Pegvisomant With Glucagon Test to Assess for Adult Growth Hormone Deficiency
Palabras clave
Abstracto
Descripción
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.
fechas
Verificado por última vez: | 09/30/2013 |
Primero enviado: | 02/17/2013 |
Inscripción estimada enviada: | 03/02/2013 |
Publicado por primera vez: | 03/04/2013 |
Última actualización enviada: | 10/22/2013 |
Última actualización publicada: | 10/23/2013 |
Fecha de inicio real del estudio: | 02/28/2011 |
Fecha estimada de finalización primaria: | 10/31/2013 |
Fecha estimada de finalización del estudio: | 11/30/2013 |
Condición o enfermedad
Intervención / tratamiento
Drug: Pegvisomant-glucagon test
Drug: Regular insulin
Fase
Grupos de brazos
Brazo | Intervención / tratamiento |
---|---|
Active Comparator: 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. | Drug: Pegvisomant-glucagon test Pegvisomant 1 mg/kg injection 3 days before the glucagon test. |
Active Comparator: 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. |
Criterio de elegibilidad
Edades elegibles para estudiar | 21 Years A 21 Years |
Sexos elegibles para estudiar | All |
Acepta voluntarios saludables | si |
Criterios | 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 |
Salir
Medidas de resultado primarias
1. 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. [9 weeks]
Medidas de resultado secundarias
1. Correlation of peak GH and cortisol levels to BMI and fasting glucose, and effects of pegvisomant on IGF-I bioactivity. [9 weeks]