NDMA SUBMITS ATTAPULGITE STUDY PROTOCOL TO FDA, REQUESTS "EXPEDITED REVIEW"

NDMA SUBMITS ATTAPULGITE STUDY PROTOCOL TO FDA, REQUESTS "EXPEDITED REVIEW" of the submission supporting the antidiarrheal clay's classification in Category I (safe and effective) in the antidiarrheal products final monograph. In an Oct. 18 letter to the agency, the Nonprescription Drug Manufacturers Association requested that the agency meet with the NDMA Attapulgite Task Group after reviewing the submission "in order to finalize the protocol so that the clinical study may be initiated at the earliest possible time." The study is designed as a single-center, randomized, double- blind, parallel, and placebo-controlled comparison involving between 200 to 250 subjects suffering from acute, "mild-to- moderate" non-specific diarrhea. It will measure the efficacy of attapulgite liquid 750 mg per tablespoon in contrast with placebo liquid over a two-day dosing regimen. The task group's study responds to an April 9 recommendation of the Nonprescription Drugs and Gastrointestinal Drugs Advisory Committees that efficacy data from attapulgite studies were insufficient to support inclusion in Category I, where the ingredient has been listed since 1986 ("The Tan Sheet," April 12, p. 1). In September, FDA denied a request by NDMA to defer acting on the upcoming antidiarrheal monograph, and indicated to that attapulgite would lose its monograph status ("The Tan Sheet" Oct. 4, p. 1). The study duration spans four days, with a pre-trial assessment including a diagnosis, subject physical examination and medical history, and a post-trial examination and interview. The efficacy endpoints will be measured by comparing responses between the matched placebo and attapulgite groups during the first 24 hours after first dose of study medication, and 25 to 48 hours after first dose. The endpoints specified in the NDMA protocol include: the total number of unformed stools passed; the consistency of unformed stools; the occurrence of such associated symptoms as cramping and nausea; the maximum severity of associated symptoms; and the time until last unformed stool. The subjects in the study will maintain diaries of their experience and "attend required clinic visits . . . and generally communicate intelligently with doctor, nurse, or assistant," NDMA's task group said. They will be asked to record their symptoms on a scale of mild to moderate to severe. Test subjects will be randomized into attapulgite and control groups of no fewer than 100 people each, and allowed to self-medicate for 48 hours following the initial dose. They will be told to ingest two tablespoons of the assigned medication after each bowel movement, not to exceed six doses (12 tablespoons) in 24 hours. Test subjects who do not receive relief from the study medications will be allowed to take Lomotil tablets or other treatment at the discretion of the investigator, NDMA said. However, the "subject must answer all the prior diary questions prior to taking rescue medication," and record "the date and the time when the supplemental medication or other non-study medication is taken." Aside from Lomotil, study subjects will refrain from taking "other antidiarrheals or any other medication which might interfere with the determination of subject status during the study and for eight hours pre-study," the task group said. Potential subjects who have used antibiotics within 72 hours of the study, systemic investigational drugs within 30 days prior to the study, or who are concurrently participating in "another research study involving systemic medication" will be excluded from participation. Enrollment in the study is open to males and females between the ages of 12 and 70. The females must have "no childbearing potential." Study participants must have "diarrhea without blood or mucous, which is defined in this study as the passage of three or more unformed stools per 24 hours," NDMA stated. The exclusion criteria are: pregnancy or breast feeding; severe malnutrition or dehydration; fever greater than 102 degrees Fahrenheit; lower bowel disease histories; symptoms of intestinal obstruction; complicating illnesses or illnesses which might require surgical intervention; evidence of major diseases; presence of certain parasites, bacteria or enteric pathogens in the stools; or "known hypersensitivity (or evidence of intolerance or contraindication) to attapulgite, Lomotil or to [a] particular rescue medication." The study's principal investigator will be Herbert DuPont, MD, who is affiliated with the University of Texas Health Science Center in Houston. The principle monitors named by the NDMA task group will be representatives from antidiarrheal manufacturers Upjohn (Kaopectate) and Wyeth-Ayerst (Donnagel).