Randomized Trial of Maternal Progesterone Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Children's Hospital of Philadelphia
Sponsor:
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT02133573
First received: May 7, 2014
Last updated: July 21, 2014
Last verified: July 2014
  Purpose

Neurodevelopmental disability is now recognized as the most common long-term complication after cardiac surgery in neonates. Research studies have shown that progesterone is critical to the development of the brain and in a variety of clinical situations including brain injury can protect the brain.

The purpose of this research study is to determine whether progesterone administered during the 3rd trimester of pregnancy (24-39 weeks) to pregnant women protects the brain of unborn babies with CHD and improves their neurodevelopmental outcomes after heart surgery.


Condition Intervention Phase
Congenital Heart Disease
Periventricular Leucomalacia
Brain Development
Cardiac Surgery
Neurodevelopmental Disability
Fetal Neuroprotection
Drug: Progesterone
Drug: Vaginal lubricant
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Trial of Maternal Progesterone Therapy to Improve Neurodevelopmental Outcomes in Infants With Congenital Heart Disease

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Motor Scale of the Bayley Scales of Infant and Toddler Development-III [ Time Frame: When baby is 18 months of age ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Cognitive and Language Scales of the Bayley Scale of Infant and Toddler Development-III [ Time Frame: When baby is 18 months of age ] [ Designated as safety issue: No ]
  • Fetal brain growth and maturation by MRI [ Time Frame: Change from 24-28 weeks gestational age to 34-36 weeks gestational age ] [ Designated as safety issue: No ]
  • Myelination during fetal brain development by MRI [ Time Frame: Change from 24-28 weeks gestational age to 34-36 weeks gestational age ] [ Designated as safety issue: No ]
  • Brain white matter injury by MRI [ Time Frame: Preoperative on day of surgery ] [ Designated as safety issue: No ]
    Heart surgery with cardiopulmonary bypass (CPB) prior to 44 weeks corrected gestational age (GA)

  • Brain white matter injury by MRI [ Time Frame: Postoperative within 10 days of surgery ] [ Designated as safety issue: No ]
    Heart surgery with cardiopulmonary bypass (CPB) prior to 44 weeks corrected gestational age (GA)


Estimated Enrollment: 130
Study Start Date: May 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Progesterone
Vaginal gel, 90mg BID
Drug: Progesterone
Crinone is supplied in a single use, disposable, white polypropylene vaginal applicator with a teal twist-off cap. Each applicator delivers 1.125 grams of Crinone gel containing 90 mg (8% gel) of progesterone in a base containing glycerin, mineral oil, polycarbophil, carbomer 934P, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide. Crinone 8% is administered vaginally at a dose of 90 mg twice daily. The rounded tip of the applicator is inserted into the vagina. After insertion, the plunger is pushed to release the gel into the vagina. The applicator is removed.
Other Name: Crinone 8%
Placebo Comparator: Vaginal Lubricant
Vaginal BID
Drug: Vaginal lubricant
Replens Long-Lasting Moisturizer is supplied in pre-filled, sealed and individually wrapped applicators.Replens Long-Lasting Moisturizer will also be dosed at one applicator intravaginally twice daily.
Other Name: Replens

Detailed Description:

In the United States, approximately 1 in every 100 newborns is diagnosed with congenital heart disease (CHD). Many of these newborns (25%-35%) will require either corrective or palliative open heart surgery. As recently as the 1960's, only 20% of newborns with critical CHD survived to adulthood. Today, thanks to better diagnostic technologies and methods (including prenatal diagnosis), advances in surgery, and improved postoperative care, early survival is over 90%. However, with improved early outcomes has come the sobering recognition that there is an ongoing risk of late mortality, as well as significant morbidity for these children. In particular, neurodevelopmental disability is now recognized as the most common complication of critical CHD (i.e. those patients requiring cardiac surgery in infancy) and has the most negative impact on quality of life, academic performance and opportunity for independence as an adult.

The altered fetal hemodynamics secondary to CHD lead to decreased blood flow and/or oxygen delivery to the fetal brain. In turn, this impairment in blood flow and oxygenation results in impaired brain growth and altered structural and cellular maturation, particularly of the white matter. Fetal MRI studies have shown that during the third trimester, normally a time of rapid brain growth and development, brains of infants with CHD fail to grow at the same rate as the brains of fetuses without CHD. This growth delay results in microcephaly, immature cellular elements of the white matter and decreased cortical folding at birth. It has been demonstrated that brain immaturity at birth is a primary major risk factor underlying the hypoxic-ischemic white matter brain injury and subsequent neurodevelopmental disability seen in over 50% of infants following surgery for CHD. In addition, there is increasing evidence in the CHD population that even late pre-term birth (prior to 39 weeks GA) is associated with increased mortality, increased peri-operative morbidity, and worse neurodevelopmental outcomes.

Progesterone is an essential hormone in the occurrence and maintenance of pregnancy. Progesterone administration has also been shown to be neuroprotective in a variety of clinical situations, including traumatic brain injury (TBI). Sex steroid hormones, including progesterone, are critically involved in axonal myelination, forming the basis of white matter connectivity in the central nervous system (CNS). Progesterone and its metabolites not only promote the viability and regeneration of neurons, but also act on myelinating glial cell oligodendrocytes in the CNS and play an important role in the formation of myelin sheaths. Progesterone has also been shown to increase myelination and enhance maturation of immature oligodendrocytes progenitor cells to mature oligodendrocytes, which are more resistant to hypoxic/ischemic injury. Therapeutic administration of progesterone has also been demonstrated to prevent preterm birth. Thus, there are two potential mechanisms by which pre-natal progesterone therapy may improve neurodevelopmental outcomes in neonates with CHD: 1) a direct neuroprotective effect, and 2) decreasing the occurrence of pre-term birth.

Study Objectives

Primary: Develop preliminary evidence to support a multi-institutional study to determine whether, in women carrying fetuses (maternal-fetal dyad) with CHD, prophylactic vaginal natural progesterone therapy is neuroprotective, and compared to placebo improves neurodevelopmental outcomes at 18 months of age.

Secondary: Develop preliminary evidence to support a multi-institutional study to determine whether, in women carrying fetuses (maternal-fetal dyad) with CHD, prophylactic vaginal natural progesterone therapy is neuroprotective, and compared to placebo:

  1. improves fetal brain growth and maturation,
  2. increases myelination during fetal brain development,
  3. reduces pre-operative brain white matter injury, and
  4. reduces post-operative white matter injury.
  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Mother carrying a fetus with CHD (maternal-fetal dyad) requiring surgery with cardiopulmonary bypass (CPB) prior to 44 weeks corrected gestational age (GA) identified prior to 28 weeks GA.

Exclusion Criteria:

  1. Major genetic or extra-cardiac anomaly other than 22q11 deletion
  2. Language other than English spoken in the home
  3. Known sensitivity or listed contraindication to progesterone (known allergy or hypersensitivity to progesterone, severe hepatic dysfunction, undiagnosed vaginal bleeding, mammary or genital tract carcinoma, thrombophlebitis, thromboembolic disorders, cerebral hemorrhage, porphyria)
  4. Prescription or ingestion of medications known to interact with progesterone (e.g. Bromocriptine, Rifamycin, Ketoconazole or Cyclosporin)
  5. Maternal use of progesterone within 30 days of enrollment
  6. History of preterm birth or short cervix (defined as cervical length ≤ 25 mm at 18-24 weeks GA necessitating progesterone therapy
  7. Multiple gestation
  8. Maternal contraindication for magnetic resonance imaging (MRI)
  9. Subjects with a known history of non-compliance with medical therapy
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02133573

Contacts
Contact: Katherine Drangula, BSN 215-906-9596 drangulak@email.chop.edu
Contact: Nancy Burnham, MSN 215-410-0721 burnhamn@email.chop.edu

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Katherine Drangula, BSN    267-844-1155    drangulak@email.chop.edu   
Contact: Nancy Burnham, MSN    215-410-0721    burnhamn@email.chop.edu   
Sponsors and Collaborators
Children's Hospital of Philadelphia
Investigators
Principal Investigator: J. William Gaynor, MD Children's Hospital of Philadelphia
  More Information

Additional Information:
No publications provided

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT02133573     History of Changes
Other Study ID Numbers: 13-010710
Study First Received: May 7, 2014
Last Updated: July 21, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Hospital of Philadelphia:
progesterone
congenital heart disease
periventricular leucomalacia
brain development
cardiac surgery
neurodevelopmental disability
fetus
fetal neuroprotection

Additional relevant MeSH terms:
Leukomalacia, Periventricular
Heart Diseases
Heart Defects, Congenital
Cardiovascular Diseases
Cardiovascular Abnormalities
Congenital Abnormalities
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Encephalomalacia
Vascular Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Progesterone
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014