FDA withdrawal of Oxandrin NDA and generic ANDAs

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.

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.

Inclusion Criteria:

1. HLHS and other single ventricle of right ventricular morphology
2. Age and Norwood procedure ≤14 days of age
3. Informed consent from parent/guardian

Exclusion Criteria:

1. Small for gestational age (birth weight <10th percentile for gestational age)
2. Prematurity, defined as gestational age <37 weeks
3. Intrauterine growth retardation (birth weight ≤2.5 kg and gestational age ≥38 weeks)
4. Chromosomal abnormality, recognizable genetic syndrome or congenital anomalies of more than minor severity associated with growth failure
5. Moderate or greater right ventricular systolic dysfunction and/or moderate or greater tricuspid regurgitation prior to the Norwood procedure
6. Extracorporeal membrane oxygenation support (ECMO) prior to or within 24 hours of Norwood procedure
7. Pre-Norwood interventions (fetal intervention, balloon atrial septostomy for an intact or restrictive atrial septum)
8. Pre-Norwood pulmonary venous obstruction
9. Pre-Norwood procedure necrotizing enterocolitis and/or other gastrointestinal syndromes
10. Known contraindication to oxandrolone
11. Planned or current warfarin therapy at screening (warfarin effects are increased by anabolic drugs)
12. Significant hepatic dysfunction (elevation of serum transaminase levels greater than two times the upper limit of normal local laboratory standard at screening)
13. Hypercalcemia (>1.5 times upper normal range for lab)
14. Nephrotic syndrome
15. Unwillingness or inability to return to surgical center for follow-up evaluation
16. Participation in another clinical study that may impact growth