Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial

BackgroundThis exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19.MethodsThis phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18-65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population.FindingsThe mITT population included 186 patients: mean age (SD) 34.9 (10.3) years, body weight 78.2 (17.1) kg. Day 7 SARS-CoV-2 clearance rates (n/N; risk ratio [95% CI]) were: SOC 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV + NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) and SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; SOF-DCV 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There were no deaths. Adverse events occurred in 55.3% (105/190) of patients, including one serious adverse event (pancytopenia; FPV + NTZ).InterpretationThere was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated.FundingMedicines for Malaria Venture, with funding from the UK Foreign, Commonwealth and Development Office, within the Covid-19 Therapeutics Accelerator in partnership with Wellcome, the Bill and Melinda Gates Foundation, and Mastercard

Ethnic Differences in Brain-derived Neurotrophic Factor Val66Met Polymorphism in Croatian and Korean Healthy Participants

Aim To compare the frequency of alleles and genotypes in brain-derived neurotrophic factor (BDNF) val66met polymorphism in ethnically homogenous Caucasian (from Croatia) and ethnically homogenous Asian (from South Korea) healthy participants, as inter-population differences in BDNF val66met may be responsible for the divergent findings in genetic and association studies. Methods BDNF val66met was genotyped in 800 (556 Croatian and 244 Korean) healthy participants. Frequencies of alleles and genotypes were evaluated using a χ2 test. Results The frequencies for genotypes (χ2 2 = 114.69; P < 0.001) and alleles (χ2 1 = 120.07; P < 0.001) between Korean and Croatian individuals differed significantly, due to significantly lower (46.3% and 19.5%, P < 0.001) frequency of “Met” allele and significantly higher (53.7% and 80.5%, P < 0.001) frequency of “Val” allele in Croatian than in Korean participants. Conclusion The study found significant ethnic differences in BDNF val66met polymorphism. The most frequent genotype among Korean participants was “Met/Val” and they had similar distribution of “Met” and “Val” alleles. In contrast, the most frequent genotype among Caucasian participants was “Val/Val” and they had different distribution of “Met” and “Val” alleles. These ethnic differences require matching participants for ethnicity in pharmacogenetic studies and in the studies investigating genetic variations in neuropsychiatric disorders