Novartis' latest trial for the irritable bowel syndrome agent Zelmac focuses on a 12 mg daily dosing regimen in 1,500 females, with results to be submitted to FDA by the end of the year.

The 6 mg twice-daily dose was chosen because it has been shown to have the most consistent efficacy in past trials, Novartis explained.

Optimal dosing for tegaserod was one of the issues debated at the June 26 FDA advisory committee meeting on the drug, with no consensus reached (¹ Also see "Novartis Zelmac Dosing Instructions Among Remaining Issues In FDA Review" - Pink Sheet, 3 July, 2000.). The daily doses considered were 4 mg, a 4 mg to 12 mg titration regimen, and 12 mg.

The current study will satisfy an Aug. 11 "approvable" letter's request for additional data, Novartis maintained. Recruitment for the study, designed to generate more focused Zelmac data in women, was completed in May.

FDA had expressed concern that the pivotal efficacy trial results presented in support of the drug consisted of pooled data from three separate trials, which over-inflated statistical power for finding a difference from placebo (² Also see "Zelmac Pooled Study Results May Not Be Reflective Of Efficacy - FDA" - Pink Sheet, 26 June, 2000.).

Moreover, FDA had pointed out that two of the original trials were problematic if taken individually - in one, primary endpoints were changed after unblinding; another did not present statistically significant results.

The committee agreed with Novartis' suggestion that the indication be limited to women, since the trial results seemed to demonstrate efficacy only in females.

The newest trial is aimed at supporting an indication for treatment of "abdominal pain/discomfort and constipation in female patients with constipation-predominant IBS," a news release stated. This phrasing follows the description of the indication in the approvable letter, the company said.

The 1,500-women, multi-site trial B358 is the biggest single IBS trial to date, Novartis said, and is designed similarly to previous trials. The trial started with a four-week placebo-free period when patients were observed for symptoms and study eligibility to ensure that only constipation-predominant patients receive treatment.

Advisory committee members had commented that a greater Zelmac treatment benefit could probably be observed in a more homogeneous study population - one that does not include "alternators," or those who "swing" from constipation to diarrhea. The committee had surmised that some alternators participated in the original studies.

After the evaluation period, the current study proceeded to a 12-week randomized, placebo-controlled treatment phase. The primary endpoint is subjects' global assessment of relief, defined as complete or considerable relief at least 50% of the time; or complete, considerable or somewhat relief 100% of the time.

The trial's secondary endpoints use the same SGA of relief definition, but consider each symptom individually. The symptoms being evaluated are abdominal pain/discomfort, bloating, degree of improvement in bowel movements, stool consistency and degree of straining.

A new element being added to the study that has not been included in previous trials, according to Novartis, is a four-week post-treatment patient tracking period, designed to see if symptoms return.

Such follow-up may help resolve the issue of whether longer-term treatment studies - which were recommended by the committee - would be desirable.

Like previous studies, the current study will allow patients to use laxatives as a "rescue" after four days without a bowel movement, with all such use recorded in patient diaries.

FDA had expressed concern about laxative use not being factored into the analyses for the pivotal studies, though Novartis maintained that laxative use between placebo and treatment groups was comparable. The company said that some of the analyses for the new study will take such use into account.

Novartis indicated that it plans to launch Zelmac in the first half of 2001 as originally planned, and is ramping up its sales force accordingly.

Latest Zelmac Trial Focuses On 12 Mg Dose In Women; Drug Is "Approvable"

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