The Safety, Tolerability And Metabolism Of GSK221149A, In Pregnant Women (30-36 Weeks), In Pre-Term Labor
- Conditions
- Obstetric Labour, Premature
- Interventions
- Drug: GSK221149ADrug: Placebo
- Registration Number
- NCT00404768
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
Pre-Term Labor (prior to 37 weeks gestation) is the largest single cause of infant morbidity and mortality and is frequently associated with long-term disability. Oxytocin is a hormone produced by the body during labor. GSK221149A is an experimental drug that will be used to block the effects of oxytocin, and therefore pause or prevent contractions. In this study, patients with preterm labor will be given an intravenous infusion of GSK221149A over approximately 12 hours followed by an oral tablet in Parts A and B. In part C of this study, patients with preterm labor will be give an intravenous infusion of GSK221149A over approximately 48 hours. The use of a rescue tocolytic is allowed in the study.
- Detailed Description
A randomized, double-blind, placebo-controlled, dose ranging study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK221149A administered intravenously and to investigate the pharmacokinetics of GSK221149A administered orally to healthy, pregnant females with uncomplicated pre-term labor between 300/7 and 356/7 weeks' gestation
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 93
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment GSK221149A GSK221149A Placebo Placebo Placebo
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) Up to Follow-up (Week 12) An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, is a congenital anomaly or birth defect. Any SAEs assessed as related to study participation (e.g. study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product was recorded from the time a participant consents to participate in the study up to and including any follow-up contact.
Number of Participants With Clinical Chemistry and Hematology Parameter Values of Potential Clinical Concern Up to 24 hours post-treatment Hematology parameters included complete blood count with red blood cell indices and white blood cell differential, platelet count, human immune deficiency virus, Hepatitis C antibody and Hepatitis B surface antigen. Clinical chemistry parameters included blood urea nitrogen (BUN), creatinine, glucose, sodium, potassium, phosphate, chloride, total CO2, calcium, aspartate amino transferase (AST), alanine amino transferase (ALT), gamma glutamyltransferase (GGT), alkaline phosphatase, total bilirubin, uric acid, albumin and total protein. Only those parameters for which at least one value of potential clinical concern was reported are summarized. Number of participants with clinical chemistry and hematology parameter values of potential clinical concern are presented.
Number of Participants With Vital Sign Values of Potential Clinical Concern Up to Follow-up (Week 12) Vital signs included blood pressure (systolic and diastolic) and heart rate. Maternal blood pressure and heart rate were measured with the participant in the semi-supine position. Blood pressure was measured in millimeters of mercury (mmHg) and heart rate in beats per minute (bpm). Potential clinical concern range for systolic blood pressure: \<85 and \>160 mmHg, for diastolic: \<45 and \>100 mmHg and heart rate: \<40 and \>110 bpm. Only those parameters for which at least one value of potential clinical concern was reported are summarized. Number of participants with vital sign values of potential clinical concern are presented.
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern Up to Follow-up (Week 12) All scheduled 12-lead ECGs were obtained after the participant was rested in the semi-supine position for approximately 15 minutes. Whenever 12-lead ECGs were performed at the same nominal time as a blood draw or blood pressure and pulse rate measurement, the 12-lead ECG were obtained first. ECGs were repeated or recorded in triplicate and the average value recorded at the investigators discretion. The potential clinical concern range for ECG parameters were: Absolute QT corrected (QTc) interval: \>450 milliseconds (msec), Increase from Baseline (Day 0): QTc \>60 msec, PR interval: \<110 and \>220 msec and QRS interval: \<75 and \>110 msec. All 12-lead ECGs obtained throughout the study day were evaluated for safety and were reviewed by the investigator or investigator designee. Number of participants with electrocardiogram values of potential clinical concern are presented.
Number of Participants Achieving Uterine Quiescence Up to 48 hours post-dose Uterine quiescence was defined as 4 contractions per/hour or less with no cervical change within the first 6 hours of therapy. Number of participants (from part A,B,C) achieving uterine Quiescence are presented.
Fetal Heart Rate Monitoring up to 48 Hours Up to 48 hours post-dose Fetal heart rate monitoring was incorporated to assess fetal tolerability. Fetal heart rate was monitored continuously at 2, 4, 6, 8, 12, 18, 24, 36 and up to 48 hours post-therapy. Mean fetal heart rate is presented. Data for only key-time points values have been presented.
Assessment of Amniotic Fluid Index (AFI) Up to 48 hours-post dose AFI is a quantitative estimate of amniotic fluid and an indicator of fetal well-being. AFI is the score (expressed in centimetes) given to the amount of amniotic fluid seen on ultrasonography of a pregnant uterus. An AFI between 8 to 18 is considered normal. An AFI \< 5 to 6 is considered as oligohydramnios characterized by deficiency of amniotic fluid. An AFI \> 18 to 24 is considered as polyhydramnios characterized by excess of amniotic fluid in the amniotic sac.
Number of Participants With 50% Reduction in Uterine Contractions Per Hour in Part A and B Up to 48 hours post-dose For uterine contraction assessment, an external tocodynamometer was fastened around the participant's abdomen. The number and duration of contraction was recorded at screening and up to 48 hours post-dose.The number of participants that achieve a reduction of at least 50% in uterine contractions with no cervical change within 6 hours and to maintain that reduction until 12 hours of therapy has been presented.
- Secondary Outcome Measures
Name Time Method Neonatal Head Circumference in Part A and B At Birth and Follow-up (Week 12) Neonatal safety was assessed through assessment of head circumference. Head circumference was measured at birth and follow-up (Week 12). Mean head circumference is presented.
Derived Plasma GSK221149 Pharmacokinetic Parameters- Area Under Concentration-time Curve From Time Zero to Infinity (AUC [0 to Infinity]) and Area Under Concentration-time Curve From Time Zero to Last Quantifiable Concentration (AUC [0 to Last]) Pre-dose, 2, 4, 8, 12, 24 and 48 (just before infusion was stopped) hours after the start of the infusion Blood samples (approximately 2mL) were collected for the PK measurement of plasma GSK221149 at pre-dose, 2, 4, 8, 12, 24 and 48 (just before infusion was stopped) hours after the start of the infusion.
Neonatal Weight Gain in Part A and B At birth and Follow-up (Week 12) Neonatal safety was assessed through assessment of weight gain. Weight gain was measured at birth and follow-up (Week 12). Mean weight gain is presented.
Number of Participants With Preterm Births in Part C Up to 48 hours post-dose Preterm is defined as babies born alive before 37 weeks of pregnancy are completed. There are sub-categories of preterm birth, based on gestational age: extremely preterm (\<28 weeks) very preterm (28 to \<32 weeks). Number of participants with preterm births are presented.
Neonatal Apgar Scores in Part A and B 1 minute and 5 minutes after birth APGAR scores range from 0 to 2 for each condition (color, reflex response, muscle tone, respiration and heart rate) with a maximum final total score of 10. For heart rate: 0=no heart rate, 1=\<100 bpm (baby not very responsive), 2=\>100 bpm (baby vigorous); for respiration: 0=no breathing, 1= weak cry, 2=good, strong cry; for muscle tone: 0=limp, 1=some flexing of arms and legs, 2=active motion; for reflex response: 0=no response, grimace during stimulation, 2=grimace and cough or sneeze during stimulation; for color: 0=blue/pale, 1=good body color but blue hands and feet, 3=completely pink or good color. APGAR total score is the sum of sub-scores ranging from 0 to 10, where lower score indicates worst condition and higher score indicates best condition.
Neonatal Weight Gain Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C At birth and Follow-up (Week 12) Neonatal safety was assessed through assessment of weight gain. Weight gain was measured at birth and follow-up (Week 12). Mean weight gain is presented.
Neonatal Length Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C At Birth and Follow-up (Week 12) Neonatal safety was assessed through assessment of neonatal length. Neonatal length was measured at birth and follow-up (Week 12). Mean neonatal length is presented.
Neonatal Length Measured at 4-6 Weeks of Age in Part A and B At birth and follow-up (approximately 4 to 6 weeks of age) Neonatal safety was assessed through assessment of neonatal length. Neonatal length was measured at birth and follow-up (approximately 4 to 6 weeks of age). Mean Neonatal length is presented.
Derived Plasma GSK221149 Pharmacokinetic Parameters- Observed Elimination Half-life (T-half) and Time to Maximum Observed Drug Concentration (T-max) Pre-dose, 2, 4, 8, 12, 24 and 48 (just before infusion was stopped) hours after the start of the infusion Blood samples (approximately 2 mL) were collected for the PK measurement of plasma GSK221149 at pre-dose, 2, 4, 8, 12, 24 and 48 (just before infusion was stopped) hours after the start of the infusion.
Percentage Reduction From Baseline in Number of Uterine Contractions [>30 Sec] Per Hour Within First 6 Hours of Therapy in Part C First 6 hours of therapy For uterine contraction assessment, an external tocodynamometer was fastened around the participant's abdomen. The number and duration of contraction was recorded at screening and up to 48 hours post-dose. Baseline was Day 0. Reduction from Baseline was calculated by subtracting Baseline values from post-Baseline values. Percentage reduction from Baseline in number of uterine contractions \[\>30 sec\] per hour within first 6 hours of therapy are presented.
Derived Plasma GSK221149 Pharmacokinetic Parameters- Maximum Plasma Concentration (Cmax) Pre-dose, 2, 4, 8, 12, 24 and 48 (just before infusion was stopped) hours after the start of the infusion Blood samples (approximately 2 mL) were collected for the PK measurement of plasma GSK221149 at pre-dose, 2, 4, 8, 12, 24 and 48 (just before infusion was stopped) hours after the start of the infusion.
Number of Participants Who Remained Undelivered Without Rescue Tocolytic Therapy After 48 Hours in Part C 48 hours post-dose Tocolytics are medications used to suppress premature labor. They are given when delivery would result in premature birth. Number of participants who remained undelivered without rescue tocolytic therapy after 48 hours are presented.
Neonatal Apgar Scores (at Birth) Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C 1 minute and 5 minute after birth at 4 to 12 weeks post adjusted gestational age APGAR scores range from 0 to 2 for each condition (color, reflex response, muscle tone, respiration and heart rate) with a maximum final total score of 10. For heart rate: 0=no heart rate, 1=\<100 bpm (baby not very responsive), 2=\>100 bpm (baby vigorous); for respiration: 0=no breathing, 1= weak cry, 2=good, strong cry; for muscle tone: 0=limp, 1=some flexing of arms and legs, 2=active motion; for reflex response: 0=no response, grimace during stimulation, 2=grimace and cough or sneeze during stimulation; for color: 0=blue/pale, 1=good body color but blue hands and feet, 3=completely pink or good color. APGAR total score is the sum of sub-scores ranging from 0 to 10, where lower score indicates worst condition and higher score indicates best condition.
Neonatal Head Circumference Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C At Birth and Follow-up (Week 12) Neonatal safety was assessed through assessment of head circumference. Head circumference was measured at birth and follow-up (Week 12). Mean head circumference is presented.
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧London, United Kingdom