Use of Oxandrolone to Promote Growth in Infants With HLHS
Primary Purpose
Hypoplastic Left Heart, Congenital Heart Disease
Status
Suspended
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Oxandrolone
Sponsored by
About this trial
This is an interventional supportive care trial for Hypoplastic Left Heart
Eligibility Criteria
Inclusion Criteria:
- HLHS and other single ventricle of right ventricular morphology
- Age and Norwood procedure ≤14 days of age
- Informed consent from parent/guardian
Exclusion Criteria:
- Small for gestational age (birth weight <10th percentile for gestational age)
- Prematurity, defined as gestational age <37 weeks
- Intrauterine growth retardation (birth weight ≤2.5 kg and gestational age ≥38 weeks)
- Chromosomal abnormality, recognizable genetic syndrome or congenital anomalies of more than minor severity associated with growth failure
- Moderate or greater right ventricular systolic dysfunction and/or moderate or greater tricuspid regurgitation prior to the Norwood procedure
- Extracorporeal membrane oxygenation support (ECMO) prior to or within 24 hours of Norwood procedure
- Pre-Norwood interventions (fetal intervention, balloon atrial septostomy for an intact or restrictive atrial septum)
- Pre-Norwood pulmonary venous obstruction
- Pre-Norwood procedure necrotizing enterocolitis and/or other gastrointestinal syndromes
- Known contraindication to oxandrolone
- Planned or current warfarin therapy at screening (warfarin effects are increased by anabolic drugs)
- Significant hepatic dysfunction (elevation of serum transaminase levels greater than two times the upper limit of normal local laboratory standard at screening)
- Hypercalcemia (>1.5 times upper normal range for lab)
- Nephrotic syndrome
- Unwillingness or inability to return to surgical center for follow-up evaluation
- Participation in another clinical study that may impact growth
Sites / Locations
- Children's Hospital of Atlanta
- Boston Children's Hospital
- University of Michigan Health System, Ann Arbor
- Cincinnati Children's Hospital Medical Center
- Children's Hospital of Philadelphia
- Medical University of South Carolina
- Cook Children's Medical Center
- Texas Children's Hospital
- Primary Children's Medical Center
- The Hospital for Sick Children
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Oxandrolone Cohort 1
Standard of Care
Arm Description
Participants randomized to Oxandrolone Cohort 1 will receive 0.1mg/kg of oxandrolone suspended in a multi-chain triglyceride (MCT) oil buccally twice per day.
Participants randomized to standard of care will receive the standard therapies provided at the institution at which they are being treated. Control subjects will receive standard therapy with no placebo and no oxandrolone.
Outcomes
Primary Outcome Measures
Biochemical evidence of hepatic dysfunction
Elevation of serum transaminase levels (alanine transaminase (ALT) and/or aspartate transaminase (AST)) >4 times the local laboratory upper limit of normal
Virilization
Standardized physical examination will be performed. Because there are no standard normal values for the various measurements included, each subject will serve as their own control
SAE probably or definitely related to oxandrolone therapy
Any SAE probably or definitely related to oxandrolone therapy in the opinion of the medical monitor
Secondary Outcome Measures
Length-for-age z-score
The efficacy of buccally administered oxandrolone will be evaluated by measuring length-for-age z-score at the end of study drug therapy
Weight-for-age z-score
The efficacy of buccally administered oxandrolone will be evaluated by measuring weight-for-age z-score at the end of study drug therapy
Change in Weight-for-age z-score
The efficacy of buccally administered oxandrolone will be evaluated by measuring the change in weight-for-age z-score at the end of study drug therapy
Change in length-for-age z-score
The efficacy of buccally administered oxandrolone will be evaluated by measuring the change in length-for-age z-score at the end of study drug therapy
Prealbumin levels
Serum prealbumin levels will be measured weekly
Lean Body Mass
Lean body mass will be assessed using dual energy x-ray absorptiometry (DXA)
Decreased right ventricular systolic function
Evidence of ≥moderate right ventricular systolic dysfunction or tricuspid valve regurgitation based on qualitative assessment of clinical echocardiograms if performed
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04090697
Brief Title
Use of Oxandrolone to Promote Growth in Infants With HLHS
Official Title
Use of Oxandrolone to Promote Growth in Infants With Hypoplastic Left Heart Syndrome: A Phase I/II Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Suspended
Why Stopped
FDA withdrawal of Oxandrin NDA and generic ANDAs
Study Start Date
December 20, 2019 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
June 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Carelon Research
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary aim of this study is to determine if clinically relevant doses of buccally administered oxandrolone are safe and tolerable in neonates with hypoplastic left heart syndrome (HLHS) or other single right ventricular anomalies who have undergone a Norwood procedure. The secondary aim is to evaluate the efficacy of buccally administered oxandrolone in improving objective indices of growth and nutrition in neonates who have undergone a Norwood procedure.
Detailed Description
The proposed investigation is a Phase I/II randomized trial of 28 days of open label oxandrolone vs. no oxandrolone treatment to assess optimal dosing, safety/tolerability, and preliminary efficacy of this therapy in post-Norwood neonates with HLHS. Control subjects will receive standard therapy with no placebo and no oxandrolone.
This trial is aimed at cumulative dose finding as well as a preliminary assessment of safety/tolerability and efficacy. The design and dosing are based upon preliminary phase I data obtained as part of an ongoing protocol under IND #107706. This trial will initially include two arms (control and 0.1 mg/kg oxandrolone BID). This initial oxandrolone dose was chosen based on the preliminary data collected in the background studies conducted for this trial. There were no adverse safety outcomes in the small cohort of subjects receiving 0.1 mg/kg of oxandrolone BID.
In Cohort 1, subjects will be block randomized into each arm in a 1:4 (control to oxandrolone) ratio. An interim analysis of the safety data will be performed after the first 25 subjects in Cohort 1 have been randomized and have completed 28 days of oxandrolone therapy or observation (control group). If there are no significant differences in the primary safely/tolerability outcome and safety reviews are favorable for BID dosing, then Cohort 2 (25 subjects) will be randomized in a 1:4 ratio to the control and TID dosing arms. A similar interim analysis will be performed after Cohort 2 subjects have been randomized and completed 28 days of oxandrolone therapy. Enrollment will again be suspended during this second interim analysis to determine if dose escalation is warranted. Cohort 3A, utilizing 0.15 mg/kg oxandrolone TID would be possible if both Cohorts 1 (0.1 mg/kg BID) and 2 (0.1 mg/kg/dose TID) do not demonstrate any differences in the primary safety/tolerability outcome compared to controls and safety reviews are favorable (Figure 4). If the safety threshold is crossed, then a dose of 0.1 mg/kg/dose BID will be used for cohort 3B. An interim safety analysis will be performed after 25 subjects have been enrolled in this highest dosing arm. If at any point a risk-benefit balance in any cohort is found to be negative, then further enrollment will proceed at the lower dosing arm determined to be safe/tolerable based on the primary outcome and safety review with a 1:4 control:oxandrolone ratio and a total subject number of 100.
If the second interim safety analysis leads to the conclusion that the lower dose (0.1 mg/kg oxandrolone BID) appears to be safe and well tolerated, while the higher dose (0.1 mg/kg oxandrolone TID) is not, then the enrollment will proceed in the 0.1 mg/kg BID arm with a 1:4 ratio. If the lowest dose of oxandrolone (0.1 mg/kg BID) is found to be unsafe, then the trial will be stopped. The benefit of this approach lies in the ability to allocate patients to the highest safe dose arm thus enriching the relevance of safety/tolerability and efficacy information obtained. A higher-dose treatment arm will be used if the data reveal the initial treatment arm is not different from control with regards to the primary outcome. If no safety/tolerability effect is demonstrated, the trial will, by design, function as a randomized, controlled trial with dose-escalation. It is anticipated that the study will conclude with approximately 80 oxandrolone patients (in up to three dosing arms) and 20 control patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoplastic Left Heart, Congenital Heart Disease
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Oxandrolone Cohort 1
Arm Type
Experimental
Arm Description
Participants randomized to Oxandrolone Cohort 1 will receive 0.1mg/kg of oxandrolone suspended in a multi-chain triglyceride (MCT) oil buccally twice per day.
Arm Title
Standard of Care
Arm Type
No Intervention
Arm Description
Participants randomized to standard of care will receive the standard therapies provided at the institution at which they are being treated. Control subjects will receive standard therapy with no placebo and no oxandrolone.
Intervention Type
Drug
Intervention Name(s)
Oxandrolone
Other Intervention Name(s)
Anavar, Oxandrin
Intervention Description
Oxandrolone 2.5mg tabs will be suspended in multi-chain triglyceride (MCT) oil and administered buccally.
Primary Outcome Measure Information:
Title
Biochemical evidence of hepatic dysfunction
Description
Elevation of serum transaminase levels (alanine transaminase (ALT) and/or aspartate transaminase (AST)) >4 times the local laboratory upper limit of normal
Time Frame
From date of treatment initiation until the pre-SCPC evaluation or end of study participation, whichever comes first, up to 9 months
Title
Virilization
Description
Standardized physical examination will be performed. Because there are no standard normal values for the various measurements included, each subject will serve as their own control
Time Frame
From date of treatment initiation until the completion of study drug therapy or end of study participation, whichever comes first, up to 28 days
Title
SAE probably or definitely related to oxandrolone therapy
Description
Any SAE probably or definitely related to oxandrolone therapy in the opinion of the medical monitor
Time Frame
From date of treatment initiation until the pre-SCPC evaluation or end of study participation, whichever comes first, up to 9 months
Secondary Outcome Measure Information:
Title
Length-for-age z-score
Description
The efficacy of buccally administered oxandrolone will be evaluated by measuring length-for-age z-score at the end of study drug therapy
Time Frame
At the time of completion of study drug therapy, up to 28 days after date of treatment initiation
Title
Weight-for-age z-score
Description
The efficacy of buccally administered oxandrolone will be evaluated by measuring weight-for-age z-score at the end of study drug therapy
Time Frame
At the time of completion of study drug therapy, up to 28 days after date of treatment initiation
Title
Change in Weight-for-age z-score
Description
The efficacy of buccally administered oxandrolone will be evaluated by measuring the change in weight-for-age z-score at the end of study drug therapy
Time Frame
From date of pre-Norwood procedure until completion of study drug therapy, up to 28 days
Title
Change in length-for-age z-score
Description
The efficacy of buccally administered oxandrolone will be evaluated by measuring the change in length-for-age z-score at the end of study drug therapy
Time Frame
From date of pre-Norwood procedure until completion of study drug therapy, up to 28 days
Title
Prealbumin levels
Description
Serum prealbumin levels will be measured weekly
Time Frame
During the duration of therapy
Title
Lean Body Mass
Description
Lean body mass will be assessed using dual energy x-ray absorptiometry (DXA)
Time Frame
At the completion of study drug therapy, assessed up to 35 days after initiation of study drug therapy
Title
Decreased right ventricular systolic function
Description
Evidence of ≥moderate right ventricular systolic dysfunction or tricuspid valve regurgitation based on qualitative assessment of clinical echocardiograms if performed
Time Frame
At the time of Norwood discharge and at the time of pre-SCPC evaluation, up to 9 months
10. Eligibility
Sex
All
Maximum Age & Unit of Time
14 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
HLHS and other single ventricle of right ventricular morphology
Age and Norwood procedure ≤14 days of age
Informed consent from parent/guardian
Exclusion Criteria:
Small for gestational age (birth weight <10th percentile for gestational age)
Prematurity, defined as gestational age <37 weeks
Intrauterine growth retardation (birth weight ≤2.5 kg and gestational age ≥38 weeks)
Chromosomal abnormality, recognizable genetic syndrome or congenital anomalies of more than minor severity associated with growth failure
Moderate or greater right ventricular systolic dysfunction and/or moderate or greater tricuspid regurgitation prior to the Norwood procedure
Extracorporeal membrane oxygenation support (ECMO) prior to or within 24 hours of Norwood procedure
Pre-Norwood interventions (fetal intervention, balloon atrial septostomy for an intact or restrictive atrial septum)
Pre-Norwood pulmonary venous obstruction
Pre-Norwood procedure necrotizing enterocolitis and/or other gastrointestinal syndromes
Known contraindication to oxandrolone
Planned or current warfarin therapy at screening (warfarin effects are increased by anabolic drugs)
Significant hepatic dysfunction (elevation of serum transaminase levels greater than two times the upper limit of normal local laboratory standard at screening)
Hypercalcemia (>1.5 times upper normal range for lab)
Nephrotic syndrome
Unwillingness or inability to return to surgical center for follow-up evaluation
Participation in another clinical study that may impact growth
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Phillip T Burch, MD
Organizational Affiliation
Cook Children's Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Richard V Williams, MD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Michigan Health System, Ann Arbor
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Primary Children's Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84113
Country
United States
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
12. IPD Sharing Statement
Plan to Share IPD
No
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Use of Oxandrolone to Promote Growth in Infants With HLHS
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