Linzess (Page 4 of 6)

14.2 Chronic Idiopathic Constipation (CIC) in Adults

The efficacy of LINZESS for the treatment of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 [overall mean age of 48 years (range 18 to 85 years), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy. All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months:

  • Straining during greater than 25% of bowel movements
  • Lumpy or hard stools during greater than 25% of bowel movements
  • Sensation of incomplete evacuation during greater than 25% of bowel movements

Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.

The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation.

The efficacy of LINZESS was assessed using a responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.

A CSBM responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. The CSBM responder rates are shown in Table 6. During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose. Therefore, the 145 mcg dose is the recommended dose. Only the data for the approved 145 mcg dose of LINZESS are presented in Table 6.

In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo.

Table 6: Efficacy Responder Rates in Two Placebo-Controlled Trials of Adults with CIC (Trials 3 and 4): At Least 9 Out of 12 Weeks
Trial 3 Trial 4
LINZESS 145 mcg Once Daily (N=217) Placebo (N=209) Treatment Difference [95% CI] LINZESS 145 mcg Once Daily (N=213) Placebo (N=215) Treatment Difference [95% CI]
CSBM Responder* (≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline) 20% 3% 17%[11.0%, 22.8%] 15% 6% 10%[4.2%, 15.7%]
*Primary Endpoint CI=Confidence Interval

CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs.

On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).

In each trial, in addition to improvements in CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in each of the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the BSFS], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool].

During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period. In LINZESS-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period.

A 72 mcg dose of LINZESS was established in a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients (Trial 5). A total of 1223 patients [overall mean age of 46 years (range 18 to 90 years), 77% female, 71% white, 24% black, 43% Hispanic] received treatment with LINZESS 72 mcg or placebo once daily and were evaluated for efficacy. All patients met modified Rome III criteria for functional constipation. Trial 5 was identical to Trials 3 and 4 through the first 12 weeks. The efficacy of the 72 mcg dose was assessed using a responder analysis where a CSBM responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period, which was the same as the one defined in Trials 3 and 4. The response rates for the CSBM responder endpoint were 13% for LINZESS 72 mcg and 5% for placebo. The difference between LINZESS 72 mcg and placebo was 9% (95% CI: 4.8%, 12.5%).

A separate analysis was performed using an alternate CSBM responder definition. In this analysis a CSBM responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period and at least 3 of the last 4 weeks of the treatment period. The response rates for the alternate CSBM responder endpoint were 12% for LINZESS 72 mcg and 5% for placebo. The difference between LINZESS 72 mcg and placebo was 8% (95% CI: 3.9%, 11.5%).

14. 3 Functional Constipation (FC) in Pediatric Patients 6 to 17 Years of Age

The efficacy of LINZESS for the treatment of FC in pediatric patients 6 to 17 years of age was established in a 12-week double-blind, placebo-controlled, randomized, multicenter, clinical trial (Trial 7; NCT04026113). A total of 328 patients received treatment with LINZESS 72 mcg or placebo once daily and were evaluated for efficacy. Patients in the trial had a mean age of 11 years (range 6 to 17 years); 55% were female; 45% identified as Hispanic or Latino; 70% identified as White, 26% as Black or African American, 2% as Asian, and 2% identified as another racial group. For trial enrollment, Rome III criteria for child/adolescent FC were modified to require that patients have less than 3 Spontaneous Bowel Movements (SBMs) per week (defined as a BM that occurred in the absence of laxative, enema, or suppository use on the calendar day of or before the BM) and 1 or more of the following criteria at least once per week for at least 2 months before the screening visit:

  • History of stool withholding or excessive voluntary stool retention
  • History of painful or hard bowel movements (BMs)
  • History of large diameter stools that may obstruct the toilet
  • Presence of a large fecal mass in the rectum
  • At least 1 episode of fecal incontinence per week

Patients were also required to have an average of less than 3 SBMs per week during the 2-week baseline period. Patients were excluded if they met criteria for pediatric IBS-C or had fecal impaction. Patients were allowed to continue previously stable doses of bulk laxatives, fiber, stool softeners, or probiotics. During the trial, patients could use bisacodyl or senna as needed, but were not allowed to take other laxatives, bismuth, prokinetic agents, or other drugs to treat functional constipation.

The efficacy of LINZESS in the treatment of FC in pediatric patients 6 to 17 years of age was assessed using change-from-baseline endpoints. The primary efficacy endpoint was the 12-week change from baseline in SBM frequency rate. The results demonstrated that patients who received LINZESS had statistically significant improvements compared with placebo as shown in Table 7.

Table 7: Efficacy Endpoint in Placebo-Controlled Trial of Pediatric Patients 6 to 17 Years of Age with FC (Trial 7): 12-week Change from Baseline in SBM Frequency Rate (SBMs/week)
Trial 7
LINZESS 72 mcg Once Daily (N=164) Placebo (N=164) Treatment Difference [95% CI]
Baseline SBM Frequency Rate 1.2 1.3
Least Squares 12-week Mean Change from Baseline in SBM Frequency Rate* 2.6 1.3 1.3 [0.7, 1.8]
* Primary EndpointCI = Confidence Interval

SBM frequency improved during week 1 and was maintained throughout the remainder of the 12-week treatment period.

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