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TB Notes 1, 2000
Introduction
Where We've Been and Where We're Going: Perspectives from CDC's Partners in TB Control
Changes I've Seen
TB Control in New York City: A Recent History
Not by DOT Alone
Baltimore at the New Millennium
From Crickets to Condoms and Beyond
The Denver TB Program: Opportunity, Creativity, Persistence, and Luck
National Jewish: The 100-Year War Against TB
Earthquakes, Population Growth, and TB in Los Angeles County
TB in Alaska
CDC and the American Lung Association/ American Thoracic Society: an Enduring Public/Private Partnership
The Unusual Suspects
The Model TB Prevention and Control Centers: History and Purpose
My Perspective on TB Control over the Past Two to Three Decades
History of the IUATLD
Thoughts about the Future of TB Control in the United States
Where We've Been and Where We're Going: Perspectives from CDC
Early History of the CDC TB Division, 1944-1985
CDC Funding for TB Prevention and Control
Managed Care and TB Control - A New Era
Early Research Activities of the TB Control Division
The First TB Drug Clinical Trials
Current TB Drug Trials: The Tuberculosis Trials Consortium (TBTC)
TB Communications and Education
TB Control in the Information Age
Field Services Activities
TB's Public Health Heroes
Infection Control Issues
A Decade of Notable TB Outbreaks: A Selected Review
International Activities
The Role of CDC's Division of Quarantine in the Fight Against TB in the U.S.
The STOP TB Initiative, A Global Partnership
Seize the Moment - Personal Reflections
 
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This is an archived document. The links are no longer being updated.

TB Notes 1, 2000

The First TB Drug Clinical Trials

by Rick O'Brien, MD
Chief, Research and Evaluation Branch, DTBE
and George Comstock, MD, DrPH, FACE
Alumni Centennial Professor of Epidemiology
Johns Hopkins University
School of Hygiene and Public Health

The United States Public Health Service (USPHS), together with the British Medical Research Council (MRC) and the US Armed Forces–Veterans Administration Cooperative Trials, played a key role in the development of the chemotherapy of TB.

The first USPHS trial, a placebo-controlled study of streptomycin, was initiated by the Field Studies Section and the Tuberculosis Study Section of the National Institutes of Health (NIH) in 1947, the same year as the much smaller but better known MRC study of streptomycin. In the PHS study, a total of 541 patients with moderate to far-advanced pulmonary TB were enrolled at 14 hospitals and sanatoria throughout the US and Alaska. The published account gives no hint of how this controlled evaluation of streptomycin was saved from being only the series of uncontrolled observations that was initially proposed. Funds for a study of streptomycin in the treatment of TB had been allocated, probably in 1946, to a number of prominent hospitals. When Carroll Palmer heard that there were to be no controls, he was upset and expressed his concerns to Dr. Van Slyke, director of the NIH. Van Slyke agreed with Palmer, and directed that a controlled trial be planned and conducted under the general supervision of the newly convened Tuberculosis Study Section. Dr. Esmond Long, from Phipps Clinic in Philadelphia, was the chairman of the Study Section's Steering Committee. Ms. Ferebee, Chief of the Therapy Evaluation Branch, Field Studies Section, became the study administrator. With some grumbling from those who had lost their streptomycin allocation, a controlled trial was conducted, although without the placebo controls Palmer and Ferebee had wished. All investigators took part in various reviews of clinical and radiographic findings and in committees set up to consider appeals from the protocol, procedures continued in future PHS therapy trials as a way to bring investigators together and give them a real part in major decisions.

Image 1: Major advances in TB treatment occurred with the development of chemotherapy.

The study demonstrated the remarkable ability of streptomycin to reduce mortality and improve clinical status. However, monotherapy with streptomycin led to the development of drug resistance in a significant number of patients. In 1951, the one-year status was reported for the patients given streptomycin: 40% had negative cultures, 5% had died, 17% still had tubercle bacilli sensitive to streptomycin, and 39% had resistant organisms. In another 1951 report, PAS was found to be highly effective in preventing resistance to dihydrostreptomycin (similar in action to streptomycin but with a higher risk of ototoxicity.)

The second USPHS study, begun in 1949 at 11 institutions, randomized a total of 315 patients to either streptomycin or streptomycin-PAS. After 6 months of treatment, over 40% of patients receiving monotherapy developed streptomycin resistance, compared to only 12% of patients on combination therapy.

A major advance in TB treatment occurred in 1952 with the initial report of an MRC study of isoniazid. During the next 2 years, a total of 5,324 patients were enrolled in three USPHS trials (which became known as Studies 1, 2, and 3), examining a variety of combinations of the three drugs. The conclusion of these studies was that the triple combination did not appear to be more efficacious than the combinations of any two of the drugs. However, the combination of isoniazid and PAS was much better tolerated. Evidence from an MRC study indicated that initial streptomycin did contribute to treatment efficacy in patients with advanced disease. Another MRC study determined that the optimal duration of therapy with these drugs was 2 years.

With the scientific basis for TB chemotherapy firmly established, the PHS turned its attention to the next drugs that became available for clinical study, pyrazinamide and cycloserine. However, initial evaluation of pyrazinamide at much higher dosages than are currently used suggested that the drug was too toxic for use in initial treatment, although it appeared to have a role in the treatment of drug-resistant disease. Subsequently, through a series of elegant studies in Africa and Asia, the MRC defined the critial role of that agent in modern short-course therapy.

While continuing to conduct treatment efficacy studies, the USPHS also embarked on pioneering studies of isoniazid for the prevention of TB in persons with latent TB infection (LTBI). Between 1955 and 1959, nearly 65,000 persons including children with primary TB, contacts of infectious TB patients, patients in mental institutions, and Alaskan villagers, were entered into placebo-controlled trials that demonstrated the efficacy of isoniazid for treatment for LTBI.

In 1960, CDC was given responsibility for TB control and research. However, the research division resisted pressure to move to Atlanta and continued its work from Washington. In USPHS studies 12 to 16, the role of ethambutol as a first-line drug replacing PAS was defined. In 1969, the USPHS began the first of a series of studies of rifampin, ushering in the modern era of short-course therapy. Study 18 found that the combination of isoniazid and rifampin was superior to the best regimen that had been evaluated up to that time. USPHS Study 19 evaluated various dosages of rifampin and found that the optimal daily dosage was 10 mg/kg or 600 mg for most adults.

As rifampin-based short-course therapy became firmly established, support for therapy trials in the US began to wane. Study 20, the first USPHS study initiated after the research division moved to CDC, attempted to duplicate a smaller MRC study of a 6-month regimen of isoniazid and rifampin and found that the relapse rate of 10% was unacceptably high. Study 21, which began enrollment in 1981, was plagued by continuing shortages in financial support such that the study was nearly terminated several times before it successfully completed enrollment. That study confirmed the results found by the MRC and led to the adoption of 6-month therapy in the US. It was not until the resurgence of TB in the US, with the concomitant increased support for TB research, that the capacity of the USPHS to conduct high-quality TB treatment trials was restored.

 


Released October 2008
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