The TBRU has three international and one U.S. clinical trials sites. The international sites are located at Mulago Hospital, Makerere University, Kampala, Uganda; the Federal University of Espírito Santo, Vitória, Brazil; and the Tropical Diseases Foundation, Makati City, the Philippines. The clinical trials group conducts phase I, II and III studies of new drugs, immunotherapeutic agents, vaccines and regimens for the prevention and treatment of tuberculosis. Trials investigators also support TBRU pilot immunological and microbiological studies focusing on novel surrogate markers of response to TB treatment and correlates of protective immunity. Dr. John L. Johnson, an experienced chest physician at Case Western Reserve University, heads the Clinical Trials Component.

Work Statement

The primary objective of the clinical trials component of the TBRU is to conduct clinical human studies of potential interventions such as new vaccines, prophylactics or therapeutic regimens, using developed surrogate markers of M. tuberculosis infection, tuberculosis progression and/or host protection to validate the usefulness of these markers in clinical trials and evaluate safety and efficacy of new regimens. This includes Phase I, II, and III clinical trials using potential new surrogate markers, evaluation of new assays for the rapid diagnosis of tuberculosis and drug susceptibility testing, and developing and implementing strategies for long-term follow-up.

Completed Clinical Trials

Safety and Preliminary Evidence for Microbiologic and Immunologic Activity of Heat-Killed Mycobacterium vaccae Immunotherapeutic Agent as an Adjunct to Combination Chemotherapy for the Initial Treatment of Pulmonary Tuberculosis in HIV-non-infected Adults in Uganda (DMID 94-120)

Adjunctive immunotherapy with heat-killed Mycobacterium vaccae was studied in a randomized, phase II, placebo-controlled trial of 120 HIV-non-infected adults with newly diagnosed, smear-positive pulmonary tuberculosis. Patients were randomized to receive a single dose of intradermal M. vaccae or placebo 1 week after beginning standard 6 month short course chemotherapy and were followed up for 1 year. M. vaccae immunotherapy was safe and well tolerated. The rate of sputum culture conversion after 1 month of tuberculosis treatment was 35% in the M. vaccae group compared to 14% in the placebo group (P=.01) but was comparable at 2 months and thereafter. Patients receiving M. vaccae had greater improvement on chest radiography at 6 months (91% vs. 77% for placebo recipients; P=.04) and 12 months (94% vs. 80%; P=.04) after initiation of tuberculosis treatment.

Open Label Multiple Dose Study of the Safety and Early Bactericidal Activity of KRM 1648 in the Treatment of Smear-Positive Pulmonary TB - PC-KRM-005 (DMID 97-012)

Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against M. tuberculosis in vitro and in animal models of tuberculosis. Prior studies in healthy volunteers showed that once-weekly doses of 25 to 50 mg of rifalazil were well tolerated.

This study was a phase II randomized, open label clinical trial performed to assess the safety, pharmacokinetics and early bactericidal activity of the rifamycin, KRM-1648 (rifalazil), as a therapeutic agent in the treatment of HIV-non-infected adults with sputum smear positive, fully drug susceptible pulmonary tuberculosis. The trial was conducted at the Federal University of Espírito Santo, Vitória, Brazil. Sixty-five patients with newly-diagnosed pulmonary tuberculosis received one of the following regimens for the first 2 weeks of therapy: 16 subjects received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then treated with 6 months of standard short course chemotherapy.

Pretreatment and day 15 sputum CFU of M. tuberculosis were measured to assess the bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to less than 2,000 cells/mm3 was detected in 10 to 20% of patients in the rifalazil- and rifampin-containing treatment arms without clinical consequences. Decreases in CFU counts were comparable among the four treatment arms; however, the CFU results were statistically inconclusive due to the variability in the control arms. Acquired drug resistance did not occur in any patient.

Phase II Study of Safety and Preliminary Evidence for Microbiologic and Immunologic Activity of rhIL-2 (Proleukin â) in HIV-non-infected Adults with Pulmonary TB (DMID 98-002)

Interleukin (IL)-2 has a central role in regulating T cell responses to M. tuberculosis. Adjunctive immunotherapy with recombinant human IL-2 was studied in a randomized, placebo-controlled, double-blinded trial in Uganda in 110 HIV-non-infected adults with newly diagnosed, smear-positive, drug-susceptible pulmonary tuberculosis. Patients were randomly assigned to receive twice daily injections of 225, 000 IU of IL-2 or placebo for the first 30 days of treatment in addition to standard chemotherapy. Subjects were followed for one year. The primary endpoint was the proportion of patients with sputum culture conversion after 1 and 2 months of treatment. After 1 month, the proportion of patients who converted their sputum culture to negative was 17% for the IL-2 group compared to 30% in the control group (p= 0.14; c2). After 2 months, 77% in the IL-2 group were culture negative compared to 85% of those receiving placebo (p=0.29, c2). Results were similar when patients with isoniazid monoresistance were included in the analysis. There were no differences in weight gain, and improvement in fever, cough and chest pain between groups. One patient in each arm relapsed. IL-2 did not enhance bacillary clearance or improvement in symptoms in HIV-negative adults with drug-susceptible tuberculosis.

Current Clinical Trials

A Prospective Study of Shortening the Duration of Standard Short Course Chemotherapy from 6 Months to 4 Months in HIV-non-infected Patients with Fully Drug-Susceptible, Non-cavitary Pulmonary Tuberculosis with Negative Sputum Cultures after 2 Months of Anti-TB Treatment (DMID 01-009)

This study is a prospective randomized, open-label, phase III equivalence trial comparing 4 and 6 months of TB treatment (2 months of daily treatment with INH, rifampicin, ethambutol and pyrazinamide followed by either 2 or 4 months of daily INH and rifampicin) in HIV-non-infected adults with non-cavitary pulmonary tuberculosis who become sputum culture negative after the initial 2 months of anti-TB treatment. This study is recruiting patients in Kampala, Uganda, Vitória, Brazil and Makati City, the Philippines.

Patients meeting initial eligibility criteria are enrolled and started on standard chemotherapy (2EHRZ/4HR). Drug susceptibility testing to INH, streptomycin, rifampicin, pyrazinamide and ethambutol is performed on initial isolates from all patients. Sputum smear and culture are performed monthly during treatment. Treatment is administered by directly observed therapy. Patients with drug-susceptible TB who are sputum culture negative after 2 months of treatment are randomly assigned at 4 months (when the final results of 2 month cultures are available) to stop treatment or to receive an additional 2 months of daily INH and rifampicin. The primary study endpoint is bacteriologic or clinical relapse at 30 months after the onset of anti-TB treatment.

Randomized, Open Label, Multiple Dose Phase I Study of the Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, and Moxifloxacin in HIV-non-infected Adults with Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis (DMID 01-553)

This study is a randomized, open label, multiple dose phase I clinical trial to evaluate the early and extended early bactericidal activity (EBA) of gatifloxacin, levofloxacin, moxifloxacin, and linezolid compared with an INH control arm. The study will be conducted at the Federal University of Espírito Santo, Vitória, Brazil in two parts.

Part 1, which has been completed, compared the bactericidal activity of the new respiratory fluoroquinolones, levofloxacin, gatifloxacin and gatifloxacin, and INH.  Part 2 of the study will compare the activity of linezolid at two doses and INH.  All subjects will undergo pharmacokinetic sampling on day 5.  Drug susceptibility testing and MIC determinations of initial and day 7 M. tuberculosis isolates from all subjects will be done.

In Part 1, we compared the bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in adults with newly diagnosed initial episodes of smear-positive pulmonary TB in a randomized, open label clinical trial.  Forty patients (10 per arm) were assigned to receive isoniazid 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days.  All subjects were then treated with 6 months of standard short course chemotherapy.  Sputum for quantitative culture (cfu assay) was collected for 2 days before and daily during 7 days of monotherapy.  Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity, EBA) and last 5 days of monotherapy (extended early bactericidal activity).  Laboratory staff were blinded to treatment assignment.  The EBA of isoniazid (0.67 log₁₀ cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log₁₀ cfu/ml/day, respectively), but not levofloxacin 1000 mg daily (0.45 log₁₀ cfu/ml/day).  Bactericidal activity between day 2 and 7 was similar for all three fluoroquinolones.  In a pooled comparison the extended EBA of the three fluoroquinolones was greater than isoniazid.  Moxifloxacin, gatifloxacin, and high dose levofloxacin have excellent EBA only slightly less than isoniazid and greater extended EBA.

In Part 2 of the study, the EBA and extended EBA of linezolid 600 mg twice daily, linezolid 600 mg once daily and INH 300 mg daily for 7 days will be studied using a similar study design.