Clinical trial NCT02636270: IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency
Official title: Treatment With Recombinant Human Insulin-like Growth Factor 1 (rhIGF-1) in Patients With Pappalysin-2 (PAPP-A2) Gene Mutation.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Short Stature
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
First posted: 2015-12-21
Enrollment: 7
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: PAPP-A2 deficient

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

Primary outcomes:
measure: Height Velocity
timeFrame: Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years)
Secondary outcomes:
measure: Height Standard Deviation Score
timeFrame: Annually until completion of study, up to 6 years
measure: Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
timeFrame: Yearly until completion of the study, up to 6 years
Other outcomes:
measure: Glucose Pre- and Post-treatment With Recombinant Human IGF-I
timeFrame: Yearly until completion of the study, up to 6 years
measure: Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
timeFrame: Annually through completion of the study, up to 6 years
measure: Body Mass Index at Baseline and on Treatment With rhIGF-I
timeFrame: Annually until completion of the study, up to 6 years
measure: Body Composition at Baseline and on Treatment With rhIGF-I
timeFrame: Annually until completion of the study, up to 6 years
measure: Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
timeFrame: Annually until completion of the study, up to 6 years
measure: C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
timeFrame: Yearly until completion of the study, up to 6 years
measure: Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
timeFrame: Annually until completion of therapy, up to 6 years
measure: Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I
timeFrame: At baseline, prior to the ongoing treatment phase with rhIGF-1
measure: Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I
timeFrame: At baseline, prior to the ongoing treatment phase with rhIGF-1
measure: Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve
timeFrame: At baseline, prior to the ongoing treatment phase with rhIGF-1
Locations:
Study officials:
affiliation: Cincinnati Childrens Hospital
name: Philippe Backeljauw, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cincinnati Childrens Hospital Medical Center
name: Gajanathan Muthuvel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Andrew M, Hwa V, Backeljauw P. Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency. Horm Res Paediatr. 2023;96(5):449-457. doi: 10.1159/000529071. Epub 2023 Jan 16.
citation: Cabrera-Salcedo C, Mizuno T, Tyzinski L, Andrew M, Vinks AA, Frystyk J, Wasserman H, Gordon CM, Hwa V, Backeljauw P, Dauber A. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4568-4577. doi: 10.1210/jc.2017-01411.