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Vosoritide for Selected Genetic Causes of Short Stature

Primary Purpose

Short Stature

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Vosoritide
Sponsored by
Andrew Dauber
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Short Stature focused on measuring Hypochondroplasia, SHOX Deficiency, Rasopathy, NPR2, CNP, Noonan Syndrome, Aggrecan, ACAN

Eligibility Criteria

3 Years - 10 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of 18 are willing and able to provide assent (if required) after the nature of the study has been explained and prior to performance of any research-related procedure.
  2. Stated willingness to comply with all study procedures and availability for the duration of the study
  3. Age >3 years 0 days AND <10 years 364 days for males, <9 years 364 days for females
  4. Pre-pubertal defined as Tanner Stage 1 breasts in females and testicular volumes <3 cc in males. This must be confirmed at the Day 1 visit prior to initiation of vosoritide.
  5. Patient height <-2.25 SDS. All height SDS values are calculated using the CDC growth charts/data tables (Center for Disease Control and Prevention, 2000).
  6. Patients with pathogenic or likely pathogenic variants in genes known to cause the specific genetic subgroups of short stature listed below are eligible for inclusion in the study. Pathogenicity of variants will be classified as per the American College of Medical Genetics criteria with the exception of ACAN mutations as detailed below (Richards et al., 2015). Documentation of the presence of the variant must be obtained using a lab results report from a CLIA certified laboratory. Classification of the variant's pathogenicity status will be performed by the Children's National study team.

    A. CNP deficiency due to mutations in NPPC - Subjects with heterozygous or homozygous defects in NPPC are eligible.

    B. Hypochondroplasia - Subjects with heterozygous variants in FGFR3 gene associated with hypochondroplasia are eligible. Subjects with variants in FGFR3 known to cause achondroplasia or thanatophoric dysplasia or SADDAN syndrome will be excluded. (NOTE: Hypochondroplasia cohort is closed to enrollment).

    C. Patients with heterozygous defects in NPR2 are eligible. Patients with homozygous defects in NPR2 will be excluded.

    D. Rasopathy patients (including Noonan syndrome, Costello syndrome, Cardiofaciocutaneous syndrome, Neurofibromatosis Type 1) - This include patients with heterozygous variants in the following genes:

    i. BRAF ii. CBL iii. HRAS iv. KRAS v. LZTR1 vi. MAP2K1 vii. MAP2K2 viii. MRAS ix. NF1 x. NRAS xi. PPP1CB xii. PTPN11 xiii. RAF1 xiv. RRAS xv. RIT1 xvi. SHOC2 xvii. SOS1 xviii. SOS2

    E. Patients with SHOX deficiency - Patients with either heterozygous, compound heterozygous or homozygous defects in SHOX including patients with heterozygous or homozygous deletions of the SHOX regulatory region known to cause SHOX deficiency.

    F. Patients with heterozygous defects in ACAN - Patients must be heterozygous for a mutation in the ACAN gene. As there are no validated in vitro assays that reliably assess an individual variant's effect on aggrecan function, for the purpose of this clinical trial a mutation in ACAN will be defined as:

    1. A heterozygous deletion of the entire gene or of >1 complete exons of the gene
    2. Any truncating mutation including frameshift, nonsense, splice site mutations within 2 bases of the exon/intron boundary, and start loss variants
    3. Any missense mutation which meets all of the following criteria:

    i. It has an aggregate minor allele frequency less than 1X10-5 based on the gnomAD data (gnomad.broadinstitute.org) ii. It is predicted to be damaging by BOTH Polyphen2 and SIFT iii. It segregates with the short stature phenotype in available family members 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.

  7. Absence of growth hormone deficiency defined as an IGF-1 level above the lower limit of the normal range of the assay. The IGF-1 may be repeated during the 6 month observation period and prior to the Day 1 visit. If this repeat IGF-1 is above the lower limit of the normal range of the assay, then the subject is deemed eligible. If a patient has an IGF-1 level below the lower limit of the normal range of the assay, two growth hormone stimulation tests must be performed using the routine local protocols. Patients with a peak growth hormone level >7 ng/ml will be considered growth hormone sufficient and will be eligible for inclusion as per the Growth Hormone Research Society International consensus (Collett-Solberg et al., 2019). If indicated based on IGF-1 level from the referring clinician, the growth hormone stimulation test must be done as part of routine clinical care prior to enrollment. The rationale for using an IGF-1 below the normal range as the cut-off for further evaluation for growth hormone deficiency is that in patients with a clear genetic explanation for their short stature, an IGF-1 level anywhere within the normal range would be considered reassuring and would not lead to a growth hormone stimulation test in a routine clinical setting.
  8. The subject and their guardian must speak one of the 11 languages for which the QoLISSY survey (a quality of life survey for short stature) is available. These include: English, Spanish, German, Russian, Swedish, Flemish, Italian, Turkish, French, Japanese, and Ukrainian.

Exclusion Criteria:

  1. Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13 years in females and 15 years in males. These patients have limited remaining growth potential.
  2. Concomitant treatment with growth hormone or recombinant IGF-1. Patients may have been previously treated with growth hormone or IGF-1 therapy. If the patient is currently on one of these therapies, they will be required to discontinue treatment in order to begin the baseline observation period for this trial. That decision will be deferred to their treating clinical endocrinologists in conjunction with the patient's guardians. We anticipate that only patients who are having a poor response to their therapy will be interested in enrolling in the current study as there is no rationale for a patient who is receiving growth hormone therapy and having a positive response to enroll in the current study.
  3. Prior treatment with a GnRH analog, aromatase inhibitor or oxandrolone
  4. History of any type of malignancy
  5. 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 - ADHD treated with a stimulant and treated hypothyroidism with a normal TSH will NOT exclude the subject from participating in the trial.

    H. Turner Syndrome or any other chromosomal aneuploidy I. Congenital heart disease which places the subject at increased risk of an adverse cardiac outcome in the setting of hypotension including but not limited to: hypertrophic cardiomyopathy, aortic stenosis with peak gradient >50mmHg, severe aortic regurgitation (defined as pressure half time >500ms by echocardiogram), coronary insufficiency, or any anatomy with a need for an afterload reducing agent. Any patient with baseline abnormalities on echocardiogram will be reviewed with a pediatric cardiologist for appropriateness for inclusion in the study.

  6. Malnutrition - Defined as a BMI <5th percentile (CDC growth charts)
  7. Any clinically significant abnormality on screening tests as determined by the principal investigator. Abnormal screening labs may be repeated during the 6 month observation period prior to Day 1. If they return to normal or non-clinically significant deviations per the PI's determination, the subject may proceed with the study.
  8. Known or suspected allergy to trial medication, excipients, or related products
  9. The receipt of any investigational drug within 90 days prior to this trial

Sites / Locations

  • Children's National HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Genetic Short Stature

Arm Description

Vosoritide, also known as BMN 111 or modified recombinant human C-type natriuretic peptide (CNP), is a 39-amino-acid peptide analog that includes the 37 C-terminal amino acids of the human CNP53 sequence plus the addition of 2 amino acids (Pro-Gly) on the N-terminus. This structural modification conveys resistance to neutral endopeptidase (NEP) degradation, resulting in prolonged half-life (t1/2) in comparison to endogenous CNP. This increase in t1/2 allows once daily subcutaneous (SC) administration. Vosoritide will be administered as a single 15 μg/kg subcutaneous injection given daily for 12 months.

Outcomes

Primary Outcome Measures

Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]
Number of treatment-emergent adverse events or serious adverse events per study participant
Incidence of Symptomatic Hypotension events [Safety and Tolerability]
Number of symptomatic hypotension events per study participant
Change from Baseline in annualized growth velocity
To evaluate the change from baseline in age-sex standardized annualized growth velocity in cm/year after 12 months of daily SC injections of vosoritide in patients with selected genetic causes of short stature.
Change from Baseline in standardized height SDS
To evaluate the change from baseline in age-sex standardized height SDS after 12 months of daily SC injections of vosoritide in patients with selected genetic causes of short stature.

Secondary Outcome Measures

Changes in the seated height ratio as a measure of body proportions
To evaluate the seated height ratio (expressed as a percentage) as a measure of body proportions. Measurement after 12 months of treatment will be compared to baseline.
Changes in the difference between arm span and height from baseline
To evaluate the difference between arm span and height (measured as cm) as a measure of body proportions. Measurement after 12 months of treatment will be compared to baseline.
Changes from Baseline in bone age/chronological age
To evaluate changes from baseline in bone age/chronological age after 12 months of daily SC injections of vosoritide

Full Information

First Posted
December 26, 2019
Last Updated
December 14, 2022
Sponsor
Andrew Dauber
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1. Study Identification

Unique Protocol Identification Number
NCT04219007
Brief Title
Vosoritide for Selected Genetic Causes of Short Stature
Official Title
Vosoritide for Selected Genetic Causes of Short Stature
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 4, 2020 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
June 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Andrew Dauber

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Short stature can be caused by a number of genetic etiologies, many of which directly affect the growth plate. The FGFR3/CNP pathway is central to growth of the chondrocyte. The study team hypothesizes that patients with selected genetic causes of short stature that interact with this pathway will benefit from treatment with vosoritide, a CNP analog, a selective NPR-B agonist which directly targets the growth plate. This study will enroll patients with short stature in selected genetic categories and will follow them for a 6 month observation period to obtain a baseline growth velocity, safety profile and quality of life assessment. Patients will then be treated with vosoritide for 12 months and will be assessed for safety monitoring and improvement in height outcomes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Short Stature
Keywords
Hypochondroplasia, SHOX Deficiency, Rasopathy, NPR2, CNP, Noonan Syndrome, Aggrecan, ACAN

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Genetic Short Stature
Arm Type
Experimental
Arm Description
Vosoritide, also known as BMN 111 or modified recombinant human C-type natriuretic peptide (CNP), is a 39-amino-acid peptide analog that includes the 37 C-terminal amino acids of the human CNP53 sequence plus the addition of 2 amino acids (Pro-Gly) on the N-terminus. This structural modification conveys resistance to neutral endopeptidase (NEP) degradation, resulting in prolonged half-life (t1/2) in comparison to endogenous CNP. This increase in t1/2 allows once daily subcutaneous (SC) administration. Vosoritide will be administered as a single 15 μg/kg subcutaneous injection given daily for 12 months.
Intervention Type
Drug
Intervention Name(s)
Vosoritide
Other Intervention Name(s)
BMN-111
Intervention Description
After enrollment, subjects will be followed for a 6 month observation only period to establish a baseline height velocity as well as safety profile and quality of life assessment. Vosoritide will then be administered daily via subcutaneous injection at a dose of 15 µg/kg/day for 12 months.
Primary Outcome Measure Information:
Title
Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]
Description
Number of treatment-emergent adverse events or serious adverse events per study participant
Time Frame
12 months
Title
Incidence of Symptomatic Hypotension events [Safety and Tolerability]
Description
Number of symptomatic hypotension events per study participant
Time Frame
12 months
Title
Change from Baseline in annualized growth velocity
Description
To evaluate the change from baseline in age-sex standardized annualized growth velocity in cm/year after 12 months of daily SC injections of vosoritide in patients with selected genetic causes of short stature.
Time Frame
12 months
Title
Change from Baseline in standardized height SDS
Description
To evaluate the change from baseline in age-sex standardized height SDS after 12 months of daily SC injections of vosoritide in patients with selected genetic causes of short stature.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Changes in the seated height ratio as a measure of body proportions
Description
To evaluate the seated height ratio (expressed as a percentage) as a measure of body proportions. Measurement after 12 months of treatment will be compared to baseline.
Time Frame
12 months
Title
Changes in the difference between arm span and height from baseline
Description
To evaluate the difference between arm span and height (measured as cm) as a measure of body proportions. Measurement after 12 months of treatment will be compared to baseline.
Time Frame
12 months
Title
Changes from Baseline in bone age/chronological age
Description
To evaluate changes from baseline in bone age/chronological age after 12 months of daily SC injections of vosoritide
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Characterize the area under the plasma concentration time-curve from time 0 to infinity (AUC0-∞)
Description
Estimated by non-compartmental analysis for Day 1, 6 months, and 12 months per study participant
Time Frame
3 hours at each visit
Title
Characterize the area under the plasma concentration-time curve from 0 to the time of last measurable concentration (AUC0-t)
Description
Estimated by non-compartmental analysis for Day 1, 6 months, and 12 months per study participant
Time Frame
3 hours at each visit
Title
Characterize maximum concentration (Cmax) of vosoritide in plasma
Description
Estimated by non-compartmental analysis for Day 1, 6 months, and 12 months per study participant
Time Frame
3 hours at each visit
Title
Characterize the elimination half-life of vosoritide (t½)
Description
Estimated by non-compartmental analysis for Day 1, 6 months, and 12 months per study participant
Time Frame
3 hours at each visit
Title
Characterize the apparent clearance of drug (CL/F)
Description
Estimated by non-compartmental analysis for Day 1, 6 months, and 12 months per study participant
Time Frame
3 hours at each visit
Title
Characterize the apparent volume of distribution based upon the terminal phase (Vz/F)
Description
Estimated by non-compartmental analysis for Day 1, 6 months, and 12 months per study participant
Time Frame
3 hours at each visit
Title
Changes from Baseline in bone mineral density
Description
To evaluate changes from baseline in bone mineral density (BMD) after 12 months of daily SC injections of vosoritide (expressed as height adjusted Z-score).
Time Frame
12 months
Title
Evaluate immunogenicity and assess impact on safety and efficacy measures
Description
To evaluate immunogenicity and assess impact on safety and efficacy measures after 12 months of daily SC injections of vosoritide as evidenced by rates of vosoritide antibody development, which is a standard safety metric.
Time Frame
12 months
Title
Changes from baseline in quality of life after daily SC injections of vosoritide: Quality of Life of Short Stature Youth (QoLISSY) questionnaire score is expressed as a percentage
Description
To evaluate changes from baseline in quality of life using the QoLISSY scale after 12 months of daily SC injections of vosoritide. The Quality of Life of Short Stature Youth (QoLISSY) questionnaire score is expressed as a percentage, with scores ranging from 0% to 100% (100% is the best score).
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
10 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of 18 are willing and able to provide assent (if required) after the nature of the study has been explained and prior to performance of any research-related procedure. Stated willingness to comply with all study procedures and availability for the duration of the study Age >3 years 0 days AND <10 years 364 days for males, <9 years 364 days for females Pre-pubertal defined as Tanner Stage 1 breasts in females and testicular volumes <3 cc in males. This must be confirmed at the Day 1 visit prior to initiation of vosoritide. Patient height <-2.25 SDS. All height SDS values are calculated using the CDC growth charts/data tables (Center for Disease Control and Prevention, 2000). Patients with pathogenic or likely pathogenic variants in genes known to cause the specific genetic subgroups of short stature listed below are eligible for inclusion in the study. Pathogenicity of variants will be classified as per the American College of Medical Genetics criteria with the exception of ACAN mutations as detailed below (Richards et al., 2015). Documentation of the presence of the variant must be obtained using a lab results report from a CLIA certified laboratory. Classification of the variant's pathogenicity status will be performed by the Children's National study team. A. CNP deficiency due to mutations in NPPC - Subjects with heterozygous or homozygous defects in NPPC are eligible. B. Hypochondroplasia - Subjects with heterozygous variants in FGFR3 gene associated with hypochondroplasia are eligible. Subjects with variants in FGFR3 known to cause achondroplasia or thanatophoric dysplasia or SADDAN syndrome will be excluded. (NOTE: Hypochondroplasia cohort is closed to enrollment). C. Patients with heterozygous defects in NPR2 are eligible. Patients with homozygous defects in NPR2 will be excluded. D. Rasopathy patients (including Noonan syndrome, Costello syndrome, Cardiofaciocutaneous syndrome, Neurofibromatosis Type 1) - This include patients with heterozygous variants in the following genes: i. BRAF ii. CBL iii. HRAS iv. KRAS v. LZTR1 vi. MAP2K1 vii. MAP2K2 viii. MRAS ix. NF1 x. NRAS xi. PPP1CB xii. PTPN11 xiii. RAF1 xiv. RRAS xv. RIT1 xvi. SHOC2 xvii. SOS1 xviii. SOS2 E. Patients with SHOX deficiency - Patients with either heterozygous, compound heterozygous or homozygous defects in SHOX including patients with heterozygous or homozygous deletions of the SHOX regulatory region known to cause SHOX deficiency. F. Patients with heterozygous defects in ACAN - Patients must be heterozygous for a mutation in the ACAN gene. As there are no validated in vitro assays that reliably assess an individual variant's effect on aggrecan function, for the purpose of this clinical trial a mutation in ACAN will be defined as: A heterozygous deletion of the entire gene or of >1 complete exons of the gene Any truncating mutation including frameshift, nonsense, splice site mutations within 2 bases of the exon/intron boundary, and start loss variants Any missense mutation which meets all of the following criteria: i. It has an aggregate minor allele frequency less than 1X10-5 based on the gnomAD data (gnomad.broadinstitute.org) ii. It is predicted to be damaging by BOTH Polyphen2 and SIFT iii. It segregates with the short stature phenotype in available family members 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. Absence of growth hormone deficiency defined as an IGF-1 level above the lower limit of the normal range of the assay. The IGF-1 may be repeated during the 6 month observation period and prior to the Day 1 visit. If this repeat IGF-1 is above the lower limit of the normal range of the assay, then the subject is deemed eligible. If a patient has an IGF-1 level below the lower limit of the normal range of the assay, two growth hormone stimulation tests must be performed using the routine local protocols. Patients with a peak growth hormone level >7 ng/ml will be considered growth hormone sufficient and will be eligible for inclusion as per the Growth Hormone Research Society International consensus (Collett-Solberg et al., 2019). If indicated based on IGF-1 level from the referring clinician, the growth hormone stimulation test must be done as part of routine clinical care prior to enrollment. The rationale for using an IGF-1 below the normal range as the cut-off for further evaluation for growth hormone deficiency is that in patients with a clear genetic explanation for their short stature, an IGF-1 level anywhere within the normal range would be considered reassuring and would not lead to a growth hormone stimulation test in a routine clinical setting. The subject and their guardian must speak one of the 11 languages for which the QoLISSY survey (a quality of life survey for short stature) is available. These include: English, Spanish, German, Russian, Swedish, Flemish, Italian, Turkish, French, Japanese, and Ukrainian. Exclusion Criteria: Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13 years in females and 15 years in males. These patients have limited remaining growth potential. Concomitant treatment with growth hormone or recombinant IGF-1. Patients may have been previously treated with growth hormone or IGF-1 therapy. If the patient is currently on one of these therapies, they will be required to discontinue treatment in order to begin the baseline observation period for this trial. That decision will be deferred to their treating clinical endocrinologists in conjunction with the patient's guardians. We anticipate that only patients who are having a poor response to their therapy will be interested in enrolling in the current study as there is no rationale for a patient who is receiving growth hormone therapy and having a positive response to enroll in the current study. Prior treatment with a GnRH analog, aromatase inhibitor or oxandrolone History of any type of malignancy 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 - ADHD treated with a stimulant and treated hypothyroidism with a normal TSH will NOT exclude the subject from participating in the trial. H. Turner Syndrome or any other chromosomal aneuploidy I. Congenital heart disease which places the subject at increased risk of an adverse cardiac outcome in the setting of hypotension including but not limited to: hypertrophic cardiomyopathy, aortic stenosis with peak gradient >50mmHg, severe aortic regurgitation (defined as pressure half time >500ms by echocardiogram), coronary insufficiency, or any anatomy with a need for an afterload reducing agent. Any patient with baseline abnormalities on echocardiogram will be reviewed with a pediatric cardiologist for appropriateness for inclusion in the study. Malnutrition - Defined as a BMI <5th percentile (CDC growth charts) Any clinically significant abnormality on screening tests as determined by the principal investigator. Abnormal screening labs may be repeated during the 6 month observation period prior to Day 1. If they return to normal or non-clinically significant deviations per the PI's determination, the subject may proceed with the study. Known or suspected allergy to trial medication, excipients, or related products The receipt of any investigational drug within 90 days prior to this trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Andrew Dauber, MD MMSc
Phone
202-476-2121
Email
adauber@childrensnational.org
First Name & Middle Initial & Last Name or Official Title & Degree
Kimberly Boucher
Phone
202-476-1403
Email
kboucher@childrensnational.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Dauber, MS MMSc
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's National Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tara McCarthy
Phone
202-476-6894
Email
tmccarthy@childrensnational.org

12. IPD Sharing Statement

Plan to Share IPD
No

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Vosoritide for Selected Genetic Causes of Short Stature

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