An Open-Label Phase 3 Study of the Safety and Efficacy of Pegvisomant in Children With Growth Hormone Excess

Description

Study Description:

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-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:

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 younger than 18 years.

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 and according to the timeline at page 10-11) 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 and 1 year
• Annual liver ultrasound
• ECG and echocardiogram at baseline, 6 months (EKG) and 1-year to monitor for the presence of cardiac arrhythmias and growth hormone 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.

We propose a 60-week (+/-2 weeks) study of once daily dosing of pegvisomant in children and adolescents ages 24 months to <18 years of age with gigantism. We propose the recruitment of up to 40 patients over the 3 years of the study.

Details