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

Short Stature Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02636270
• Other study ID #: 2015-6218
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 21, 2015
• Est. completion date: December 1, 2022

Study information

• Verified date: February 2024
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: December 1, 2022
• Est. primary completion date: October 14, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 10 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Dwarfism
• Short Stature

Intervention

Drug:
• Increlex
Treat PAPP-A2 deficient patients with Increlex

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati

References & Publications (2)

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 Endocr — View 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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