A Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 6-17 Years Who Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC)

SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. SBM rate was defined as SBMs/week during the 4-week Treatment period. Participants recorded the occurrence of BMs and use of rescue medication, morning and evening, daily in an eDiary since pretreatment period. The SBM frequency rate (SBMs/week) during the analysis period for each participant were calculated as \[(total number of SBMs in the analysis period/number of days in the analysis period)\*7\]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at baseline. A positive change from Baseline indicates improvement. Least squares mean (LSM) and standard error (SE) were calculated using analysis of covariance (ANCOVA) method.

Time frame: Baseline (14-day prior to randomization and up to randomization) to Week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Participants recorded their assessment of abdominal bloating in the evening eDiary. Participants answered the question: How big and full did your tummy feel? on a scale, where: 0=none, 1=a tiny bit, 2=a little, 3=medium or 4=very, with a higher score indicating more severe bloating. Baseline value was the average of values collected 14 days before randomization. The 4-week daytime abdominal bloating symptoms were calculated as the average of non-missing scores reported in the evening eDiary during the treatment period. Change from Baseline was calculated as the 4-week daytime abdominal bloating score during the treatment period - daytime abdominal bloating score at baseline. A negative change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.

Time frame: Baseline (14-day prior to randomization) to Week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

The abdominal pain score was measured using 5-point scale. Participants answered the questions, How much did your tummy hurt as: 0=none, 1=a tiny bit, 2=a little, 3=some, and 4=a lot. The 4-week daytime abdominal pain was calculated as the average of nonmissing scores in evening eDiary during the Treatment Period with higher value indicating greater symptom severity. Baseline value was the average of non-missing values collected 14 days before randomization. Change from Baseline was calculated as the daytime abdominal pain score during the 4-week treatment period (i.e. average of non-missing daytime scores during 4-week treatment period) - daytime abdominal pain score at baseline. A negative change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.

Time frame: Baseline (14-day prior to randomization) to Week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Severity of straining was scored on 5-point scale for question-When you pooped, how hard did you push? The score ranges from 0= not hard at all,1= I pushed a tiny bit hard,2= I pushed a little hard,3= I pushed hard,4= I pushed very hard with higher scores indicating more severe straining. Participants recorded degree of straining for each BM in morning and evening eDiary. Data was derived as adult derivation and weighted average. Scores during 4-week treatment period were calculated following two approaches - (1) following derivation similar in earlier adult studies, as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period (adult derivation) and (2) as observed weighted average of daily straining scores during that period. Daily straining score was the average of non-missing morning and/or evening assessments of straining score from the SBMs reported by the participants on that specific day. LSM and SE were calculated using ANCOVA method.

Time frame: Baseline (14-day prior to randomization and up to randomization) to Week 4

Population: ITT population-participants who had at least 1 postbaseline entry on BM characteristic that determined occurrences of SBMs (BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was exploratory arm group. Observed-cases approach used. Overall number of participants analyzed = who had data at Baseline and post-baseline.

SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. A CSBM was an SBM that was associated with a sense of complete evacuation. Participants recorded their assessment of the sensation of incomplete evacuation for each BM in the morning and evening eDiary. The 4-week overall CSBM frequency rate was calculated as \[total number of CSBMs in the analysis period/number of days in the analysis period\]\*7). Baseline value was based on values collected 14 days before randomization and up to randomization. Change from Baseline was calculated as the CSBM frequency rate during the 4-week treatment period - CSBM frequency rate at baseline. A positive change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.

Time frame: Baseline (14-day prior to randomization and up to randomization) to Week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Participants used 7-point pediatric Bristol Stool Form (p-BSFS) scale to rate stool consistency for each BM in morning and evening eDiary where 1=small hard lumps or balls like pebbles,2=fat sausage shape but lumpy and hard,3=a sausage but with cracks on it,4=sausage or snake, smooth and soft,5=chicken nuggets, soft smooth blobs,6=oatmeal, fluffy mushy pieces,7=milkshake, watery. Scores in 4-week treatment period were calculated by 2 approaches-1) following derivation similar in earlier adult studies, mean of participants non-missing, SBM associated p-BSFS scores during 4-week treatment period (adult derivation),2) observed weighted average of daily p-BSFS scores during that period. Daily p-BSFS score was average of non-missing morning and/or evening assessments of p-BSFS score from SBMs reported by participants on that specific day. Baseline value was based on values collected 14 days before randomization up to randomization. LSM and SE were calculated using ANCOVA method.

Time frame: Baseline (14-day prior to randomization and up to randomization) to Week 4

Population: ITT population-participants who had at least 1 postbaseline entry on BM characteristic that determined occurrences of SBMs (BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was exploratory arm group. Observed-cases approach used. Overall number of participants analyzed = who had data at Baseline and post-baseline.

Participants recorded the presence of incontinence episodes in daytime daily since pre-treatment period (14-day prior to randomization) in the evening eDiary for participants randomized following protocol amendment #3. The 4-week daytime fecal incontinence was calculated as the mean of non-missing participant scores reported in the evening eDiary during the Treatment Period. Baseline value was the average of values collected 14 days before randomization. Change from Baseline was calculated as the 4-week fecal incontinence daytime symptoms during the treatment period - fecal incontinence daytime symptoms at baseline. A negative change from Baseline indicates improvement. No data is reported for LIN 145 μg as it was an exploratory arm group.

Time frame: Baseline (14-day prior to randomization) to Week 4

Population: Participants from ITT population included all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use) who were randomized following the implementation of fecal incontinence assessment in the protocol (amendment #3).