Beta-blocker Administration for Cardiomyocyte Division

Официальное название

Mechanistic Clinical Trial of Beta-Blocker Administration For Reactivating Cardiomyocyte Division In Tetralogy of Fallot

Обзор

Heart failure is a common long-term complication in patients with congenital heart disease (CHD). Medical treatments to promote regeneration of new healthy heart muscle cells have the potential to provide new heart failure treatments for these patients. The development of such therapies is limited by the poor understanding of the ways in which heart muscles grow after birth. Investigators have learned that humans without heart disease generate new heart muscles cells up to the age of 20 years old and that this is decreased in patients with congenital heart disease like Tetralogy of Fallot. Investigators are trying to determine if treatment with a medicine called Propranolol can increase heart muscle cell proliferation and, with that, normalize heart growth. Investigators will examine discarded heart muscle tissue that is obtained during surgery for the presence of new heart muscle cells. Propranolol is approved by the Food and Drug Administration (FDA) to treat a certain kind of benign tumor in infants (hemangioma), but it is not currently approved by the FDA to increase heart muscle growth.

Вмешательства

• Другое N-thymidine
  15N-thymidine will be administered to patients in order to quantify cardiomyocyte proliferation. 15N-thymidine will be administered as 5 separate syringes. Each syringe will contain the recommended daily dose based on participants weight. Subjects will be given the labeled thymidine by mouth once a day for 5 consecutive days. The dosing will begin one week after starting the study drug.The caregiver (parent or nurse) will administer the labeled thymidine by mouth via a syringe once a day for 5 c
• Другое Urine Collection
  Parents will be asked to keep a diary of the child's feeding and diaper changes during the administration of thymidine. To monitor how the labeled thymidine is processed in the body, investigators will analyze urine from the child's diapers. Each time a diaper is changed, a cotton ball will be placed in the diaper. At the next diaper change, this cotton ball will be removed from the diaper, placed in a Ziploc bag, and stored in the freezer. They will be collected and stored cotton balls starting
• Процедура Echocardiogram
  On Study Day 1 to obtain baseline assessment of cardiac size. A second research dedicated echocardiogram will be done after being anesthetized for surgery. Echocardiography is routinely performed to determine right ventricle (RV) structure of the heart and function in Tetrology of Fallot/ Pulmonary Stenosis (ToF/PS) and is non-invasive.
• Процедура Cardiac MRI (CMR)
  A limited study protocol will be performed using the feed-and-bundle technique at the time of study enrollment, The feed and bundle technique is utilized so that the infant will be as comfortable as possible and asleep during the procedure. This is done to prevent the risk of sedation and allow for a more natural sleep. The baby is undressed, prepared with ECG-leads and an oxygen saturation probe, and fed. With this "feed, swaddle, and sleep" technique, scanning times of 30-60 minutes can be ach
• Препарат Propranolol Hydrochloride
  For patients who are randomized to receive propranolol, The target dose for this study will be 4 mg/kg/day divided in 4 doses. The first dose will be given in the Pediatric Clinical and Translational Research Center (PCTRC) at 1mg/kg. Parents will administer propranolol (1 mg/kg po x 4 doses per day). Parents will be instructed to administer propranolol with feeding or soon after feeding, but not before feeding. families will also be given instructions for regarding 15N-thymidine dosing frequenc
• Препарат Placebo
  For patients who are randomized to receive placebo, the first dose will be given in the Pediatric Translational Research Center (PCTRC) and will be based on the patients weight. Parents will administer placebo 4 doses per day. Treatment with placebo will begin at 1 month of age and continue until 4 months of age or 24hrs prior to surgical repair, whichever comes first.
• Процедура Physical Exam
  On Study Day 1; monthly until surgery in conjunction with patient's clinical cardiology appointment; and at the time of surgery. Will include vital signs.
• Другое Specimen Collection
  On the morning of surgery, after IV access is obtained for anesthesia 2 ml of blood will be collected for analysis. A small piece of heart tissue and fat that has already been removed during surgery will be collected for analysis.

Первичные конечные точки

• Cardiomyocyte Division [Срок оценки: At the time of complete surgical repair, at approximately 3-9 months old, it is expected that a piece of RV myocardium will be resected. This tissue will be collected and analyzed using a multiple isotope mass spectrometer.]

Вторичные конечные точки (3)

• Hypertrophy as assessed by echocardiography [Срок оценки: At 1 month and at time of surgery]
• Hypertrophy as assessed by Cardiac MRI [Срок оценки: At 1 month and at time of surgery]
• Hypertrophy assessed by microscopy [Срок оценки: At time of Surgery]

Критерии участия

Критерии включения

• Male and female infants < 60 days of age with a diagnosis of tetralogy of Fallot (ToF) with pulmonary stenosis (PS) or double outlet right ventricle (DORV), tetralogy type by echocardiogram, who weigh greater than 2 kg at the time of consent and are tolerating enteral feeds.
• DORV variant

Критерии исключения

• congenital atrio-ventricular block on EKG (PR interval > 120 ms),
• concomitant medication administration that interacts with propranolol,
• patient family is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason,
• gestation age < 35 weeks,
• infants of diabetic mothers, asthma or underlying respiratory disease,
• presence of metal implants in infants.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 3 центра

• Weill Cornell Medicine — New York
• Children's Hospital of Philadelphia — Philadelphia
• Upmc Children'S Hospital of Pittsburgh — Pittsburgh

Публикации

• El Khoudary SR, Fabio A, Yester JW, Steinhauser ML, Christopher AB, Gyngard F, Adams PS, Morell VO, Viegas M, Da Silva JP, Da Silva LF, Castro-Medina M, McCormick A, Reyes-Mugica M, Barlas M, Liu H, Thomas D, Ammanamanchi N, Sada R, Cuda M, Hartigan E, Groscost DK, Kuhn B. Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot. Int J Cardiol PMID 34265312

Идентификаторы

NCT: NCT04713657 · 23-12026881 · R01HL155597

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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