Short Stature
Conditions
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.
Interventions
DRUGIncrelex
Treat PAPP-A2 deficient patients with Increlex
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Body Composition at Baseline and on Treatment With rhIGF-I | Annually until completion of the study, up to 6 years | 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. |
| Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Annually until completion of the study, up to 6 years | 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. |
| C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Yearly until completion of the study, up to 6 years | 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 |
| Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Yearly until completion of the study, up to 6 years | 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). |
| Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | At baseline, prior to the ongoing treatment phase with rhIGF-1 | 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. |
| Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | At baseline, prior to the ongoing treatment phase with rhIGF-1 | 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. |
| Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | At baseline, prior to the ongoing treatment phase with rhIGF-1 | 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. |
| Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Annually until completion of therapy, up to 6 years | 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. |
| Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Annually through completion of the study, up to 6 years | 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). |
| Body Mass Index at Baseline and on Treatment With rhIGF-I | Annually until completion of the study, up to 6 years | 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. |
Participant flow
Recruitment details
This is an n=7 study. A total of seven individuals will be recruited to participate in this study. Among the participants, we will have the three affected siblings with Pappalysin-2 (PAPP-A2) mutation (two males and one female), their heterozygous relatives (2 parents) and 2 healthy adult controls.
Pre-assignment details
Not applicable to this research study. All participants that were eligible for the study and agreed to participate were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| PAPP-A2 Deficient Patients Three siblings with PAPP-A2 deficiency due to homozygous PAPP-A2 mutation. The two younger siblings were recruited for extension trial treatment with recombinant human Insulin-like Growth Factor 1 (IGF-1). | 3 |
| PAPP-A2 Heterozygous Relatives Unaffected heterozygous PAPP-A2 deficient relatives (2 parents). | 2 |
| Health Control Participants Healthy adult controls with no known variants in PAPP-A2. | 2 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | subject had completed growth prior to enrollment, so never started on recombinant IGF-1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | PAPP-A2 Deficient Patients | PAPP-A2 Heterozygous Relatives | Health Control Participants | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 3 | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 1 / 3 | 0 / 2 | 0 / 2 |
Outcome results
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.
Time frame: Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years)
Population: The untreated comparison sibling was not evaluated at year 5 past completion of growth.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Height Velocity | Baseline | 3.0 cm/y |
| Treatment With rhIGF-1 | Height Velocity | Year 1 | 6.2 cm/y |
| Treatment With rhIGF-1 | Height Velocity | Year 2 | 5.0 cm/y |
| Treatment With rhIGF-1 | Height Velocity | Year 3 | 5.3 cm/y |
| Treatment With rhIGF-1 | Height Velocity | Year 4 | 7.6 cm/y |
| Treatment With rhIGF-1 | Height Velocity | Year 5 | 6.5 cm/y |
| Untreated Comparison | Height Velocity | Baseline | 4.3 cm/y |
| Untreated Comparison | Height Velocity | Year 4 | 1.4 cm/y |
| Untreated Comparison | Height Velocity | Year 1 | 4.8 cm/y |
| Untreated Comparison | Height Velocity | Year 3 | 3.4 cm/y |
| Untreated Comparison | Height Velocity | Year 2 | 5.3 cm/y |
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.
Time frame: Annually until completion of study, up to 6 years
Population: The participant treated with rhIGF-1 continued on treatment for five years, when he elected to discontinue treatment after reviewing current growth trajectory and skeletal maturation. His untreated sibling was followed for four years through completion of growth.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Height Standard Deviation Score | Baseline | -2.86 standard deviation score |
| Treatment With rhIGF-1 | Height Standard Deviation Score | Year 1 | -2.53 standard deviation score |
| Treatment With rhIGF-1 | Height Standard Deviation Score | Year 2 | -2.54 standard deviation score |
| Treatment With rhIGF-1 | Height Standard Deviation Score | Year 3 | -2.61 standard deviation score |
| Treatment With rhIGF-1 | Height Standard Deviation Score | Year 4 | -2.43 standard deviation score |
| Treatment With rhIGF-1 | Height Standard Deviation Score | Year 5 | -2.27 standard deviation score |
| Untreated Comparison | Height Standard Deviation Score | Baseline | -2.92 standard deviation score |
| Untreated Comparison | Height Standard Deviation Score | Year 4 | -2.63 standard deviation score |
| Untreated Comparison | Height Standard Deviation Score | Year 1 | -2.99 standard deviation score |
| Untreated Comparison | Height Standard Deviation Score | Year 3 | -2.69 standard deviation score |
| Untreated Comparison | Height Standard Deviation Score | Year 2 | -2.84 standard deviation score |
Secondary
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Assess the PK/PD relationship (PD marker being IGFBP-3) annually while on treatment with rhIGF-1
Time frame: Yearly until completion of the study, up to 6 years
Population: Biochemical measurements in patient treated with rhIGF-1 over five years.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 5 | 16.80 ng/mL |
| Treatment With rhIGF-1 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 2 | 4.03 ng/mL |
| Treatment With rhIGF-1 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Baseline | 0.79 ng/mL |
| Treatment With rhIGF-1 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 1 | 1.17 ng/mL |
| Treatment With rhIGF-1 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 4 | 6.75 ng/mL |
| Treatment With rhIGF-1 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 3 | 5.13 ng/mL |
| Untreated Comparison | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 4 | 1200 ng/mL |
| Untreated Comparison | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 5 | 1200 ng/mL |
| Untreated Comparison | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 1 | 709.1 ng/mL |
| Untreated Comparison | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 2 | 814.4 ng/mL |
| Untreated Comparison | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Baseline | 546.8 ng/mL |
| Untreated Comparison | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 3 | 961.7 ng/mL |
| IGFBP-3 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 5 | 6053 ng/mL |
| IGFBP-3 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 4 | 6956 ng/mL |
| IGFBP-3 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 3 | 6953 ng/mL |
| IGFBP-3 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 1 | 6362 ng/mL |
| IGFBP-3 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Baseline | 10000 ng/mL |
| IGFBP-3 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 2 | 4001 ng/mL |
| PAPP-A2 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 5 | 0 ng/mL |
| PAPP-A2 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Baseline | 0.110 ng/mL |
| PAPP-A2 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 1 | 0.190 ng/mL |
| PAPP-A2 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 2 | 0.122 ng/mL |
| PAPP-A2 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 3 | 0.077 ng/mL |
| PAPP-A2 | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Year 4 | 0.050 ng/mL |
Other Pre-specified
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.
Time frame: Annually until completion of the study, up to 6 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Body Composition at Baseline and on Treatment With rhIGF-I | Baseline | 15274 g |
| Treatment With rhIGF-1 | Body Composition at Baseline and on Treatment With rhIGF-I | Year 1 | 18961 g |
| Treatment With rhIGF-1 | Body Composition at Baseline and on Treatment With rhIGF-I | Year 2 | 21366 g |
| Treatment With rhIGF-1 | Body Composition at Baseline and on Treatment With rhIGF-I | Year 3 | 23876 g |
| Treatment With rhIGF-1 | Body Composition at Baseline and on Treatment With rhIGF-I | Year 4 | 29779 g |
| Treatment With rhIGF-1 | Body Composition at Baseline and on Treatment With rhIGF-I | Year 5 | 36398 g |
| Untreated Comparison | Body Composition at Baseline and on Treatment With rhIGF-I | Year 4 | 12060 g |
| Untreated Comparison | Body Composition at Baseline and on Treatment With rhIGF-I | Baseline | 6543 g |
| Untreated Comparison | Body Composition at Baseline and on Treatment With rhIGF-I | Year 3 | 10084 g |
| Untreated Comparison | Body Composition at Baseline and on Treatment With rhIGF-I | Year 1 | 7390 g |
| Untreated Comparison | Body Composition at Baseline and on Treatment With rhIGF-I | Year 5 | 13998 g |
| Untreated Comparison | Body Composition at Baseline and on Treatment With rhIGF-I | Year 2 | 10501 g |
Other Pre-specified
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.
Time frame: Annually until completion of the study, up to 6 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Body Mass Index at Baseline and on Treatment With rhIGF-I | Baseline | 12.96 percentile |
| Treatment With rhIGF-1 | Body Mass Index at Baseline and on Treatment With rhIGF-I | Year 1 | 30.83 percentile |
| Treatment With rhIGF-1 | Body Mass Index at Baseline and on Treatment With rhIGF-I | Year 2 | 56.60 percentile |
| Treatment With rhIGF-1 | Body Mass Index at Baseline and on Treatment With rhIGF-I | Year 3 | 42.76 percentile |
| Treatment With rhIGF-1 | Body Mass Index at Baseline and on Treatment With rhIGF-I | Year 4 | 54.20 percentile |
| Treatment With rhIGF-1 | Body Mass Index at Baseline and on Treatment With rhIGF-I | Year 5 | 70.42 percentile |
Other Pre-specified
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.
Time frame: Annually until completion of therapy, up to 6 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Baseline | -0.9 z-score |
| Treatment With rhIGF-1 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 1 | -0.2 z-score |
| Treatment With rhIGF-1 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 2 | -0.2 z-score |
| Treatment With rhIGF-1 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 3 | -0.3 z-score |
| Treatment With rhIGF-1 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 4 | -0.5 z-score |
| Treatment With rhIGF-1 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 5 | -0.9 z-score |
| Untreated Comparison | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 5 | 0.2 z-score |
| Untreated Comparison | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 3 | 0.5 z-score |
| Untreated Comparison | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Baseline | -0.2 z-score |
| Untreated Comparison | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 2 | 0.7 z-score |
| Untreated Comparison | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 1 | 0.3 z-score |
| Untreated Comparison | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 4 | 0.4 z-score |
| IGFBP-3 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 1 | -0.5 z-score |
| IGFBP-3 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 2 | -0.4 z-score |
| IGFBP-3 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 3 | -0.3 z-score |
| IGFBP-3 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 5 | -0.9 z-score |
| IGFBP-3 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 4 | -0.7 z-score |
| IGFBP-3 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Baseline | -0.6 z-score |
| PAPP-A2 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 4 | -1.0 z-score |
| PAPP-A2 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 5 | -0.8 z-score |
| PAPP-A2 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 1 | -0.1 z-score |
| PAPP-A2 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 3 | -1.0 z-score |
| PAPP-A2 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Baseline | -0.6 z-score |
| PAPP-A2 | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Year 2 | -0.4 z-score |
Other Pre-specified
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
Time frame: Yearly until completion of the study, up to 6 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Baseline | 1744 ng/mL |
| Treatment With rhIGF-1 | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 1 | 2262 ng/mL |
| Treatment With rhIGF-1 | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 2 | 1762 ng/mL |
| Treatment With rhIGF-1 | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 3 | 2098 ng/mL |
| Treatment With rhIGF-1 | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 4 | 3216 ng/mL |
| Treatment With rhIGF-1 | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 5 | 2729 ng/mL |
| Untreated Comparison | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 4 | 152 ng/mL |
| Untreated Comparison | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Baseline | 86 ng/mL |
| Untreated Comparison | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 3 | 110 ng/mL |
| Untreated Comparison | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 1 | 123 ng/mL |
| Untreated Comparison | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 5 | 126 ng/mL |
| Untreated Comparison | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Year 2 | 88 ng/mL |
Other Pre-specified
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).
Time frame: Yearly until completion of the study, up to 6 years
Population: OGTT results at baseline, 12 months, 24 months, 36 months, 48 months, 60 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 111.4 mg/dL |
| Treatment With rhIGF-1 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 84.1 mg/dL |
| Treatment With rhIGF-1 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 103.5 mg/dL |
| Treatment With rhIGF-1 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 103.9 mg/dL |
| Treatment With rhIGF-1 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 97.3 mg/dL |
| Treatment With rhIGF-1 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 93.1 mg/dL |
| Untreated Comparison | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 203.1 mg/dL |
| Untreated Comparison | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 198.9 mg/dL |
| Untreated Comparison | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 193.9 mg/dL |
| Untreated Comparison | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 183.4 mg/dL |
| Untreated Comparison | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 185.6 mg/dL |
| Untreated Comparison | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 144.1 mg/dL |
| IGFBP-3 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 153.8 mg/dL |
| IGFBP-3 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 249.3 mg/dL |
| IGFBP-3 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 203.9 mg/dL |
| IGFBP-3 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 132.0 mg/dL |
| IGFBP-3 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 78.8 mg/dL |
| IGFBP-3 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 224.5 mg/dL |
| PAPP-A2 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 126.0 mg/dL |
| PAPP-A2 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 96.9 mg/dL |
| PAPP-A2 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 122.7 mg/dL |
| PAPP-A2 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 199.3 mg/dL |
| PAPP-A2 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 198.7 mg/dL |
| PAPP-A2 | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 156.6 mg/dL |
| OGTT - 120 Minutes | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 169.7 mg/dL |
| OGTT - 120 Minutes | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 116.2 mg/dL |
| OGTT - 120 Minutes | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 90.6 mg/dL |
| OGTT - 120 Minutes | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 151.6 mg/dL |
| OGTT - 120 Minutes | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 104.3 mg/dL |
| OGTT - 120 Minutes | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 127.5 mg/dL |
Other Pre-specified
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).
Time frame: Annually through completion of the study, up to 6 years
Population: insulin levels measured with OGTT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 18.3 mcIU/mL |
| Treatment With rhIGF-1 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 4.5 mcIU/mL |
| Treatment With rhIGF-1 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 8.7 mcIU/mL |
| Treatment With rhIGF-1 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 20.4 mcIU/mL |
| Treatment With rhIGF-1 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 12.3 mcIU/mL |
| Treatment With rhIGF-1 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 14.9 mcIU/mL |
| Untreated Comparison | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 102.3 mcIU/mL |
| Untreated Comparison | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 84.2 mcIU/mL |
| Untreated Comparison | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 88.1 mcIU/mL |
| Untreated Comparison | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 51.2 mcIU/mL |
| Untreated Comparison | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 120.6 mcIU/mL |
| Untreated Comparison | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 38.1 mcIU/mL |
| IGFBP-3 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 67.6 mcIU/mL |
| IGFBP-3 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 116.3 mcIU/mL |
| IGFBP-3 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 113.2 mcIU/mL |
| IGFBP-3 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 33.8 mcIU/mL |
| IGFBP-3 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 11.2 mcIU/mL |
| IGFBP-3 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 98.5 mcIU/mL |
| PAPP-A2 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 58.9 mcIU/mL |
| PAPP-A2 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 22.6 mcIU/mL |
| PAPP-A2 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 26.9 mcIU/mL |
| PAPP-A2 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 116.9 mcIU/mL |
| PAPP-A2 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 114.1 mcIU/mL |
| PAPP-A2 | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 131.9 mcIU/mL |
| OGTT - 120 Minutes | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 48 Months | 134.4 mcIU/mL |
| OGTT - 120 Minutes | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 24 Months | 25.8 mcIU/mL |
| OGTT - 120 Minutes | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 12 Months | 22.3 mcIU/mL |
| OGTT - 120 Minutes | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 60 Months | 94.4 mcIU/mL |
| OGTT - 120 Minutes | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | 36 Months | 50.3 mcIU/mL |
| OGTT - 120 Minutes | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Baseline | 107 mcIU/mL |
Other Pre-specified
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.
Time frame: At baseline, prior to the ongoing treatment phase with rhIGF-1
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment With rhIGF-1 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | AUC_total IGF-1_0-12h | 2118 mcg*h/L |
| Treatment With rhIGF-1 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | AUC_free IGF-I_0-12h | 115.7 mcg*h/L |
| Untreated Comparison | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | AUC_total IGF-1_0-12h | 2405 mcg*h/L |
| Untreated Comparison | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | AUC_free IGF-I_0-12h | 135 mcg*h/L |
| IGFBP-3 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | AUC_total IGF-1_0-12h | 2878.5 mcg*h/L |
| IGFBP-3 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | AUC_free IGF-I_0-12h | 155.5 mcg*h/L |
Other Pre-specified
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.
Time frame: At baseline, prior to the ongoing treatment phase with rhIGF-1
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment With rhIGF-1 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | Maximum corrected total IGF-I | 225 mcg/L |
| Treatment With rhIGF-1 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | Maximum corrected free IGF-I | 32 mcg/L |
| Untreated Comparison | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | Maximum corrected total IGF-I | 243 mcg/L |
| Untreated Comparison | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | Maximum corrected free IGF-I | 30.5 mcg/L |
| IGFBP-3 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | Maximum corrected total IGF-I | 284.5 mcg/L |
| IGFBP-3 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | Maximum corrected free IGF-I | 33.5 mcg/L |
Other Pre-specified
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.
Time frame: At baseline, prior to the ongoing treatment phase with rhIGF-1
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment 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 | Time to maximum corrected total IGF-I | 4.2 h |
| Treatment 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 | Time to maximum corrected free IGF-I | 2.0 h |
| Untreated Comparison | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | Time to maximum corrected total IGF-I | 3.3 h |
| Untreated Comparison | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | Time to maximum corrected free IGF-I | 2.3 h |
| IGFBP-3 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | Time to maximum corrected total IGF-I | 5.5 h |
| IGFBP-3 | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | Time to maximum corrected free IGF-I | 2.3 h |
Other Pre-specified
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.
Time frame: Annually until completion of the study, up to 6 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With rhIGF-1 | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Baseline | 29.0 percentage of total body fat |
| Treatment With rhIGF-1 | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Year 1 | 27.1 percentage of total body fat |
| Treatment With rhIGF-1 | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Year 2 | 32.0 percentage of total body fat |
| Treatment With rhIGF-1 | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Year 3 | 28.7 percentage of total body fat |
| Treatment With rhIGF-1 | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Year 4 | 28.0 percentage of total body fat |
| Treatment With rhIGF-1 | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Year 5 | 27.0 percentage of total body fat |