Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial

Abstract Objective To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia. Design Randomised, double blind, placebo controlled trial. Setting Referral hospital in Cape Town, South Africa. Participants 180 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. Intervention 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery. Main outcome measure The primary outcome was prolongation of gestation. Results Of 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. Conclusions This 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 registration Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/ .

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708 RESULTS OF A RANDOMIZED, DOUBLE‐BLIND, PLACEBO‐AND ACTIVE‐CONTROLLED TRIAL OF TAPENTADOL EXTENDED RELEASE FOR CHRONIC LOW BACK PAIN

European Journal of Pain ◽

10.1016/s1090-3801(09)60711-4 ◽

2009 ◽

Vol 13 (S1) ◽

Cited By ~ 1

Author(s):

D.Y. Shapiro ◽

R. Buynak ◽

A. Okamoto ◽

I. Hove ◽

A. Steup ◽

...

Keyword(s):

Low Back Pain ◽

Back Pain ◽

Chronic Low Back Pain ◽

Extended Release ◽

Controlled Trial ◽

Low Back ◽

Double Blind ◽

Double Blind Placebo

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Effects of Dalfampridine Extended-release Tablets on 6-minute Walk Distance in Patients With Multiple Sclerosis: A Post Hoc Analysis of a Double-blind, Placebo-controlled Trial

Clinical Therapeutics ◽

10.1016/j.clinthera.2015.10.014 ◽

2015 ◽

Vol 37 (12) ◽

pp. 2780-2787 ◽

Cited By ~ 16

Author(s):

Angela Applebee ◽

Andrew D. Goodman ◽

Angeli S. Mayadev ◽

Francois Bethoux ◽

Myla D. Goldman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Extended Release ◽

Controlled Trial ◽

Walk Distance ◽

Double Blind ◽

Double Blind Placebo ◽

Post Hoc Analysis ◽

Post Hoc ◽

Minute Walk Distance ◽

Minute Walk

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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Extended-Release Carbamazepine Capsules as Monotherapy for Bipolar Disorder Patients With Manic or Mixed Episodes

The Journal of Clinical Psychiatry ◽

10.4088/jcp.v65n0405 ◽

2004 ◽

Vol 65 (4) ◽

pp. 478-484 ◽

Cited By ~ 131

Author(s):

Richard H. Weisler ◽

Amir H. Kalali ◽

Terence A. Ketter ◽

Keyword(s):

Bipolar Disorder ◽

Extended Release ◽

Controlled Trial ◽

Double Blind ◽

Double Blind Placebo

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Lithium vs valproate in the maintenance treatment of bipolar I disorder: A post- hoc analysis of a randomized double-blind placebo-controlled trial

Australian & New Zealand Journal of Psychiatry ◽

10.1177/0004867419894067 ◽

2019 ◽

Vol 54 (3) ◽

pp. 298-307

Author(s):

Mehar G Kang ◽

Hong Qian ◽

Kamyar Keramatian ◽

Trisha Chakrabarty ◽

Gayatri Saraf ◽

...

Keyword(s):

Confidence Interval ◽

Atypical Antipsychotic ◽

Maintenance Treatment ◽

Atypical Antipsychotics ◽

Controlled Trial ◽

Hazard Ratio ◽

Double Blind ◽

Double Blind Placebo ◽

Post Hoc Analysis ◽

Post Hoc

Objective: Lithium and valproate are commonly used either in monotherapy or in combination with atypical antipsychotics in maintenance treatment of bipolar I disorder; however, their comparative efficacy is not well understood. This study aimed to compare the efficacy of valproate and lithium on mood stability either in monotherapy or in combination with atypical antipsychotics. Methods: We performed a post hoc analysis using data from a 52-week randomized double-blind, placebo-controlled trial, that recruited 159 patients with recently remitted mania during treatment with lithium or valproate and adjunctive atypical antipsychotic therapy. Patients were randomized to discontinue adjunctive atypical antipsychotic at 0, 24 or 52 weeks. Results: No significant differences in efficacy were observed between valproate and lithium (hazard ratio: 0.99; 95% confidence interval: [0.66, 1.48]) in time to any mood event. Valproate with 24 weeks of atypical antipsychotic was significantly superior to valproate monotherapy in preventing any mood relapse (hazard ratio: 0.46; 95% confidence interval: [0.22, 0.97]) while lithium with 24 weeks of atypical antipsychotic was superior to lithium monotherapy in preventing mania (hazard ratio: 0.27; 95% confidence interval: [0.09, 0.85]) but not depression. Conclusion: Overall, this study did not find significant differences in efficacy between the two mood-stabilizing agents when used as monotherapy or in combination with atypical antipsychotics. However, study design and small sample size might have precluded from detecting an effect if true difference in efficacy existed. Further head-to-head investigations with stratified designs are needed to evaluate maintenance therapies.

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Studies of Carbamazepine Extended-Release Capsules in Bipolar Disorder

CNS Spectrums ◽

10.1017/s1092852900023075 ◽

2005 ◽

Vol 10 (6) ◽

pp. 3-5

Author(s):

Richard H. Weisler

Keyword(s):

Extended Release ◽

Rating Scale ◽

Controlled Trial ◽

Controlled Study ◽

Mixed States ◽

Open Label ◽

Young Mania ◽

Double Blind ◽

Double Blind Placebo ◽

Bipolar Patients

This discussion reviews data from two 3-week, double-blind, placebo-controlled pivotal trials of carbamazepine extended release capsules (CBZ ERC; SPD417.301 and SPD417.304); pooled results from these trials; data from a 3-week, double-blind, placebo-controlled trial in lithium non-responders or non-tolerators (SPD417.302); and additional supportive data from a 6-month, open-label, extension trial (SPD417.303). In addition, information on a retrospective chart review of 600 adolescent and adult bipolar patients on CBZ ERC is presented.In the first large double-blind, placebo-controlled study assessing CBZ ERC in acute mania, manic and mixed bipolar patients from multiple centers were hospitalized and all medications were discontinued. After reaching a stable baseline 2–5 days later, the patients were randomized to CBZ ERC (n=101; 59% with mixed states) or placebo (n=103; 47% with mixed states) for 3 weeks. An aggressive initial titration schedule was implemented, beginning with 200 mg BID and increased by 200 mg/day until good clinical response was achieved or the patient could not tolerate the dosage. Many patients were taking 1,200–1,600 mg/day by the end of week 1. Efficacy was assessed using the Young Mania Rating Scale (YMRS). The Clinical Global Impressions (CGI) scale and the Hamilton Rating Scale for Depression (HAM-D) were also followed.

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Cinnarizine and sodium valproate as the preventive agents of pediatric migraine: A randomized double-blind placebo-controlled trial

Cephalalgia ◽

10.1177/0333102419888485 ◽

2019 ◽

Vol 40 (7) ◽

pp. 665-674

Author(s):

Man Amanat ◽

Mansoureh Togha ◽

Elmira Agah ◽

Mahtab Ramezani ◽

Ali Reza Tavasoli ◽

...

Keyword(s):

Placebo Group ◽

Adverse Effects ◽

Confidence Interval ◽

Children And Adolescents ◽

Sodium Valproate ◽

Medical Center ◽

Controlled Trial ◽

Migraine Prophylaxis ◽

Double Blind ◽

Double Blind Placebo

Background Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents. Methods We carried out a randomized double-blind placebo-controlled trial in the Children’s Medical Center and Sina hospital, Tehran, Iran. Eligible participants were randomly assigned in 1:1:1 ratio via interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The primary endpoints were the mean change in frequency and intensity of migraine attacks from baseline to the last 4 weeks of trial. The secondary endpoint was the efficacy of each drug in the prevention of migraine. The drug was considered effective if it decreased migraine frequency by more than 50% in the double-blind phase compared with the baseline. Safety endpoint was adverse effects that were reported by children or their parents. Results A total of 158 children participated. The frequency of migraine attacks significantly reduced compared to baseline in cinnarizine (difference: −8.0; 95% confidence interval (CI): −9.3 to −6.6), sodium valproate (difference: −8.3; 95% confidence interval: −9.3 to −7.2), and placebo (difference: −4.4; 95% confidence interval: −5.4 to −3.4) arms. The decrease was statistically greater in cinnarizine (difference: −3.6; 95% confidence interval: −5.5 to −1.6) and sodium valproate (difference: −3.9; 95% confidence interval: −5.8 to −1.9) arms, compared to placebo group. Children in all groups had significant reduction in intensity of episodes compared to baseline (cinnarizine: −4.6; 95% confidence interval: −5.2 to −4.0; sodium valproate: −4.0; 95% confidence interval: −4.8 to −3.3; placebo: −2.6; 95% confidence interval: −3.4 to −1.8). The decrease was statistically greater in cinnarizine (difference: −2.0; 95% confidence interval: −3.2 to −0.8) and sodium valproate (difference: −1.5; 95% confidence interval: −2.7 to −0.3) arms, compared to the placebo group. Seventy-one percent of individuals in the cinnarizine group, 66% of cases in the sodium valproate group, and 42% of people in the placebo arm reported more than 50% reduction in episodes at the end of the trial. The odds ratio for >50% responder rate was 3.5 (98.3% confidence interval: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% confidence interval: 1.0 to 6.9) for sodium valproate versus placebo. Nine individuals reported adverse effects (three in cinnarizine, five in sodium valproate, and one in the placebo group) and one case in the sodium valproate group discontinued the therapy due to severe sedation. Conclusion Cinnarizine and sodium valproate could be useful in migraine prophylaxis in children and adolescents. Trial registration: IRCT201206306907N4.

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