Treatment & diagnosis of Crohn's Disease

Treatment of Crohn's Disease

Diagnosis of MAP infection

Antibiotic Clinical Trial

Vaccine Research

An Interview with TJ Borody

Phase III Clinical Trial of Anti-paratuberculosis Antibiotic Therapy Underway in Australia.

Introduction

A phase III clinical trial of anti-paratuberculosis antibiotic therapy for Crohn's disease is ongoing in Australia. The antibiotic regimen under trial is a combination of Rifabutin (Mycobutin, Pharmacia), Clarithromycin (Biaxin/Klacid/Klaricid, Abbott Laboratories) and Clofazimine (Lamprene, Novartis). The Australian phase III trial involves over 200 patients with Crohn's disease, in all major cities across Australia. The purpose of the trial is to determine if anti-paratuberculosis antibiotic therapy is a more effective treatment for Crohn's disease than standard immunosuppressant therapy. This trial is a continuation of previous phase II trials which showed promising results using this and similar treatment regimes.

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About the trial

COMBINATION ANTI-PARATUBERCULOSIS THERAPY WITH RIFABUTIN, CLARITHROMYCIN AND CLOFAZIMINE IN THE TREATMENT OF ACTIVE CROHN'S DISEASE.

This clinical trial, ongoing at twenty hospitals throughout Australia, will test the theory that long-term combination antibiotic treatment may benefit people with Crohn's disease.

Gastroenterologists have been inviting volunteers with active Crohn's disease to participate in this important Australian-owned clinical trial since it began in September 1999. The 214th and last subject was entered on 21^st September 2001.

Currently, 94 individuals are actively ongoing in the trial, half of whom are taking active antibiotic treatment, and half are taking placebo. 63 participants have been on the study beyond 1 year and 15
individuals have now completed the full 2-year treatment program.

120 participants have withdrawn from the study thus far, the majority (35%) of whom did not meet the remission criteria at the 16 week interval. Some other reasons for withdrawal include side-effects (10%) and relapse/disease progression (29%).

An independent data monitoring committee (IDMC) has reviewed the interim study data on two separate occasions and recommended unanimously the continuation of the study in the current form.

An interim update on the study was presented at Asia Pacific Digestive Week in Sydney, September 2001, and the abstract by Selby, W. et al is published in The Journal of Gastroenterology and Hepatology (2001, 16 (Suppl), A8.

Objectives of the trial

The Primary objective of the trial is

• To determine whether the proportion (%) of patients who have experienced at least one relapse of Crohn's disease at 12, 24 and 36 months is significantly different between those treated with anti-paratuberculosis therapy or placebo for 24 months

The Secondary objectives of the trial are

• To compare the safety of the anti-paratuberculosis antibiotic treatment regime with the safety of placebo treatment.
• To determine if the proportion of patients in remission after 4 months of anti-paratuberculosis antibiotic treatment is significantly different from the proportion of patients in remission after 4 months of placebo treatment.

• To determine if the frequency of relapse is significantly different between patients receiving anti-paratuberculosis antibiotic treatment and patients receiving placebo treatment, after 12, 24 and 36 months.
• To determine if the time to first relapse is significantly different between patients receiving anti-paratuberculosis antibiotic treatment and patients receiving placebo.
• To determine the difference in clinical outcomes (colonoscopic, surgical and immunologic) between patients receiving anti-paratuberculosis antibiotic treatment and patients receiving placebo treatment.
• To compare the effect on patient Quality-of-Life (QOL) of anti-paratuberculosis antibiotic treatment to the effect on QOL of placebo treatment.
• To compare cost-effectiveness of anti-paratuberculosis antibiotic treatment with the cost-effectiveness of placebo treatment. This is discussed further below.

Clinical Trial Design

The design of the Australian phase III clinical trial is as follows

1. Multi-center. The trial will be conducted in at least 20 centers across Australia, with centers in most major cities, including Sydney, Canberra, Melbourne, Hobart, Adelaide, Perth and Brisbane.
2. Controlled. The trial will consist of two arms. Patients in the active arm will be given a combination of Rifabutin, Clarithromycin and Clofazimine, while patients in the placebo arm will be given treatment which is identical to that given to patients in the active arm, with the exception that it will contain no active ingredients. Patients in both arms will also be treated a standard course of acute steroid therapy.
3. Randomized. Patients who take part in the trial will be randomly allocated to the active or placebo arms of the trial. Patients have a 50% chance of being allocated to the active arm and a 50% chance of being allocated to the placebo arm.
4. Prospective. The trial has been designed to explicitly measure the effectiveness of anti-paratuberculosis antibiotic therapy for treating Crohn's disease.
5. Double-blind. Neither patients taking part in the trial nor medical personnel treating the trial patients will be aware into which arm of the trial any given patient has been placed, in order to assure statistical correctness of the results.

Health Economics and Health-related Quality of Life

Crohn's disease is well known to have a significant impact on the quality of life of patients. This can often be exacerbated by the wide range of side-effects of standard treatments for Crohn's disease.

In order to the determine the effect on health and on quality of life of anti-paratuberculosis antibiotic treatment, patients taking part in the trial will fill out two forms every three months. The first form is designed to measure the patients general state of health, and will record information such as the patient's perception of their general state of health, ability to partake in physical activity, social and work activity, etc.

The second form is specific to Inflammatory Bowel Disease, and will record information relating to the effect of bowel problems on emotional state, social activity, sexual activity, lifestyle, etc.

Additionally, a goal of this clinical trial is to determine if anti-paratuberculosis antibiotic therapy is more cost-effective than existing treatments.

Previous Phase II Clinical Trials

The Australian phase III clinical trial is a continuation from  previous phase II trials:

1. A phase II trial conducted in London, England, found that 43 out of 52 patients with severe Crohn's disease experienced remission when treated with a combination of Rifabutin and Clarithromycin, for between 6 and 35 months.
   
   
2. The other phase II trial, conducted in Sydney, Australia, found that 10 of 12 patients with severe Crohn's disease experienced remission when treated with a combination of Rifabutin, Clarithromycin and Clofazimine, for a period of 24 months.  Note:  The full study has been published in 2002 (Digest Liver Dis 2002; 34:29-38).  The paper is entitled "Treatment of Severe Crohn's Disease Using Antimycobacterial Triple Therapy - Approaching a Cure?" 
   
   
3. A trial conducted in Orlando, Florida, treated 29 Crohn's disease patients with a combination of Rifabutin and Clarithromycin. After three months of treatment, the investigators found that 8 of the 29 patients were in clinical remission, 9 of the 29 patients experienced marked improvement, 8 of the 29 patients experienced minor improvement, and 4 of the 29 patients had to be taken off the medication, due to intolerance of side-effects.
   

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