Pegvisomant With Glucagon Test to Assess for Adult Growth Hormone Deficiency
NCT ID: NCT01804413
Last Updated: 2013-10-24
Study Results
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Basic Information
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UNKNOWN
NA
10 participants
INTERVENTIONAL
2011-03-31
2013-12-31
Brief Summary
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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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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
CROSSOVER
DIAGNOSTIC
NONE
Study Groups
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Pegvisomant-glucagon test
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.
Pegvisomant
Pegvisomant 1 mg/kg injection 3 days before the glucagon test.
Regular insulin
0.1-0.15 units/kg
Insulin tolerance test
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.
Regular insulin
0.1-0.15 units/kg
Interventions
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Pegvisomant
Pegvisomant 1 mg/kg injection 3 days before the glucagon test.
Regular insulin
0.1-0.15 units/kg
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
21 Years
55 Years
ALL
No
Sponsors
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Aarhus University Hospital
OTHER
Oregon Health and Science University
OTHER
Responsible Party
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Kevin Yuen
Associate Professor of Endocrinology
Locations
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Oregon Health & Science University
Portland, Oregon, United States
Countries
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Central Contacts
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Facility Contacts
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Kevin C.J. Yuen, MRCP(UK),MD
Role: primary
Sharon A. Rhoads, RN
Role: backup
References
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Yuen KC, Biller BM, Molitch ME, Cook DM. Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency? J Clin Endocrinol Metab. 2009 Aug;94(8):2702-7. doi: 10.1210/jc.2009-0299. Epub 2009 Jun 9.
Berg C, Meinel T, Lahner H, Yuece A, Mann K, Petersenn S. Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery. Eur J Endocrinol. 2010 Mar;162(3):477-82. doi: 10.1530/EJE-09-0824. Epub 2009 Dec 8.
Conceicao FL, da Costa e Silva A, Leal Costa AJ, Vaisman M. Glucagon stimulation test for the diagnosis of GH deficiency in adults. J Endocrinol Invest. 2003 Nov;26(11):1065-70. doi: 10.1007/BF03345251.
Gomez JM, Espadero RM, Escobar-Jimenez F, Hawkins F, Pico A, Herrera-Pombo JL, Vilardell E, Duran A, Mesa J, Faure E, Sanmarti A. Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults. Clin Endocrinol (Oxf). 2002 Mar;56(3):329-34. doi: 10.1046/j.1365-2265.2002.01472.x.
di Iorgi N, Napoli F, Allegri A, Secco A, Calandra E, Calcagno A, Frassinetti C, Ghezzi M, Ambrosini L, Parodi S, Gastaldi R, Loche S, Maghnie M. The accuracy of the glucagon test compared to the insulin tolerance test in the diagnosis of adrenal insufficiency in young children with growth hormone deficiency. J Clin Endocrinol Metab. 2010 May;95(5):2132-9. doi: 10.1210/jc.2009-2697. Epub 2010 Mar 29.
Veldhuis JD, Bidlingmaier M, Anderson SM, Wu Z, Strasburger CJ. Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men. J Clin Endocrinol Metab. 2001 Jul;86(7):3304-10. doi: 10.1210/jcem.86.7.7656.
Veldhuis JD, Bidlingmaier M, Anderson SM, Evans WS, Wu Z, Strasburger CJ. Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men. J Clin Endocrinol Metab. 2002 Dec;87(12):5737-45. doi: 10.1210/jc.2001-011885.
Radetti G, Wu Z, Elsedfy HH, El Kholy M, Bozzola M, Strasburger CJ. Pegvisomant-primed GH stimulation test. Clin Endocrinol (Oxf). 2008 Jun;68(6):951-6. doi: 10.1111/j.1365-2265.2007.03132.x. Epub 2007 Nov 19.
Yuen KC, Frystyk J, Rhoads SA, Bidlingmaier M. Pegvisomant-primed glucagon stimulation test in assessing GH reserve and GH/IGF kinetics in adults suspected of GH deficiency. Pituitary. 2016 Feb;19(1):65-74. doi: 10.1007/s11102-015-0688-8.
Other Identifiers
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IRB6961
Identifier Type: -
Identifier Source: org_study_id