Short Stature Homeobox- Containing Gene SHOX Deficiency, Noonan Syndrome, Turner Syndrome
Conditions
Keywords
Short Stature, Musculoskeletal Diseases, Bone Diseases, Developmental Endocrine System Diseases Natriuretic Peptide, C-Type
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 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.
Detailed description
This is a Phase 2, randomized, multicenter, basket study of vosoritide in children with Turner syndrome, short stature homeobox-containing gene (SHOX) deficiency, or Noonan syndrome who have inadequate growth during or after human growth hormone (hGH) treatment. The study is intended to characterize the short-term efficacy and safety of 3 dosing regimens of vosoritide. The efficacy and safety of the vosoritide therapeutic dose will be further evaluated, and an analysis of the impact of vosoritide on final adult height (FAH).
Interventions
Modified recombinant human C-type natriuretic peptide Vosoritide
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Years to 11 Years
Healthy volunteers
No
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 ≤ -1.28 SDs (below the 10th percentile for height) in reference to the general population of the same age and sex. 4. Tanner Stage 1, at time of signing the ICF. 5. Previous or current hGH treatment for short stature associated with their condition. 6. Inadequate growth confirmed with an AGV that is less than age- and sex-matched average stature AGV determined using median heights from CDC growth charts
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change from baseline in Annualized Growth Velocity (AGV) | At 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Change from pre-dose in urine cyclic guanine monophosphate (cGMP) | Every 6 months through the end of the study, up to 15 years |
| Incidence of treatment-emergent adverse events | Until the end of the study, up to 15 years |
| Incidence of new diagnosis of hypertrophic cardiomyopathy in children with Noonan syndrome | Every 12 months through the end of the study, up to 15 years |
| Incidence of cardiac conditions requiring discontinuation of study treatment | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in height | Every 6 months through the end of the study, up to 15 years |
| Change from baseline in height Z-score | Every 6 months through the end of the study, up to 15 years |
| Change from baseline in 12-month interval AGV | Until the end of the study, up to 15 years |
| Change from baseline in upper to lower body segment ratio | Until the end of the study, up to 15 years |
| Change from baseline in arm span to height ratio | Until the end of the study, up to 15 years |
| Change from baseline in height up to Final Adult Height (FAH) | Every 6 months through the end of the study, up to 15 years |
| Change from baseline in height Z-score up to FAH | Every 6 months through the end of the study, up to 15 years |
| 12-month interval AGV summarized by age and sex up to FAH | Every 12 months through the end of the study, up to 15 years |
| Tanner stage over the course of the study | Every 6 months through the end of the study, up to 15 years |
| Time vosoritide is present at maximum concentration (Tmax) | Every 6 months through the end of the study, up to 15 years |
| Maximum vosoritide observed plasma concentration (Cmax) | Every 6 months through he end of the study, up to15 years |
| Area under the plasma vosoritide concentration time-curve from time 0 to the last measurable concentration (AUC0-t) | Every 6 months through the end of the study, up to 15 years |
| Area under the plasma vosoritide concentration time-curve from time 0 to infinity (AUC0-∞) | Every 6 months through the end of the study, up to 15 years |
| Elimination half-life of vosoritide (t½) | Every 6 months through the end of the study, up to 15 years |
| Apparent clearance of vosoritide (CL/F) | Every 6 months through the end of the study, up to 15 years |
| Change from baseline in serum collagen X marker (CXM) | Every 6 months through the end of the study, up to 15 years |
| Change from baseline in bone age/chronological age | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in total body (less head) BMD Z-score | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in lumbar spine bone mineral density (BMD) Z-score | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in total body (less head) bone mineral content (BMC) | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in lumbar spine BMC. Change from baseline in lower extremity BMD/BMC [Time Frame: Every 12 months through the end of the study, up to 15 years]. | Every 12 months through the end of the study, up to 15 years |
| Change in the growth plates, long bone growth and bone morphology based on whole length lower extremity X-rays [Time Frame: Every 12 months through the end of the study, up to 15 years] | Every 6 months through the end of the study, up to 15 years |
| Incidence of bone-related events of special interest (fracture, slipped capital femoral epiphysis and avascular necrosis or osteonecrosis) | Throughout study |
| Change from baseline in the physical domain score and total score of the QoLISSY | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in the physical and social domain scores and total score of the PedsQL | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in PGI-S and CaGI-S item scores | Every 12 months through the end of the study, up to 15 years |
| PGI-C and CaGI-C item scores | Every 12 months through the end of the study, up to 15 years |
| Change from baseline in PROMIS-SF Physical Activity score | Every 12 months through the end of the study, up to 15 years |
| Apparent volume of distribution of vosoritide (Vz/F) | Every 6 months through the end of the study, up to 15 years |
| Change from baseline in KABC-II NVI scores | Every 12 months through the end of the study, up to 15 years |
Countries
Australia, France, Italy, Spain, United States
Contacts
CONTACTTrial Specialist
CONTACTStudy Manager
STUDY_DIRECTORMedical Director, MD, PhD
BioMarin Pharmaceutical
Outcome results
None listed