B107-24 Clofazimine Monotherapy for Mild Pulmonary Mycobacterium Avium Complex (mac) Disease

Rationale

Mycobacterium avium complex (MAC) pulmonary disease (MAC-PD) frequently requires long-term multi-drug therapy. However, MAC is highly drug resistant, limiting treatment options. Clofazimine, originally developed for M. tuberculosis and later repurposed for M. leprae is frequently prescribed off label for MAC-PD, but no randomized controlled trials have assessed its efficacy or safety. Objectives: We conducted a phase II placebo-controlled, randomized clinical trial evaluating the safety and efficacy of clofazimine monotherapy in treatment naïve patients with mild (non-cavitary, stable or slowly progressing) MAC-PD.

Methods

Patients were randomized to monotherapy placebo or clofazimine 200mg daily for 16 weeks, then 100mg daily for 8 weeks. Sputum cultures were collected every 2 weeks and centrally processed. Multiple microbiologic endpoints were a priori specified (figure 1), with a primary endpoint of culture conversion (two consecutive negative monthly sputum cultures without reversion) at 24 weeks. Secondary outcomes included change in Quality of Life-Bronchiectasis respiratory symptom score (QOL-B RSS), as well as treatment-emergent adverse events (AE) including skin discoloration and QT prolongation.

Results

101 participants were randomized and started therapy (n = 52 clofazimine, n = 49 placebo) with median age 72.7 years (range, 37-87 years), 86 (85%) female sex, and 96 (95%) white race and similar between groups. Culture conversion was numerically more common in the clofazimine group (12 (24.0%) versus 6 (16.7%), p = 0.46) but did not reach statistical significance (Figure). When cultures collected throughout the study were pooled together, negative results were more likely to occur in the clofazimine group (37% clofazimine versus 25% placebo, OR [95% CI]: 1.89 [1.44, 2.47]). Mean (95% CI) change in QOL-B RSS in the clofazimine group was -2.4 points (-7.7, 2.8) and -0.11 (-3.3, 3.1) in the placebo group (p = 0.45). Median (IQR) change in QT interval corrected using Fridericia’s formula (QTcF) from baseline to the highest recorded value per participant was 36 ms (19-51) in the clofazimine group and 11 ms (1-21) in the placebo group (p < 0.001). Skin discoloration (38 [73%] clofazimine vs 1 (2%) placebo) and QT prolongation (15 [29%] vs 1 [2%] placebo) were common with clofazimine. Serious AEs occurred similarly between groups (5 clofazimine vs 4 placebo).

Conclusions

Culture conversion was more common with six months of clofazimine monotherapy vs placebo for mild MAC-PD although the difference was not statistically significant. Clofazimine was safe and well-tolerated. Mild QT prolongation and skin discoloration were common but did not require discontinuation.

This abstract is funded by: FDA