteria
* Participant has conditions that could interfere with drug absorption, including, but not limited to, short bowel syndrome. * History of clinically significant medical conditions or any other reason that the investigator determines would interfere with the individual's participation in this study or would make the participant an unsuitable candidate to receive study drug. * Participant has history of: * Celiac disease, or positive serological test for celiac disease or the condition is suspected but has not been ruled out by endoscopic biopsy * Cystic fibrosis * Hypothyroidism that is untreated or treated with thyroid hormone at a dose that has not been stable for at least 3 months prior to Screening (Visit 1) * Down's syndrome or any other chromosomal disorder * Active anal fissure (investigator has confirmed an active anal fissure and participant reports known anal fissure symptoms \[i.e., streaks of blood on the stool or on diaper or toilet paper and pain/crying with bowel movement within 2 weeks prior to Screening\]). (Note: Anal fissures that have resolved at least 2 weeks prior to screening would not be exclusionary). However, if in the investigator's opinion, an anal fissure(s) may be the primary cause of participant's Rome IV FC criteria, the subject would not be eligible to participate in the study. * Anatomic malformations (e.g., imperforate anus, anal stenosis, anterior displaced anus) * Intestinal nerve or muscle disorders (e.g., Hirschprung disease, visceral myopathies, visceral neuropathies) * Neuropathic conditions (e.g., spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma) * Lead toxicity, hypercalcemia * Inflammatory bowel disease * Lactose intolerance that is associated with symptoms which could confound the assessments in this study * History of cancer. (Note: Participants with a history of cancer are allowed provided that the malignancy has been in a complete remission before enrollment/randomization (Visit 3). A complete remission is defined as the disappearance of all signs of cancer in response to treatment)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | Baseline to Week 4 | An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on the calendar day of the BM or the calendar day before the BM. The caregiver/parent/guardian/legally authorized representative (LAR) will complete the electronic diary (eDiary), providing data for the SBM frequency rate up to the last dose date equivalent to the 4-week SBM frequency rate. |
| Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period | Baseline to Week 4 | The caregiver/parent/guardian/legally authorized representative (LAR) will rate and record in an eDiary the consistency of the stool for each BM using the Bristol Stool Form 7-point scale in which 1=Separate hard lumps, like nuts (hard to pass); 2=Sausage-shaped, but lumpy; 3=Like a sausage but with cracks on its surface; 4=Like a sausage or snake, smooth and soft; 5=Soft blobs with clear cut edges (easy to pass); 6=Fluffy pieces with ragged edges, a mushy stool; and 7=Watery, no solid pieces, entirely liquid. |
| Change From Baseline in Straining During the Study Intervention Period | Baseline to Week 4 | Straining for each LAR/parent/guardian/caregiver-observed BM the child passes was collected daily in the eDiary device, using a 4-point scale (0 = No, not at all; 1 = Yes, a little; 2 = Yes, a lot; 3 = I don't know) based on two questions (did he/she grunt or make a face like he/she was straining). Lower value represents a better outcome and I don't know is considered as a missing response. The subject's average straining score for each caregiver-observed BM was derived based on the average of non-missing responses of the two straining questions. The participant's straining score in the 4-week Study Intervention Period was the average of the non-missing average straining scores from all caregiver-observed SBMs during the 4-week Study Intervention Period. If a subject had no caregiver-observed SBMs at baseline, then the baseline straining score reported by the caregiver was missing and, therefore, that subject was not included in the change from baseline straining analysis. |
| Number of Participants With Adverse Events (AEs) | Up to Week 5 | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. |
Countries
Bulgaria, Croatia, Germany, Hungary, Serbia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open-Label Linaclotide 9 µg (Part 1) Linaclotide capsules, mixed with water (or apple juice or apple sauce) and administered orally, once daily for 4 weeks in Part 1.
Linaclotide: Capsule; oral | 7 |
| Double-Blind Placebo (Part 2) Participants will receive placebo capsules mixed with water (or apple juice or apple sauce) and administered orally in Part 2 for 4 weeks.
Placebo: Capsule; oral | 6 |
| Double-Blind Linaclotide 9 µg (Part 2) Participants will receive Linaclotide capsules mixed with water (or apple juice or apple sauce) and administered orally in Part 2 for 4 weeks.
Linaclotide: Capsule; oral | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Open-Label Linaclotide 9 µg (Part 1) | Double-Blind Placebo (Part 2) | Double-Blind Linaclotide 9 µg (Part 2) | Total |
|---|---|---|---|---|
| Age, Continuous | 17.1 months STANDARD_DEVIATION 5.49 | 15.8 months STANDARD_DEVIATION 5.34 | 18.5 months STANDARD_DEVIATION 4.97 | 17.1 months STANDARD_DEVIATION 5.27 |
| Age, Customized 12 - 24 months | 6 Participants | 5 Participants | 5 Participants | 16 Participants |
| Age, Customized 6 - <12 months | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 5 Participants | 2 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 4 Participants | 2 Participants | 12 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 7 |
| other Total, other adverse events | 1 / 6 | 3 / 6 | 3 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 7 |
Outcome results
Primary
Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period
An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on the calendar day of the BM or the calendar day before the BM. The caregiver/parent/guardian/legally authorized representative (LAR) will complete the electronic diary (eDiary), providing data for the SBM frequency rate up to the last dose date equivalent to the 4-week SBM frequency rate.
Time frame: Baseline to Week 4
Population: The ITT population was used for all efficacy and baseline analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-Label Linaclotide 9 µg (Part 1) | Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | Observed by the LAR/Parent/Guardian/Caregiver | 3.181 SBMs/Week | Standard Deviation 0.9563 |
| Open-Label Linaclotide 9 µg (Part 1) | Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | All Reported by the LAR/Parent/Guardian/Caregiver | 3.371 SBMs/Week | Standard Deviation 0.9858 |
| Double-Blind Placebo (Part 2) | Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | Observed by the LAR/Parent/Guardian/Caregiver | 2.503 SBMs/Week | Standard Deviation 1.3791 |
| Double-Blind Placebo (Part 2) | Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | All Reported by the LAR/Parent/Guardian/Caregiver | 2.577 SBMs/Week | Standard Deviation 1.4293 |
| Double-Blind Linaclotide 9 µg (Part 2) | Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | Observed by the LAR/Parent/Guardian/Caregiver | 0.246 SBMs/Week | Standard Deviation 0.7035 |
| Double-Blind Linaclotide 9 µg (Part 2) | Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period | All Reported by the LAR/Parent/Guardian/Caregiver | 0.895 SBMs/Week | Standard Deviation 1.1475 |
Primary
Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period
The caregiver/parent/guardian/legally authorized representative (LAR) will rate and record in an eDiary the consistency of the stool for each BM using the Bristol Stool Form 7-point scale in which 1=Separate hard lumps, like nuts (hard to pass); 2=Sausage-shaped, but lumpy; 3=Like a sausage but with cracks on its surface; 4=Like a sausage or snake, smooth and soft; 5=Soft blobs with clear cut edges (easy to pass); 6=Fluffy pieces with ragged edges, a mushy stool; and 7=Watery, no solid pieces, entirely liquid.
Time frame: Baseline to Week 4
Population: The ITT population was used for all efficacy and baseline analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open-Label Linaclotide 9 µg (Part 1) | Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period | 0.845 units on a scale | Standard Deviation 2.1137 |
| Double-Blind Placebo (Part 2) | Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period | 1.062 units on a scale | Standard Deviation 0.8043 |
| Double-Blind Linaclotide 9 µg (Part 2) | Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period | 1.201 units on a scale | Standard Deviation 1.0192 |
Primary
Change From Baseline in Straining During the Study Intervention Period
Straining for each LAR/parent/guardian/caregiver-observed BM the child passes was collected daily in the eDiary device, using a 4-point scale (0 = No, not at all; 1 = Yes, a little; 2 = Yes, a lot; 3 = I don't know) based on two questions (did he/she grunt or make a face like he/she was straining). Lower value represents a better outcome and I don't know is considered as a missing response. The subject's average straining score for each caregiver-observed BM was derived based on the average of non-missing responses of the two straining questions. The participant's straining score in the 4-week Study Intervention Period was the average of the non-missing average straining scores from all caregiver-observed SBMs during the 4-week Study Intervention Period. If a subject had no caregiver-observed SBMs at baseline, then the baseline straining score reported by the caregiver was missing and, therefore, that subject was not included in the change from baseline straining analysis.
Time frame: Baseline to Week 4
Population: The ITT population was used for all efficacy and baseline analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open-Label Linaclotide 9 µg (Part 1) | Change From Baseline in Straining During the Study Intervention Period | -1.087 score on a scale | Standard Deviation 0.6511 |
| Double-Blind Placebo (Part 2) | Change From Baseline in Straining During the Study Intervention Period | -0.821 score on a scale | Standard Deviation 0.9659 |
| Double-Blind Linaclotide 9 µg (Part 2) | Change From Baseline in Straining During the Study Intervention Period | -0.561 score on a scale | Standard Deviation 0.3779 |
Primary
Number of Participants With Adverse Events (AEs)
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study.
Time frame: Up to Week 5
Population: The SA analysis population was used for safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-Label Linaclotide 9 µg (Part 1) | Number of Participants With Adverse Events (AEs) | 3 participants |
| Double-Blind Placebo (Part 2) | Number of Participants With Adverse Events (AEs) | 1 participants |
| Double-Blind Linaclotide 9 µg (Part 2) | Number of Participants With Adverse Events (AEs) | 3 participants |