Brief Summary
The purpose of this basket study in children with Turner syndrome, SHOX deficiency, and Noonan syndrome is to evaluate the effect of 3 doses of vosoritide versus hGH on growth as measured by AGV after 6 months of treatment. The long-term efficacy and safety of vosoritide at the therapeutic dose will be evaluated up to FAH.
Brief Title
A Phase 2 Basket Study of Vosoritide in Children With Turner Syndrome, SHOX Deficiency and Noonan Syndrome With an Inadequate Response to Human Growth Hormone
Detailed Description
This is a Phase 2, randomized, active-controlled, multicenter, basket study of vosoritide in children with Turner syndrome, short stature homeobox-containing gene (SHOX) deficiency, or Noonan syndrome who have an inadequate response to human growth hormone (hGH) treatment. The study is intended to characterize the short-term efficacy and safety of 3 dosing regimens of vosoritide versus hGH. The efficacy and safety of the vosoritide therapeutic dose will be further evaluated, with a comparison to hGH after 2 years of treatment, and an analysis of the impact of vosoritide on final adult height (FAH).
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
1-800-983-4587
Central Contact Email
medinfo@bmrn.com
Central Contact Role
Contact
Central Contact Phone
1-800-983-4587
Central Contact Email
Medinfo@bmrn.com
Completion Date
Completion Date Type
Estimated
Conditions
Short Stature Homeobox- Containing Gene SHOX Deficiency
Noonan Syndrome
Turner Syndrome
Eligibility Criteria
Inclusion Criteria:
1. Participants must be ≥ 3 years old, and \< 11 years old (females) or \< 12 years old (males), at the time of signing the informed consent form
2. A genetically confirmed diagnosis of Turner syndrome, SHOX deficiency or Noonan syndrome.
3. A height assessment corresponding to a height Z-score of \> -2.00 SDs and ≤ -1.75 SDs (up to 20% of participants)/≤ -2.00 SDs (at least 80% of participants) in reference to the general population of the same age and sex.
4. Tanner Stage 1, at time of signing the ICF.
5. Have been receiving continuous hGH for the treatment of short stature associated with their condition for a minimum of 1 year immediately prior to enrollment and be receiving a dose of ≥ 0.35 mg/kg weekly, with no weight-based dosing changes in the last 6 months and none planned in the future.
6. Are willing to continue on hGH at their current dose for the Baseline Growth Phase, and for 2 years post randomization if randomized to the hGH arm.
7. Inadequate response to prior hGH treatment.
Exclusion Criteria:
1. Participants with Turner syndrome known to have Y-chromosome material unless they have undergone gonadectomy and have fully external female genitalia.
2. Diagnosis of systemic disease or condition that may cause short stature other than Turner syndrome, SHOX deficiency, or Noonan syndrome, eg, renal, neoplastic, pulmonary, cardiac, gastrointestinal, immunologic and metabolic disease.
3. Bone age advanced beyond chronological age by more than 2 years.
4. Uncorrected congenital heart disease which places the participant at increased risk of an adverse cardiac outcome in the setting of hypotension,
5. Have an unstable condition likely to require surgical intervention during the study.
6. Evidence of decreased growth velocity (AGV \< 1.5 cm/year) as assessed over a period of at least 6 months and growth plate closure assessed using bilateral lower extremity X-rays.
7. Previous limb-lengthening surgery, or planned or expected to have limb lengthening surgery during the study period.
8. Planned or expected bone-related surgery (ie, surgery involving disruption of bone cortex, excluding tooth extraction), during the study period.
1. Participants must be ≥ 3 years old, and \< 11 years old (females) or \< 12 years old (males), at the time of signing the informed consent form
2. A genetically confirmed diagnosis of Turner syndrome, SHOX deficiency or Noonan syndrome.
3. A height assessment corresponding to a height Z-score of \> -2.00 SDs and ≤ -1.75 SDs (up to 20% of participants)/≤ -2.00 SDs (at least 80% of participants) in reference to the general population of the same age and sex.
4. Tanner Stage 1, at time of signing the ICF.
5. Have been receiving continuous hGH for the treatment of short stature associated with their condition for a minimum of 1 year immediately prior to enrollment and be receiving a dose of ≥ 0.35 mg/kg weekly, with no weight-based dosing changes in the last 6 months and none planned in the future.
6. Are willing to continue on hGH at their current dose for the Baseline Growth Phase, and for 2 years post randomization if randomized to the hGH arm.
7. Inadequate response to prior hGH treatment.
Exclusion Criteria:
1. Participants with Turner syndrome known to have Y-chromosome material unless they have undergone gonadectomy and have fully external female genitalia.
2. Diagnosis of systemic disease or condition that may cause short stature other than Turner syndrome, SHOX deficiency, or Noonan syndrome, eg, renal, neoplastic, pulmonary, cardiac, gastrointestinal, immunologic and metabolic disease.
3. Bone age advanced beyond chronological age by more than 2 years.
4. Uncorrected congenital heart disease which places the participant at increased risk of an adverse cardiac outcome in the setting of hypotension,
5. Have an unstable condition likely to require surgical intervention during the study.
6. Evidence of decreased growth velocity (AGV \< 1.5 cm/year) as assessed over a period of at least 6 months and growth plate closure assessed using bilateral lower extremity X-rays.
7. Previous limb-lengthening surgery, or planned or expected to have limb lengthening surgery during the study period.
8. Planned or expected bone-related surgery (ie, surgery involving disruption of bone cortex, excluding tooth extraction), during the study period.
Inclusion Criteria
Inclusion Criteria:
1. Participants must be ≥ 3 years old, and \< 11 years old (females) or \< 12 years old (males), at the time of signing the informed consent form
2. A genetically confirmed diagnosis of Turner syndrome, SHOX deficiency or Noonan syndrome.
3. A height assessment corresponding to a height Z-score of \> -2.00 SDs and ≤ -1.75 SDs (up to 20% of participants)/≤ -2.00 SDs (at least 80% of participants) in reference to the general population of the same age and sex.
4. Tanner Stage 1, at time of signing the ICF.
5. Have been receiving continuous hGH for the treatment of short stature associated with their condition for a minimum of 1 year immediately prior to enrollment and be receiving a dose of ≥ 0.35 mg/kg weekly, with no weight-based dosing changes in the last 6 months and none planned in the future.
6. Are willing to continue on hGH at their current dose for the Baseline Growth Phase, and for 2 years post randomization if randomized to the hGH arm.
7. Inadequate response to prior hGH treatment.
1. Participants must be ≥ 3 years old, and \< 11 years old (females) or \< 12 years old (males), at the time of signing the informed consent form
2. A genetically confirmed diagnosis of Turner syndrome, SHOX deficiency or Noonan syndrome.
3. A height assessment corresponding to a height Z-score of \> -2.00 SDs and ≤ -1.75 SDs (up to 20% of participants)/≤ -2.00 SDs (at least 80% of participants) in reference to the general population of the same age and sex.
4. Tanner Stage 1, at time of signing the ICF.
5. Have been receiving continuous hGH for the treatment of short stature associated with their condition for a minimum of 1 year immediately prior to enrollment and be receiving a dose of ≥ 0.35 mg/kg weekly, with no weight-based dosing changes in the last 6 months and none planned in the future.
6. Are willing to continue on hGH at their current dose for the Baseline Growth Phase, and for 2 years post randomization if randomized to the hGH arm.
7. Inadequate response to prior hGH treatment.
Gender
All
Gender Based
false
Keywords
Short Stature
Musculoskeletal Diseases
Bone Diseases
Developmental Endocrine System Diseases Natriuretic Peptide, C-Type
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
11 Years
Minimum Age
3 Years
NCT Id
NCT06668805
Org Class
Industry
Org Full Name
BioMarin Pharmaceutical
Org Study Id
111-211
Overall Status
Recruiting
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase 2, Randomized, Human Growth Hormone-Controlled, Multicenter, Basket Study of Vosoritide in Children With Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome With an Inadequate Response to Human Growth Hormone. (CANOPY NS, TS, SHOX-D-2)
Primary Outcomes
Outcome Measure
Change from baseline in Annualized Growth Velocity (AGV)
Outcome Time Frame
At 6 months
Secondary Outcomes
Outcome Time Frame
Until the end of the study, up to 15 years
Outcome Measure
Incidence of treatment-emergent adverse events
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Incidence of new diagnosis of hypertrophic cardiomyopathy in children with Noonan syndrome
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Incidence of cardiac conditions requiring discontinuation of study treatment
Outcome Time Frame
At 6 months and at 24 months
Outcome Measure
Change from baseline in height
Outcome Time Frame
At 6 months and at 24 months
Outcome Measure
Change from baseline in height Z-score
Outcome Time Frame
24 months
Outcome Measure
Change from baseline in 12-month interval AGV
Outcome Time Frame
At 12 and 24 months
Outcome Measure
Change from baseline in upper to lower body segment ratio
Outcome Time Frame
At 12 and 24 months
Outcome Measure
Change from baseline in arm span to height ratio
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in height up to Final Adult Height (FAH)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in height Z-score up to FAH
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
12-month interval AGV summarized by age and sex up to FAH
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Tanner stage over the course of the study
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Time vosoritide is present at maximum concentration (Tmax)
Outcome Time Frame
Every 6 months through he end of the study, up to15 years
Outcome Measure
Maximum vosoritide observed plasma concentration (Cmax)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Area under the plasma vosoritide concentration time-curve from time 0 to the last measurable concentration (AUC0-t)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Area under the plasma vosoritide concentration time-curve from time 0 to infinity (AUC0-∞)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Elimination half-life of vosoritide (t½)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Apparent clearance of vosoritide (CL/F)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Apparent volume of distribution of vosoritide (Vz/F)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Change from pre-dose in urine cyclic guanine monophosphate (cGMP)
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in serum collagen X marker (CXM)
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in bone age/chronological age
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in total body (less head) BMD Z-score
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in lumbar spine bone mineral density (BMD) Z-score
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in total body (less head) bone mineral content (BMC)
Outcome Time Frame
Every 12 months through the end of the study, up to 15 years
Outcome Measure
Change from baseline in lumbar spine BMC
Outcome Time Frame
Every 6 months through the end of the study, up to 15 years
Outcome Measure
Change in bone morphology based on whole length lower extremity X-rays
Outcome Time Frame
Throughout study
Outcome Measure
Incidence of bone-related events of special interest (fracture, slipped capital femoral epiphysis and avascular necrosis or osteonecrosis)
Outcome Time Frame
At 24 months
Outcome Measure
Change from baseline in the physical domain score and total score of the QoLISSY
Outcome Time Frame
At 24 months
Outcome Measure
Change from baseline in the physical and social domain scores and total score of the PedsQL
Outcome Time Frame
At 24 months
Outcome Measure
Change from baseline in PGI-S and CaGI-S item scores
Outcome Time Frame
At 24 months
Outcome Measure
PGI-C and CaGI-C item scores
Outcome Time Frame
At 24 months
Outcome Measure
Change from baseline in PROMIS-SF Physical Activity score
Outcome Time Frame
At 24 months
Outcome Measure
Change from baseline in KABC-II NVI scores
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Maximum Age Number (converted to Years and rounded down)
11
Minimum Age Number (converted to Years and rounded down)
3
Investigators
Investigator Type
Principal Investigator
Investigator Name
Laurie Cohen
Investigator Email
lacohen@montefiore.org