Vosoritide for Selected Genetic Causes of Short Stature
概览
- 阶段
- 2 期
- 干预措施
- Vosoritide
- 疾病 / 适应症
- Short Stature
- 发起方
- Andrew Dauber
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Change from Baseline in standardized height SDS
- 状态
- 进行中（未招募）
- 最后更新
- 上个月
概览
简要总结
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.
研究者
Andrew Dauber
Chief of Endocrinology
Children's National Research Institute
入排标准
入选标准
- •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:
排除标准
- •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-
- •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
研究组 & 干预措施
Genetic Short Stature
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.
干预措施: Vosoritide
结局指标
主要结局
Change from Baseline in standardized height SDS
时间窗: 12 months
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.
Incidence of Symptomatic Hypotension events [Safety and Tolerability]
时间窗: 12 months
Number of symptomatic hypotension events per study participant
Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]
时间窗: 12 months
Number of treatment-emergent adverse events or serious adverse events per study participant
Change from Baseline in annualized growth velocity
时间窗: 12 months
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.
次要结局
- Changes in the seated height ratio as a measure of body proportions(12 months)
- Changes in the difference between arm span and height from baseline(12 months)
- Changes from Baseline in bone age/chronological age(12 months)