Regulatory Decision Summary for Trulance

The purpose of this Supplement to a New Drug Submission (SNDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drug Regulations, for Trulance filed by Bausch Health Canada Inc. This submission was filed for Trulance (plecanatide), 3 mg, tablet, oral route of administration, for the treatment of chronic idiopathic constipation in adults. Upon review of the submitted data package, Health Canada authorized Trulance as filed for the treatment of chronic idiopathic constipation in adults, 3 mg, tablet, oral route of administration, as applicable.

The proposed indication was supported by two identically designed, double-blind, randomized, placebo-controlled multi-center Phase 3 studies, SP304203-00 and SP304203-03. In these studies, 2,880 adults aged ≥ 18 and ≤ 80 with a confirmed diagnosis of chronic idiopathic constipation (CIC) based on the modified Rome III criteria for CIC were administered once daily either Trulance 3 mg, Trulance 6 mg, or placebo for 12 weeks in a 1:1:1 ratio. The modified Rome III criteria define CIC in adults as experiencing less than 3 bowel movements per week, loose stools absent without the use of laxatives and at least two of the following: straining during at least 25% of defecations, lumpy or hard stool in at least 25% of defecations, sensation of incomplete evacuation for at least 25% of defecations or sensation of anorectal obstruction/blockage for at least 25% of defecations. Additionally, patients should not meet the criteria for irritable bowel syndrome with constipation nor require manual maneuvers to facilitate defecation. Patients had to demonstrate compliance with reporting daily bowel movements and symptoms using the electronic hand-held device. The recommended dose of Trulance is 3 mg daily; therefore, the results for this dose are presented below.

The primary endpoint investigated was the proportion of patients who were overall complete spontaneous bowel movement (CSBM) responders after the 12-week treatment period. A CSBM weekly responder was defined as a patient who has ≥ 3 bowel movements (BMs) per week and increase from baseline of ≥ 1 for that week. An overall responder was defined as a patient who is a weekly responder for at least 9 of the 12 treatment weeks, including at least 3 of the last 4 weeks. Key secondary efficacy endpoints included change from baseline in frequency rate of CSBM and spontaneous bowel movement (SBM) over the 12-week treatment period, change from baseline in stool consistency based on Bristol stool form scale (BSFS), change from baseline in straining score, time to first CSBM and SBM, and treatment satisfaction. The timepoint of 12 weeks is considered adequate for the assessment of treatment efficacy.

The primary endpoint in the Phase 3 studies was met. A statistically significantly higher proportion of patients in the Trulance 3 mg group were overall CSBM responders at Week 12 compared to placebo-control. In study SP304203-00, in the Trulance 3 mg treatment group 95/453 (21%) were overall responders, respectively, compared to 46/452 (10.2%) in the placebo-control. This led to a treatment difference of 10.8% for Trulance 3 mg compared to placebo-control. In study SP304203-03, in the Trulance 3 mg treatment group 89/443 (20.1%) were overall responders compared to 57/445 (12.8%) in the placebo-control. This led to a treatment difference of 7.3% for Trulance 3 mg compared to placebo-control. Trulance 3 mg was numerically and statistically superior to placebo-control for all key secondary endpoints, which were multiplicity controlled. This included increased CSBMs/week over the 12 week treatment period, increased SBMs/week over the 12 week treatment period, improved stool consistency and stool score, improved straining score, faster onset of CSBM and SBM, and higher percentage of patients with a CSBM and SBM within the first 24 hours. Results from sensitivity studies demonstrated consistent results.

In the placebo-controlled CIC clinical trials, including both Phase 3 studies and a Phase 2b study, the most common reported treatment emergent adverse events (TEAEs) that were more frequent with Trulance 3 mg compared to placebo-control were diarrhea (5.6%), abdominal distension (2.1%), flatulence (2.1%), headache (2.1%), upper respiratory tract infection (1.9%), and urinary tract infection (1.9%). Diarrhea more frequently led to study drug discontinuation in Trulance 3 mg compared to placebo-control. All other TEAEs that led to study drug discontinuation were similar between placebo-control and Trulance treatment groups. The safety data from the open-label extension study was consistent with the safety data from placebo-controlled studies in patients with CIC. Overall, no new safety issues were identified. The available data support the use of Trulance 3 mg as a treatment for CIC in adult patients. The final labelling and Product Monograph were considered acceptable.

An updated Risk Management Plan for Trulance was submitted, and after review by Health Canada, considered acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the RMP, with routine pharmacovigilance activities.

Overall, the benefit-harm-uncertainty profile was favourable for Trulance 3 mg for the treatment of CIC in adult patients when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Trulance. please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.