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The Safety, Tolerability And Metabolism Of GSK221149A, In Pregnant Women (30-36 Weeks), In Pre-Term Labor

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00404768
First Posted: November 29, 2006
Last Update Posted: December 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
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.

Condition Intervention Phase
Obstetric Labour, Premature Drug: GSK221149A Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Vital Sign Values of Potential Clinical Concern [ Time Frame: 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 [ Time Frame: 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 With Clinical Chemistry and Hematology Parameter Values of Potential Clinical Concern [ Time Frame: 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 Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: 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.

  • Assessment of Amniotic Fluid Index (AFI) [ Time Frame: 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 [ Time Frame: 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.

  • Fetal Heart Rate Monitoring up to 48 Hours [ Time Frame: 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.

  • Number of Participants Achieving Uterine Quiescence [ Time Frame: 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.


Secondary Outcome Measures:
  • Number of Participants With Preterm Births in Part C [ Time Frame: 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 [ Time Frame: 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 in Part A and B [ Time Frame: 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 Head Circumference in Part A and B [ Time Frame: 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.

  • Neonatal Length Measured at 4-6 Weeks of Age in Part A and B [ Time Frame: 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- 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]) [ Time Frame: 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.

  • Derived Plasma GSK221149 Pharmacokinetic Parameters- Observed Elimination Half-life (T-half) and Time to Maximum Observed Drug Concentration (T-max) [ Time Frame: 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.

  • Derived Plasma GSK221149 Pharmacokinetic Parameters- Maximum Plasma Concentration (Cmax) [ Time Frame: 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.

  • Neonatal Apgar Scores (at Birth) Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C [ Time Frame: 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 Weight Gain Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C [ Time Frame: 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 Head Circumference Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C [ Time Frame: 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.

  • Neonatal Length Measured at 4 to 12 Weeks Post Adjusted Gestational Age in Part C [ Time Frame: 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.

  • Number of Participants Who Remained Undelivered Without Rescue Tocolytic Therapy After 48 Hours in Part C [ Time Frame: 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.

  • Percentage Reduction From Baseline in Number of Uterine Contractions [>30 Sec] Per Hour Within First 6 Hours of Therapy in Part C [ Time Frame: 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.


Enrollment: 93
Actual Study Start Date: October 12, 2007
Study Completion Date: July 7, 2011
Primary Completion Date: July 7, 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment
GSK221149A
Drug: GSK221149A
6mg/h and 12 mg/h
Placebo Comparator: Placebo
Placebo
Drug: Placebo
Matched Placebo to Drug

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
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Healthy pregnant females, 30 -36 weeks pregnant, without ruptured membranes
  • 18-45 inclusive
  • Symptoms of pre-term labor, (greater than or equal to 6 uterine contractions per hour, each of which at least 30 sec in duration, with cervical dilatation of less than or equal to 4 cm, (measured by tocodynamometry).

Exclusion criteria:

  • Any clinically relevant abnormality identified on the screening examination or any other medical condition or circumstance making the patient (mother and/or fetus) unsuitable for participation in the study
  • Any clinically relevant pre-existing or pregnancy-related co-morbid condition that may affect maternal pregnancy outcome or neonatal outcome (eg. hypertension, diabetes mellitus, bleeding/clotting diathesis)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00404768


  Show 58 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Publications:
Study Data/Documents: Informed Consent Form  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00404768     History of Changes
Other Study ID Numbers: OTA105256
First Submitted: November 27, 2006
First Posted: November 29, 2006
Results First Submitted: October 2, 2017
Results First Posted: December 13, 2017
Last Update Posted: December 13, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
URL: http://

Keywords provided by GlaxoSmithKline:
Premature Labor
Pre Term Labor
intravenous
fetal fibronectin

Additional relevant MeSH terms:
Premature Birth
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications