Safety and Efficacy of Pegvisomant in Children With Growth Hormone Excess

• ClinicalTrials.gov Identifier: NCT03882034
• Recruitment Status: Recruiting
• First Posted: March 20, 2019
• Last Update Posted: July 7, 2022
• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )

Study Description

Brief Summary:

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.

...

Condition or disease	Intervention/treatment	Phase
Pituitary Disease	Drug: Pegvisomant	Phase 3

Detailed 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-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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 140 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Phase 3 Study of the Safety and Efficacy of Pegvisomant in Children With Growth Hormone Excess
• Actual Study Start Date: October 21, 2019
• Estimated Primary Completion Date: January 1, 2024
• Estimated Study Completion Date: January 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Intervention arm, Patient received pegvisomant	Drug: Pegvisomant; A fixed dose of pegvisomant 10-mg started on Day 1 of intervention and continued daily afterwards, will be administered subcutaneously according to manufacturer's recommendations. Adjustment of the dose will occur as per protocol.

Outcome Measures

Primary Outcome Measures :

1. Percent change of IGF-1 z-score from baseline to end of study (12 month visit). [ Time Frame: 1 year ]
   The primary endpoint is decrease in IGF-1 z-score >50% from baseline. This criterion will be used to determine efficacy.
2. Determine the safety and tolerability of pegvisomant in children with GH excess [ Time Frame: During 1 year ]
   Safety will be determined by the periodical description of vital signs, laboratory and imaging studies, and other reported side effects.

Secondary Outcome Measures :

1. Normalization of IGF-1 for age and sex from baseline to end of study (12 month visit) [ Time Frame: 1 year ]
   Normalization of the IGF-1 for age and sex from baseline to end of study (normal value defined as +/- 2 SD from the mean).
2. Normalization of growth velocity [ Time Frame: 1 year ]
   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.
3. Improvement in signs and symptoms of GH excess and quality of life from baseline to end of study (12 month visit) [ Time Frame: 1 year ]
   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).
4. Left ventricular ejection fraction change on echocardiogram from baseline to end of study (12 month visit). [ Time Frame: 1 year ]
   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).
5. Reduction of the left ventricular mass index (LVMi) on echocardiogram from baseline to end of study (12 month visit) [ Time Frame: 1 year ]
   (LVMi), and change of the left ventricular ejection fraction (EF) on echocardiogram from baseline to the end of the study (12 month visit).

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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 regular 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.

Contacts and Locations

Contacts

Contact: Christina Tatsi, M.D.; (301) 451-7170; christina.tatsi3@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Christina Tatsi, M.D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000 Apr 20;342(16):1171-7.

Lodish MB, Trivellin G, Stratakis CA. Pituitary gigantism: update on molecular biology and management. Curr Opin Endocrinol Diabetes Obes. 2016 Feb;23(1):72-80. doi: 10.1097/MED.0000000000000212. Review.

Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA; Endocrine Society. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):3933-51. doi: 10.1210/jc.2014-2700. Epub 2014 Oct 30.

• Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT03882034
• Other Study ID Numbers: 190071; 19-CH-0071
• First Posted: March 20, 2019
• Last Update Posted: July 7, 2022
• Last Verified: December 22, 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: .Protocol is silent on IPD sharing.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) ):

Pediatric; Gigantism; Growth Hormone

Additional relevant MeSH terms:

Acromegaly; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Bone Diseases, Endocrine; Bone Diseases; Musculoskeletal Diseases; Hyperpituitarism