Pasireotide in Hyperinsulinemic Hypoglycemia

Study Overview
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Brief Summary
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This is a small controlled pilot study to assess the effect of subcutaneous pasireotide on preventing hypoglycemia due to hyperinsulinism, including congenital hyperinsulinism and insulinoma.

Detailed Description
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Pasireotide is a somatostatin analog with affinity for several somatostatin receptors including those on pancreatic beta cells; when activated these receptors affect the secretion of glucagon and insulin. Pasireotide is also known to decrease glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) secretion. Hyperglycemia is a well-documented adverse effect of pasireotide in its approved indications for treatment of Cushing's disease and acromegaly. In light of this, the investigators hypothesize that pasireotide may be an effective therapy for hypoglycemia due to hyperinsulinism. Therefore a small controlled pilot study to assess the effect of subcutaneous (s.c.) pasireotide on preventing hypoglycemia due to hyperinsulinism over 7 hours of observation in both fasting and fed states is proposed.

Official Title
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Pasireotide for Prevention of Hypoglycemia in Patients With Hyperinsulinemic Hypoglycemia

Conditions
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Congenital Hyperinsulinism, Insulinoma, Hyperinsulinism

Intervention / Treatment
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* Drug: Pasireotide 0.6Mg Solution for Injection
* Drug: Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients aged 18 to 70 years old Patients with hyperinsulinemic hypoglycemia due to either congenital hyperinsulinemic hypoglycemia or insulinoma, as determined by an endocrinologist If no prior diagnosis of either insulinoma or congenital hyperinsulinemic hypoglycemia by an endocrinologist, the participant must meet the following criteria: A history of symptoms of hypoglycemia, (with or without a blood glucose <50mg/dL at time of symptoms) Improvement of symptoms with ingestion of carbohydrates At least one documented blood glucose <50mg/dL with concomitant insulin >3 mmol/L and c-peptide >0.2nmol/L, with a negative sulfonylurea screen At least 1 episode of glucose <50mg/dL in the last year Written informed consent obtained prior to treatment to be consistent with local regulatory requirements No evidence of significant liver disease: Serum total bilirubin < 2 x ULN INR < 1.3 unless on anticoagulation ALT and AST < 2 x ULN Alkaline phosphatase < 2.5 x ULN Patients receiving anti-hypoglycemic treatment are eligible Patients who are treatment naïve, or those who were previously, but not currently, treated with anti-hypoglycemic therapy are also eligible Patients with insulinoma who are operative candidates are eligible if surgery is not emergently needed, and study participation would not delay the timing of a surgical intervention Exclusion criteria: Age <18, age >70 (for both insulinoma and congenital hyperinsulinism) Known hypersensitivity to somatostatin or analogues Diabetic patients with poor glycemic control as evidenced by HbA1c >8% Patients who are hypothyroid and not on adequate replacement therapy Patients with symptomatic cholelithiasis and acute or chronic pancreatitis QTcF at screening > 450 msec in males and QTcF > 460 msec in females Hypokalaemia, hypomagnesaemia, family history of long QT syndrome or concomitant medications with known risk of Torsades de pointes (TdP) Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function Severe non-malignant medical illness that may be jeopardized by treatment with a single dose of pasireotide History of another primary malignancy, with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix unless there is no evidence of disease in the last year Patients with serum creatinine >2.0 X ULN Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L Patients with the presence of active or suspected acute or chronic uncontrolled infection Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks prior screening History of unexplained syncope or family history of idiopathic sudden death Sexually active males unless they use a condom during intercourse while taking drug and for 3 months following last dose of pasireotide and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and 30 days following last dose of pasireotide.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Normal saline s.c. injection once | Drug: Saline Solution<br>* Saline Solution injection will be given once per study visit<br>* Other names: Placebo;|
| Experimental: Pasireotide<br>Pasireotide 0.6mg s.c. once | Drug: Pasireotide 0.6Mg Solution for Injection<br>* Pasireotide 0.6Mg Solution for Injection will be given once per study visit<br>* Other names: SOM230;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoglycemia | Occurence, frequency and severity of hypoglycemia (serum glucose < 55 mg/dL) | 7 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum glucose regulators | Insulin, GLP-1, glucagon and cortisol levels | 7 hours |