Pasireotide in Hyperinsulinemic Hypoglycemia

Hyperinsulinism Clinical Trial

Official title:

Pasireotide for Prevention of Hypoglycemia in Patients With Hyperinsulinemic Hypoglycemia

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03053284
• Other study ID #: 2016-7044
• Status: Withdrawn
• Phase: Phase 2
• Start date: April 2017
• Est. completion date: April 2018

Study information

• Verified date: May 2021
• Source: Montefiore Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: April 2018
• Est. primary completion date: January 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion criteria:

1. Male or female patients aged 18 to 70 years old

2. Patients with hyperinsulinemic hypoglycemia due to either congenital hyperinsulinemic hypoglycemia or insulinoma, as determined by an endocrinologist

3. 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

4. Written informed consent obtained prior to treatment to be consistent with local regulatory requirements

5. 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

6. Patients receiving anti-hypoglycemic treatment are eligible

7. Patients who are treatment naïve, or those who were previously, but not currently, treated with anti-hypoglycemic therapy are also eligible

8. 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:

1. Age <18, age >70 (for both insulinoma and congenital hyperinsulinism)

2. Known hypersensitivity to somatostatin or analogues

3. Diabetic patients with poor glycemic control as evidenced by HbA1c >8%

4. Patients who are hypothyroid and not on adequate replacement therapy

5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis

6. QTcF at screening > 450 msec in males and QTcF > 460 msec in females

7. Hypokalaemia, hypomagnesaemia, family history of long QT syndrome or concomitant medications with known risk of Torsades de pointes (TdP)

8. 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

9. Severe non-malignant medical illness that may be jeopardized by treatment with a single dose of pasireotide

10. 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

11. Patients with serum creatinine >2.0 X ULN

12. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L

13. Patients with the presence of active or suspected acute or chronic uncontrolled infection

14. Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks prior screening

15. History of unexplained syncope or family history of idiopathic sudden death

16. 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.

17. 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

18. 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.

Related Conditions & MeSH terms

• Congenital Hyperinsulinism
• Hyperinsulinism
• Hypoglycemia
• Insulinoma

Intervention

Drug:
• Pasireotide 0.6Mg Solution for Injection
Pasireotide 0.6Mg Solution for Injection will be given once per study visit
• Saline Solution
Saline Solution injection will be given once per study visit

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Montefiore Medical Center	Novartis Pharmaceuticals

References & Publications (9)

Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M, Snyder P, Tabarin A, Biller BM, Findling J, Melmed S, Darby CH, Hu K, Wang Y, Freda PU, Grossman AB, Frohman LA, Bertherat J. Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009 Jan;94(1):115-22. doi: 10.1210/jc.2008-1008. Epub 2008 Oct 28. — View Citation

Braun M. The somatostatin receptor in human pancreatic ß-cells. Vitam Horm. 2014;95:165-93. doi: 10.1016/B978-0-12-800174-5.00007-7. Review. — View Citation

de Heide LJ, Laskewitz AJ, Apers JA. Treatment of severe postRYGB hyperinsulinemic hypoglycemia with pasireotide: a comparison with octreotide on insulin, glucagon, and GLP-1. Surg Obes Relat Dis. 2014 May-Jun;10(3):e31-3. doi: 10.1016/j.soard.2013.11.006. Epub 2013 Dec 4. — View Citation

Eigler T, Ben-Shlomo A. Somatostatin system: molecular mechanisms regulating anterior pituitary hormones. J Mol Endocrinol. 2014 Aug;53(1):R1-19. doi: 10.1530/JME-14-0034. Epub 2014 Apr 29. Review. — View Citation

Hansen L, Hartmann B, Mineo H, Holst JJ. Glucagon-like peptide-1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum. Regul Pept. 2004 Apr 15;118(1-2):11-8. — View Citation

Quinn TJ, Yuan Z, Adem A, Geha R, Vrikshajanani C, Koba W, Fine E, Hughes DT, Schmid HA, Libutti SK. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery. 2012 Dec;152(6):1068-77. doi: 10.1016/j.surg.2012.08.021. Epub 2012 Oct 24. — View Citation

Schmid HA, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. J Endocrinol. 2012 Jan;212(1):49-60. doi: 10.1530/JOE-11-0224. Epub 2011 Oct 10. — View Citation

Tirosh A, Stemmer SM, Solomonov E, Elnekave E, Saeger W, Ravkin Y, Nir K, Talmor Y, Shimon I. Pasireotide for malignant insulinoma. Hormones (Athens). 2016 Apr;15(2):271-276. doi: 10.14310/horm.2002.1639. — View Citation

Yorifuji T. Congenital hyperinsulinism: current status and future perspectives. Ann Pediatr Endocrinol Metab. 2014 Jun;19(2):57-68. doi: 10.6065/apem.2014.19.2.57. Epub 2014 Jun 30. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Collection of safety and adverse event data	7 hours
Primary	Hypoglycemia	Occurence, frequency and severity of hypoglycemia (serum glucose < 55 mg/dL)	7 hours
Secondary	Serum glucose regulators	Insulin, GLP-1, glucagon and cortisol levels	7 hours