lticenter 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 - 85 years with 12% at least 65 years of age), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were eva luated 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.
Efficacy of LINZESS was assessed using overall responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.
A CSBM overall 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 5. 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 5.
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 5: Efficacy Responder Rates in the Two Placebo-controlled CIC Trials: at Least 9 Out of 12 Weeks *Primary Endpoint
CI=Confidence Interval
Trial 3 Trial 4
LINZESS
145 mcg
(N=217) Placebo
(N=209) Treatment Difference
[95% CI] LINZESS
145 mcg
(N=213) Placebo
(N=215) Treatment Difference
[95% CI]
CSBM Overall Responder
(≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline) 20.3% 3.3% 16.9%
[11.0%, 22.8%] 15.5% 5.6% 9.9%
[4.2%, 15.7%]
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 me
