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A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol.

ABSTRACT: INTRODUCTION:Pre-eclampsia is a major complication of pregnancy, globally responsible for 60?000 maternal deaths per year, and far more fetal losses. There is no definitive treatment other than delivery. A therapeutic that could quench the disease process would be useful to treat preterm pre-eclampsia, as it could allow these pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have published preclinical data to show that metformin, a drug known to be safe in pregnancy and commonly used to treat gestational diabetes, has potent biological effects making it another promising candidate to treat pre-eclampsia. Here, we describe a phase II clinical trial to examine whether administering extended-release metformin may be effective in treating women with preterm pre-eclampsia (PI2 Trial). METHODS:The PI2 Trial is a phase II, double blind, randomised controlled trial that aims to recruit 150 women with preterm pre-eclampsia (gestational age 26+0?to 31+6 weeks) who are being managed expectantly. Participants will be randomised to receive either 3 g of metformin or placebo daily. The primary outcome is time from randomisation until delivery. A delay in delivery of 5 days is assumed to be clinically relevant. The secondary outcomes will be a maternal composite and neonatal composite outcome. All other outcomes will be exploratory. We will record adverse events. ETHICS AND DISSEMINATION:This study has ethical approval (Protocol number M16/09/037 Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), is registered with the Pan African Clinical Trial Registry (PACTR201608001752102) and the South African Medicine Control Council (20170322). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:PACTR201608001752102; Pre-results.

SUBMITTER: Cluver C

PROVIDER: S-EPMC6503454 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol.

Cluver Catherine C Walker Susan P SP Mol Ben W BW Hall David D Hiscock Richard R Brownfoot Fiona C FC Kaitu'u-Lino Tu'uhevaha J TJ Tong Stephen S

BMJ open 20190424 4

<h4>Introduction</h4>Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far more fetal losses. There is no definitive treatment other than delivery. A therapeutic that could quench the disease process would be useful to treat preterm pre-eclampsia, as it could allow these pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have published preclinical data to show that metformin, a drug kno ...[more]

PMID: 31023758

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Project description:ObjectiveTo evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia.DesignRandomised, double blind, placebo controlled trial.SettingReferral hospital in Cape Town, South Africa.Participants180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo.Intervention3 g of oral extended release metformin or placebo daily, in divided doses, until delivery.Main outcome measureThe primary outcome was prolongation of gestation.ResultsOf 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm.ConclusionsThis trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible.Trial registrationPan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.

Project description:BackgroundReducing 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 METHODS: 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.FindingsBetween 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.InterpretationCalcium 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.FundingThe 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.

Project description:Introduction:Pre-eclampsia contributes to maternal and fetal morbidity and mortality all over the world. Endothelial dysfunction is postulated to be the crux of the pathogenesis. Recent meta-analysis of aspirin trials showed aspirin to be effective when started early in pregnancy (at ? 16-week gestation). We aimed to study the effect of low-dose prophylactic isosorbide mononitrate (ISMN) 20 mg/day on the incidence of hypertensive diseases in high-risk women receiving standard aspirin prophylaxis. Methods:Design: Randomized double-blind placebo-controlled parallel-arm superiority trial. Setting: Antenatal clinic of a tertiary teaching hospital, South India. Participants and methods: One hundred women fulfilling NICE guideline criteria for aspirin prophylaxis recruited at 12-16 weeks were randomized to receive either 20 mg/day of ISMN or placebo, in addition to 75 mg/day of oral aspirin from recruitment till delivery. Main outcome measure: Rate of hypertensive disorder of pregnancy (HDP). Sample Size: One hundred women (50 in each arm) to detect a decrease of HDP from 20% in the placebo group to 5% in the ISMN group with a power of 80% and at 0.05. Results:One hundred women (50 in each arm) participated and completed the trial. Intention to treat analysis of these 100 women showed that the groups were comparable in terms of age, BMI, parity, and vascular indices (such as mean arterial pressure, uterine artery pulsatility index, flow-mediated vasodilatation index, brachial-ankle pulse wave velocity, Ankle-Brachial Index, brachial arterial stiffness index, and ankle arterial stiffness index). The rate of hypertensive disorders (gestational hypertension, pre-eclampsia, or superimposed pre-eclampsia) was not significantly different between the groups (14/50, 28% in ISMN vs. 12/50, 24% in placebo group; p = 0.7). The mean gestational age at diagnosis of hypertensive disease (35.4 vs. 36 weeks, ISMN vs. placebo groups, p = 0.7) or the rate of severe disease (8/50, 16% in ISMN vs. 7/50, 14% in the placebo group; p = 0.9) did not differ significantly between the two groups. Stillbirths (1 vs. 2), NICU admission rates (18 vs. 10%), and neonatal mortality (2 vs. 2) were also similar between the groups. Conclusion:The results of the randomized controlled trial of nitric oxide in the prevention of pre-eclampsia (NOPE) showed that in high-risk women receiving standard aspirin prophylaxis from less than 16 weeks, there is no significant reduction in the incidence of hypertensive disorders of pregnancy in the ISMN group, to the desired extent. There was no significant effect on the severity of disease, gestational age at diagnosis of disease or maternal-perinatal morbidity due to low-dose isosorbide mononitrate.

Project description:BackgroundTuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex.MethodsIn this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30.FindingsBetween 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and - 20.8% (IQR - 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin).InterpretationMetformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified.FundingThis study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB).

Project description:Aim: To investigate whether the early administration of Euphrasia eye drops® in preterm neonates presenting with ocular discharge fosters the resolution of the ocular discharge and reduces the need for topical antibiotic therapy, as compared to placebo. Methods: We conducted a randomized double-blind placebo-controlled trial at the University Children's Hospital Bern, Switzerland. Preterm neonates with white, yellow, or green ocular discharge were included. Infants were randomly assigned (1:1) to the Euphrasia arm (Euphrasia eye drops®, Weleda AG, Arlesheim) or the placebo arm (NaCl 0.9%). Euphrasia or placebo was administrated at a dose of one drop in each eye four times a day over a period of 96 h. The primary outcome was the treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. Results: A total of 114 neonates were screened and 84 were randomized. Among neonates in the Euphrasia arm, 22 (55.0%) achieved our primary outcome compared to 21 (51.2%) in the placebo arm (p = 0.85). In the Euphrasia arm, time to resolution of reddening tended to fall within the shorter bracket of 24 to 48 h (24 (92.3%) vs. 12 (80.0%) in the placebo arm, p = 0.34) and relapse or first signs of reddening during the 96-h intervention tended to be lower [3 (7.9%) eyes vs. 8 (18.2%) eyes in the placebo arm, p = 0.17]. Tearing at 96 h tended to be lower in the Euphrasia arm [5 (12.8%) eyes in the Euphrasia arm vs. 12 (27.3%) eyes in the placebo arm, p = 0.10]. Discussion: Euphrasia did not significantly improve treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. However, results suggest that Euphrasia may be of benefit for symptoms such as reddening and tearing, and thus improve the comfort of patients. Trial Registration: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04122300 and at the portal for human research in Switzerland SNCTP000003490.

Dataset Information

A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol.

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A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol.

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