Theophylline Prophylaxis During Hypothermia to Limit Neonatal Nephron Damage

Study Overview
=================
Brief Summary
-----------------
Acute kidney injury is a significant complication for infants who experience hypoxic ischemic encephalopathy, being associated with increased rates of death and prolonged hospitalization. This pilot study of theophylline administration soon after birth for the prevention of kidney injury will lay the foundation for the conduct of a larger clinical trial that seeks to identify a theophylline as a novel therapy to prevent kidney injury in thousands of at-risk infants.

Detailed Description
-----------------
Acute kidney injury (AKI) is commonly seen in infants diagnosed with hypoxic-ischemic encephalopathy (HIE) and is associated with increased rates of morbidity and mortality. Currently, there are no approved therapies that target the prevention of AKI. Several small trials in infants with HIE suggest that a single dose of theophylline given soon after birth attenuates the development of AKI. However, these studies were not performed in infants being treated with therapeutic hypothermia (the current standard of care for moderate to severe HIE), and only reported short-term outcomes. Therefore, few clinicians use theophylline in the management of these patients. The long-term goal is to undertake an appropriately powered multicenter clinical trial to test the hypothesis that for infants > 35 weeks gestation treated with therapeutic hypothermia for HIE, intravenous theophylline (or aminophylline) within the first 12 hours after birth will result in a decreased incidence and/or severity of AKI or death (composite primary outcome) and improved long-term (2 year) renal outcomes. Before the conduct of a large trial, the feasibility of implementing the intervention and ability to measure relevant clinical outcomes need to be demonstrated. Therefore, the investigators propose a small pilot and feasibility clinical trial to i) evaluate recruitment, protocol adherence, and data collection procedures in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to standard treatment in infants with HIE being treated with therapeutic hypothermia; ii) evaluate the utility and applicability of established measures (serum creatinine, urine output, fluid balance) and novel, exploratory approaches to identify AKI in infants; and iii) determine theophylline pharmacokinetic, pharmacodynamic, safety and preliminary effectiveness profiles of two different theophylline dosing regimens in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to standard treatment. Using a mixed methods data analysis strategy to assess the research and intervention process and examine outcomes of the intervention, the investigators will generate the requisite data to inform development and implementation of an appropriately powered study to determine whether theophylline attenuates the risk and severity of AKI in infants with HIE treated with therapeutic hypothermia.

Official Title
-----------------
Theophylline Prophylaxis During Hypothermia to Limit Neonatal Nephron Damage

Conditions
-----------------
HIE, Acute Kidney Injury

Intervention / Treatment
-----------------
* Drug: Single Dose Theophylline
* Drug: Repeat Dose Theophylline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: gestational age at birth >= 35 weeks by best obstetrical dating birth weight > 1800 grams clinical determination of HIE and treatment with hypothermia being initiated within six hours of birth according to institutional guidelines no known congenital abnormalities involving the brain, kidneys, heart or lungs ability to administer theophylline via intravenous route within 12 hours of birth Exclusion Criteria: infants with suspected or diagnosed significant renal, urinary tract, brain, heart, or lung abnormalities infant with known chromosomal anomaly evidence of head trauma or skull fracture causing major intracranial hemorrhage inability to initiate hypothermia within six hours of birth attending physician unwilling to have infant participate in the study inability to obtain informed consent within 12 hours of birth

Ages Eligible for Study
-----------------
Minimum Age: 1 Hour
Maximum Age: 12 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Dose Theophylline<br>Single dose of theophylline or aminophylline (5mg/kg IV) given within 12 hours after birth | Drug: Single Dose Theophylline<br>* Subjects are given a single loading dose of theophylline, 5mg/kg IV, within 12 hours after birth. A bioequivalent dose of aminophylline, a more soluble, ethylenediamine salt of theophylline, may be substituted for theophylline. The bioequivalent dose of aminophylline is 120% of the theophylline dose.<br>|
| Experimental: Repeat Dose Theophylline<br>Loading dose of theophylline or aminophylline (5mg/kg IV) given within 12 hours of birth, with two subsequent doses (1.2 mg/kg IV) given at12 and 24 hours after the loading dose | Drug: Repeat Dose Theophylline<br>* Subjects are given a loading dose of theophylline, 5mg/kg IV, within 12 hours of birth, and then two subsequent doses (1.2mg/kg iv) at 12 hours and 24 hours after loading dose. A bioequivalent dose of aminophylline, a more soluble, ethylenediamine salt of theophylline, may be substituted for theophylline. The bioequivalent dose of aminophylline is 120% of the theophylline dose.<br>|
| No Intervention: Standard treatment<br>Infants cared for according to standard practice. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment of patients | Examine the ability to recruit and enroll patients in trial. We will assess the number of eligible patients and compare that number to those actually enrolled. This ratio will inform regarding the ability to recruit patients in a larger, randomized, appropriately powered trial. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Profile of Theophylline#1 | Evaluate plasma concentrations (mg/dl) of theophylline at time points ranging from 30 minutes to 48 hours after dosing | 2 years | 
| Safety profile of theophylline#1 | Incidence of tachycardia (heart rate > 200 beats per minute for 15 minutes) after theophylline dosing defined by pediatric neurologist | 2 years | 
| Safety profile of theophylline#2 | Incidence of hyperglycemia, defined as two sequential serum glucose values over 200 mg/dl) over one hour apart after theophylline dosing | 2 years | 
| Safety profile of theophylline#3 | Incidence of clinical seizures as diagnosed by a trained pediatric neurologist | 2 years | 
| Demonstration of successful adherence to study protocol | Evaluate the incidence of protocol deviations both per subject and study-wide. Incidence will be expressed as number of study violations per enrolled subject | 2 years | 
| Successful data collection procedures | Percent of incomplete data entry points per subject will be evaluated by reviewing data in REDCap | 2 years | 
| Successful biospecimen collection procedures | Rate of successful collection and analysis of biospecimens per study logs. Data will be etermined as percentage of successful completions (successful completions divided by opportunities per protocol). | 2 years | 
| Pharmacokinetic Profile of Theophylline#2 | Determine area under the curve profile of serum theophylline concentration (mg/dl) over time (hours) up to 48 hours after dosing of theophylline | 2 years | 
| Acute kidney injury#1 | Incidence of acute kidney injury as defined by modified neonatal KDIGO criteria using serum creatinine values | 2 years | 
| Acute kidney injury#2 | Incidence of acute kidney injury as defined by modified neonatal KDIGO criteria using urine output values (ml/kg/hour) | 2 years |