IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency

Phase 1

Completed

Conditions: Short Stature

Interventions: Drug: Increlex

Registration Number: NCT02636270

Lead Sponsor: Children's Hospital Medical Center, Cincinnati

Brief Summary: With this study we want to investigate the pharmacokinetic (PK) effect of a single injection of rhIGF-1 in patients with PAPP-A2 mutations compared to heterozygous carriers and healthy controls. This will be followed by treatment of PAPP-A2 deficient patients with IGF-1 for a period of one-year to assess growth velocity. Additionally, we want to further describe the phenotypic characteristics of patients with PAPP-A2 deficiency.

Detailed Description: The 24-hour pharmacokinetic response of free and total IGF-1 and IGF binding protein-3 (IGFBP-3) to a single dose of rhIGF-1 (120 mcg/kg) in three patients with PAPP-A2 mutation compared to up to four unaffected heterozygous relatives and 2 healthy adult controls.

One-year trial of rhIGF-1 at standard dose given to the two youngest males with PAPP-A2 mutation. The primary end point of this trial will be first year height velocity. Secondary outcomes will include height standard deviation score (SDS), height velocity, and whole body and lumbar spine bone mineral density assessment. The study was amended to extend the treatment period to continue until the subject has stopped growing (or elects to withdraw). All study procedures remain the same. Important note: the treatment phase continues to follow the youngest affected male. The older affected male developed an adverse event that resulted in discontinuation of treatment.

A post-treatment follow up visit (either in-person or remote) will be completed for the study participant who remained on Increlex approximately one-year after their discontinuation of therapy.

Description of additional phenotypic characteristics of patients with PAPP-A2 mutation will be studied by collecting information on glucose and insulin metabolism, body composition, bone geometry and bone density before and after treatment with rhIGF-1. These measures will be collected at the 12-month time period, and every year thereafter until the completion of the study. All three affected siblings will take part in the phenotyping activities.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Defect in PAPP-A2 (heterozygous or homozygous mutation)

Exclusion Criteria

None

Healthy Volunteers

Inclusion Criteria:

Between the ages of 18 and 30
In general good health

Exclusion Criteria:

Any medications (with the exception of contraceptives)
Pregnancy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PAPP-A2 deficient patients	Increlex	Patients deficient in PAPP-A2 with short stature will be treated with Increlex (rhIGF-1)

Primary Outcome Measures

Name	Time	Method
Height Velocity	Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years)	Height velocity in a patient with PAPP-A2 deficiency treated with rhIGF-1 for five years (when the patient elected to discontinue treatment after reviewing growth velocity and skeletal maturation). Ultimately only one patient was treated for the study duration with results reported, as the other recruited participant (sibling of the treated patient) experienced pseudotumor cerebri and discontinued treatment after 51 days. He nevertheless was followed, with height velocity also reported.

Secondary Outcome Measures

Name	Time	Method
Height Standard Deviation Score	Annually until completion of study, up to 6 years	Height Standard Deviation Score is the standard deviation above or below the mean the height is for age and gender. Values were obtained by plotting heights on Centers for Disease Control and Prevention growth charts. An increase in Height Standard Deviation Score correlates with increase in height. Results are reported for the participant with PAPP-A2 deficiency treated with rhIGF-1, as well as sibling who did not continue treatment with rhIGF-1.
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship	Yearly until completion of the study, up to 6 years	Assess the PK/PD relationship (PD marker being IGFBP-3) annually while on treatment with rhIGF-1