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Based on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis. Clo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine–isoniazid–pyrazinamide–ethambutol–clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine–isoniazid–pyrazinamide–clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid–rifampicin–pyrazinamide–ethambutol followed by 18 weeks of rifampicin–isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502. 104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82–1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14–45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37–69) in group 1 versus 27% (14–50) in group 2 (p=0·049). Although the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events. US National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

WHO recommends a 2-month optimal duration for new drug regimens for rifampicin-susceptible tuberculosis. We aimed to investigate the efficacy and safety of the 8-week regimens that were assessed as part of the TRUNCATE management strategy of the TRUNCATE-TB trial. TRUNCATE-TB was a multi-arm, multi-stage, open-label, randomised controlled trial in which participants aged 18–65 years with rifampicin-susceptible pulmonary tuberculosis were randomly assigned via a web-based system, using permuted blocks, to 24-week standard treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol) or the TRUNCATE management strategy comprising initial 8-week treatment, then post-treatment monitoring and re-treatment where needed. The four 8-week regimens comprised five drugs, modified from standard treatment: high-dose rifampicin and linezolid, or high-dose rifampicin and clofazimine, or bedaquiline and linezolid, all given with isoniazid, pyrazinamide, and ethambutol; and rifapentine, linezolid, and levofloxacin, given with isoniazid and pyrazinamide. Here, we report the efficacy (proportion with unfavourable outcome; and difference from standard treatment, assessed via Bayesian methods) and safety of the 8-week regimens, assessed in the intention-to-treat population. This prespecified exploratory analysis is distinct from the previously reported 96-week outcome of the strategy in which the regimens were deployed. This trial is registered with ClinicalTrials.gov (NCT03474198). Between March 21, 2018, and March 26, 2020, 675 participants (674 in the intention-to-treat population) were enrolled and randomly assigned to the standard treatment group or one of the four 8-week regimen groups. Two 8-week regimens progressed to full enrolment. An unfavourable outcome (mainly relapse) occurred in seven (4%) of 181 participants on standard treatment; 46 (25%) of 184 on the high-dose rifampicin and linezolid-containing regimen (adjusted difference 21·0%, 95% Bayesian credible interval [BCI] 14·3–28·1); and 26 (14%) of 189 on the bedaquiline and linezolid-containing regimen (adjusted difference 9·3% [4·3–14·9]). Grade 3–4 adverse events occurred in 24 (14%) of 181 participants on standard treatment, 20 (11%) of 184 on the rifampicin-linezolid regimen, and 22 (12%) of 189 on the bedaquiline-linezolid regimen. Efficacy was worse with 8-week regimens, although the difference from standard treatment varied between regimens. Even the best 8-week regimen (bedaquiline-linezolid) should only be used as part of a management strategy involving post-treatment monitoring and re-treatment if necessary. Singapore National Medical Research Council; UK Department of Health and Social Care; UK Foreign, Commonwealth, and Development Office; UK Medical Research Council; Wellcome Trust; and UK Research and Innovation Medical Research Council.

Background. Clofazimine (Cfz) has shown activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) strains in vitro and in animal studies. Here we evaluate the clinical efficacy and tolerability of using Cfz to treat MDR tuberculosis in China. Methods. We enrolled 105 patients who had sputum culture-positive MDR tuberculosis in 6 major tuberculosis specialty hospitals in China. Patients were randomly assigned to either the Cfz therapy group (n = 53) or control group (n = 52). Patients in the 2 groups were given 21 months of individual-based chemotherapy regimens based on medication history and drug susceptibility test results. The Cfz therapy group regimens incorporated 100 mg of Cfz once daily for 21 months. Results. Three patients in each group discontinued therapy because of side effects or other reasons. Sputum culture conversion to negative was earlier in patients who received Cfz compared with controls (P = .042 by log-rank test). Chest computed tomography showed cavitary changes in 46 patients in the Cfz therapy group and 45 in the control group. Cavity closure was earlier in patient who received Cfz compared with controls (P = .047 by log-rank test). The treatment success rate in the Cfz group was 73.6%, higher than that in control group (53.8%; P = .035). Side effects in skin only occurred in the Cfz group. The rates of skin discoloration and ichthyosis were 94.3% and 47.2%, respectively. Conclusions. Using Cfz to treat MDR tuberculosis promotes cavity closure, accelerates sputum culture conversion, and improves treatment success rates.

Background We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. Methods This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. Results Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI − 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). Conclusions The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide. ClinicalTrials.gov: NCT00669643.

Background Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6–18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo , in HIV-infected patients with cryptosporidial diarrhea are not known. Methods CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose. Discussion This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6–18 months of age. Trial registration ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.

Objective We aimed to investigate the efficacy and safety of a regimen combining bedaquiline and clofazimine in the treatment of refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC) or Mycobacterium abscessus subsp. abscessus (here Mab). Methods In this open-label, prospective pilot study, patients with refractory non-tuberculous mycobacterial pulmonary disease (NTM-PD) were enrolled to receive a regimen of bedaquiline and clofazimine alongside individualized background therapies. No control group was established in the study. Sputum samples were collected for culture at baseline (prior to treatment initiation) and then monthly thereafter. After the initial 6-month period, sputum collection frequency was reduced to every two months until trial completion. The primary end-point was sputum culture conversion rate. However, due to insufficient patient enrollment, we present these findings as a case series. Results A total of 11 patients were enrolled in this study, including 8 cases infected with Mycobacterium abscessus subsp. abscessus , 2 with Mycobacterium avium , and 1 with Mycobacterium intracellulare . Nine patients were resistant to clarithromycin. All 11 patients completed 18 months of follow-up. After 6 months of treatment, 45% (5/11) patients achieved culture conversion. However, after 18 months’ treatment, only 27% (3/11) maintained culture conversion. Chest CT imaging showed improvement in 5 patients, stability in 4 patients, and progression of lesions in 2 patients. The longest duration of bedaquiline use was 20 months. QTc interval prolongation was observed in 64% (7/11) of patients within 24 weeks, leading to permanent discontinuation of bedaquiline in one patient. The minimum inhibitory concentration (MIC) of bedaquiline ranged from ≤ 0.06 to 0.25 µg/mL prior to treatment, and two patients experienced an increase in MIC from ≤ 0.06 µg/mL to 0.12 µg/mL after treatment. The MICs of clofazimine were between 0.06 and 1 µg/mL. Conclusion The combination of bedaquiline and clofazimine may offer some clinical benefit in selected cases of advanced Mab and MAC lung diseases, but larger controlled studies are needed to confirm these preliminary findings. Trial registration This clinical study (ChiCTR2000037403) was registered on the ‌Chinese Clinical Trial Registry‌ website ( http://www.chictr.org.cn ) on ‌August 28, 2020‌.

Background This study aims to evaluate the effectiveness, safety, and impact on health-related quality of life (HQoL) of a fully oral shortened regimen for Rifampicin-Resistant/Multidrug-Resistant Tuberculosis (RR/MDR-TB) over 9 to 12 months under programmatic conditions. Methods A prospective cohort study was conducted on an all-oral modified Shortened Treatment Regimen (mSTR) comprising linezolid (Lzd), bedaquiline (Bdq), levofloxacin (Lfx), clofazimine (Cfz), and cycloserine (Cs). Patients with RR/MDR-TB were enrolled between January and December 2022 across seven drug-resistant TB units in the Dominican Republic. Results A total of 113 patients were enrolled, with 87% achieving culture conversion at two months. Treatment outcomes revealed that 79% of patients were successfully treated and didn’t relapse six months after the end of the treatment, 14% were lost to follow-up during the treatment, 6% deceased, and one experienced treatment failure due to Adverse Drug Reactions (ADRs). Adverse events of Special interest (AESI) were common, with 82% of patients experiencing at least one AE with high proportion of QT interval prolongation, elevated transaminases, and anemia. A total of 12% of the patients experiencing Serious Adverse Events (SAEs). Improvement in HQoL dimensions was noted throughout treatment, with the EQ-VAS score increasing by an average of 15.5 by treatment end. Conclusion The high treatment success rate of the 5-drug mSTR facilitated the adaptation and integration of a shortened treatment regimen lasting 9 to 12 months in routine care in Dominican Republic. SAEs were -rare. Although AESI were frequent, they were manageable in most cases. Continuous monitoring, particularly with regard to the use of Lzd and Bdq, is crucial to effectively mitigating risks. Since September 2023, this short all oral treatment regimen is the recommended approach for patients with RR/MDR-TB in the Dominican Republic.

PurposeThis study was undertaken to develop novel mucoadhesive formulations of clofazimine (CFZ), a drug candidate for the treatment of cryptosporidiosis, with the aim of strategic delivery to the small intestine, the main site of the disease parasites.MethodsCFZ-loaded nanoparticles (nCFZ) coated with non-biodegradable anionic polymer (nCFZ/A) and biodegradable anionic protein complex (nCFZ/dA) were prepared by Flash NanoPrecipitation (FNP) and evaluated for their physicochemical and biopharmaceutical properties.ResultsThe mean diameters of nCFZ/A and nCFZ/dA were ca. 90 and 240 nm, respectively, and they showed narrow size distributions and negative ζ-potentials. Both formulations showed higher solubility of CFZ in aqueous solution than crystalline CFZ. Despite their improved dispersion behaviors, both formulations exhibited significantly lower diffusiveness than crystalline CFZ in a diffusion test using artificial mucus (AM). Quartz crystal microbalance analysis showed that both formulations clearly interacted with mucin, which appeared to be responsible for their reduced diffusiveness in AM. These results suggest the potent mucoadhesion of nCFZ/A and nCFZ/dA. After the oral administration of CFZ samples (10 mg-CFZ/kg) to rats, nCFZ/dA and nCFZ/A exhibited a prolongation in Tmax by 2 and >9 h, respectively, compared with crystalline CFZ. At 24 h after oral doses of nCFZ/A and nCFZ/dA with mucoadhesion, there were marked increases in the intestinal CFZ concentration (4–7 fold) compared with Lamprene®, a commercial CFZ product, indicating enhanced CFZ exposure in the small intestine.ConclusionThe use of FNP may produce mucoadhesive CFZ formulations with improved intestinal exposure, possibly offering enhanced anti-cryptosporidium therapy.

As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.