Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency

NCT03288103 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 2017-1956
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single-arm prospective pilot study to study the effects of a single dose regimen of daily growth hormone medication (Norditropin) on pre-pubertal children with Aggrecan deficiency. The growth response will be tracked over a 12 month period. A protocol extension has been approved to continue subjects on treatment for an additional 2 years.

Conditions

Short Stature

Outcome Measures

Primary Outcomes (2)

• Height Standard Deviation Score

  Height Standard Deviation Score is the standard deviation above or below the mean the height is for age and gender. Values were obtained by plotting heights on Centers for Disease Control and Prevention growth charts. An increase in Height Standard Deviation Score correlates with increase in height. Results are reported for 10 patients treated with recombinant human growth hormone.

  Annually through three years of treatment

• Height Velocity After Three Years of Treatment With Recombinant Human Growth Hormone (rhGH)

  A participants calculated height velocity derived from height measurements taken over a period of 36 months (baseline visit to 36 month visit). Only those in the treatment arm were treated with growth hormone and observed for response.

  Annually through three years of treatment

Secondary Outcomes (2)

• Number of Participants With Clinical Features of ACAN Deficiency - Osteochondritis Dissecans

  Baseline

• Number of Participants With Clinical Features of ACAN Deficiency - Osteoarthritis

  Baseline

Study Arms (1)

Growth Hormone Treatment for Participants with ACAN Deficiency

EXPERIMENTAL

Pre-pubertal children with ACAN deficiency on daily growth hormone (Norditropin) regimen for a 3 year period.

Drug: Norditropin

Interventions

Norditropin DRUG

Single dose of daily growth hormone regimen. Dose will be 50 micrograms/kg/day.

Also known as: somatropin

Growth Hormone Treatment for Participants with ACAN Deficiency

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ACAN Deficiency - Patients must be heterozygous for a mutation in the ACAN gene. A mutation will be defined as:
• a. A heterozygous deletion of the entire gene or of \>1 complete exons of the gene b. Any truncating mutation including frameshift, nonsense, splice site mutations within 2 bases of the exon/intron boundary, and start loss variants c. Any missense mutation which meets the following criteria: i. It is absent in the Exome Aggregation Consortium Database (exac.broadinstitute.org) ii. It is predicted to be damaging by both Polyphen2 and Sorting Intolerant From Tolerant (SIFT) iii. It segregates with the short stature phenotype in the family or is a de novo mutation d. In-frame insertions or deletions of \>1 amino acid e. In-frame insertions or deletions of 1 amino acid must meet the same criteria as missense mutations. For the prediction programs, Alanine will be substituted for the deleted amino acid.
• f. Note - Retrospective data does not show any correlation between the type of mutation and the severity of short stature. Therefore, all mutations meeting the above criteria will be included as a single group.
• Age - Greater than or equal to 2 years 0 days. There is no specific upper age limit, but the onset of puberty will make the patient ineligible.
• Pre-pubertal
• Male subjects must have a testicular volume \<4 cc as determined on physical examination by a pediatric endocrinologist at the time of the screening visit
• Female subjects must be Tanner 1 for breast development as determined on physical examination by a pediatric endocrinologist at the time of the screening visit
• Bone Age - The bone age as determined by the Greulich and Pyle method must be equal to or greater than the chronological age. Bone ages will be determined at the screening visit by a single centralized radiologist.
• Insulin-like growth factor (IGF-I) level within normal range for age and sex.
• Ability to provide informed consent before any trial-related activities

You may not qualify if:

• Prior treatment with any of the following therapies:
• A. Growth hormone B. Insulin-like Growth Factor (IGF-I) C. Gonadotropin releasing hormone (GnRH) analog D. Aromatase Inhibitor E. Oxandrolone
• History of any type of malignancy
• Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13 years in females and 15 years in males
• Chronic medical condition known to affect growth including but not limited to:
• A. Cystic fibrosis B. Diabetes C. Inflammatory Bowel Disease D. Celiac Disease E. Asthma requiring a daily inhaled steroid dose \> 400 micrograms of inhaled budesonide per day or equivalent F. Taking daily oral glucocorticoids for any reason G. Note - attention deficit hyperactivity disorder (ADHD) treated with a stimulant and treated hypothyroidism with a normal thyroid stimulating hormone (TSH) will not exclude the subject from participating in the trial.
• (BMI) \<5th percentile (CDC growth charts)
• Any clinically significant abnormality on screening laboratory tests as determined by the principal investigator.
• Known or suspected allergy to trial medication, excipients, or related products.
• Contraindications to study medications, worded specifically as stated in the product's prescribing information.
• The receipt of any investigational drug within 90 days prior to this trial.

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead

Study Sites (1)

Cincinnati Childrens Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (2)

• Alexandrou E, Dauber A, Tyzinski L, Hwa V, Andrew M, Kim H, Elangovan S, Gubanich P, Taylor-Haas JA, Paterno M, Backeljauw P. Clinical phenotype and musculoskeletal characteristics of patients with aggrecan deficiency. Am J Med Genet A. 2022 Apr;188(4):1193-1203. doi: 10.1002/ajmg.a.62639. Epub 2022 Jan 9.

  PMID: 35001504 RESULT

• Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Andrew M, Hwa V, Backeljauw P. Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human Growth Hormone: 1-Year Response. J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2103-e2109. doi: 10.1210/clinem/dgab904.

  PMID: 34922359 RESULT

MeSH Terms

Conditions

Dwarfism

Interventions

Human Growth Hormone

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Growth Hormone; Pituitary Hormones, Anterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Philippe Backeljauw, MD
• Organization: Cincinnati Childrens Hospital Medical Center

Philippe.backlejauw@cchmc.org

15136368444

Study Officials

• Philippe Backeljauw, MD

  Cincinnati Childrens Hospital Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2017
• First Posted: September 19, 2017
• Study Start: February 1, 2018
• Primary Completion: March 31, 2023
• Study Completion: August 31, 2023
• Last Updated: July 30, 2024
• Results First Posted: July 30, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)