Pegvisomant With Glucagon Test to Assess for Adult Growth Hormone Deficiency

Study Overview
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Brief Summary
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Hypothesis: Pegvisomant combined with the glucagon stimulation test (GST) can improve the accuracy of this test when used to diagnose adult GH and cortisol (steroid hormone)insufficiency. Study aims: Diagnosing GH and cortisol deficiency in adults requires a special test. At present, the insulin tolerance test (ITT) is considered the test of choice. However, this test is difficult to perform as it involves giving insulin through the veins to decrease blood sugars to very low levels, and this can be unpleasant, and cannot be performed in elderly adults and in those with a history of heart disease, seizure disorders or stroke. For this reason there is an urgent need for an alternative reliable test. At present, the GST is considered the alternative test to the ITT but its accuracy in obese patients and in those with diabetes remains unclear. Pegvisomant is a medication that can increase GH production in the body. The purpose of this study is to find out if combining pegvisomant with the GST can help improve the accuracy of this test so that it is comparable with the ITT in diagnosing adult GH and cortisol insufficiency. Study design: Subjects will be recruited from the Oregon Health & Science University Dynamic Endocrine Testing Unit. A written informed consent will be obtained and a screening interview will be carried out. During the screening interview, the study will be explained to the subject in detail. For women of child-bearing age, a pregnancy test will be performed. The subjects will then take part in three studies on separate days: (1) GST; (2) pegvisomant (1 mg/kg) injection into the abdomen 3 days before the glucagon stimulation test (ii) insulin tolerance test. For the GST, glucagon will be injected into the muscle and blood draws will be performed every 30 mins for 240 mins. For the insulin tolerance test, a blood draw will be performed and insulin will be given into the vein followed by blood draws every 15 mins for 120 mins. The data from all three studies will be analyzed in the study where the peak growth hormone and cortisol levels for all three tests will be compared. A questionnaire will be used at the end of the study for the subjects to rank the level of preference of the three tests. The data of the study will be analyzed using a computer statistical program where the identity of the subjects will be coded to maintain confidentiality.

Detailed Description
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Background: The diagnosis of GH deficiency in adults is established by provocative testing of GH secretion. The insulin tolerance test (ITT) is widely regarded as the gold standard test for diagnosing adult GH deficiency despite concerns about its practicality, safety, reproducibility, and its contraindications in elderly adults, adults with seizures and patients with ischemic heart disease. The glucagon stimulation test (GST) has been proposed as the alternative to the ITT for the following reasons: 1) availability; 2) low cost and 3) safety. This test has been validated in the past as a reliable test in assessing the GH reserve in both adults and children. In addition, a number of studies have also shown that the GST is capable of stimulating not only GH but also ACTH release. However, the accuracy and reliability of the GST in assessing the hypothalamic-pituitary-adrenal (HPA) axis and GH reserve in obese and diabetic patients are still lacking. Pegvisomant (PV) (Somavert®) is a GH receptor antagonist and is currently licensed by the FDA for the treatment of acromegaly. Physiological studies have demonstrated that acute high dose administration of PV can enhance endogenous GH stimulation. These data was more recently utilized by Radetti et al. to prime the L-DOPA test in assessing its reliability in the diagnostic work up of GH deficiency in short children. Using a PV dose of 1 mg/kg to prime the L-DOPA test in 21 short children, these investigators demonstrated an improvement in the reliability of the L-DOPA stimulation test in diagnosing GH deficiency with 10 out of the 18 (56%) children that initially failed the L-DOPA test successfully passed the L-DOPA test following PV-priming. These investigators postulate that PV-priming unmasked potentially false diagnoses of GH deficiency by exploiting the acute IGF-lowering effect and reducing the negative feedback of GH on the hypothalamus. We therefore propose this proof-of-concept pilot study to investigate the potential of acute GH receptor blockade using PV to reduce false positive rates in adults undergoing GH testing with the GST. In addition, we plan to investigate the effects of PV on IGF-I bioactivity, as measured by the IGF-I kinase receptor activation (KIRA) assay (30). Subjects: Ten subjects with suspected pituitary disease will be invited to participate in the study. Subjects will be screened for eligibility before enrollment into the study. Intervention: After completing the GST, eligible subjects will be randomized to undergo either the PV-GST or the ITT. Subjects who are randomized to undergo the PV-GST first will then undergo the ITT, and vice versa, 4-6 weeks later. For the PV-GST, a blood test for serum IGF-I and IGF-I KIRA level will be measured and the patient will then receive PV at a dose of 1 mg/kg injected subcutaneously. The patient will then return in 3 days' time to undergo the GST. For this part of the test, subjects will receive glucagon administered intramuscularly at a dose of 1 mg if subject weighs 90 kg or less and 1.5 mg if subject weighs more than 90 kg. Measurements: Blood samples for the measurement of glucose, IGF-I, IGF-I KIRA, GH and cortisol will be performed at various time-points for the GST, PV-GST and ITT Specific Aims: Primary aims: 1) To investigate the potential of acute GH receptor blockade priming with PV to glucagon (PV-GST test) on the characteristics of peak GH and cortisol levels; 2) To ascertain cut-point levels for GH and cortisol with the PV-GST in comparison to the ITT in defining GH and cortisol deficiency. Secondary aims: 1) Correlation between peak GH and cortisol levels induced by the PV-GST and BMI; 2) Correlation between peak GH and cortisol levels induced by the PV-GST and fasting blood glucose levels; 3) Effects of PV on IGF-I bioactivity as determined by the IGF-I KIRA.

Official Title
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Effects of Pegvisomant-Priming With the Glucagon Stimulation Test in Assessing GH and Cortisol Reserve in Adults: a Randomized Proof-of-Concept Pilot Study

Conditions
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Adults Growth Hormone Deficiency.

Intervention / Treatment
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* Drug: Pegvisomant
* Drug: Regular insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent and comply with study assessments for the full duration of the study. Age 21 to 55 years Body weight 60 to 120 kg inclusive Stable weight and diet for at least 3 months prior to study entry Exclusion Criteria: Poor IV access Known hypersensitivity to glucagon Inability or unwillingness to comply with study procedures Clinically significant cardiovascular or cerebrovascular disease Current active malignancy other than non-melanoma skin cancer Active acromegaly or Cushing's disease Pheochromocytoma Pregnancy Renal failure (serum creatinine > 2 mg/dl) Severe acute illness Uncontrolled hypertension (BP > 160/100 mmHg) Emotional/social instability likely to prejudice study completion Recurrent or severe unexplained hypoglycemia Known or suspected drug/alcohol abuse Patients with history of coronary artery disease, cerebrovascular disease, congestive heart failure, arrhythmias and seizure disorder that would be excluded from the ITT arm regardless of age Participation in another simultaneous medical investigation or trial

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 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: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pegvisomant-glucagon test<br>To compare the combined pegvisomant with the glucagon test to the insulin tolerance test and the glucagon test in diagnosing adult growth hormone and cortisol insufficiency. | Drug: Pegvisomant<br>* Pegvisomant 1 mg/kg injection 3 days before the glucagon test.<br>* Other names: Somavert.;Drug: Regular insulin<br>* 0.1-0.15 units/kg<br>|
| Active Comparator: Insulin tolerance test<br>To compare the combined pegvisomant with the glucagon test to the insulin tolerance test and the glucagon test in diagnosing adult growth hormone and cortisol insufficiency. | Drug: Regular insulin<br>* 0.1-0.15 units/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak growth hormone and cortisol levels induced by the pegvisomant-glucagon test compared to those by the insulin tolerance test in assessing the growth hormone and cortisol reserve in adults suspected of adult growth hormone and cortisol deficiencies. | Presently, the insulin tolerance test (ITT) is regarded as the gold standard test in diagnosing adult GH deficiency but this test is difficult to perform in patients with diabetes mellitus, and contraindicated in the elderly, and in adults with seizures and ischemic heart disease. Glucagon test is the alternative test to the ITT but its accuracy and reliability is questionable in obesity and diabetes mellitus. Pegvisomant is a GH receptor blocker that increases GH secretion. When primed with glucagon, pegvisomant may enhance GH secretion by providing a stronger stimulus than glucagon alone. We plan to assess if by priming pegvisomant with glucagon will improve the accuracy of this test in diagnosing adult GH cortisol deficiency. Specifically, we will examine the characteristics of peak GH and cortisol levels, and ascertain the peak GH and cortisol levels in comparison to those generated using the ITT in diagnosing GH and cortisol deficiency. | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of peak GH and cortisol levels to BMI and fasting glucose, and effects of pegvisomant on IGF-I bioactivity. | We plan to assess the correlation between peak growth hormone and cortisol levels induced by the pegvisomant-glucagon test and BMI, fasting blood glucose levels, and evaluate the effects of pegvisomant on insulin-like growth factor-I bioactivity using the insulin-like growth factor-I kinase receptor activity assay. | 9 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pegvisomant, Growth hormone, Cortisol, Glucagon, Insulin