Sirolimus for the Treatment of Hyperinsulinism

The purpose of this pilot study is to generate data to assess feasibility of study design/procedures and for formal sample size estimation for a larger multicenter study of the efficacy and safety of sirolimus in infants with medically-unresponsive congenital hyperinsulinism (HI) due to inactivating mutations of adenosine triphosphate-sensitive potassium (KATP) channels.

Treatment options for children with diffuse adenosine triphosphate-sensitive potassium (KATP) channel hyperinsulinism (KATPHI) are limited and most of them require a near-total pancreatectomy to control the hypoglycemia. However, at least 40% of these children continue to have persistent hypoglycemia after surgery and their long-term outcomes are complicated by the development of diabetes.

There is evidence that suggests that mammalian target of rapamycin (mTOR) inhibitors are useful in controlling the hypoglycemia in hyperinsulinemic hypoglycemia. But before adapting this as standard therapy for children with hyperinsulinism, a carefully controlled study of the efficacy and safety of sirolimus for hyperinsulinism is clearly needed.

Sirolimus is an mTOR inhibitor, which is FDA-approved for the prophylaxis of organ rejection in patients age 13 years and older receiving kidney transplantation. This is an open label pilot study to assess the effect, safety and tolerability of sirolimus in infants with diazoxide-unresponsive HI due to mutations in the genes encoding the KATP channels. Subjects will be treated with sirolimus for 6 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females age ≥14 days to 12 months.
2. Confirmed diagnosis of hyperinsulinism.
3. Mutation analysis results demonstrating bi-allelic mutations in either ABCC8 or KCNJ11.
4. Failure to respond to maximal dose of diazoxide (15 mg/kg/day), if diazoxide is indicated.

   1. Unable to wean intravenous dextrose after at least 3 days of diazoxide therapy and/or
   2. Persistent hypoglycemia after at least 3 days of diazoxide therapy
5. High glucose infusion rate requirement (greater or equal to 10 mg/kg/min).
6. Parental/guardian permission (informed consent).

Exclusion Criteria:

1. Infants with suspected or confirmed focal hyperinsulinism who are candidates for surgical resection
2. Current therapy with diazoxide. Subjects may be eligible for participation 48 hrs after discontinuation of diazoxide.
3. Laboratory abnormalities that indicate clinically significant hematologic, hepatobiliary, or renal disease:

   1. AST/SGOT \> 2.5 times the upper limit of normal
   2. ALT/SGPT \> 2.5 times the upper limit of normal
   3. Total bilirubin \> 2.5 times the upper limit of normal
   4. Hemoglobin \< 9 gm/dL
   5. White blood cell count \< 3,000/ mm3
   6. Platelet count \< 100,000/mm3
   7. Creatinine \> 2.5 times the upper limit of normal
4. Evidence of active infection.
5. Evidence of cardiac or respiratory failure.
6. Known immune deficiency.
7. Preterm (\< 37 week gestation at birth).
8. Treatment with immunosuppressants.
9. Treatment with any drug known to interact significantly with sirolimus (strong inducers and strong inhibitors of CYP3A4 and P-gp with risk category D and X) including:

   Cyclosporine, clozapine, conivaptan, crizotinib, dabrafenib, dipyrone, boceprevir, echinacea, efavirenz, enzalutamide, fluconazole, fosphenytoin, fusidic acid, idelalisib, leflunomide, lomitapide, mifepristone, mitotane, natalizumab, nelfinavir, phenytoin, pimecrolimus, pimozide, posaconazole, roflumilast, St Johns Wort, stiripentol, tacrolimus, telaprevir, tofacitinib, rifampin, rifabutin, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin
10. Any investigational drug use within 5 half-lives of the drug prior to initiation of therapy.

    Subjects who had participated in other investigational drug studies will be eligible to participate after 5 half-lives from the last dose of the investigational agent and have recovered from acute investigational agent associated toxicity
11. History of surgical procedure within 8 weeks of enrollment.
12. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.