Randomized, Double-Blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor - NEWBORN-1

Start Date29 Apr 2016

Sponsor / Collaborator

GlaxoSmithKline Research & Development

NCT02377466 / TerminatedPhase 3

Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor

The study's primary objective is to demonstrate the superiority of retosiban to prolong pregnancy and improve neonatal outcomes compared with placebo. It is a Phase III, randomized, double-blind, parallel-group, multicenter study and will be conducted in approximately 900 females, aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact membranes in preterm labor between 24^0/7 and 33^6/7 weeks of gestation. Eligible maternal subjects will be randomly assigned in a 1:1 ratio to receive either retosiban IV infusion or placebo IV infusion over 48 hours. If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of betamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the antecedent treatment was at least 7 days prior to study enrolment. Investigators have discretion to use a standardized regimen of magnesium sulphate, as well as intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. Prior to randomization, each subject will be stratified by progesterone treatment and gestational age. The progesterone strata will consist of subjects on established progesterone therapy or subjects not on established progesterone therapy at Screening. The study will comprise 6 phases: Screening, Inpatient Randomized Treatment, Post Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal Medical Review. The duration of any subject's (maternal or neonatal) participation in the study will be variable and dependent on gestational ages (GA) at study entry and the date of delivery.

Start Date29 Feb 2016

Sponsor / Collaborator

GSK Plc

[+1]

EUCTR2014-003326-41-GB / Not yet recruitingPhase 3

Randomized, Double-Blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor - NEWBORN-1

Start Date13 Jan 2016

Sponsor / Collaborator

GlaxoSmithKline Research & Development Ltd.

100 Clinical Results associated with Retosiban

100 Translational Medicine associated with Retosiban

100 Patents (Medical) associated with Retosiban

Literatures (Medical) associated with Retosiban

01 Jul 2023·American Journal of PerinatologyQ4 · MEDICINE

Safety and Outcomes in Infants Born to Mothers Participating in Retosiban Treatment Trials: ARIOS Follow-up Study

Q4 · MEDICINE

Article

Author: Powell, Marcy ; Haque, Nazneen ; Pimenta, Jeanne M. ; Thornton, Steve ; Scott, Rhona ; Correa, Erika Ochoa ; Beach, Kathleen J. ; Saade, George R. ; Snidow, Jerry ; Miller, Diane

Objective Retosiban, an oxytocin receptor antagonist, was developed for treating spontaneous preterm labor (sPTL) in women with intact membranes. This ARIOS follow-up study aimed to characterize clinical safety, morbidity, and mortality of infants exposed to retosiban or comparator over 2 years. Study Design ARIOS prospectively assessed outcomes in infants whose mothers received at least one dose of retosiban or comparator (placebo/atosiban) in two Phase 3 sPTL trials. Both trials were terminated prematurely owing to poor enrolment. Infants could be enrolled into ARIOS from 28 days after estimated due date until hospital discharge or up to 9 months (corrected age). An internally developed questionnaire detailing medical conditions, mortality and resource use (Child Health Inventory; CHI), Ages and Stages Questionnaire-3 (ASQ-3), Modified Checklist for Autism in Toddlers–Revised with Follow-Up, and Child Behavior Checklist for Ages 1.5 to 5 were completed remotely by parents or legal guardians at prespecified intervals. Serious adverse events (SAEs) were primarily captured via CHI. No comparative statistical analysis was conducted between treatment arms. Results A total of 49 (86%) infants who had received retosiban and 49 (78%) infants who had received a comparator were enrolled in ARIOS. No deaths occurred during the study. Nine infants experienced SAEs: 6/49 (12.2%) infants in the comparators group and 3/49 (6.1%) in the retosiban group. Of the nine SAEs, seven were due to infections, three, and four in the retosiban and comparators groups, respectively. Based on ASQ-3 score, the incidence of neurodevelopmental delay at 18 and 24 months were 0/18 (0%) and 2/25 (8%) with retosiban and 7/22 (31.8%) and 3/21 (14.3%) with comparator, respectively. Conclusion The current study showed no unexpected adverse outcome or impairment with retosiban based on safety monitoring and neurodevelopment assessments. No further follow-up is intended owing to the discontinuation of clinical development of retosiban. Key Points

02 Sep 2021·Current Medical Research and OpinionQ4 · MEDICINE

Novel oxytocin receptor antagonists for tocolysis: a systematic review and meta-analysis of the available data on the efficacy, safety, and tolerability of retosiban

Q4 · MEDICINE

Review

Author: Masoud, Ahmed Taher ; Ruuska, Alexandra D. ; Cieminski, Kaitlynne ; Calteux, Nicolas ; Marchand, Greg ; Ulibarri, Hollie ; Brazil, Giovanna ; Ware, Kelly ; King, Alexa ; Sainz, Katelyn ; Blumrick, Richard ; Ruther, Stacy

OBJECTIVETo assess the efficacy, safety, and tolerability of retosiban-a novel tocolytic unavailable in the US-in the management of preterm labor.METHODSWe searched ClinicalTrials.Gov, MEDLINE, PubMed, SCOPUS, Web of Science, and the Cochrane Library for relevant clinical trials using the terms "retosiban" and "preterm labor" through 09/2020. We included all published randomized clinical trials (three) that compared retosiban to placebo for preterm labor, excluding conferences, books, reviews, posters, case reports, and animal studies. We analyzed homogeneous data under the fixed-effects model and heterogeneous data under the random-effects model.RESULTSWe included all randomized clinical trials addressing this topic, which ultimately resulted in three trials with a total of 116 patients. There were no significant differences between retosiban and placebo in births at term (RR = 0.41, p = .02), births ≤7 days from the first study treatment (RR = 0.59, p = .23), or administration of rescue tocolytic (RR = 0.36, p = .07); the maternal adverse events of headache, anemia, constipation, or urinary tract infection (p > .05); or neonatal outcomes of Apgar score at 1 min (p = .88) or 5 min (p = .69), weight (p = .23), head circumference (p = .55), malnutrition (p = .27), hyperbilirubinemia (RR = 0.56, p = .21), jaundice (RR = 1.21, p = .84), respiratory distress (RR = 0.53, p = .49), or tachypnea (RR = 0.40, p = .42).CONCLUSIONWith the limited high quality evidence available, retosiban demonstrates no clear benefit over placebo in the management of preterm labor. Nevertheless, its favorable safety profile, oral bioavailability, and novel mechanism of action and the limited number of studies available for review warrant further analysis.

01 Sep 2021·The Cochrane database of systematic reviews

Oxytocin antagonists for assisted reproduction.

Review

Author: Raine-Fenning, Nick ; Tsampras, Nikolaos ; Choudhary, Meenakshi ; Kollmann, Martina ; Craciunas, Laurentiu

BACKGROUNDEmbryo transfer (ET) is a crucial step of in vitro fertilisation (IVF) treatment, and involves placing the embryo(s) in the woman's uterus. There is a negative association between endometrial wave-like activity (contractile activities) at the time of ET and clinical pregnancy, but no specific treatment is currently used in clinical practice to counteract their effects. Oxytocin is a hormone produced by the hypothalamus and released by the posterior pituitary. Its main role involves generating uterine contractions during and after childbirth. Atosiban is the best known oxytocin antagonist (and is also a vasopressin antagonist), and it is commonly used to delay premature labour by halting uterine contractions. Other oxytocin antagonists include barusiban, nolasiban, epelsiban, and retosiban. Administration of oxytocin antagonists around the time of ET has been proposed as a means to reduce uterine contractions that may interfere with embryo implantation. The intervention involves administering the medication before, during, or after the ET (or a combination).OBJECTIVESTo evaluate the effectiveness and safety of oxytocin antagonists around the time of ET in women undergoing assisted reproduction.SEARCH METHODSWe searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in March 2021; and checked references and contacted study authors and experts in the field to identify additional studies.SELECTION CRITERIAWe included randomised controlled trials (RCTs) of the use of oxytocin antagonists for women undergoing ET, compared with the non-use of this intervention, the use of placebo, or the use of another similar drug.DATA COLLECTION AND ANALYSISWe used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth and miscarriage; secondary outcomes were clinical pregnancy and other adverse events.MAIN RESULTSWe included nine studies (including one comprising three separate trials, 3733 women analysed in total) investigating the role of three different oxytocin antagonists administered intravenously (atosiban), subcutaneously (barusiban), or orally (nolasiban). We found very low- to high-certainty evidence: the main limitations were serious risk of bias due to poor reporting of study methods, and serious or very serious imprecision. Intravenous atosiban versus normal saline or no intervention We are uncertain of the effect of intravenous atosiban on live birth rate (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.88 to 1.24; 1 RCT, N = 800; low-certainty evidence). In a clinic with a live birth rate of 38% per cycle, the use of intravenous atosiban would be associated with a live birth rate ranging from 33.4% to 47.1%. We are uncertain whether intravenous atosiban influences miscarriage rate (RR 1.08, 95% CI 0.75 to 1.56; 5 RCTs, N = 1424; I² = 0%; very low-certainty evidence). In a clinic with a miscarriage rate of 7.2% per cycle, the use of intravenous atosiban would be associated with a miscarriage rate ranging from 5.4% to 11.2%. Intravenous atosiban may increase clinical pregnancy rate (RR 1.50, 95% CI 1.18 to 1.89; 7 RCTs, N = 1646; I² = 69%; low-certainty evidence), and we are uncertain whether multiple or ectopic pregnancy and other complication rates were influenced by the use of intravenous atosiban (very low-certainty evidence). Subcutaneous barusiban versus placebo One study investigated barusiban, but did not report on live birth or miscarriage. We are uncertain whether subcutaneous barusiban influences clinical pregnancy rate (RR 0.96, 95% CI 0.69 to 1.35; 1 RCT, N = 255; very low-certainty evidence). Trialists reported more mild to moderate injection site reactions with barusiban than with placebo, but there was no difference in severe reactions. They reported no serious drug reactions; and comparable neonatal outcome between groups. Oral nolasiban versus placebo Nolasiban does not increase live birth rate (RR 1.13, 95% CI 0.99 to 1.28; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence). In a clinic with a live birth rate of 33% per cycle, the use of oral nolasiban would be associated with a live birth rate ranging from 32.7% to 42.2%. We are uncertain of the effect of oral nolasiban on miscarriage rate (RR 1.45, 95% CI 0.73 to 2.88; 3 RCTs, N = 1832; I² = 0%; low-certainty evidence). In a clinic with a miscarriage rate of 1.5% per cycle, the use of oral nolasiban would be associated with a miscarriage rate ranging from 1.1% to 4.3%. Oral nolasiban improves clinical pregnancy rate (RR 1.15, 95% CI 1.02 to 1.30; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence), and probably does not increase multiple or ectopic pregnancy, or other complication rates (moderate-certainty evidence).AUTHORS' CONCLUSIONSWe are uncertain whether intravenous atosiban improves pregnancy outcomes for women undergoing assisted reproductive technology. This conclusion is based on currently available data from seven RCTs, which provided very low- to low-certainty evidence across studies. We could draw no clear conclusions about subcutaneous barusiban, based on limited data from one RCT. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of atosiban and barusiban before ET. Oral nolasiban appears to improve clinical pregnancy rate but not live birth rate, with an uncertain effect on miscarriage and adverse events. This conclusion is based on a phased study comprising three trials that provided low- to high-certainty evidence. Further large, well-designed RCTs, reporting on live births and adverse clinical outcomes, should focus on identifying the subgroups of women who are likely to benefit from this intervention.

100 Deals associated with Retosiban

External Link

KEGG	Wiki	ATC	Drug Bank
D08986	Retosiban	-	DB11818

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Obstetric Labor, Premature	Phase 3	SE	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	ES	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	BE	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	ES	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	GB	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	KR	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	SE	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	GB	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	BE	GSK Plc	16 Mar 2015
Obstetric Labor, Premature	Phase 3	KR	GSK Plc	16 Mar 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02292784 (ARIOS, CTgov)	Phase 3	Obstetric Labor, Premature	98	Placebo (Placebo (200719 Study))	bodsnqrysl(mehlwphxhp) = yijqqquwxk nslauajwlo (hjptrehjid, gfpfvhekit - jdkssueglw) View more	-	09 Jul 2020
				Atosiban (Atosiban (200721 Study))	bodsnqrysl(mehlwphxhp) = keaeocykmi nslauajwlo (hjptrehjid, vcuegzwbvy - jnhixuqctm) View more
NCT02292771 (CTgov)	Phase 3	Obstetric Labor, Premature	97	Retosiban (Retosiban)	veuxamirfj(sbopqjociu) = tuxpnaehcg odzidudavb (kjllzwtdpc, asjuffbtoc - fvqfzzkrri) View more	-	10 Sep 2018
				Atosiban (Atosiban)	veuxamirfj(sbopqjociu) = naieqmuefa odzidudavb (kjllzwtdpc, zfyzwbqzqd - kimcifcrsp) View more
NCT02377466 (NEWBORN-1, CTgov)	Phase 3	Obstetric Labor, Premature	25	Placebo IV infusion (Placebo)	pmoqdoczel(qvpwamnurg) = ecwvrofefk mozstwnrsj (tgxhwjfrlg, rvwmtxsrjm - whsamhqqzj) View more	-	19 Jul 2018
				Retosiban IV infusion (Retosiban)	pmoqdoczel(qvpwamnurg) = oqromqohvz mozstwnrsj (tgxhwjfrlg, yygkedrpkr - hzewoqbymd) View more
NCT00404768 (Pubmed \| Br J Clin Pharmacol) Manual	Phase 2	Obstetric Labor, Premature	64	retosiban	klplqjpuck(xpkogjsbdx) = uvcxhtyenj vrhihuqksy (zhcqvbrebd ) View more	Positive	01 Oct 2015
				Placebo	klplqjpuck(xpkogjsbdx) = tjudpyglll vrhihuqksy (zhcqvbrebd ) View more
NCT01702376 (Pubmed \| Med Lett Drugs Ther)	Phase 1	-	52	Retosiban 100 mg	wzncifvjqx(vuecaqgolr) = yrmykblpgg nefkbmmsva (wqmllcdzcc )	-	01 Jul 2015
				Retosiban 800 mg	wzncifvjqx(vuecaqgolr) = booryywzju nefkbmmsva (wqmllcdzcc )

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