Clinical trial: Vosoritide for Selected Genetic Causes of Short Stature (NCT04219007)

Eligibility criteria:
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 (40).

          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 (41). 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.

             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 heterozygous defects in SHOX
             including patients with heterozygous deletions of the SHOX regulatory region known to
             cause SHOX deficiency.

          7. Absence of growth hormone deficiency defined as an IGF-1 level above the lower limit
             of the normal range of the assay. 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 (42). 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

          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
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 3 Years old.
Subject must be at most 10 Years

Patient description (medical language): A 3-year-old girl is brought to the clinic by her parents for assessment of her short stature. Physical examination reveals short limbs and a relatively large head. She has a flat nasal bridge and a small midface. The girl's father exhibits similar physical features; however, her mother looks normal. The genetic testing reveals an autosomal dominant point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene consistent with achondroplasia in both father and the child. The girl has not received any treatment yet, and it is her first visit after immigration to the US. The other mental and developmental examinations are unremarkable.

Patient description (patient's own words): I just brought my little 3-year-old girl to the clinic to have her checked up by the doctor. I was worried sick because she was smaller than her classmates. The lovely doctor performed a physical exam and she told me that she has short limbs and a larger head. My girl also has a flat nasal bridge and a small midface. My baby just has the face of her father, unlike me! They performed some genetic testing on my child and my husband and found out that both my husband and her have a mutation of the FGFR3 gene, which led the doctor to diagnose them with dwarfism. My baby never received any treatment and it was our first visit to the doctor since we arrived in the US. The other tests regarding her mental and physical development were perfectly fine.

Does the patient match the trial criteria? 0