| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The aims of the study are to compare two dosing levels and the mode of administration of thyroid hormones or iodine supplementation in premature infants to achieve optimal plasma hormone targets. The health problem is that infants, have low thyroid hormones levels based on studies in which severe hypothyroxinemia is associated with an increased risk of Cerebral Palsy. Evidence suggests that a result from our trial will define the mode of therapy that improve long-term neurological outcomes . |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective:
The purpose of the pilot study is to establish the dosing schedules needed to achieve the optimal plasma hormone targets in the neonatal period, without increasing measures of neonatal morbidity, mortality or physiological dysfunction.
Primary Hypothesis
The central null hypothesis to be tested is that there is no difference in mean FT4 levels between any of the five treatment groups and the saline infusion placebo control group.
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| E.2.2 | Secondary objectives of the trial |
a) A particular goal is to avoid suppression of thyroid stimulating hormone (TSH) due to administration of thyroid hormone and to determine its effects on endogenous cortisol levels.
b) Does the iodine background contribute to variation in thyroid status and can iodine alone produce a euthyroid state in premature infants?
Long Term Objectives
a) We also aim to demonstrate cooperation among an international consortium of five participating institutions before initiating a trial to involve about 20 clinical study sites.
c) The ultimate long-term goal of this Phase 1 pilot study is to set the stage for a large multicenter randomized trial. The long-term trial will test the hypothesis that thyroid hormone replacement therapy in preterm infants with transient hypothyroxinemia results in clinically significant improvement in cognitive functioning and reduction in the frequency of cerebral palsy.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
The target population for this treatment is infants born prior to 28 completed weeks of gestation. All neonates admitted to the three clinical study sites (NY, Amsterdam, Madrid) will be screened for eligibility, regardless of ethnicity, race, nationality, religion, creed or gender.
a. Patient Eligibility
All neonates <28 weeks gestational age are eligible, unless fulfilling one or more exclusion criteria (see below). Gestational age will be based on the best estimate made by the attending neonatologist. Guidelines for study estimation of gestational age will prioritize data in the following order: fetal size on obstetrical ultrasound prior to 18 weeks, maternal history of date of last menses, fetal size on 2nd trimester ultrasound, progression of uterine height in pregnancy, physical exam of the neonate.
The study population is any neonate > 24 0/7 to < 27 6/7 weeks gestational age (and in general < 1000g birth weight) based on the best consensus made by the attending neonatologist utilizing a combination of information from: the obstetrician (sonography, dates, fetal movement, etc.) plus their own personal Dubowitz Scoring Physical Exam.
Guidelines for study estimation of gestational age will prioritize data in the following order:
a) Fetal size on obstetrical ultrasound prior to 18 weeks
b) Maternal history of date of last menses
c) Fetal size on 2nd trimester ultrasound
d) Progression of uterine height in pregnancy
e) Physical exam of the neonate
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| E.4 | Principal exclusion criteria |
a) Absence of parental consent or assent of the treating physician
b) A concurrent clinical trial with another randomized drug
c) Other concern by treating physician that either mandates or prohibits study treatment
d) Gestational age out of target range 24 0/7 weeks through 27 6/7 weeks. Eligibility only based
on gestational age. No prior blood tests required.
e) Death expected within 48 hours of birth due to severity of initial cardiopulmonary disease
f) Mother of potential study subjects is a minor < 18 completed years old
4.2.2 Maternal – Neonatal Clinical or Laboratory Exclusions
a) Maternal or congenital thyroid disease (if present, refer to endocrinologist at enrollment)
b) Known disorders of fatty acid metabolism
c) Congenital brain structural anomalies (e.g. hydrocephalus, migration disorders, etc.)
d) Liver Failure (e.g. enzymes in the thousands)
e) Proven sepsis at birth (clinical signs, positive body fluid culture, and antibiotic treatment > 5
contiguous days)
f) Major congenital malformations requiring surgery
i) Structural congenital heart disease (e.g. cyanotic heart defects)
ii) Anomalies of the gastrointestinal tract (e.g. gastroschesis)
g) Known chromosomal anomalies (e.g. Trisomy 21, 13 & 18)
h) Neonatal cardiac arrhythmia’s causing output failure
4.2.3 Exclusions Based on Milk or Medications in Breast Milk
a) Breast Milk
i) Women taking anti-thyroid medications or supplemental iodine in therapeutic doses.
ii) Issues of contraception are not applicable, as women do not typically receive these
medications in the first 6 weeks post-partum.
b) Formula
Use of soy based formulas will be avoided since they are associated with prolonged increases in
TSH even after treatment for congenital hypothyroidism.
4.2.4 Exclusions Based Upon Drug Exposures
Since enrollment will be < 24 hours postnatal age, only maternal medications are of concern:
a) Drugs that WILL be cause for exclusion at enrollment:
i) Thyroid Drugs and Iodine Products at Any Time:
-No maternal or neonatal thyroid drugs (e.g. propylthiouracil, PTU)
-Supplemental iodine from a non-dietary source (i.e. table salt) will not be allowed (subjects to be
excluded).
-Povidine Iodine (excessive iodine exposure) will be cause for exclusion at enrollment since there
are other skin cleansing alternatives (e.g. chlorhexidine) that are not absorbed, and have no known organ toxicity;
ii) Substance/Drug Abuse: Maternal alcoholism (> 1 ounce daily) or any use of heroin or methadone during the pregnancy are drugs that can interfere with thyroid hormone transport in serum51
b) Drugs that will NOT be cause for exclusion at enrollment:
i) Common Drugs of Concern Include:
-Dopamine, dobutamine & epinephrine drips: can cause TSH suppression. Dopamine will be
tracked for use throughout the hospitalization but will not be cause for exclusion.
-Steroid Use: Similar effects arise from the use of steroids as for dopamine. However, >90 % or
all ELBW newborns are exposed to antepartum steroids during the pregnancy so it will not be a novel confounding factor. Use of antepartum steroids will be tracked along with achieved cortisol blood levels during the protocol. It will not be cause for exclusion.
ii) Other Rarely Used Medications during Pregnancy: These substances are uncommonly used in
the perinatal period and may affect thyroid status51 through effects on.:
-Thyroid hormone metabolism: Phenobarbital
-Displacement from protein binding sites: furosemide
iii) Substance/Drug Abuse
-Cocaine by history
-Marijuana by history
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| E.5 End points |
| E.5.1 | Primary end point(s) | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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