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

Phase 2RecruitingNCT06668805

BioMarin Pharmaceutical72 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Short Stature Homeobox- Containing Gene SHOX Deficiency Noonan Syndrome

Eligibility

Sex: ALLMin age: 3 YearsMax age: 11 Years

Medical Language ↔ Plain English

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.

Locations (20)

Children's Hospital Colorado

Aurora, Colorado, United States

RECRUITING

Nemours Children's Hospital, Delaware (Alfred I. Dupont Hospital for Children)

Wilmington, Delaware, United States

RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, United States

RECRUITING

Nicklaus Children's Hospital

Miami, Florida, United States

NOT_YET_RECRUITING

St. Luke's Children's Endocrinology and Diabetes

Boise, Idaho, United States

RECRUITING

Kentucky Children's Hospital

Lexington, Kentucky, United States

RECRUITING

New York Medical College

Boston, Massachusetts, United States

RECRUITING

M Health Fairview Pediatric Specialty Clinic - Explorer

Minneapolis, Minnesota, United States

RECRUITING

Icahn School of Medicine at Mount Sinai

New York, New York, United States

RECRUITING

Children's Hospital at Montefiore

The Bronx, New York, United States

RECRUITING

...and 10 more locations

Outcomes

Primary Outcomes

Change from baseline in Annualized Growth Velocity (AGV)

Time frame: At 6 months

Secondary Outcomes

Incidence of treatment-emergent adverse events

Time frame: Until the end of the study, up to 15 years

Incidence of new diagnosis of hypertrophic cardiomyopathy in children with Noonan syndrome

Time frame: Every 12 months through the end of the study, up to 15 years

Incidence of cardiac conditions requiring discontinuation of study treatment

Time frame: Every 12 months through the end of the study, up to 15 years

Change from baseline in height

Time frame: At 6 months and at 24 months

Change from baseline in height Z-score

Time frame: At 6 months and at 24 months

Change from baseline in 12-month interval AGV

Time frame: 24 months

Change from baseline in upper to lower body segment ratio

Time frame: At 12 and 24 months

Change from baseline in arm span to height ratio

Time frame: At 12 and 24 months

Change from baseline in height up to Final Adult Height (FAH)

Time frame: Every 6 months through the end of the study, up to 15 years

Change from baseline in height Z-score up to FAH

Time frame: 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

Time frame: Every 12 months through the end of the study, up to 15 years

Tanner stage over the course of the study

Time frame: Every 6 months through the end of the study, up to 15 years

Time vosoritide is present at maximum concentration (Tmax)

Time frame: Every 6 months through the end of the study, up to 15 years

Maximum vosoritide observed plasma concentration (Cmax)

Time frame: 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)

Time frame: 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-∞)

Time frame: Every 6 months through the end of the study, up to 15 years

Elimination half-life of vosoritide (t½)

Time frame: Every 6 months through the end of the study, up to 15 years

Apparent clearance of vosoritide (CL/F)

Time frame: Every 6 months through the end of the study, up to 15 years

Apparent volume of distribution of vosoritide (Vz/F)

Time frame: Every 6 months through the end of the study, up to 15 years

Change from pre-dose in urine cyclic guanine monophosphate (cGMP)

Time frame: Every 6 months through the end of the study, up to 15 years

Change from baseline in serum collagen X marker (CXM)

Time frame: Every 6 months through the end of the study, up to 15 years

Change from baseline in bone age/chronological age

Time frame: Every 12 months through the end of the study, up to 15 years

Change from baseline in total body (less head) BMD Z-score

Time frame: 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

Time frame: 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)

Time frame: Every 12 months through the end of the study, up to 15 years

Change from baseline in lumbar spine BMC

Time frame: Every 12 months through the end of the study, up to 15 years

Change in bone morphology based on whole length lower extremity X-rays

Time frame: 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)

Time frame: Throughout study

Change from baseline in the physical domain score and total score of the QoLISSY

Time frame: At 24 months

Change from baseline in the physical and social domain scores and total score of the PedsQL

Time frame: At 24 months

Change from baseline in PGI-S and CaGI-S item scores

Time frame: At 24 months

PGI-C and CaGI-C item scores

Time frame: At 24 months

Change from baseline in PROMIS-SF Physical Activity score

Time frame: At 24 months

Change from baseline in KABC-II NVI scores

Time frame: At 24 months

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

Overview

Conditions

Interventions

Eligibility

Locations (20)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts