Frequency and Clinical Impact of Serious Adverse Events on Post-Stroke Recovery with NeuroAiD (MLC601) versus Placebo: The CHInese Medicine Neuroaid Efficacy on Stroke Recovery Study.

BACKGROUND: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke. METHODS: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution. RESULTS: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p < 0.001). This benefit was seen throughout the study period and during the initial hospitalisation. The main clinical impact of SAEs was an increase in hospitalisation time, reduced in the MLC601 arm with the rate of subjects hospitalised for a prolonged period being significantly threefold lower in surviving subjects (1.1 vs. 3.7%; p < 0.01). CONCLUSIONS: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs.

Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial.

BACKGROUND: Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis. METHODS: This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851). FINDINGS: Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin. INTERPRETATION: Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin. FUNDING: National Medical Research Council, Singapore.