Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency

This is a single center study. All participants will be recruited from the USA. The study intends to recruit pre-pubertal children for inclusion in the 1 year growth hormone treatment trial. The study also plans to collect the following detailed phenotypic data at the first study visit: height, weight, musculoskeletal evaluation, photographs, radiographs (knees, left hand), MRI of the knees. The participants will be required to return to Cincinnati Childrens Hospital Medical Center (CCHMC) for 3 study visits over the 12 month period. At the follow up visits participants will receive a routine physical/pubertal exam, joint exam, have vitals sign checked, height/weight taken, and labs drawn. A funduscopic exam will be performed to look for signs of intracranial pressure. Study participants are also required to complete phone check ins at scheduled intervals, and a locally drawn blood sample to check insulin-like growth factor (IGF1) levels approximately 3 months after treatment start date. Concomitant medications, adverse events will be recorded and updated at all study visits and phone check ins. Medication will be resupplied and shipped to the participant as needed at every point of follow up contact. If the subjects grow well enough in the first 12 months per study protocol, they are eligible to continue treatment through the study for an additional 2 years. They will continue to come to CCHMC every 6 months for follow up study visits. Study procedures will remain the same as the initial 1 year trial with the following additions: (1) local labs may need to be obtained for dose adjustment purposes, (2) repeat knee MRI may be completed for participants that are found to have early signs of joint disease on their baseline knee MRI scan.

The study will enroll interested and affected relatives of the participant in the joint phenotyping protocol as well. These participants will come to CCHMC only one time to complete the phenotyping visit. This is not an outcome of the study but the information gathered from the imaging will provide insight into the effects of ACAN mutation on the joint cartilage.

• Norditropin (Drug), also known as somatropin: Single dose of daily growth hormone regimen. Dose will be 50 micrograms/kg/day.

Primary outcomes

• Height Standard Deviation Score [Annually through three years of treatment]: 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.
• Height Velocity After Three Years of Treatment With Recombinant Human Growth Hormone (rhGH) [Annually through three years of treatment]: 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.

Secondary outcomes

• Number of Participants With Clinical Features of ACAN Deficiency - Osteochondritis Dissecans [Baseline]: Evidence of osteochondritis dissecans on MRI (in those who could cooperate to perform such unsedated between the ages of 6 years-old and 20 years-old) or radiograph examination of affected participant's knees.
• Number of Participants With Clinical Features of ACAN Deficiency - Osteoarthritis [Baseline]: Evidence of early joint pathology evident (osteoarthritis) on MRI (in those who could cooperate to perform such unsedated between the ages of 6 years-old and 20 years-old) or radiograph examination of affected participant's knees, performed in those who were age appropriate and would cooperate.

Sex: All, ages: 2 Years to any

Inclusion Criteria:

1. 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.
2. 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.
3. Pre-pubertal

   1. 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
   2. 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
4. 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.
5. Insulin-like growth factor (IGF-I) level within normal range for age and sex.
6. Ability to provide informed consent before any trial-related activities
7. Note - There is no specific height standard deviation criteria for inclusion in this study.

Exclusion Criteria:

1. 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
2. History of any type of malignancy
3. Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13 years in females and 15 years in males
4. 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.
5. (BMI) <5th percentile (CDC growth charts)
6. Any clinically significant abnormality on screening laboratory tests as determined by the principal investigator.
7. Known or suspected allergy to trial medication, excipients, or related products.
8. Contraindications to study medications, worded specifically as stated in the product's prescribing information.
9. The receipt of any investigational drug within 90 days prior to this trial.

Participant flow

Outcome results

• Height Standard Deviation Score (Primary), Median, standard deviation score: Growth Hormone Treatment for Participants With ACAN Deficiency -2.52 (-4.27 to -1.07)
• Height Velocity After Three Years of Treatment With Recombinant Human Growth Hormone (rhGH) (Primary), Median, cm/year: Growth Hormone Treatment for Participants With ACAN Deficiency 5.2 (3.8 to 7.1)
• Number of Participants With Clinical Features of ACAN Deficiency - Osteochondritis Dissecans (Secondary), Number, participants: Pediatric Phenotype Group 3; Adult Phenotype Group 1
• Number of Participants With Clinical Features of ACAN Deficiency - Osteoarthritis (Secondary), Number, participants: Pediatric Phenotype Group 0; Adult Phenotype Group 8

Adverse events

Time frame: Adverse event data was collected for treatment group participants from the time of enrollment until 3 months post treatment discontinuation. Adverse event data for phenotype participants was collected from time of enrollment until one week after the completion of their one-time study visit.

Other adverse events by term

• Results publication: 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
• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2021-04-02)
• Informed Consent Form (PDF, 2021-04-23)

• Philippe Backeljauw, MD, Principal investigator, Cincinnati Childrens Hospital Medical Center