Pharmacodynamics of CNP During Growth Hormone Treatment

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
Children's Hospital Los Angeles
Novo Nordisk A/S
Information provided by (Responsible Party):
Rob Olney, Nemours Children's Clinic
ClinicalTrials.gov Identifier:
NCT01504802
First received: July 20, 2011
Last updated: February 13, 2012
Last verified: February 2012
  Purpose

It is now widespread practice to treat children with short stature with growth hormone. However, how an individual child will respond to growth hormone treatment is unpredictable and highly variable. Some children will not respond to growth hormone treatment at all. Currently, the only way to determine how well growth hormone therapy is working is to wait until they have been treated for six months and to compare the pre-treatment growth velocity with the growth velocity on treatment. It would be helpful to have a blood test that could be done shortly after starting growth hormone that could predict whether how well a child is responding to treatment. Such a blood test would allow endocrinologists to adjust the growth hormone dose (or possibly stop it altogether, if it is not working) long before the six months it currently takes.

C-type natriuretic peptide (CNP) and its partner amino-terminal propeptide of CNP (NTproCNP) are proteins that play a critical role in regulating growth. The investigators have previously shown that blood levels of these proteins increase in children being treated with growth hormone. The investigators believe that a blood test for these proteins will be useful in predicting a child's response to growth hormone treatment.

The purpose of this study is to determine when after starting growth hormone, the blood levels of CNP and NTproCNP start to increase.


Condition
Pituitary Dwarfism
Idiopathic Short Stature

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pharmacodynamics of C-Type Natriuretic Peptide During Growth Hormone Treatment in Children: A Potential Biomarker of Efficacy

Resource links provided by NLM:


Further study details as provided by Nemours Children's Clinic:

Primary Outcome Measures:
  • Determine the time after starting rhGH that NTproCNP level reaches 95% of its peak level [ Time Frame: One year ] [ Designated as safety issue: No ]
    NTproCNP will be modeled over time for each individual subject and the time it reaches 95% of its peak value determined. This value will then be averaged for the cohort.


Secondary Outcome Measures:
  • Correlate NTproCNP levels at the time it reaches 95% of its peak with six-month and one year growth velocity on rhGH treatment [ Time Frame: one year ] [ Designated as safety issue: No ]
  • Compare NTproCNP levels with other biomarkers of growth (serum IGF-I, bone-specific alkaline phosphatase, and leptin, and urine deoxypyridinoline) during rhGH treatment [ Time Frame: One year ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples Without DNA

Serum, plasma, and urine will be saved for potential future studies.


Estimated Enrollment: 22
Study Start Date: November 2010
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
Growth hormone deficient
Children with short stature, a peak growth hormone response on stimulation testing of less than 7 ng/ml, and no other identifiable cause of short stature
Idiopathic short stature
Children with short stature, a peak growth hormone response on stimulation testing of greater than or equal to 7 ng/ml, and no identifiable cause for the short stature

Detailed Description:

Treatment of children with short stature with recombinant human growth hormone is widespread practice. However, the growth response to growth hormone treatment is highly variable, particularly for those children who do not have classic growth hormone deficiency. The availability of a biomarker of efficacy that can be measured early in treatment would be beneficial.

C-type natriuretic peptide (CNP) plays a critical role in linear growth. CNP is produced in the growth plate and signals through a paracrine mechanism. Its bioinactive amino-terminal propeptide (NTproCNP) is easily measurable in plasma and levels reflect rate of CNP biosynthesis. Previous studies in lambs and children have shown that the plasma concentration of NTproCNP correlates with linear growth velocity and the investigators have also shown that levels are increased during growth hormone therapy. The investigators have proposed that NTproCNP is a biomarker for linear growth and consider it the first "growth plate function test." Such a growth biomarker is likely to reflect efficacy of growth hormone therapy soon after starting growth hormone, possibly as soon as a few days. Before the clinical utility of this can be determined, the investigators need to ascertain the pharmacodynamics of CNP and NTproCNP in response to growth hormone.

The goal of this study is to describe the pharmacodynamics of the CNP response to the initiation of growth hormone in two sets of children with short stature, those with growth hormone deficiency and those in whom normal growth hormone secretion (idiopathic short stature) and to compare these data to the pharmacodynamics of other peptides previously identified as potential biomarkers. The investigators hypothesize that plasma NTproCNP levels will increase within four days of starting growth hormone therapy and that the response in children with growth hormone deficiency will be more prompt and greater than those with idiopathic short stature. The investigators second hypothesis is that the increase in NTproCNP in response to growth hormone will correlate with the increase in growth velocity after six and twelve months of treatment.

The study is a prospective observational study of children with growth hormone deficiency (n=10) and with idiopathic short stature (n=10) being started on rhGH therapy. The study consists of frequent monitoring of analyte levels over one year of treatment.

This is a two site study, Nemours Children's Clinic, Jacksonville, Florida and Children's Hospital Los Angeles.

  Eligibility

Ages Eligible for Study:   3 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Children with short stature

Criteria

Inclusion Criteria:

  • Age greater than 3 years
  • Prepubertal
  • Height SD score less than -2.25
  • Had a growth hormone stimulation test

Exclusion Criteria:

  • History of any other disease or drug treatment that might interfere with linear growth, including amphetamine derivatives for treatment of ADD or ADHD
  • Previous treatment with any growth-promoting medication, including growth hormone
  • Any contraindication to growth hormone therapy
  • Minor acute illness (upper respiratory infections, strep throat, gastroenteritis, urinary tract infection, etc.) less than one month prior to starting growth hormone
  • Major acute illness (pneumonia, meningitis, pyelonephritis, any illness requiring hospitalization, etc.), any surgery, or bone fracture less than six months prior to starting growth hormone
  • Weight less than 13 kg (NCC-J) or 15 kg (CHLA), due to blood volume being drawn.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01504802

Locations
United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
United States, Florida
Nemours Children Clinic
Jacksonville, Florida, United States, 32207
Sponsors and Collaborators
Nemours Children's Clinic
Children's Hospital Los Angeles
Novo Nordisk A/S
Investigators
Principal Investigator: Robert Olney, MD Nemours Children's Clinic
  More Information

Additional Information:
No publications provided

Responsible Party: Rob Olney, Physician/Researcher, Nemours Children's Clinic
ClinicalTrials.gov Identifier: NCT01504802     History of Changes
Other Study ID Numbers: NCC 167624
Study First Received: July 20, 2011
Last Updated: February 13, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Nemours Children's Clinic:
Growth hormone
C-type natriuretic peptide
amino-terminal propeptide of C-type natriuretic peptide
insulin-like growth factor-I
bone specific alkaline phosphatase
leptin
deoxypyridinoline
growth velocity
pharmacodynamic
biomarker

Additional relevant MeSH terms:
Dwarfism
Dwarfism, Pituitary
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Genetic Diseases, Inborn
Endocrine System Diseases
Bone Diseases, Endocrine
Hypopituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hormones
Natriuretic Peptide, C-Type
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Natriuretic Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 15, 2014