The Canadian Multicentre MAC Treatment Study

Mycobacierium avium complex (MAC) infeclion is a common complication of the advanced stages of human immunodeficiency virus (HIV) infection 
causing both morbidity and premature mortality. While it is acknowledged thal MAC infection requires treatment with a combination of antimycobacterial drugs. the optimal regimen has not been defined. A Canadian Multicentre MAC Treatment Trial was proposed in 1990 and finally implemented in late 1992 via the Canadian HIV Trials Network with the assistance of 6 pharmaceutical companies. The specific drug regimens and study design are outlined and the timetable for analysis and completion are also indicated. 
Collaborative, Canadian, multicentre clinical trials in HIV disease can be successfully implemented.

mortality in AJDS, even adjusting for CD4 lymphocyte count (7,8).There are considerable data from uncontrolled studies showing that antimycobactertal drugs can result in both bactertological improvement (either sterilization or reduction in bactertal load), as well as MAC-related symptoms of fever, night sweats and weight loss (9)(10)(11)(12)(13).In addition.three retrospective case-control studies have demonstrated a survival advantage for MAC-infected AJDS patients who receive antimycobac1.ertaltherapy, compared with MAC-infected AJDS patients who do not receive antimycobactertal therapy (14)(15)(16).
In response to the recognition of the importance of MAC infection in AJDS patients and the recent data suggesting that therapy is beneficial, the United St.ates Public Health Service convened a Task Force on MAC USE Ol~Y • DO OT (17) which recommended that all AJDS patients with disseminated MAC infection be treated with a combination of antimycobacterial drugs.
This article describes the development of the Canadian Multicentre MAC Treatment Study.which started long before the US Public Health Service Task Force on MAC was established.

DEVELOPMENT OF THE STUDY
As a consequence of discussions held by the mycobacterial disease study group at the University of Alberta, a proposal for a prospective, randomized, comparative trial of MAC therapy in AJDS patients was first submitted to the Canadian HIV Trials Network (CTN) for the May 1990 grant competition.The CTN responded that it was very interested in supporting a study in this area, but wished to convene a workshop for the further development of this protocol.The workshop was held in September 1990, and participants included potential investigators, primary care physicians with experience in HIV medicine and representatives from the medical departments of several pharmaceutical companies.A study protocol was further developed and resubmitted to the CTN for the January 1991 competition, and this protocol was subsequently approved by both the Scientific Review Committee and the Steering Committee.
Subsequent to the approval of the protocol, a number of advances in the treatment of MAC infection occurred.First, two comparative studies evaluating the efficacy of rifabutin monotherapy for the prevention of MAC bacteremia were completed and showed clear efficacy of rifabutin for this indication (18).Therefore, there was clear evidence for an in vivo beneficial effect of rifabutin on MAC.Second.the new macrolide, clarithromycin, which was known to possess good in vitro activity against MAC, was shown to possess potent in vivo activity as well (12).Third.the California Collaborative Treatment.Group (CCTG) demonstrated that a four-drug oral regimen consisting of rifampin, ethambutol, clofazimine and ciprofloxacin resulted in both clinical and bacteriological improvement in a substantial proportion of patients (11).As a result, two major review papers on MAC infection, published in 1991, recommended the use of the CCTG regimen (1,2).
A logistical problem that needed to be overcome was the general reluctance of both the Health Protection Branch of Health and Welfare Canada and individual pharmaceutical companies to permit the use of more than one investigational drug in the same research study.
Finally, funding of the study presented significant challenges since, unlike the AJDS Clinical T:tial Group (ACTG) in the United States, which is fully funded by the United States government to conduct AIDS-related clinical trials, the cm is funded only as an infrastructure and is unable to provide complete funding for clinical trials.

22B
Ultimately, the cooperation of six member companies of the Pharmaceutical Manufacturers' Association of Canada was obtained, and these companies provided all six study medications.Pharmacia, the manufacturer of rifabutin, provided a major grant towards the study as well as providing their clinical research associates to help in the monitoring of the study.Abbott Laboratories, the manufacturer of clarithromycin, also provided financial support for the study.A key principle of this study is that it is open to all Canadian centres affiliated with the CTN.

THE FINAL PROTOCOL
The protocol was finalized in September 1992 after a meeting of site investigators.The study design is prospective, randomized, multicentre and comparative.There are two treatment arms, each receiving equal allocation, and the randomization is blocked by centre.Twenty-four centres in 15 cities in nine provinces agreed to participate.
The major inclusion criteria are age 16 years or older, Hrv-seropositivity and MAC bacteremia.Patients are excluded if they have an enrollment Kamofsky score below 20, a serum creatinine level greater than 250 µmol/L, a serum aspartate aminotransferase level greater than five times the upper limit of normal (unless due to MAC infection), have undergone previous treatment for MAC infection or have received drugs with antimycobacterial activity in the four weeks preceding randomization.Pregnant and lactating women are also excluded.
The two drug regimens under study are the CCTG regimen: rifampin 600 mg daily, ethambutol 15 mg/kg daily, clofazimine 100 mg daily, and ciprofloxacin 750 mg bid; and the 'experimental' arm consisting of clarithromycin 1000 mg bid, ethambutol 15 mg/kg daily, and rifabutin 600 mg daily.The study could not be blinded for practical reasons.Although open-label ethambutol could be given, it.would be necessary to provide placebo controls for the five other study drugs in a group of patients with advanced HIV disease who are generally receiving multiple other medications.In addition, the central reference mycobacteriology laboratory staff are blinded to patient assignment and since the primary efficacy parameter is bacteriological (see later), the assessment of the bacteriological response is unlikely to be affected by blinding.
The study consists of an intense phase of 16 weeks duration with the option for life-time continuation of study medications.During the intense phase, patients are assessed at baseline, and at weeks 2, 4, 8. 12 and 16.At each study visit, a medical history is taken, a physical examination is performed and the patient completes the 30 question medical outcome survey adapted for HN (MOS-Hrv); in addition, the investigator calculates the MAC symptom score, which was created expressly for this study.A mycobacterial blood culture is collected and processed centrally and quantitatively by the mycobacteriology section at the Provincial Laboratory of Public Health for Northern Alberta, Edmonton .
After the 16-week inlense phase, patients are followed every four weeks until death.Mycobacterial blood cultures (nonquantitative) are performed in local laboratories and the MAC treatment record is monitored.
The primary analysis will be bacteriological.Specifically, this will involve the comparison of the proportion of patients in each of the two treatment arms who achieve blood culture sterilization, defmed as two consecutive negative blood cultures after a positive baseline blood culture.In addition, the clinical response will be measured in several ways.The principal clinical outcome will be the MOS-HN scale.As well, the MAC symptom score and individual MAC symptoms will be assessed and compared between the two groups.Additional analyses will include survival, tolerance of each of the regimens, tolerance of individual drugs, drug toxicities and in vitro susceptibility studies.The intended sample size is 200 patients, and one interim analysis will be performed.

TI METABLE
The first patient.was enrolled on November 23. 1992.At I.he time of the MAC symposium in September 1993, 102 patients had been randomized in the study.An interim analysis will be done early in 1994 and if the study continues after the interim analysis, I.he final analysis will likely be performed in either late 1994 or early 1995.

ADDENDUM
The interim analysis was reviewed by I.he Safety and Efficacy Review Commit.lee of the Canadian 111v Trials Network in March 1994; I.he committee recommended that this study be continued.As of March 22, 1994, 147 patients had been enrolled.