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

Treatment With Recombinant Human Insulin-like Growth Factor 1 (rhIGF-1) in Patients With Pappalysin-2 (PAPP-A2) Gene Mutation.

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.

Study Overview

• Status: Completed
• Conditions: Short Stature
• Intervention / Treatment: Drug: Increlex

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PAPP-A2 deficient patients; Patients deficient in PAPP-A2 with short stature will be treated with Increlex (rhIGF-1)	Drug: Increlex; Treat PAPP-A2 deficient patients with Increlex; Other Names: rhIGF-1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Height Velocity	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.	Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Height Standard Deviation Score	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.	Annually until completion of study, up to 6 years
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship	Assess the PK/PD relationship (PD marker being IGFBP-3) annually while on treatment with rhIGF-1	Yearly until completion of the study, up to 6 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose Pre- and Post-treatment With Recombinant Human IGF-I	Observe nonparametric measures of glucose pre and post ongoing treatment with rhIGF-1. Oral glucose tolerance tests (OGTT) were performed annually during the five-year treatment period at pre-treatment (baseline) and post-initiation of treatment (after 12 months, 24 months, 36 months, 48 months, and 60 months).	Yearly until completion of the study, up to 6 years
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I	Observe nonparametric measures of insulin metabolism in each individual pre (baseline) and post ongoing treatment with rhIGF-1. Oral glucose tolerance testing (OGTT) was performed pre-treatment (baseline) and post-treatment (after 12 months, 24 months, 36 months, 48 months, and 60 months).	Annually through completion of the study, up to 6 years
Body Mass Index at Baseline and on Treatment With rhIGF-I	Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). BMI percentiles were determined utilizing Centers for Disease Control and Prevention growth charts.	Annually until completion of the study, up to 6 years
Body Composition at Baseline and on Treatment With rhIGF-I	Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). Body fat content and lean body mass were evaluated with dual energy x-ray absorptiometry.	Annually until completion of the study, up to 6 years
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I	Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). Body fat content and lean body mass were evaluated with dual energy x-ray absorptiometry.	Annually until completion of the study, up to 6 years
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.	Observe nonparametric measures of bone turnover pre-treatment (baseline) and post initiation of ongoing treatment (at 12 months, 24 months, 36 months, 48 months, and 60 months) while on rhIGF-1	Yearly until completion of the study, up to 6 years
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1	Observe nonparametric measures of bone density at baseline (pre-treatment) and post initiation of ongoing treatment with rhIGF-1. Dual energy x-ray absorptiometry (DXA) was performed of total body less head, lumbar spine, hip, and forearm. Results are reported as height adjusted z-scores for age and gender, commonly done for bone density. A z-score of 0 is equivalent to population mean, positive above the mean, and negative below the mean. Z-scores within 2 standard deviations of the mean (Z-score 2 to -2) are generally considered normal, however are not sufficient to comment on presence or absence of osteoporosis in the pediatric population.	Annually until completion of therapy, up to 6 years
Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I	This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include maximum corrected total IGF-I and free IGF-I. Due to constraints of reporting platform, time to maximum values and area under the curve (AUC) 12 hours after the dose are reported as separate outcomes.	At baseline, prior to the ongoing treatment phase with rhIGF-1
Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I	This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include time to maximum corrected total IGF-I and free IGF-I. Due to constraints of reporting platform, maximum corrected total IGF-I and free IGF-I values and area under the curve (AUC) 12 hours after the dose are reported as separate outcomes.	At baseline, prior to the ongoing treatment phase with rhIGF-1
Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve	This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include area under the curve (AUC) 12 hours after the dose. Due to constraints of reporting platform, maximum corrected total IGF-I and free IGF-I, as well as time to maximum values separate outcomes.	At baseline, prior to the ongoing treatment phase with rhIGF-1

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Philippe Backeljauw, MD, Cincinnati Childrens Hospital; Principal Investigator: Gajanathan Muthuvel, MD, Cincinnati Childrens Hospital Medical Center

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2015
• Primary Completion (Actual): October 14, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: November 10, 2015
• First Submitted That Met QC Criteria: December 16, 2015
• First Posted (Estimated): December 21, 2015

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Developmental; Dwarfism; Physiological Effects of Drugs; Growth Substances; Mecasermin
• Other Study ID Numbers: 2015-6218

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identifiable data may be shared with physician that is treating the only other two patients in the world with this genetic mutation.
• IPD Sharing Time Frame: The participant data will be available when the treatment trial is actively ongoing. Per study protocol, the study will provide clinical updates to the participants primary Endocrinologist. Should the family request any further information be shared once the study is closed, it can be given to a physician specified by the family.
• IPD Sharing Access Criteria: De-identifiable data may be shared with physician that is treating the only other two patients in the world with this genetic mutation.
• IPD Sharing Supporting Information Type: CSR