Pegvisomant With Glucagon Test to Assess for Adult Growth Hormone Deficiency
| Status: | Completed |
|---|---|
| Conditions: | Endocrine |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 21 - 55 |
| Updated: | 4/2/2016 |
| Start Date: | March 2011 |
| End Date: | December 2013 |
| Contact: | Kevin C.J. Yuen, MRCP(UK),MD |
| Email: | yuenk@ohsu.edu |
| Phone: | 503 4940175 |
Effects of Pegvisomant-Priming With the Glucagon Stimulation Test in Assessing GH and Cortisol Reserve in Adults: a Randomized Proof-of-Concept Pilot Study
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.
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.
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.
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.
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
We found this trial at
1
site
3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
Portland, Oregon 97239
503 494-8311
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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