Safety and Efficacy of Pegvisomant in Children With Growth Hormone Excess

• INCLUSION CRITERIA:

• Subjects who are eligible for enrollment must meet the following eligibilitycriteria:

Cohort 1: Patients with GH excess

• Males and females 24 months to <18 years at enrollment

• 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/mLwitholder radioimmunoassays or <0.4ng/ml with sensitive immunoradiometric orimmunochemiluminescent assays within 2 hours during Oral Glucose Tolerance Test (OGTT) after the administration of 1.75gr/kg (max 75gr) of glucose or elevatedGH secretion profile during overnight sampling.

• History of inadequate response to trans-sphenoidal surgery or radiation therapy forGH secreting pituitary tumor, or inability to tolerate surgery or radiationtherapies or patient deemed inappropriate candidate for surgery and/or pituitaryradiation therapy, as determined by review of the medical records by the PI. Theevaluation of the patient should be performed at 3 months after the surgery date inorder to ensure that there is persistent GH excess after the transsphenoidalresection of the tumor unless there are clear evidence of persistent disease, e.g.residual tumor, based on the PI s assessment. If the patient has receivedirradiation, there is no minimum time to be considered before enrolling in thestudy. The effects of radiation therapy take place over many years after receivingit (mean time to remission for stereotactic radiation therapy of 12-60 months), and,thus, a medical therapy is required during that period.

• Patient is either not receiving any other medication for GH excess or is receivingstable dose/frequency of other medications for the treatment of GH excess prior toinitiation of pegvisomant and no further adjustment or addition of new medication ismade for the duration of the study.

• Medications that may be co-administered for GH excess include but are notlimited to: IM/SC/oral first- or second-generation somatostatin analogues (octreotide, lanreotide, pasireotide), oral dopamine agonist (cabergoline) andany other medication/formulation that may become available during this study.For each medication, its specific formulation and route of administration,patient will need to be on stable dose/frequency for a duration that is atleast the minimum time recommended for adjusting the dose by the manufacturerwhich usually incorporates the time needed to reach plasma steady-state levelsand a new plateau on the effect of the medication on IGF-1 (cabergoline: 4weeks; SC octreotide/pasireotide administered twice or three times daily: 2weeks; oral octreotide: 2 weeks; depot IM octreotide/SC lanreotide/IMpasireotide administered Q4 weeks: 3 months). The duration needed for thestable dose for patients on alternative schedules of administration of theabove or other medications will be assessed based on available information andthe longest estimated interval to achieve the full effect.

• If a patient has been receiving a medication for GH excess but is notinterested to continue that medication a minimum period of 6-weeks ofdiscontinuation of the medication will be required for washout. This period wasdefined in the prior version of the protocol and is designed to minimize thetime the patient may not be receiving any treatment for GH excess.

• Able to provide consent/assent if developmentally appropriate

• Willing to use non-hormonal method of contraception in patients of reproductivepotential from the start of the study until at least 28 days after they stop themedication. Females of reproductive age (Tanner 3 or more, and/or having menstrualcycle) will be educated on the risks of unknown potential fetal harm while using theinvestigational medication, and they will be educated on the alternativepreventative methods for contraception (condoms). Females already receiving oralcontraceptive pills (OCPs) will be evaluated by gynecology consult service todiscuss effective non-hormonal contraception. Sexually active female subjects mustagree 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 regular heightand 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).

Cohort 2: Parents

-Biological parents of a participant enrolled in the study enrolled for anthropometric measurements only.

EXCLUSION CRITERIA:

Cohort 1: Patients

An individual who meets any of the following criteria will be excluded from participation in this study:

• Liver function abnormalities (ALT, AST) greater than or equal to 3 x ULN

• Positive pregnancy test in females, current pregnancy and/or female patients who arebreastfeeding.

• 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 performedand, thus, chronic use of opioids (>2 weeks) will be an exclusion criterion.

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

Cohort 2: Patients Parents:

Subjects enrolled as parents of patients do not have to be tested for the above exclusion criteria as their participation is limited to anthropometric measurements (no risk).