Understanding metabolism of drug and changes in human functioning for drug given to pregnant women at risk of late preterm birth
- Conditions
- Respiratory distress syndrome of newborn,
- Registration Number
- CTRI/2023/10/058248
- Lead Sponsor
- World Health Organization
- Brief Summary
**Burden of Preterm Birth**
Preterm birth is the single largest cause of neonatal death, and over80% of all preterm births occur in low and middle-income countries. It is amajor contributor to under five mortality. In spite of lowermortality/morbidity in late preterm compared to early preterm they contributesignificantly because of larger number
**Antenatal Corticosteroids (ACS) in preterm birth**
The current standard of care is to administer antenatal corticosteroids(ACS) to women at risk of preterm birth prior to 34 weeks’ gestation. This isto accelerate fetal lung maturation and thus improve neonatal outcomes in theevent of delivery. Recently completed ACTION-I trial showed benefit of ACS inearly preterm (26-34 wks). Benefit of ACS in late preterm (34-36 weeks) is lessclear
**Pharmacokinetics & Pharmacodynamics**
Recent animal studies have suggested that lung maturational changes canbe effected at much lower doses of ACS than those conventionally used inclinical practice. As ACS is one of the most effective strategies available toreduce neonatal mortality and morbidity from preterm birth, it is critical toascertain the PK/PD of ACS, to ensure that fetal exposure is optimal. WHO iscurrently conducting the ACTION-III trial, a multi-country trial recruiting13,500 women at risk of late preterm birth, and randomizing them to one ofthree arms (This study is registered in CTRI with registration number:CTRI/2021/03/032429. The knowledge gained from PK/PD study of ACS can be usedfor future calibration of optimal ACS dosing in the light of their demonstratedefficacy in early preterm birth, and in the event that efficacy is alsodemonstrated for late preterm birth.
**Primary Objectives**
- To study the population PK of betamethasone phosphate 2 mg IM administered every 12 hours and dexamethasone phosphate 6 mg IM administered every 12 hours in pregnant women at risk of late preterm birth.
- To study PD effects of betamethasone and dexamethasone in the above doses on pregnant women; and to compare these parameters to those in pregnant women who do not receive either betamethasone or dexamethasone.
**Secondary Objectives**
- To assess levels of dexamethasone phosphate and betamethasone phosphate in cord blood at birth and identify a fetal: maternal ratio of the drugs.
- To study PD parameters in cord blood of ACS-treated women and compare these parameters with those obtained from cord blood of placebo-treated women
- To compare the above (i-iv) in African (Nigerian) and South Asian (Indian) pregnant populations.
**Study Design**
- PK/PD study nested within a Phase III clinical trial (WHO ACTION-III trial), using sparse sampling approach
**Study Sites**
This PK/PD study will be conducted at two Nigerian and two Indian sitesrecruiting for the ACTION III trial. These two countries are selected becauseof:
- Representativeness of women from the India and Nigeria sites to reflect the BMI of South Asian and West African pregnant women.
- Ability of facilities to closely follow the protocol (particularly sample timing, processing and storage requirements) of this study at these sites
- Ease of transportation of samples to India where the assay will be done.
The following hospitals recruiting for the ACTION III trial willparticipate in this study:
- Safdarjung Hospital, New Delhi, India
- KLE Hospital, Belgavi, India
- University of Abuja hospital, Nigeria
- Ife University hospital Ife, Nigeria
- Island Maternity, Lagos, Nigeria
- University college hospital Ibadan, Nigeria
**Study Population**
Consecutive women enrolled into the ACTION III trial will be approachedover a period of 4 months. A subgroup of women enrolled into the threearms of the ACTION III trial will be invited to participate in the PK PD study.The three arms of the ACTION III trial include the following:
**Arm 1:** Dexamethasone phosphate 6mg IM 12hrly for 4 doses
**Arm 2:** Betamethasone phosphate 2mg IM 12hrly for 4 doses
**Arm 3:** Saline placebo
**Inclusion Criteria**
A subgroup of women from each of the three arms of the ACTION IIItrial
**Exclusion Criteria**
ACTION III participants who are diabetic, severely anaemic or withfeatures of HELLP syndrome will be excluded
**Blinding**
Blinded: Random IDs to be approached will be provided centrally(consecutive as far as possible – to facilitate logistics)
**Approach**
A population PK approach will be conducted to describe the PK ofbetamethasone and dexamethasone. Population PK modelling approaches relyon data from multiple individuals and often utilize pooled data from multiplepatients, sampled at pragmatic intervals (sparse sampling). This approachis generally used to analyse clinical data collected in a setting where intensePK sampling are not practical, such as in Phase 3 trials, for ethical reasons(this method was used in determining dose of antiretrovirals in pregnancy)
**Sample collection**
Serial maternal venipuncture samples will be collected from prior toadministration of the first dose of the study intervention, up to 2 hour afterbirth. Maximum of 5 draws per participant will be collected for the PKstudy. These same draws will also be used for the PD measures. Anadditional 2 samples on day 2 and day 3 will be drawn to allow the measure ofPD parameters as they approach baseline. As far as possible, study drawswill be combined with sample draws necessary for routine care to minimizestress and discomfort to the patient.
**Outcome**
Outcomes of interest include ACS levels and PD parameter levels(cortisol, glucose, white cell counts). One study form will be developedfor data collection. This will be piloted in participating centers to identifyany problems in form structure or content. Sample collection, processing,and measurement
**Plasma steroid concentration measurement**
The plasma steroid levels will be assayed at central FDA approvedfacility in India. Dexamethasone and betamethasone will be analysed usinga validated LCMS (liquid chromatography mass spectrometry) method.
**Pharmacokinetics**
A maximum of 5 samples per woman will be collected:
- prior to administration of the first dose of the ACTION III study medication,
- 3 hours after,
- 12 hours after and,
- 1 day after birth.
Cord blood at birth will be used to study the levels in foetalcirculation. Using all collected samples, steroid levels will be measured usinga validated liquid chromatography-mass spectrometry assay.
**Pharmacodynamic biomarker measurement**
Three parameters will be measured as PD markers at an FDA approvedfacility in India. These include:
- serum cortisol
- glucose and
- white cell counts
**Sample size**
A total of 150 women from India and 150 women from Nigerian sites (thisincludes 50 women from each of the three arms adding to 150 women from eachcountry).
**Implications**
Information on the PK and PD of ACS will generate new knowledge that caninform further ACS dose optimization. This study will contribute towardsmaking ACS safer for mothers and newborns globally.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Open to Recruitment
- Sex
- Female
- Target Recruitment
- 300
Consecutive women enrolled into the ACTION III trial at the two Indian sites, KLE Academy of Higher Education and Research and VMMC & Safdarjung hospital will be approached over a period of 4 months.
ACTION III participants who are diabetic, severely anaemic or with features of HELLP syndrome will be excluded.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 2. Pharmacodynamics (serum cortisol, glucose and white cell counts measurement) in betamethasone phosphate and dexamethasone phosphate treated pregnant women at risk of late preterm birth For PK and PD outcome measurement: | 1. Baseline (prior to administration of 1st dose) (PK and PD outcome measurement) | 2. 2-4 hrs after 1st dose | 3. 8-12 hrs after 1st does | 4. 24-36 hrs after last dose | 5. At time of birth | For PD outcome measurement , 2 additional timepoints: | 6. 48-60 hrs after last dose | 7. 72-96 hrs after last dose 1. Pharmacokinetics (plasma steroid concentration measurement) of betamethasone phosphate and dexamethasone phosphate in pregnant women at risk of late preterm birth For PK and PD outcome measurement: | 1. Baseline (prior to administration of 1st dose) (PK and PD outcome measurement) | 2. 2-4 hrs after 1st dose | 3. 8-12 hrs after 1st does | 4. 24-36 hrs after last dose | 5. At time of birth | For PD outcome measurement , 2 additional timepoints: | 6. 48-60 hrs after last dose | 7. 72-96 hrs after last dose
- Secondary Outcome Measures
Name Time Method 1. Dexamethasone phosphate & Betamethasone phosphate measurement in cord blood ; feto-maternal ratio of Dexamethasone phosphate & Betamethasone phosphate 2. Pharmacodynamics (serum cortisol, glucose & white cell counts measurement) in cord blood of betamethasone phosphate & dexamethasone phosphate treated women
Trial Locations
- Locations (3)
KLES Dr Prabhakar Kore Hospital and Medical Research Centre Belgaum
🇮🇳Belgaum, KARNATAKA, India
Translational Health Science and Technology Institute
🇮🇳Faridabad, HARYANA, India
Vardhman Mahavir Medical College and Safdarjung Hospital
🇮🇳Delhi, DELHI, India
KLES Dr Prabhakar Kore Hospital and Medical Research Centre Belgaum🇮🇳Belgaum, KARNATAKA, IndiaDr Yeshita V PujarPrincipal investigator9448142989yvpujar@hotmail.com