Safety and Efficacy of Pegvisomant in Children With Growth Hormone Excess

Growth hormone excess is a rare and potentially lethal condition associated with
hypersecretion of growth hormone (GH), usually by a pituitary tumor or hyperplasia. When it
occurs prior to the complete fusion of growth plates, it leads to pathological tall stature,
and it is called gigantism. After the fusion of the growth plates, it is called acromegaly.
It may be associated with debilitating cardiovascular disease and/or diabetes. Children and
adolescents with gigantism are currently treated with surgery, radiation therapy, and
medications, such as octreotide, to reduce hypersecretion of GH; however, these treatments
may lack efficacy and have significant side effects. Pegvisomant is a genetically engineered
GH-receptor (GHR antagonist that blocks the action of GH. In adults with acromegaly,
pegvisomant has been shown to effectively reduce serum insulin-likegrowth factor type 1
(IGF-1) concentrations and lead to clinical improvement. However, experience in children and
adolescents is limited to a small number of case series. We propose the initiation of a new
protocol at the NICHD, NIH, to treat children and adolescents with GH excess that is
refractory to surgical therapy and/or radiation therapy, or in children and adolescents where
the above therapies are contraindicated.

- INCLUSION CRITERIA:

- Males and females 24 months to <18 years at informed consent

- Active GH excess as demonstrated by the following:

- IGF-1 greater than the upper limit of normal for age and sex during screening
(>+2 SD) and

- Abnormal GH levels as demonstrated by inability to suppress to <1 ng/mL within 2
hours during Oral Glucose Tolerance Test (OGTT) after the administration of
1.75gr/kg (max 75gr) of glucose or elevated GH secretion profile during overnight
sampling.

- History of inadequate response to trans-sphenoidal surgery or radiation therapy for GH
secreting pituitary tumor, or inability to tolerate surgery or radiation therapies or
patient deemed inappropriate candidate for surgery and/or pituitary radiation therapy,
as determined by review of the medical records by the Principal Investigator. The
evaluation of the patient should be performed at least 3 months after the surgery date
in order to ensure that there is persistent GH excess after the transsphenoidal
resection of the tumor. If the patient has received irradiation, there is no minimium
time to be considered before enrolling in the study. The effects of radiation therapy
take place over many years after receiving it (mean time to remission for stereotactic
radiation therapy of 12-60 months), and, thus, a medical therapy is required during
that period.

- Willingness to discontinue other medications for the treatment of GH excess for a
6-week washout period prior to initiating pegvisomant

- Able to provide consent/assent if developmentally appropriate

- Willing to use non-hormonal method of contraception in patients of reproductive
potential. Females of reproductive age (Tanner 3 or more, and/or having menstrual
cycle) will be educated on the risks of unknown potential fetal harm while using the
investigational medication, and they will be educated on the alternative preventative
methods for contraception (condoms). Females already receiving oral contraceptive
pills (OCPs) will be evaluated by gynecology consult service to discuss effective
non-hormonal contraception. Sexually active female subjects must agree to use an
effective non-hormonal contraception for the duration of the study.

- Have a primary health care provider in home location who will perform monthly height
and weight measurements, vital signs, and safety labs.

Height and weight will be requested to be performed according to the published methods
included in the CDC-NHANES manual on anthropometry procedures manual (Supplementary
Material).

They will be plotted on the respective growth charts produced by the CDC for the US
population (Supplementary Material).

EXCLUSION CRITERIA:

- Liver function abnormalities (ALT, AST) greater than or equal to 3 times ULN

- Positive pregnancy test in females, current pregnancy and/or female patients who are
breastfeeding.

- Patients currently using opioids. Opioids induce altered metabolism of pegvisomant.
Since this is a phase 3 study, opioids may affect the PK studies to be performed and,
thus, chronic use of opioids (>2 weeks) will be an exclusion criterion.

- Patients with any medical, physical, psychiatric, or social condition, which, in the
opinion of the investigators, would make participation in this protocol not in their
best interest, will be excluded from the study. Patients who are critically ill,
unstable, or with severe organ failure that may affect/limit the endocrine evaluation
and place unsustainable demands on CC or NICHD resources will be excluded.