Geraint Davies and colleagues discuss the potential for innovative early-phase clinical trial methods and technologies to reduce risk and speed up drug development for tuberculosis.

Background We evaluated efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in HIV-infected patients with cryptosporidiosis. Methods We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in Part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched HIV-infected individuals without cryptosporidiosis. Results Twenty Part A and 10 Part B participants completed the study ATP. Almost all Part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the Part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared to the placebo group. Over the inpatient period, compared to those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2Cryptosporidium per gram stool (95% upper confidence limit: 3.82), total stool weight decreased by 45.3 g (p=0.37), and number of diarrheal episodes increased by 2.32 (p=0.87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. Three CFZ and 1 placebo subjects died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than Part B controls. Conclusion Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy.

Objectives Animal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3–4 months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB). Methods A series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28 days, intracellular bacilli treated daily for 28 days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56 days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6 months with each regimen. Results Using linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56 days were 0.18 (95% credible interval=0.13–0.23) versus 0.15 (95% credible interval=0.08–0.21) log10 cfu/mL/day, compared with 0.16 (95% credible interval=0.13–0.18) versus 0.11 (95% credible interval=0.09–0.13) log10 cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1–41.34) and 72.30% (95% credible interval=71.41–73.17) at 3 and 4 months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18–94.13) at 6 months for standard therapy. Conclusions The kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6 months in most patients.