Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Therapeutic Advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I² = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

The role of adjuvant radiotherapy in stage I endometrial cancer has changed in recent years. This updated Cochrane systematic review aimed to reexamine the efficacy and toxicity of adjuvant radiotherapy vs no treatment in stage I endometrial cancer. We searched various databases including The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and the Specialised Register of the Cochrane Gynaecological Cancer Review Group (CGCRG) for randomized controlled trials that met the predefined inclusion criteria. The primary outcome was overall survival (OS); secondary outcomes were endometrial cancer-specific survival, locoregional recurrence, distant recurrence, and toxicity. Hazard ratios (HRs) were estimated and pooled if possible; otherwise, dichotomous data were extracted. All statistical tests were two-sided. Of the eight included trials, seven trials (3628 women) compared external beam radiotherapy (EBRT) and no EBRT (or vaginal brachytherapy [VBT]), and one trial (645 women) compared VBT and no additional treatment. EBRT statistically significantly reduced locoregional recurrence compared with no EBRT (or VBT alone) (HR = 0.36, 95% confidence Interval [CI] = 0.25 to 0.52; P < .001), but this did not translate into an improvement in OS (HR = 0.99, 95% CI = 0.82 to 1.20; P = .95), endometrial cancer-specific survival (HR = 0.96, 95% CI = 0.72 to 1.28; P = .80), or distant recurrence rates (risk ratio = 1.04, 95% CI = 0.80 to 1.35; P = .77). EBRT was associated with an increased risk of severe acute toxicity, severe late toxicity, and reduced quality of life scores. EBRT reduces the risk of locoregional recurrence but has no statistically significant impact on cancer-related deaths or OS. However, EBRT is associated with clinically and statistically significant morbidity and a reduction in quality of life.

Reducing deaths from hypertensive disorders of pregnancy is a global priority. Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries. Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia; however, the effect of calcium supplementation during placentation is not known. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks' gestation) prevents the development of pre-eclampsia We did a multicountry, parallel arm, double-blind, randomised, placebo-controlled trial in South Africa, Zimbabwe, and Argentina. Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks' gestation. Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant. All participants received unblinded calcium 1·5 g daily after 20 weeks' gestation. The allocation sequence (1:1 ratio) used computer-generated random numbers in balanced blocks of variable size. The primary outcome was pre-eclampsia, defined as gestational hypertension and proteinuria. The trial is registered with the Pan-African Clinical Trials Registry, number PACTR201105000267371. The trial closed on Oct 31, 2017. Between July 12, 2011, and Sept 8, 2016, we randomly allocated 1355 women to receive calcium or placebo; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks' gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks' gestation (risk ratio [RR] 0·80, 95% CI 0·61–1·06; p=0·121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks' gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0·66, CI 0·44–0·98; p=0·037). There were no serious adverse effects of calcium reported. Calcium supplementation that commenced before pregnancy until 20 weeks' gestation, compared with placebo, did not show a significant reduction in recurrent pre-eclampsia. As the trial was powered to detect a large effect size, we cannot rule out a small to moderate effect of this intervention. The University of British Columbia, a grantee of the Bill & Melinda Gates Foundation; UNDP–UNFPA–UNICEF–WHO–World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO; the Argentina Fund for Horizontal Cooperation of the Argentinean Ministry of Foreign Affairs; and the Centre for Intervention Science in Maternal and Child Health.