A combination regimen containing high-dose rifampin (also known as rifampicin) was associated with faster tuberculosis bacteria culture conversion in people with drug-sensitive TB, but moxifloxacin and the experimental drug SQ109 showed no benefit compared to standard therapy, according to results from a study presented at the recent 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.
An estimated 9 million people develop active TB disease each year and it remains a major cause of death for people with HIV worldwide. Current standard treatment for TB requires multiple drugs taken for 6 months or longer, which presents difficulties with adherence and toxicity; shorter well-tolerated regimens are urgently needed.
Martin Boeree from Radboud University Medical Center in the Netherlands and colleagues conducted the PanACEA MAMS TB 01 trial to evaluate whether high-dose rifampin, moxifloxacin, and/or the experimental drug SQ109 could reduce the time to Mycobacterium tuberculosis culture conversion. The evaluation program started in 2007 looking at high-dose rifampin, moxifloxacin, and SQ109 separately, and the MAMS TB 01 trial brought the 3 products together.
This open-label trial enrolled adult patients with drug-sensitive, smear-positive TB at 7 sites in South Africa and Tanzania. About 70% were men, the median age was approximately 33 years, and 7% were HIV-positive. A total of 368 participants were randomized and 5 were excluded due to errors, leaving 363 in the modified intent-to-treat analysis.
Participants were randomly allocated to receive the following initial regimens, followed by standard doses of rifampin and isoniazid for a total of 26 weeks of treatment:
- SQ109, 10 mg/kg standard-dose rifampin, isoniazid, and pyrazinamide for 12 weeks;
- SQ109, 20 mg/kg rifampin, isoniazid, and pyrazinamide for 12 weeks;
- 20 mg/kg rifampin, moxifloxacin, isoniazid, and pyrazinamide for 12 weeks;
- 35 mg/kg high-dose rifampin, ethambutol, isoniazid, and pyrazinamide for 12 weeks;
- Standard therapy using 10 mg/kg rifampin, ethambutol, isoniazid, and pyrazinamide for 8 weeks (control arm).
The trial had a multi-arm, multi-stage design with 1 interim analysis, after which recruitment to specific arms could be halted due to lack of efficacy based on pre-specified stopping rules. Recruitment to both SQ109 arms was terminated in March 2014 after the interim analysis.
The primary endpoint was stable culture conversion in liquid media over 12 weeks. The researchers also analyzed data at 8 weeks so it could be directly compared to previous phase 2 TB trials using shorter initial therapy.
- In the final analysis at 12 weeks, 63% and 57% of participants in the SQ109 arms, 79% in the moxifloxacin arm, and 80% in the 35 mg/kg rifampin arm experienced stable culture conversion in liquid media, compared to 70% in the standard therapy arm.
- In the 8-week analysis the proportions with stable culture conversion were 41% and 32% in the SQ109 arms, 60% in the moxifloxacin arm, and 56% in the 35 mg/kg rifampin arm, compared to 42% in the control arm.
- At 12 weeks the SQ109 arms showed no reduction in time to culture conversion (63 and 66 days) compared to standard therapy (62 days), while the moxifloxacin arm reduced clearance time somewhat (to 55 days) and the 35 mg/kg rifampin arm produced the greatest reduction (48 days).
- In the 12-week analysis the adjusted hazard ratios for the investigational arms compared to the control arm were 0.82, 0.73, 1.42, and 1.75, respectively, with the last being a statistically significant improvement.
- In the 8-week analysis the adjusted hazard ratios were 1.05, 0.91, 1.69, and 1.99, respectively, with the latter 2 being statistically significant.
- When looking at solid media, culture conversion rates were higher overall and more similar across regimens.
- At 12 weeks the culture conversion rates were 94% in both SQ109 arms, 98% in the moxifloxacin arm, 100% in the 35 mg/kg rifampin arm, and 97% in the control arm.
- Treatment with all regimens was generally safe and well-tolerated.
- Grade 3 or worse adverse events were reported by 12% of participants in both SQ109 arms and 14% of participants in both the moxifloxacin and 35 mg/kg rifampin arms, compared to 10% in the standard therapy arm.
- Overall frequency of serious adverse event was also similar across arms (7%, 9%, 6%, 6%, and 5%, respectively).
- A total of 10 people (3 in the SQ109-20 mg/kg rifampin arm, 5 in the 35 mg/kg rifampin arm, and 2 in the control arm) experienced liver-related adverse events leading to a change in treatment.
"35 mg/kg of [rifampin] resulted in an increased likelihood of, and shorter time to culture conversion in liquid media, not in solid media," the researchers concluded. "The SQ109 and moxifloxacin arms were not different from [the control arm]."
MJ Boeree, M Hoelscher, et al (on behalf of the PanACEA Consortium). High-Dose Rifampin, SQ109 and Moxifloxacin for Treating TB: The PanACEA MAMS-TB Trial. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 95LB.