Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00137501
Status:
TERMINATED
Last Update Posted:
2013-07-19
First Post:
2005-08-29
Brief Title:
Two Dose Regimens of Nifedipine for the Management of Preterm Labor
Sponsor:
American University of Beirut Medical Center
Organization:
American University of Beirut Medical Center
Study Overview
Official Title:
Study of Different Doses of Nifedipine to Treat Preterm Labor
Status:
TERMINATED
Status Verified Date:
2013-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
The trial was terminated because of difficulties in recruitement
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Preterm birth is one of the most important causes of perinatal morbidity and mortality worldwide Prevention and treatment of preterm labor is important not as an end in itself but as a means of reducing adverse events for the neonate A wide range of tocolytics drugs used to suppress uterine contractions have been tried Magnesium sulfate MgSO4 is the most widely used tocolytic at the American University of Beirut Medical Center despite the fact that an effective tocolytic role of MgSO4 has never been established Moreover the currently available data are suggestive of deleterious fetal effects of MgSO4 in the setting of preterm labor to the extent that some authorities are recommending abandoning it for routine use as a tocolytic therapy Calcium channel blockers have the ability to inhibit contractility in smooth muscle cells Consequently nifedipine has emerged as an effective and rather safe alternative tocolytic agent for the management of preterm labor after several studies have shown that the use of nifedipine in comparison with other tocolytics is associated with a more frequent successful prolongation of pregnancy resulting in significantly fewer admissions of newborns to the neonatal intensive care unit and is associated with a lower incidence of respiratory distress syndrome The unequivocal impact of this method of tocolysis on short term postponement of delivery and the opportunity that this provides for affecting in-utero transfer and steroid administration has prompted many investigators to recommend focusing future trials on testing different dose regimens of nifedipine To the best of the investigators knowledge no study comparing two different dose regimens of nifedipine has been previously published in the literature The objective of their study is to compare the effectiveness of a high versus a low dose regimen in a total of 200 patients admitted with the diagnosis of preterm labor between 24 and 34 weeks of gestation In addition the investigators study will try to assess the safety profile of the 2 dose regimens on the mother and the neonate by assessing a selected number of outcome variables The data generated will be used to change their protocol for managing patients presenting with threatened preterm delivery and will fill the existing gap regarding the most effective and safest dose regimen of nifedipine in such patients
Detailed Description:
RESEARCH DESIGN AND METHODS
Inclusion criteria
All pregnant women diagnosed with preterm labor defined as regular contractions associated with cervical change between 24 and 34 weeks of gestation
Exclusion criteria
Multiple pregnancy
Preterm rupture of membranes
Congenital fetal malformations
IUGR intra uterine growth restriction
Previous tocolysis this pregnancy
Chorioamnionitis
Cervical dilation 4 cms
Maternal medical conditions such as renal insufficiency hepatic insufficiency or myasthenia gravis
Non-reassuring fetal heart rate
Maternal hypotension defined as a blood pressure 9050 mm Hg
Randomization procedure
Randomization envelopes will be prepared by means of a random number table After informed consent is obtained the next numbered opaque envelope will be opened to assign each patient to receive either the low or high nifedipine dose regimen Because of the different doses of nifedipine neither patients nor physicians will be blinded to treatment allocation
Routine studies and procedures
A baseline ECG will be performed before starting the medication
All patients will receive a 500-mL intravenous bolus of isotonic sodium chloride solution unless they have clinical volume overload followed by a maintenance administration of 125 mLh
Maternal blood pressure and heart rate will be recorded every 15 minutes as long as the patient is in labor and every 4 hours thereafter
Fetal heart rate and uterine activity were monitored continuously throughout the study period
All patients eligible for the study will receive antibiotic prophylaxis for Group B Streptococcal infection IV Pen G or Ampicillin for at least 48 hours pending the vaginorectal swab culture that is done routinely on every patient presenting with preterm labor
All patients will receive one course of 12 mg betamethasone intramuscularly every 24 hours for 48 hours to promote fetal lung maturation and a rescue dose if they present in labor again at 34 weeks of gestation
Interventions
First arm high dose
Nifedipine Adalat 20 mg sublingual crushed repeated after 30 minutes if contractions do not decrease in intensity Maintenance of 120-160 mgs of slow-release nifedipine Nifedicor daily for 48 hours 30 mg Q 6 hrs up to a maximum of 40 mg Q 6 hrs Once contractions cease nifedipine will be maintained at 80-120 mg daily in divided doses up to 36 weeks of gestation on an outside basis
Second arm low dose
Nifedipine Adalat 10 mg sublingual crushed then 10 mg sublingual in 15 min followed by 10 mg PO Q 15 mins PRN to a maximum of 40 mg in the first hour Maintenance of 60-80 mgs of slow-release nifedipine Nifedicor daily for 48 hours 20 mg Q 8 hrs or 20 mg Q 6 hrs Once contractions cease nifedipine will be maintained at 60 mg daily in divided doses up to 36 weeks of gestation
Tocolysis will be considered to be achieved when uterine activity decrease to 4 contractionsh with the absence of cervical change
If patients continue to have uterine activity after 6 hours or have cervical dilatation 2 cm after admission examination they could be switched to another tocolytic regimen namely intravenous MgSO4 or intravenous ritodrine
Written Consent
The written consent will be handed to every pregnant patient eligible for this study She will be given enough time to read it and decide whether she is willing to participate in the trial
Outcome variables studied
Speed of onset of uterine quiescence
Uterine quiescence at 6 hours of initiating therapy
Delivery 48 hours from initiation of therapy
Delivery 7 days from initiation of therapy
Delivery 37 weeks of gestation
Delivery at 34 weeks of gestation
Side effects to nifedipine
Maternal adverse drug reactions requiring cessation of treatment
Antepartum hemorrhage
Maternal length of hospital stay
Pregnancy prolongation
Postpartum hemorrhage
Birthweight
Apgar score 7 at 5 min
Admission to NICU
Mechanical ventilation
RDS respiratory distress syndrome
IVH all grades
Neonatal nursery stay
Neonatal jaundice
NEC Necrotizing enterocolitis
Neonatal death
Side effects associated with nifedipine include a mild decrease in blood pressure and a rise in pulse headache flushing dizziness and nausea
Data Collection
The initial information in the data sheets will be filled by the resident in charge of delivery suite However the follow up on the response of the patients to the medication and data regarding the maternal side effects and neonatal outcome will be filled by a part time research assistant
Statistical Analysis
Statistical analysis will be performed using the SPSS statistical package Categoric data like maternal characteristics the rates of neonatal morbidity and mortality will be compared using Chi square when sample sizes support the approximation Otherwise categorical data will be analyzed with two-tailed Fisher exact test if the expected cell frequencies were small Continuous variables will be compared by Student t test if assumptions of normality and homogeneity of variances appeared to be reasonable Unpaired variables and differences in distributions will be compared using the Mann-Whitney test Neonatal outcomes will be analyzed comparing the total number of affected neonates in each group A p-value 005 will be considered statistically significant
Proposed budget
Personnel
A part time research assistant with BS background 450000 LL month x 29 months 13050000 LL
Tasks expected
Completing the data sheets
FU on response of mother to tocolysis and assessing maternal side effects
FU on the neonates and getting information about the neonatal outcome variables
Data entry
Medical supplies
Medications will be provided through the pharmacy
Compensation for patients
None
The total amount of money needed in Lebanese pounds
13050000 LLyear
Time frame
May 2003 - May 2006 - Collection of data and randomization of patients to the 2 arms of the study
June 2006 - Sep 2006 - Follow up on patients that were randomized during the first 5 months of 2006 to get information about their pregnancy outcome
Oct 2006 - Nov 2006 - Data analysis and writing the final paper
Data collection will be under the direct supervision of the principal investigator
Percent of time spent by principal investigator on this proposal 20 of research time which accounts for about 20 of time allocated for research activities
Co-Investigators Role
Dr Usta will help in data analysis and in writing the final paper 5 of research time
Dr Mroueh will help in writing the final paper 5 of research time Two Investigational Drug forms will be used since this trial will involve the same drug nifedipine in 2 different forms Adalat and Nifedicor
Principal Investigator
Anwar Nassar MD Assistant Professor American University of Beirut Medical Center Department of Obstetrics and Gynecology
Co-Investigators
Ihab Usta MD Associate Professor American University of Beirut Medical Center Department of Obstetrics and Gynecology
Adnan Mroueh MD Professor American University of Beirut Medical Center Department of Obstetrics and Gynecology
REFERENCES
Assessment of Risk Factors for Preterm Birth ACOG practice bulletin Number 31 October 2001
Mittendorf R Dambrosia J Pryde PG Lee KS Gianopoulos JG Besinger RE Tomich PG Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants Am J Obstet Gynecol18661111-8 June 2002
Gyetvai K Hannah ME Hodnett ED Ohlsson A Tocolytics for preterm labor a systematic review Obstet Gynecol945 Pt 2869-77 Nov 1999
Mittendorf R Covert R Elin R Pryde PG Khoshnood B Lee KS Umbilical cord serum ionized magnesium level and total pediatric mortality Obstet Gynecol 98175-8 July 2001
Weerakul W Chittacharoen A Suthutvoravut S Nifedipine versus terbutaline in management of preterm labor Int J Gynaecol Obstet763311-3 Mar 2002
Papatsonis DN Van Geijn HP Ader HJ Lange FM Bleker OP Dekker GA Nifedipine and ritodrine in the management of preterm labor a randomized multicenter trial Obstet Gynecol902230-4 Aug 1997
Larmon JE Ross BS May WL Dickerson GA Fischer RG Morrison JC Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor Am J Obstet Gynecol18161432-7 Dec1999
Koks CA Brolmann HA de Kleine MJ Manger PA A randomized comparison of nifedipine and ritodrine for suppression of preterm labor Eur J Obstet Gynecol Reprod Biol772171-6 Apr 1998
Inclusion criteria
All pregnant women diagnosed with preterm labor defined as regular contractions associated with cervical change between 24 and 34 weeks of gestation
Exclusion criteria
Multiple pregnancy
Preterm rupture of membranes
Congenital fetal malformations
IUGR intra uterine growth restriction
Previous tocolysis this pregnancy
Chorioamnionitis
Cervical dilation 4 cms
Maternal medical conditions such as renal insufficiency hepatic insufficiency or myasthenia gravis
Non-reassuring fetal heart rate
Maternal hypotension defined as a blood pressure 9050 mm Hg
Randomization procedure
Randomization envelopes will be prepared by means of a random number table After informed consent is obtained the next numbered opaque envelope will be opened to assign each patient to receive either the low or high nifedipine dose regimen Because of the different doses of nifedipine neither patients nor physicians will be blinded to treatment allocation
Routine studies and procedures
A baseline ECG will be performed before starting the medication
All patients will receive a 500-mL intravenous bolus of isotonic sodium chloride solution unless they have clinical volume overload followed by a maintenance administration of 125 mLh
Maternal blood pressure and heart rate will be recorded every 15 minutes as long as the patient is in labor and every 4 hours thereafter
Fetal heart rate and uterine activity were monitored continuously throughout the study period
All patients eligible for the study will receive antibiotic prophylaxis for Group B Streptococcal infection IV Pen G or Ampicillin for at least 48 hours pending the vaginorectal swab culture that is done routinely on every patient presenting with preterm labor
All patients will receive one course of 12 mg betamethasone intramuscularly every 24 hours for 48 hours to promote fetal lung maturation and a rescue dose if they present in labor again at 34 weeks of gestation
Interventions
First arm high dose
Nifedipine Adalat 20 mg sublingual crushed repeated after 30 minutes if contractions do not decrease in intensity Maintenance of 120-160 mgs of slow-release nifedipine Nifedicor daily for 48 hours 30 mg Q 6 hrs up to a maximum of 40 mg Q 6 hrs Once contractions cease nifedipine will be maintained at 80-120 mg daily in divided doses up to 36 weeks of gestation on an outside basis
Second arm low dose
Nifedipine Adalat 10 mg sublingual crushed then 10 mg sublingual in 15 min followed by 10 mg PO Q 15 mins PRN to a maximum of 40 mg in the first hour Maintenance of 60-80 mgs of slow-release nifedipine Nifedicor daily for 48 hours 20 mg Q 8 hrs or 20 mg Q 6 hrs Once contractions cease nifedipine will be maintained at 60 mg daily in divided doses up to 36 weeks of gestation
Tocolysis will be considered to be achieved when uterine activity decrease to 4 contractionsh with the absence of cervical change
If patients continue to have uterine activity after 6 hours or have cervical dilatation 2 cm after admission examination they could be switched to another tocolytic regimen namely intravenous MgSO4 or intravenous ritodrine
Written Consent
The written consent will be handed to every pregnant patient eligible for this study She will be given enough time to read it and decide whether she is willing to participate in the trial
Outcome variables studied
Speed of onset of uterine quiescence
Uterine quiescence at 6 hours of initiating therapy
Delivery 48 hours from initiation of therapy
Delivery 7 days from initiation of therapy
Delivery 37 weeks of gestation
Delivery at 34 weeks of gestation
Side effects to nifedipine
Maternal adverse drug reactions requiring cessation of treatment
Antepartum hemorrhage
Maternal length of hospital stay
Pregnancy prolongation
Postpartum hemorrhage
Birthweight
Apgar score 7 at 5 min
Admission to NICU
Mechanical ventilation
RDS respiratory distress syndrome
IVH all grades
Neonatal nursery stay
Neonatal jaundice
NEC Necrotizing enterocolitis
Neonatal death
Side effects associated with nifedipine include a mild decrease in blood pressure and a rise in pulse headache flushing dizziness and nausea
Data Collection
The initial information in the data sheets will be filled by the resident in charge of delivery suite However the follow up on the response of the patients to the medication and data regarding the maternal side effects and neonatal outcome will be filled by a part time research assistant
Statistical Analysis
Statistical analysis will be performed using the SPSS statistical package Categoric data like maternal characteristics the rates of neonatal morbidity and mortality will be compared using Chi square when sample sizes support the approximation Otherwise categorical data will be analyzed with two-tailed Fisher exact test if the expected cell frequencies were small Continuous variables will be compared by Student t test if assumptions of normality and homogeneity of variances appeared to be reasonable Unpaired variables and differences in distributions will be compared using the Mann-Whitney test Neonatal outcomes will be analyzed comparing the total number of affected neonates in each group A p-value 005 will be considered statistically significant
Proposed budget
Personnel
A part time research assistant with BS background 450000 LL month x 29 months 13050000 LL
Tasks expected
Completing the data sheets
FU on response of mother to tocolysis and assessing maternal side effects
FU on the neonates and getting information about the neonatal outcome variables
Data entry
Medical supplies
Medications will be provided through the pharmacy
Compensation for patients
None
The total amount of money needed in Lebanese pounds
13050000 LLyear
Time frame
May 2003 - May 2006 - Collection of data and randomization of patients to the 2 arms of the study
June 2006 - Sep 2006 - Follow up on patients that were randomized during the first 5 months of 2006 to get information about their pregnancy outcome
Oct 2006 - Nov 2006 - Data analysis and writing the final paper
Data collection will be under the direct supervision of the principal investigator
Percent of time spent by principal investigator on this proposal 20 of research time which accounts for about 20 of time allocated for research activities
Co-Investigators Role
Dr Usta will help in data analysis and in writing the final paper 5 of research time
Dr Mroueh will help in writing the final paper 5 of research time Two Investigational Drug forms will be used since this trial will involve the same drug nifedipine in 2 different forms Adalat and Nifedicor
Principal Investigator
Anwar Nassar MD Assistant Professor American University of Beirut Medical Center Department of Obstetrics and Gynecology
Co-Investigators
Ihab Usta MD Associate Professor American University of Beirut Medical Center Department of Obstetrics and Gynecology
Adnan Mroueh MD Professor American University of Beirut Medical Center Department of Obstetrics and Gynecology
REFERENCES
Assessment of Risk Factors for Preterm Birth ACOG practice bulletin Number 31 October 2001
Mittendorf R Dambrosia J Pryde PG Lee KS Gianopoulos JG Besinger RE Tomich PG Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants Am J Obstet Gynecol18661111-8 June 2002
Gyetvai K Hannah ME Hodnett ED Ohlsson A Tocolytics for preterm labor a systematic review Obstet Gynecol945 Pt 2869-77 Nov 1999
Mittendorf R Covert R Elin R Pryde PG Khoshnood B Lee KS Umbilical cord serum ionized magnesium level and total pediatric mortality Obstet Gynecol 98175-8 July 2001
Weerakul W Chittacharoen A Suthutvoravut S Nifedipine versus terbutaline in management of preterm labor Int J Gynaecol Obstet763311-3 Mar 2002
Papatsonis DN Van Geijn HP Ader HJ Lange FM Bleker OP Dekker GA Nifedipine and ritodrine in the management of preterm labor a randomized multicenter trial Obstet Gynecol902230-4 Aug 1997
Larmon JE Ross BS May WL Dickerson GA Fischer RG Morrison JC Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor Am J Obstet Gynecol18161432-7 Dec1999
Koks CA Brolmann HA de Kleine MJ Manger PA A randomized comparison of nifedipine and ritodrine for suppression of preterm labor Eur J Obstet Gynecol Reprod Biol772171-6 Apr 1998
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None