Functional Constipation, Irritable Bowel Syndrome With Constipation
Conditions
Brief summary
LIN-MD-66 is a Phase 3 open-label study with 24 weeks (Functional Constipation participants) or 52 weeks (Irritable bowel syndrome with constipation participants) of linaclotide exposure that will enroll pediatric participants (6-17 years of age) with FC or IBS-C who completed study intervention in studies LIN-MD-62, LIN-MD-63, or LIN-MD-64 based on the individual study criteria.
Interventions
DRUGIrritable Bowel Syndrome with Constipation (IBS-C) participants (LIN-MD-63 and LIN-MD-64 completers)
Participants who completed study LIN-MD-63 at their time of enrollment will be assigned a dose of 290 μg. Participants who received ≤ 145 μg linaclotide or placebo in study LIN-MD-63 at the time of completion will continue to receive 145 μg. Participants who completed study LIN-MD-64 at their time of enrollment will be assigned a dose of 290 μg if they choose to receive open-label or continue to receive blinded dose of 145 or 290 μg if they choose to remain on the same blinded dose.
DRUGFunctional Constipation (FC) participants (LIN-MD-62 and LIN-MD-64 completers)
Participants whom are between the ages of 6-11 years old at their time of enrollment will be assigned a dose of 72 μg. Participants whom are between the ages of 12-17 years old at their time of enrollment will be randomized at 1:1 ratio to 72 or 145 μg linaclotide.
Sponsors
Ironwood Pharmaceuticals, Inc.
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Participant weighs ≥ 18 kg at the time the parent/guardian/LAR and/or caregiver has provided signed consent. * Female participants who have had their first menstrual period and are sexually active must agree to use a reliable form of contraception. * Participants must have completed study intervention in their lead-in study. Inclusion Criteria for Phase 2 LIN-MD-62 or Phase 2 LIN-MD-63 and Phase 3 LIN-MD-64 completers who enroll in LIN-MD-66 after \>28 days from last study intervention: \- Female participants of childbearing potential must have a negative serum pregnancy test at the Screening Visit (Visit 1) and negative urine pregnancy test prior to the first dose on the Day 1 Visit (Visit 2).
Exclusion criteria
* Participant has a known allergy or sensitivity to the study intervention or its components or other medications in the same drug class. * Participant received an investigational drug, other than linaclotide, during the 30 days before the Screening Visit (Visit 1) or is planning to receive an investigational drug (other than that administered during this study) or use an investigational device at any time during the study. * Female participants who are currently pregnant or nursing, or plan to become pregnant or nurse during the clinical study. * Participant has required manual disimpaction any time prior to study intervention or disimpaction during in-patient hospitalization within 1 year prior to study intervention. * Participant has any of the following conditions: * a) Down's syndrome or any other chromosomal disorder * b) Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced anus) * c) Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral myopathies, visceral neuropathies) * d) Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma) * e) Neurodevelopmental disabilities (early-onset, chronic disorders that share the essential feature of a predominant disturbance in the acquisition of cognitive, motor, language, or social skills, which has a significant and continuing impact on the developmental progress of an individual) producing a cognitive delay that precludes comprehension by the participant. * Participant has a mechanical bowel obstruction or pseudo-obstruction. * Participant currently has both unexplained and clinically significant alarm symptoms (lower GI bleeding \[rectal bleeding or heme-positive stool\], iron-deficiency anemia, or any unexplained anemia, or weight loss) and systemic signs of infection or colitis, or any neoplastic process. * Participant has an active anal fissure (Note: history of anal fissure is not an exclusion). * Participant has had surgery that meets any of the following criteria: * a) Bariatric surgery for treatment of obesity, or surgery to remove a segment of the GI tract at any time before the Screening Visit (Visit 1). * b) Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before the Screening Visit (Visit 1) * c) An appendectomy or cholecystectomy during the 60 days before the Screening Visit * d) Other major surgery during the 30 days before the Screening Visit (Visit 1) * Participant is receiving enteral tube feeding * Participants who have positive urine drug screen results for cocaine, barbiturates, opiates, or cannabinoids will be excluded from study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | From first dose of study drug until 30 days following last dose of study drug [up to 24 weeks (FC participants) or 52 weeks (IBS-C participants)]. | 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 drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug. |
Countries
Canada, Israel, Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FC 72 ug Linaclotide Functional Constipation (FC) participants who completed lead-in studies LIN-MD-62 or LIN-MD-64 were dosed as follows in this study:
Participants aged 6 to 11 years received an open-label dose of linaclotide 72 ug, oral capsule, once daily for 24 weeks.
Participants aged 12 to 17 years were randomized to receive an open-label dose of linaclotide either 72 or 145 ug, oral capsule, once daily for 24 weeks. | 210 |
| FC 145 ug Linaclotide Functional Constipation (FC) participants who completed lead-in studies LIN-MD-62 or LIN-MD-64 were dosed as follows in this study:
Participants aged 12 to 17 years were randomized to receive an open-label dose of linaclotide either 72 or 145 ug, oral capsule, once daily for 24 weeks. | 73 |
| IBS-C 145 ug Linaclotide Irritable Bowel Syndrome with Constipation (IBS-C) participants were dosed as follows:
Participants who received ≤ 145 ug linaclotide or placebo in lead-in study LIN-MD-63, in this study received an open-label dose of linaclotide 145 ug, oral capsule, once daily for 52 weeks.
Participants who completed lead-in study LIN-MD-64, in this study had the option to either remain on the same blinded linaclotide dose they were receiving in lead-in study LIN-MD-64 (145 or 290 ug) or received an open-label dose of linaclotide 290 ug, oral capsule, once daily for 52 weeks. | 22 |
| IBS-C 290 ug Linaclotide Irritable Bowel Syndrome with Constipation (IBS-C) participants were dosed as follows:
Participants who completed lead-in study LIN-MD-63, in this study received an open-label dose of linaclotide 290 ug, oral capsule, once daily for 52 weeks.
Participants who completed lead-in study LIN-MD-64, in this study had the option to either remain on the same blinded linaclotide dose they were receiving in lead-in study LIN-MD-64 (145 or 290 ug) or received an open-label dose of linaclotide 290 ug, oral capsule, once daily for 52 weeks. | 76 |
| Total | 381 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 9 | 2 | 1 | 1 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 0 | 2 |
| Overall Study | Other | 1 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 | 0 | 2 |
| Overall Study | Pregnancy | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 1 | 10 |
Baseline characteristics
| Characteristic | FC 72 ug Linaclotide | FC 145 ug Linaclotide | IBS-C 145 ug Linaclotide | IBS-C 290 ug Linaclotide | Total |
|---|---|---|---|---|---|
| Age, Continuous | 10.6 years STANDARD_DEVIATION 2.96 | 14.2 years STANDARD_DEVIATION 1.78 | 13.7 years STANDARD_DEVIATION 2.68 | 12.9 years STANDARD_DEVIATION 2.98 | 11.89 years STANDARD_DEVIATION 3.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 92 Participants | 37 Participants | 8 Participants | 29 Participants | 166 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 118 Participants | 36 Participants | 14 Participants | 47 Participants | 215 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 0 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 59 Participants | 17 Participants | 3 Participants | 19 Participants | 98 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 142 Participants | 52 Participants | 18 Participants | 52 Participants | 264 Participants |
| Sex: Female, Male Female | 115 Participants | 40 Participants | 15 Participants | 45 Participants | 215 Participants |
| Sex: Female, Male Male | 95 Participants | 33 Participants | 7 Participants | 31 Participants | 166 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 210 | 0 / 73 | 0 / 22 | 0 / 76 |
| other Total, other adverse events | 14 / 210 | 5 / 73 | 0 / 22 | 11 / 76 |
| serious Total, serious adverse events | 2 / 210 | 0 / 73 | 0 / 22 | 2 / 76 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs).
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 drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
Time frame: From first dose of study drug until 30 days following last dose of study drug [up to 24 weeks (FC participants) or 52 weeks (IBS-C participants)].
Population: Safety Population: all participants who received at least 1 dose of study intervention (linaclotide) in this extension study. Number analyzed are participants with data available for analyses of the specific category.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FC 72 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TEAE | 37 Participants |
| FC 72 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TESAE | 2 Participants |
| FC 145 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TESAE | 0 Participants |
| FC 145 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TEAE | 15 Participants |
| IBS-C 145 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TEAE | 4 Participants |
| IBS-C 145 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TESAE | 0 Participants |
| IBS-C 290 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TEAE | 31 Participants |
| IBS-C 290 ug Linaclotide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | TESAE | 2 Participants |