Safety and Efficacy of Pegvisomant in Children With Growth Hormone Excess

Overview

Background: For children with gigantism, too much growth hormone (GH) in the body causes abnormal growth and many other problems. Current treatments often don t work; no medical treatment is approved by FDA. Researchers want to see if the drug pegvisomant can help. Objective: To test the role of pegvisomant in children and adolescents with gigantism. Eligibility: People ages 2-18 with GH excess for whom usual treatments have not worked or who are not eliginle for them Design: Participants will be screened with a medical history. The study will last 60 weeks and include at least 3 visits: baseline, 6-month, and 12-month visits. For the baseline visit, participants will stay a few nights for testing. They may stay overnight for the other visits. All visits will include: Medical history Physical exam Questionnaires Heart and liver tests Participants may be photographed in their underwear if they agree. Blood tests: Participants will get a catheter: A small plastic tube will be placed in an arm vein. For some tests, the blood may be drawn every 30 minutes over 3 hours. For other tests, blood will be drawn every 20 minutes over 12 hours. Only clinically necessary tests will be done in each patient. At the baseline visit, participants will have the study drug injected under the skin. They will learn to take the injection at home. They will take the injection daily during the study. The baseline and 12-month visits will include: MRI: Participants will have a dye injected into a vein. They will lie in a machine that takes pictures of the body. Hand X-ray Participants must get their height and weight at their local doctor s office monthly. Participants must have blood and urine tests at their local lab monthly for the first 6 months then every 3 months until the study ends. ...

Study Description: GH excess is a rare and potentially lethal condition associated with hypersecretion of 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-like growth 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. Objectives: PRIMARY OUTCOMES: * Percent change of IGF-1 z-score from baseline to end of study (12 month visit). * Determine the safety and tolerability of pegvisomant in children and adolescents with GH excess. SECONDARY OUTCOMES: * Percent change of IGF-1 z-score from baseline to end of the study in subgroups of patients receiving monotherapy and patients receiving additional medication that target GH excess. * Normalization of the IGF-1 for age and sex from baseline to end of study (normal value defined as +/- 2 SD from the mean). Change in growth velocity to a near-normal range (+/- 1 SD) according to the Tanner and Davies growth velocity curves for age, sex, and stage of puberty, when comparing the 6-month period prior to the study drug initiation to the growth velocity between 6 and 12 months on the study drug. * Improvement in signs and symptoms of GH excess that are common in the pediatric population (headaches, excessive perspiration, fatigue, increased appetite) and the quality of life of the patients from baseline to the end of the study (12 month visit). * Improvement of the cardiac structure and function: reduction of the left ventricular mass index (LVMi), and change of the left ventricular ejection fraction (EF) on echocardiogram from baseline to the end of the study (12 month visit). The objectives of the proposed study are to characterize the efficacy of pegvisomant as indicated by adequate control of the IGF-1 levels, the safety profile of the medication in children with GH excess, and to obtain pharmacodynamic data on the effect of pegvisomant on the GH-IGF axis in children. Because pegvisomant does not inhibit GH secretion, serum IGF-1 is the best marker of treatment efficacy. Pharmacokinetic (PK) studies will be performed in a subset of patients. This study will enroll patients with GH excess younger than 18 years and their biological parents. Endpoints: Safety Patients who have received at least 1 dose of pegvisomant will be included in the safety evaluations. Safety will be evaluated by: * Spontaneously reported adverse events * Vital signs and periodic physical examinations (performed at the Clinical Center at baseline, 6 months (if possible unless telehealth visit performed) and 12 months after the study enrollment, and at local provider s office at regular intervals between those visits) * Laboratory tests (performed periodically as indicated by previous studies) including: * Hematology * Chemistry * Lipids * Liver function panel * Thyroid function tests * IGF-1 * Glucose and insulin * MRI of the pituitary to check for tumor growth at baseline, 6 months, and 1 year * Annual liver ultrasound * ECG and echocardiogram at baseline, 6 months (EKG, if possible unless telehealth visit performed) and 1-year to monitor for the presence of cardiac arrhythmias and GH related cardiomyopathy * Care providers will complete the Gigantism Symptoms Assessment Questionnaire (GSAQ) and Child Health Questionnaire by Landgraf \& Wade for assessment of quality of life. * Patients with gigantism and diabetes mellitus may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents as pegvisomant usually has beneficial effects on glucose metabolism.7 Patients with pre-existing diabetes will continue to monitor their daily blood glucose levels, as previously instructed, and communicate with the investigational team for persistent elevation or decrease of the glucose levels. The changes of the dose of the anti-diabetic drugs and/or insulin will be done with communication of the research team with the local endocrinologist. Patients without pre-existing diabetes will be educated on the signs of hyperglycemia and will get monthly fasting blood glucose level measurements for the first 6 months along with the screening of the liver enzyme levels.