<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03288103</url>
  </required_header>
  <id_info>
    <org_study_id>2017-1956</org_study_id>
    <nct_id>NCT03288103</nct_id>
  </id_info>
  <brief_title>Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency</brief_title>
  <official_title>Clinical Characterization and Trial of Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-label, single-arm prospective pilot study to study the effects of a single&#xD;
      dose regimen of daily growth hormone medication (Norditropin) on pre-pubertal children with&#xD;
      Aggrecan deficiency. The growth response will be tracked over a 12 month period. A protocol&#xD;
      extension has been approved to continue subjects on treatment for an additional 2 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single center study. All participants will be recruited from the USA. The study&#xD;
      intends to recruit pre-pubertal children for inclusion in the 1 year growth hormone treatment&#xD;
      trial. The study also plans to collect the following detailed phenotypic data at the first&#xD;
      study visit: height, weight, musculoskeletal evaluation, photographs, radiographs (knees,&#xD;
      left hand), MRI of the knees. The participants will be required to return to Cincinnati&#xD;
      Childrens Hospital Medical Center (CCHMC) for 3 study visits over the 12 month period. At the&#xD;
      follow up visits participants will receive a routine physical/pubertal exam, joint exam, have&#xD;
      vitals sign checked, height/weight taken, and labs drawn. A funduscopic exam will be&#xD;
      performed to look for signs of intracranial pressure. Study participants are also required to&#xD;
      complete phone check ins at scheduled intervals, and a locally drawn blood sample to check&#xD;
      insulin-like growth factor (IGF1) levels approximately 3 months after treatment start date.&#xD;
      Concomitant medications, adverse events will be recorded and updated at all study visits and&#xD;
      phone check ins. Medication will be resupplied and shipped to the participant as needed at&#xD;
      every point of follow up contact. If the subjects grow well enough in the first 12 months per&#xD;
      study protocol, they are eligible to continue treatment through the study for an additional 2&#xD;
      years. They will continue to come to CCHMC every 6 months for follow up study visits. Study&#xD;
      procedures will remain the same as the initial 1 year trial with the following additions: (1)&#xD;
      local labs may need to be obtained for dose adjustment purposes, (2) repeat knee MRI may be&#xD;
      completed for participants that are found to have early signs of joint disease on their&#xD;
      baseline knee MRI scan.&#xD;
&#xD;
      The study will enroll interested and affected relatives of the participant in the joint&#xD;
      phenotyping protocol as well. These participants will come to CCHMC only one time to complete&#xD;
      the phenotyping visit. This is not an outcome of the study but the information gathered from&#xD;
      the imaging will provide insight into the effects of ACAN mutation on the joint cartilage.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 1, 2018</start_date>
  <completion_date type="Anticipated">July 31, 2023</completion_date>
  <primary_completion_date type="Actual">March 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Height Velocity After Three Years of Treatment with recombinant human growth hormone (rhGH)</measure>
    <time_frame>36 months</time_frame>
    <description>A participants calculated height velocity derived from height measurements taken over a period of 36 months (baseline visit to 36 month visit)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Describe Clinical Features of ACAN Deficiency</measure>
    <time_frame>Knee MRI data collected from baseline visit to 3 year study visit</time_frame>
    <description>Evidence of early joint pathology evident in MRI examination of affected participant's knees, and frequency of joint complaints as documented in International Knee Documentation Committee (IKDC) knee score form filled out by participants. Higher scores indicate more joint complaints/issues.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Short Stature</condition>
  <arm_group>
    <arm_group_label>Growth Hormone Treatment for Participants with ACAN Deficiency</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-pubertal children with ACAN deficiency on daily growth hormone (Norditropin) regimen for a 3 year period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Norditropin</intervention_name>
    <description>Single dose of daily growth hormone regimen. Dose will be 50 micrograms/kg/day.</description>
    <arm_group_label>Growth Hormone Treatment for Participants with ACAN Deficiency</arm_group_label>
    <other_name>somatropin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. ACAN Deficiency - Patients must be heterozygous for a mutation in the ACAN gene. A&#xD;
             mutation will be defined as:&#xD;
&#xD;
             a. A heterozygous deletion of the entire gene or of &gt;1 complete exons of the gene b.&#xD;
             Any truncating mutation including frameshift, nonsense, splice site mutations within 2&#xD;
             bases of the exon/intron boundary, and start loss variants c. Any missense mutation&#xD;
             which meets the following criteria: i. It is absent in the Exome Aggregation&#xD;
             Consortium Database (exac.broadinstitute.org) ii. It is predicted to be damaging by&#xD;
             BOTH Polyphen2 and Sorting Intolerant From Tolerant (SIFT) iii. It segregates with the&#xD;
             short stature phenotype in the family or is a de novo mutation d. In-frame insertions&#xD;
             or deletions of &gt;1 amino acid e. In-frame insertions or deletions of 1 amino acid must&#xD;
             meet the same criteria as missense mutations. For the prediction programs, Alanine&#xD;
             will be substituted for the deleted amino acid.&#xD;
&#xD;
             f. NOTE - Retrospective data does not show any correlation between the type of&#xD;
             mutation and the severity of short stature. Therefore, all mutations meeting the above&#xD;
             criteria will be included as a single group.&#xD;
&#xD;
          2. Age - Greater than or equal to 2 years 0 days. There is no specific upper age limit,&#xD;
             but the onset of puberty will make the patient ineligible.&#xD;
&#xD;
          3. Pre-pubertal&#xD;
&#xD;
               1. Male subjects must have a testicular volume &lt;4 cc as determined on physical&#xD;
                  examination by a pediatric endocrinologist at the time of the screening visit&#xD;
&#xD;
               2. Female subjects must be Tanner 1 for breast development as determined on physical&#xD;
                  examination by a pediatric endocrinologist at the time of the screening visit&#xD;
&#xD;
          4. Bone Age - The bone age as determined by the Greulich and Pyle method must be equal to&#xD;
             or greater than the chronological age. Bone ages will be determined at the screening&#xD;
             visit by a single centralized radiologist.&#xD;
&#xD;
          5. Insulin-like growth factor (IGF-I) level within normal range for age and sex.&#xD;
&#xD;
          6. Ability to provide informed consent before any trial-related activities&#xD;
&#xD;
          7. NOTE - There is no specific height standard deviation criteria for inclusion in this&#xD;
             study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior treatment with any of the following therapies:&#xD;
&#xD;
             A. Growth hormone B. Insulin-like Growth Factor (IGF-I) C. Gonadotropin releasing&#xD;
             hormone (GnRH) analog D. Aromatase Inhibitor E. Oxandrolone&#xD;
&#xD;
          2. History of any type of malignancy&#xD;
&#xD;
          3. Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13&#xD;
             years in females and 15 years in males&#xD;
&#xD;
          4. Chronic medical condition known to affect growth including but not limited to:&#xD;
&#xD;
             A. Cystic fibrosis B. Diabetes C. Inflammatory Bowel Disease D. Celiac Disease E.&#xD;
             Asthma requiring a daily inhaled steroid dose &gt; 400 micrograms of inhaled budesonide&#xD;
             per day or equivalent F. Taking daily oral glucocorticoids for any reason G. Note -&#xD;
             attention deficit hyperactivity disorder (ADHD) treated with a stimulant and treated&#xD;
             hypothyroidism with a normal thyroid stimulating hormone (TSH) will NOT exclude the&#xD;
             subject from participating in the trial.&#xD;
&#xD;
          5. (BMI) &lt;5th percentile (CDC growth charts)&#xD;
&#xD;
          6. Any clinically significant abnormality on screening laboratory tests as determined by&#xD;
             the principal investigator.&#xD;
&#xD;
          7. Known or suspected allergy to trial medication, excipients, or related products.&#xD;
&#xD;
          8. Contraindications to study medications, worded specifically as stated in the product's&#xD;
             prescribing information.&#xD;
&#xD;
          9. The receipt of any investigational drug within 90 days prior to this trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philippe Backeljauw, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cincinnati Childrens Hospital Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cincinnati Childrens Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 19, 2017</study_first_posted>
  <last_update_submitted>May 23, 2023</last_update_submitted>
  <last_update_submitted_qc>May 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dwarfism</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Potential to share de-identified data with the primary Endocrinologist in charge of participant's clinical care</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 2, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03288103/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 23, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03288103/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03288103
org study id: 2017-1956
nct id: NCT03288103
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Height Velocity After Three Years of Treatment with recombinant human growth hormone (rhGH)
time frame: 36 months
description: A participants calculated height velocity derived from height measurements taken over a period of 36 months (baseline visit to 36 month visit)
measure: Describe Clinical Features of ACAN Deficiency
time frame: Knee MRI data collected from baseline visit to 3 year study visit
description: Evidence of early joint pathology evident in MRI examination of affected participant's knees, and frequency of joint complaints as documented in International Knee Documentation Committee (IKDC) knee score form filled out by participants. Higher scores indicate more joint complaints/issues.
arm group label: Growth Hormone Treatment for Participants with ACAN Deficiency
arm group type: Experimental
description: Pre-pubertal children with ACAN deficiency on daily growth hormone (Norditropin) regimen for a 3 year period.
intervention type: Drug
intervention name: Norditropin
description: Single dose of daily growth hormone regimen. Dose will be 50 micrograms/kg/day.
arm group label: Growth Hormone Treatment for Participants with ACAN Deficiency
other name: somatropin
criteria: 
gender: All
minimum age: 2 Years
maximum age: N/A
healthy volunteers: No
last name: Philippe Backeljauw, MD
role: Principal Investigator
affiliation: Cincinnati Childrens Hospital Medical Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Dwarfism
sharing ipd: No
ipd description: Potential to share de-identified data with the primary Endocrinologist in charge of participant's clinical care
provided document: 
provided document: 