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Theophylline Prophylaxis During Hypothermia to Limit Neonatal Nephron Damage (TheoPHyLNNe)

Primary Purpose

Acute Kidney Injury, HIE

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Single Dose Theophylline
Repeat Dose Theophylline
Sponsored by
Medical College of Wisconsin
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Acute Kidney Injury

Eligibility Criteria

1 Hour - 12 Hours (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Oklahoma Health Sciences CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

No Intervention

Arm Label

Single Dose Theophylline

Repeat Dose Theophylline

Standard treatment

Arm Description

Single dose of theophylline or aminophylline (5mg/kg IV) given within 12 hours after birth

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

Infants cared for according to standard practice.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Pharmacokinetic Profile of Theophylline#1
Evaluate plasma concentrations (mg/dl) of theophylline at time points ranging from 30 minutes to 48 hours after dosing
Safety profile of theophylline#1
Incidence of tachycardia (heart rate > 200 beats per minute for 15 minutes) after theophylline dosing defined by pediatric neurologist
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
Safety profile of theophylline#3
Incidence of clinical seizures as diagnosed by a trained pediatric neurologist
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
Successful data collection procedures
Percent of incomplete data entry points per subject will be evaluated by reviewing data in REDCap
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).
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
Acute kidney injury#1
Incidence of acute kidney injury as defined by modified neonatal KDIGO criteria using serum creatinine values
Acute kidney injury#2
Incidence of acute kidney injury as defined by modified neonatal KDIGO criteria using urine output values (ml/kg/hour)

Full Information

First Posted
March 20, 2023
Last Updated
October 17, 2023
Sponsor
Medical College of Wisconsin
Collaborators
University of Oklahoma
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1. Study Identification

Unique Protocol Identification Number
NCT05853601
Brief Title
Theophylline Prophylaxis During Hypothermia to Limit Neonatal Nephron Damage
Acronym
TheoPHyLNNe
Official Title
Theophylline Prophylaxis During Hypothermia to Limit Neonatal Nephron Damage
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 17, 2023 (Actual)
Primary Completion Date
April 1, 2026 (Anticipated)
Study Completion Date
April 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical College of Wisconsin
Collaborators
University of Oklahoma

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Kidney Injury, HIE

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
54 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Single Dose Theophylline
Arm Type
Experimental
Arm Description
Single dose of theophylline or aminophylline (5mg/kg IV) given within 12 hours after birth
Arm Title
Repeat Dose Theophylline
Arm Type
Experimental
Arm Description
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
Arm Title
Standard treatment
Arm Type
No Intervention
Arm Description
Infants cared for according to standard practice.
Intervention Type
Drug
Intervention Name(s)
Single Dose Theophylline
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Repeat Dose Theophylline
Intervention Description
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.
Primary Outcome Measure Information:
Title
Recruitment of patients
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Pharmacokinetic Profile of Theophylline#1
Description
Evaluate plasma concentrations (mg/dl) of theophylline at time points ranging from 30 minutes to 48 hours after dosing
Time Frame
2 years
Title
Safety profile of theophylline#1
Description
Incidence of tachycardia (heart rate > 200 beats per minute for 15 minutes) after theophylline dosing defined by pediatric neurologist
Time Frame
2 years
Title
Safety profile of theophylline#2
Description
Incidence of hyperglycemia, defined as two sequential serum glucose values over 200 mg/dl) over one hour apart after theophylline dosing
Time Frame
2 years
Title
Safety profile of theophylline#3
Description
Incidence of clinical seizures as diagnosed by a trained pediatric neurologist
Time Frame
2 years
Title
Demonstration of successful adherence to study protocol
Description
Evaluate the incidence of protocol deviations both per subject and study-wide. Incidence will be expressed as number of study violations per enrolled subject
Time Frame
2 years
Title
Successful data collection procedures
Description
Percent of incomplete data entry points per subject will be evaluated by reviewing data in REDCap
Time Frame
2 years
Title
Successful biospecimen collection procedures
Description
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).
Time Frame
2 years
Title
Pharmacokinetic Profile of Theophylline#2
Description
Determine area under the curve profile of serum theophylline concentration (mg/dl) over time (hours) up to 48 hours after dosing of theophylline
Time Frame
2 years
Title
Acute kidney injury#1
Description
Incidence of acute kidney injury as defined by modified neonatal KDIGO criteria using serum creatinine values
Time Frame
2 years
Title
Acute kidney injury#2
Description
Incidence of acute kidney injury as defined by modified neonatal KDIGO criteria using urine output values (ml/kg/hour)
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Hour
Maximum Age & Unit of Time
12 Hours
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jeffrey Segar, MD
Phone
414-955-8296
Email
jsegar@mcw.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kathleen Meskin, BSN
Phone
414-337-7171
Email
kmeskin@mcw.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Segar, MD
Organizational Affiliation
Medical College of Wisconsin
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Birju Shah, MD
Phone
405-271-5215
Email
birju-shah@ouhsc.edu
First Name & Middle Initial & Last Name & Degree
Natalie Goodman, BA
Phone
405-271-5215
Ext
43006
Email
Natalie-Goodman@ouhsc.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Theophylline Prophylaxis During Hypothermia to Limit Neonatal Nephron Damage

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