Trial Outcomes & Findings for IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency (NCT NCT02636270)
NCT ID: NCT02636270
Last Updated: 2024-02-28
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
7 participants
Primary outcome timeframe
Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years)
Results posted on
2024-02-28
Participant Flow
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.
Not applicable to this research study. All participants that were eligible for the study and agreed to participate were enrolled.
Participant milestones
| Measure |
PAPP-A2 Deficient Patients
Patients deficient in PAPP-A2 will participate in the 24-hour pharmacokinetic study, and those who have not completed growth will be treated with Increlex (recombinant human IGF-1).
|
Healthy Control Participants
Healthy controls between the ages of 18-30 will be included in the 24-hour pharmacokinetic study.
|
PAPP-A2 Heterozygous Relatives
Unaffected heterozygous PAPP-A2 deficient relatives will be included in the 24-hour pharmacokinetic study.
|
|---|---|---|---|
|
Overall Study
STARTED
|
3
|
2
|
2
|
|
Overall Study
COMPLETED
|
1
|
2
|
2
|
|
Overall Study
NOT COMPLETED
|
2
|
0
|
0
|
Reasons for withdrawal
| Measure |
PAPP-A2 Deficient Patients
Patients deficient in PAPP-A2 will participate in the 24-hour pharmacokinetic study, and those who have not completed growth will be treated with Increlex (recombinant human IGF-1).
|
Healthy Control Participants
Healthy controls between the ages of 18-30 will be included in the 24-hour pharmacokinetic study.
|
PAPP-A2 Heterozygous Relatives
Unaffected heterozygous PAPP-A2 deficient relatives will be included in the 24-hour pharmacokinetic study.
|
|---|---|---|---|
|
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
IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency
Baseline characteristics by cohort
| Measure |
PAPP-A2 Deficient Patients
n=3 Participants
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).
|
PAPP-A2 Heterozygous Relatives
n=2 Participants
Unaffected heterozygous PAPP-A2 deficient relatives (2 parents).
|
Health Control Participants
n=2 Participants
Healthy adult controls with no known variants in PAPP-A2.
|
Total
n=7 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Categorical
<=18 years
|
2 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
2 Participants
n=4 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
1 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
5 Participants
n=4 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
3 Participants
n=4 Participants
|
|
Sex: Female, Male
Male
|
2 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
4 Participants
n=4 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Race (NIH/OMB)
Asian
|
3 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
5 Participants
n=4 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Race (NIH/OMB)
White
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
1 Participants
n=4 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
1 Participants
n=4 Participants
|
|
Region of Enrollment
United States
|
3 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
7 Participants
n=4 Participants
|
PRIMARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Height Velocity
Year 1
|
6.2 cm/y
|
4.8 cm/y
|
—
|
—
|
—
|
|
Height Velocity
Year 3
|
5.3 cm/y
|
3.4 cm/y
|
—
|
—
|
—
|
|
Height Velocity
Year 4
|
7.6 cm/y
|
1.4 cm/y
|
—
|
—
|
—
|
|
Height Velocity
Baseline
|
3.0 cm/y
|
4.3 cm/y
|
—
|
—
|
—
|
|
Height Velocity
Year 2
|
5.0 cm/y
|
5.3 cm/y
|
—
|
—
|
—
|
|
Height Velocity
Year 5
|
6.5 cm/y
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Annually until completion of study, up to 6 yearsPopulation: 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.
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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Height Standard Deviation Score
Year 2
|
-2.54 standard deviation score
|
-2.84 standard deviation score
|
—
|
—
|
—
|
|
Height Standard Deviation Score
Year 5
|
-2.27 standard deviation score
|
—
|
—
|
—
|
—
|
|
Height Standard Deviation Score
Baseline
|
-2.86 standard deviation score
|
-2.92 standard deviation score
|
—
|
—
|
—
|
|
Height Standard Deviation Score
Year 1
|
-2.53 standard deviation score
|
-2.99 standard deviation score
|
—
|
—
|
—
|
|
Height Standard Deviation Score
Year 3
|
-2.61 standard deviation score
|
-2.69 standard deviation score
|
—
|
—
|
—
|
|
Height Standard Deviation Score
Year 4
|
-2.43 standard deviation score
|
-2.63 standard deviation score
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Yearly until completion of the study, up to 6 yearsPopulation: Biochemical measurements in patient treated with rhIGF-1 over five years.
Assess the PK/PD relationship (PD marker being IGFBP-3) annually while on treatment with rhIGF-1
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=1 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
n=1 Participants
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Baseline
|
0.79 ng/mL
|
546.8 ng/mL
|
10000 ng/mL
|
0.110 ng/mL
|
—
|
|
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Year 1
|
1.17 ng/mL
|
709.1 ng/mL
|
6362 ng/mL
|
0.190 ng/mL
|
—
|
|
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Year 2
|
4.03 ng/mL
|
814.4 ng/mL
|
4001 ng/mL
|
0.122 ng/mL
|
—
|
|
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Year 3
|
5.13 ng/mL
|
961.7 ng/mL
|
6953 ng/mL
|
0.077 ng/mL
|
—
|
|
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Year 4
|
6.75 ng/mL
|
1200 ng/mL
|
6956 ng/mL
|
0.050 ng/mL
|
—
|
|
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
Year 5
|
16.80 ng/mL
|
1200 ng/mL
|
6053 ng/mL
|
0 ng/mL
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Yearly until completion of the study, up to 6 yearsPopulation: OGTT results at baseline, 12 months, 24 months, 36 months, 48 months, 60 months
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).
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=1 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
n=1 Participants
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
n=1 Participants
120 minute glucose
|
|---|---|---|---|---|---|
|
Glucose Pre- and Post-treatment With Recombinant Human IGF-I
24 Months
|
103.5 mg/dL
|
183.4 mg/dL
|
132.0 mg/dL
|
122.7 mg/dL
|
116.2 mg/dL
|
|
Glucose Pre- and Post-treatment With Recombinant Human IGF-I
48 Months
|
97.3 mg/dL
|
203.1 mg/dL
|
249.3 mg/dL
|
198.7 mg/dL
|
169.7 mg/dL
|
|
Glucose Pre- and Post-treatment With Recombinant Human IGF-I
60 Months
|
93.1 mg/dL
|
198.9 mg/dL
|
224.5 mg/dL
|
199.3 mg/dL
|
151.6 mg/dL
|
|
Glucose Pre- and Post-treatment With Recombinant Human IGF-I
Baseline
|
111.4 mg/dL
|
193.9 mg/dL
|
203.9 mg/dL
|
156.6 mg/dL
|
127.5 mg/dL
|
|
Glucose Pre- and Post-treatment With Recombinant Human IGF-I
12 Months
|
84.1 mg/dL
|
144.1 mg/dL
|
78.8 mg/dL
|
96.9 mg/dL
|
90.6 mg/dL
|
|
Glucose Pre- and Post-treatment With Recombinant Human IGF-I
36 Months
|
103.9 mg/dL
|
185.6 mg/dL
|
153.8 mg/dL
|
126.0 mg/dL
|
104.3 mg/dL
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Annually through completion of the study, up to 6 yearsPopulation: insulin levels measured with OGTT
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).
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=1 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
n=1 Participants
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
n=1 Participants
120 minute glucose
|
|---|---|---|---|---|---|
|
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
Baseline
|
18.3 mcIU/mL
|
88.1 mcIU/mL
|
113.2 mcIU/mL
|
131.9 mcIU/mL
|
107 mcIU/mL
|
|
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
12 Months
|
4.5 mcIU/mL
|
38.1 mcIU/mL
|
11.2 mcIU/mL
|
22.6 mcIU/mL
|
22.3 mcIU/mL
|
|
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
24 Months
|
8.7 mcIU/mL
|
51.2 mcIU/mL
|
33.8 mcIU/mL
|
26.9 mcIU/mL
|
25.8 mcIU/mL
|
|
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
36 Months
|
20.4 mcIU/mL
|
120.6 mcIU/mL
|
67.6 mcIU/mL
|
58.9 mcIU/mL
|
50.3 mcIU/mL
|
|
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
48 Months
|
12.3 mcIU/mL
|
102.3 mcIU/mL
|
116.3 mcIU/mL
|
114.1 mcIU/mL
|
134.4 mcIU/mL
|
|
Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I
60 Months
|
14.9 mcIU/mL
|
84.2 mcIU/mL
|
98.5 mcIU/mL
|
116.9 mcIU/mL
|
94.4 mcIU/mL
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Annually until completion of the study, up to 6 yearsObserve 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Body Mass Index at Baseline and on Treatment With rhIGF-I
Baseline
|
12.96 percentile
|
—
|
—
|
—
|
—
|
|
Body Mass Index at Baseline and on Treatment With rhIGF-I
Year 1
|
30.83 percentile
|
—
|
—
|
—
|
—
|
|
Body Mass Index at Baseline and on Treatment With rhIGF-I
Year 2
|
56.60 percentile
|
—
|
—
|
—
|
—
|
|
Body Mass Index at Baseline and on Treatment With rhIGF-I
Year 3
|
42.76 percentile
|
—
|
—
|
—
|
—
|
|
Body Mass Index at Baseline and on Treatment With rhIGF-I
Year 4
|
54.20 percentile
|
—
|
—
|
—
|
—
|
|
Body Mass Index at Baseline and on Treatment With rhIGF-I
Year 5
|
70.42 percentile
|
—
|
—
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Annually until completion of the study, up to 6 yearsObserve 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Body Composition at Baseline and on Treatment With rhIGF-I
Baseline
|
15274 g
|
6543 g
|
—
|
—
|
—
|
|
Body Composition at Baseline and on Treatment With rhIGF-I
Year 1
|
18961 g
|
7390 g
|
—
|
—
|
—
|
|
Body Composition at Baseline and on Treatment With rhIGF-I
Year 4
|
29779 g
|
12060 g
|
—
|
—
|
—
|
|
Body Composition at Baseline and on Treatment With rhIGF-I
Year 2
|
21366 g
|
10501 g
|
—
|
—
|
—
|
|
Body Composition at Baseline and on Treatment With rhIGF-I
Year 3
|
23876 g
|
10084 g
|
—
|
—
|
—
|
|
Body Composition at Baseline and on Treatment With rhIGF-I
Year 5
|
36398 g
|
13998 g
|
—
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Annually until completion of the study, up to 6 yearsObserve 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
Baseline
|
29.0 percentage of total body fat
|
—
|
—
|
—
|
—
|
|
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
Year 1
|
27.1 percentage of total body fat
|
—
|
—
|
—
|
—
|
|
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
Year 2
|
32.0 percentage of total body fat
|
—
|
—
|
—
|
—
|
|
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
Year 3
|
28.7 percentage of total body fat
|
—
|
—
|
—
|
—
|
|
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
Year 4
|
28.0 percentage of total body fat
|
—
|
—
|
—
|
—
|
|
Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I
Year 5
|
27.0 percentage of total body fat
|
—
|
—
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Yearly until completion of the study, up to 6 yearsObserve 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
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
Year 1
|
2262 ng/mL
|
123 ng/mL
|
—
|
—
|
—
|
|
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
Baseline
|
1744 ng/mL
|
86 ng/mL
|
—
|
—
|
—
|
|
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
Year 2
|
1762 ng/mL
|
88 ng/mL
|
—
|
—
|
—
|
|
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
Year 3
|
2098 ng/mL
|
110 ng/mL
|
—
|
—
|
—
|
|
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
Year 4
|
3216 ng/mL
|
152 ng/mL
|
—
|
—
|
—
|
|
C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1.
Year 5
|
2729 ng/mL
|
126 ng/mL
|
—
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Annually until completion of therapy, up to 6 yearsObserve 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=1 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=1 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=1 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
n=1 Participants
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
Baseline
|
-0.9 z-score
|
-0.2 z-score
|
-0.6 z-score
|
-0.6 z-score
|
—
|
|
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
Year 1
|
-0.2 z-score
|
0.3 z-score
|
-0.5 z-score
|
-0.1 z-score
|
—
|
|
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
Year 2
|
-0.2 z-score
|
0.7 z-score
|
-0.4 z-score
|
-0.4 z-score
|
—
|
|
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
Year 3
|
-0.3 z-score
|
0.5 z-score
|
-0.3 z-score
|
-1.0 z-score
|
—
|
|
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
Year 4
|
-0.5 z-score
|
0.4 z-score
|
-0.7 z-score
|
-1.0 z-score
|
—
|
|
Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1
Year 5
|
-0.9 z-score
|
0.2 z-score
|
-0.9 z-score
|
-0.8 z-score
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At baseline, prior to the ongoing treatment phase with rhIGF-1This 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=3 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=2 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=2 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
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
Interval 186.0 to 254.0
|
243 mcg/L
Interval 203.0 to 283.0
|
284.5 mcg/L
Interval 278.0 to 291.0
|
—
|
—
|
|
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
Interval 26.6 to 35.0
|
30.5 mcg/L
Interval 28.6 to 32.4
|
33.5 mcg/L
Interval 10.9 to 56.0
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At baseline, prior to the ongoing treatment phase with rhIGF-1This 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=3 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=2 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=2 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
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
Interval 1.0 to 3.5
|
2.3 h
Interval 2.0 to 2.5
|
2.3 h
Interval 2.0 to 2.5
|
—
|
—
|
|
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
Interval 3.5 to 5.0
|
3.3 h
Interval 3.0 to 3.5
|
5.5 h
Interval 5.0 to 6.0
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At baseline, prior to the ongoing treatment phase with rhIGF-1This 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.
Outcome measures
| Measure |
Treatment With rhIGF-1
n=3 Participants
Patient deficient in PAPP-A2 with short stature treated with recombinant human IGF-1 (rhIGF-1)
|
Untreated Comparison
n=2 Participants
Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient)
|
IGFBP-3
n=2 Participants
Total IGFBP-3 levels in ng/mL
|
PAPP-A2
PAPP-A2 levels in ng/mL
|
OGTT - 120 Minutes
120 minute glucose
|
|---|---|---|---|---|---|
|
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
Interval 1602.0 to 2406.0
|
2405 mcg*h/L
Interval 2068.0 to 2742.0
|
2878.5 mcg*h/L
Interval 2755.0 to 3002.0
|
—
|
—
|
|
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
Interval 95.0 to 133.0
|
135 mcg*h/L
Interval 118.0 to 152.0
|
155.5 mcg*h/L
Interval 64.0 to 247.0
|
—
|
—
|
Adverse Events
PAPP-A2 Deficient Patients
Serious events: 1 serious events
Other events: 2 other events
Deaths: 0 deaths
PAPP-A2 Heterozygous Relatives
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Healthy Control Participants
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
PAPP-A2 Deficient Patients
n=3 participants at risk
Patients deficient in PAPP-A2 will participate in the 24-hour pharmacokinetic study, and those who have not completed growth will be treated with Increlex (recombinant human IGF-1).
|
PAPP-A2 Heterozygous Relatives
n=2 participants at risk
Unaffected heterozygous PAPP-A2 deficient relatives (2 parents).
|
Healthy Control Participants
n=2 participants at risk
Healthy controls between the ages of 18-30.
|
|---|---|---|---|
|
Nervous system disorders
Pseudotumor cerebri in subject
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
Other adverse events
| Measure |
PAPP-A2 Deficient Patients
n=3 participants at risk
Patients deficient in PAPP-A2 will participate in the 24-hour pharmacokinetic study, and those who have not completed growth will be treated with Increlex (recombinant human IGF-1).
|
PAPP-A2 Heterozygous Relatives
n=2 participants at risk
Unaffected heterozygous PAPP-A2 deficient relatives (2 parents).
|
Healthy Control Participants
n=2 participants at risk
Healthy controls between the ages of 18-30.
|
|---|---|---|---|
|
Respiratory, thoracic and mediastinal disorders
Walking pneumonia
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Nervous system disorders
Headaches
|
33.3%
1/3 • Number of events 6 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Skin and subcutaneous tissue disorders
Hair loss
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Infections and infestations
Fever
|
33.3%
1/3 • Number of events 9 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Gastrointestinal disorders
Vomiting
|
33.3%
1/3 • Number of events 10 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Infections and infestations
Body aches and chills
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Skin and subcutaneous tissue disorders
Mild lipohypertrophy
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Infections and infestations
Flu type A
|
33.3%
1/3 • Number of events 2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Infections and infestations
Viral strep throat
|
33.3%
1/3 • Number of events 2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Gastrointestinal disorders
Diarrhea
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Musculoskeletal and connective tissue disorders
Leg pain with walking
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Metabolism and nutrition disorders
Vitamin D deficiency
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Ear and labyrinth disorders
Thrush on tongue
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Ear and labyrinth disorders
Otitis externia
|
33.3%
1/3 • Number of events 2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
|
Reproductive system and breast disorders
Priaprism
|
33.3%
1/3 • Number of events 1 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
0.00%
0/2 • The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
|
Additional Information
Philippe Backeljauw
Cincinnati Childrens Hospital Medical Center
Phone: 513-636-8444
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place