Prepubertal Children With Growth Failure Associated With Primary Insulin-Like Growth Factor-1 (IGF-1) Deficiency

• Sponsor: Ipsen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00125164
• Collaborator: (none)
• Enrollment: 137
• Location: 1
• Arms: 4
• Duration (Months): 52
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

This study is intended to determine whether twice daily weight based dosing with recombinant human insulin-like growth factor (rhIGF-1) will safely and effectively increase the growth of prepubertal children with short stature associated with low IGF-1 levels but who produce sufficient growth hormone (GH). Subjects will be randomized to either an observation arm or to active treatment.

Condition or Disease	Intervention/Treatment	Phase
Growth Disorders; Insulin-Like Growth Factor-1 Deficiency	Drug: rhIGF-1 (mecasermin, Tercica, Inc.)	Phase 3

Detailed Description

Prepubertal growth failure associated with primary IGF-1 deficiency (IGFD). Primary IGFD is a term that has been used to describe patients with intrinsic cellular defects in GH action. In this protocol, primary IGFD is defined as short stature (height standard deviation score[SDS]<-2 below the mean for age and gender), low serum IGF-1 (IGF-1 SDS <-2 below the mean for age and gender), and levels of growth hormone (GH) that are normal (≥7ng/mL) after a GH stimulation test. Primary IGFD is believed to result from a lower than normal ability to produce IGF-1 when exposed to normal levels of GH, i.e., a type of GH insensitivity or GH resistance.

This trial is one year, randomized, open label, observation-controlled, parallel-dose comparison efficacy and safety study conducted in approximately 40 centers across the United States.

Study Design

• Study Type: Interventional
• Actual Enrollment: 137 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Recombinant Human Insulin-Like Growth Factor (rhIGF-1) Treatment of Prepubertal Children With Growth Failure Associated With Primary IGF-1 Deficiency: A Phase 3, Randomized, Open Label, Observation-Controlled, Multicenter, Parallel-Dose Comparison Trial
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Untreated Observational Group
Experimental: 40 μg/kg BID (twice daily dosing) Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Drug: rhIGF-1 (mecasermin, Tercica, Inc.); Twice Daily Injection
Experimental: 80 μg/kg BID (twice daily dosing) Injection of rhIGF-1 80 μg/kg BID	Drug: rhIGF-1 (mecasermin, Tercica, Inc.); Twice Daily Injection
Experimental: 120 μg/kg BID (twice daily dosing) Injection of rhIGF-1 120 μg/kg BID	Drug: rhIGF-1 (mecasermin, Tercica, Inc.); Twice Daily Injection

Outcome Measures

Primary Outcome Measures

1. Height Velocity During the First Year - Intent to Treat (ITT)Population [Measured at baseline and at one year]

   Height to be measured standing without shoes as the average of three measurements by the same observer using identical technique with a Harpenden or other wall mounted stadiometer. Reposition subject between each measurement.

Secondary Outcome Measures

1. Change From Baseline in Height Standard Deviation (SD) Score at One Year - ITT Population [Measured at baseline and at one year]

   Height to be measured standing without shoes as the average of three measurements by the same observer using identical technique with a Harpenden or other wall mounted stadiometer. Reposition subject between each measurement. Please note that Standard Deviation (SD) Score is a term used in growth studies. The SD Score is calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child.

2. Changes in Bone Age From Baseline to One Year [Measured at baseline and at one year]

   Plain X-rays of the left hand and wrist exposed for bone age appraisal. The films are sent to a central facility for standardized evaluation.

3. Percent Changes From Baseline in Serum Concentrations of IGF-1 at One Year [Measured at baseline and at one year]

   Blood sample was collected while subject is in a fasting state for measuring the level of IGF-1 in the growth factor panel.

4. Percent Changes From Baseline in Serum Concentrations of IGF-2 at One Year [Measured at baseline and at one year]

   Blood sample was collected for measuring the level of IGF-2 in the growth factor panel.

5. Percent Changes From Baseline in Serum Concentrations of Insulin-like Growth Factor Binding Protein-2 (IGFBP-2) at One Year [Measured at baseline and at one year]

   Blood sample was collected for measuring the level of insulin-like growth factor binding protein-2 (IGFBP-2) in the growth factor panel.

6. Percent Changes From Baseline in Serum Concentrations of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) at One Year [Measured at baseline and at one year]

   Blood sample was collected while subject is in a fasting state for measuring the level of IGFBP-3 in the growth factor panel.

7. IGF Generation Test: Change of Serum IGF-1 After 7 Days Exposure to Recombinant Human Growth Hormone (rhGH) [Study Day 1 and Day 7]

   Blood drawn at Study Day 1, followed by 7 days of rhGH daily dosing at 0.05 mg/kg of body weight. Additional blood draw at Study Day 7.

8. IGF Generation Test: Change of Serum IGFBP-3 After 7 Days Exposure to Recombinant Human Growth Hormone (rhGH) [Study Day 1 and Day 7]

   Blood drawn at Study Day 1, followed by 7 days of rhGH daily dosing at 0.05 mg/kg of body weight. Additional blood draw at Study Day 7.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Chronological age ≥ 3 and chronological or bone age less than or equal to 11 years inclusive in girls;

• Chronological age ≥ 3 and chronological or bone age less than or equal to 12 years inclusive for boys

• Prepubertal

• Height SD score of < -2

• IGF-1 SD score of < -2

Exclusion Criteria:

• Prior treatment with rhGH, rhIGF-1, or other growth-influencing medications

• Growth failure associated with other identifiable causes (e.g., syndromes, chromosomal abnormality)

• Chronic illness such as diabetes, cystic fibrosis, etc.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ipsen (formerly Tercica)	Brisbane	California	United States	94005

Sponsors and Collaborators

• Ipsen

Investigators

• Study Director: Ipsen Medical Director, Ipsen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT00125164
• Other Study ID Numbers: MS301; 2019-001020-36
• First Posted: Jul 29, 2005
• Last Update Posted: Sep 18, 2019
• Last Verified: Sep 1, 2019

• Keywords provided by Ipsen: Primary IGF-1 Deficiency
• Additional relevant MeSH terms: Growth Disorders; Failure to Thrive; Mecasermin

Study Results

Participant Flow

Recruitment Details	Study Initiation Date: 14 March 2004. Study completion Date: 02 July 2008. 44 investigators screened subjects; 14 did not enroll any subjects. 137 subjects were enrolled. Consent for one randomized subject was withdrawn prior to any study measurements. This subject was excluded from all analyses.
Pre-assignment Detail	Subject screening consisted of three staged clinic visits over 6 weeks, including a medical history, complete physical examination, IGF-1 measurements, a Growth Hormone (GH) stimulation test, and an IGF-1 generation test.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Period Title: Overall Study
STARTED	25	16	44	51
COMPLETED	23	16	40	45
NOT COMPLETED	2	0	4	6

Baseline Characteristics

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)	Total
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID	Total of all reporting groups
Overall Participants	25	16	44	51	136
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.0 (2.4)	7.6 (2.4)	7.7 (2.4)	7.6 (2.7)	7.5 (2.5)
Sex: Female, Male (Count of Participants)
Female	10 40%	4 25%	14 31.8%	8 15.7%	36 26.5%
Male	15 60%	12 75%	30 68.2%	43 84.3%	100 73.5%
Race/Ethnicity, Customized (participants) [Number]
Asian	1 4%	0 0%	1 2.3%	2 3.9%	4 2.9%
Black	0 0%	0 0%	0 0%	2 3.9%	2 1.5%
Hispanic	2 8%	0 0%	4 9.1%	4 7.8%	10 7.4%
Native Hawaiian or Pacific Islander	0 0%	0 0%	0 0%	1 2%	1 0.7%
White	22 88%	16 100%	38 86.4%	41 80.4%	117 86%
Other	0 0%	0 0%	1 2.3%	1 2%	2 1.5%
Stratum (participants) [Number]
Height Standard Deviation Score < -2.6	13 52%	8 50%	25 56.8%	30 58.8%	76 55.9%
Height Standard Deviation Score >= -2.6	12 48%	8 50%	19 43.2%	21 41.2%	60 44.1%
Height Standard Deviation (SD) Score (SD) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [SD]	-2.8 (0.7)	-2.6 (0.6)	-2.7 (0.5)	-2.9 (0.8)	-2.8 (0.7)
IGF-1 Standard Deviation (SD) Score (SD) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [SD]	-2.6 (0.7)	-2.8 (0.8)	-2.6 (0.7)	-3.0 (0.8)	-2.8 (0.8)
Maximum Stimulated Growth Hormone (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	17.0 (6.5)	16.9 (6.2)	17.8 (9.0)	20.7 (16.8)	18.6 (12.1)
Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	17.8 (4.6)	18.5 (4.7)	19.4 (5.4)	18.5 (5.7)	18.6 (5.3)

Outcome Measures

1. Primary Outcome

Title	Height Velocity During the First Year - Intent to Treat (ITT)Population
Description	Height to be measured standing without shoes as the average of three measurements by the same observer using identical technique with a Harpenden or other wall mounted stadiometer. Reposition subject between each measurement.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

A modified intention-to-treat population consisting of all randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with a baseline height measurement and at least one on-treatment height measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	22	0	42	49
Mean (Standard Deviation) [cm/yr]	5.2 (1.0)	6.9 (1.0)	7.7 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Untreated, 80 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.79
	Confidence Interval	() 95%; 1.19 to 2.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.30
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Untreated, 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.58
	Confidence Interval	() 95%; 1.99 to 3.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.30
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	80 μg/kg BID (Twice Daily Dosing), 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares the 80 and 120 µg/kg BID groups using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.79
	Confidence Interval	() 95%; 0.27 to 1.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Height Standard Deviation (SD) Score at One Year - ITT Population
Description	Height to be measured standing without shoes as the average of three measurements by the same observer using identical technique with a Harpenden or other wall mounted stadiometer. Reposition subject between each measurement. Please note that Standard Deviation (SD) Score is a term used in growth studies. The SD Score is calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

A modified intention-to-treat population that consists of all randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with a baseline height measurement and at least one on-treatment height measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	22	0	42	49
Mean (Standard Deviation) [SD/year]	0.02 (0.24)	0.38 (0.17)	0.48 (0.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Untreated, 80 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.37
	Confidence Interval	() 95%; 0.24 to 0.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Untreated, 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.47
	Confidence Interval	() 95%; 0.34 to 0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	80 μg/kg BID (Twice Daily Dosing), 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares the 80 and 120 µg/kg BID groups using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0495
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.11
	Confidence Interval	() 95%; 0.00 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

3. Secondary Outcome

Title	Changes in Bone Age From Baseline to One Year
Description	Plain X-rays of the left hand and wrist exposed for bone age appraisal. The films are sent to a central facility for standardized evaluation.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with baseline measurement and Month 12 measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	23	0	40	44
Mean (Standard Deviation) [Year]	0.8 (0.3)	1.1 (0.4)	1.2 (0.5)

4. Secondary Outcome

Title	Percent Changes From Baseline in Serum Concentrations of IGF-1 at One Year
Description	Blood sample was collected while subject is in a fasting state for measuring the level of IGF-1 in the growth factor panel.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with baseline measurement and Month 12 measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	18	0	34	42
Mean (Standard Deviation) [Percent change]	64 (120)	227 (220)	266 (215)

5. Secondary Outcome

Title	Percent Changes From Baseline in Serum Concentrations of IGF-2 at One Year
Description	Blood sample was collected for measuring the level of IGF-2 in the growth factor panel.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with baseline measurement and Month 12 measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	17	0	35	40
Mean (Standard Deviation) [Percent change]	14 (28)	-38 (37)	-37 (32)

6. Secondary Outcome

Title	Percent Changes From Baseline in Serum Concentrations of Insulin-like Growth Factor Binding Protein-2 (IGFBP-2) at One Year
Description	Blood sample was collected for measuring the level of insulin-like growth factor binding protein-2 (IGFBP-2) in the growth factor panel.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with baseline measurement and Month 12 measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	15	0	32	34
Mean (Standard Deviation) [Percent change]	-16 (26)	58 (84)	61 (79)

7. Secondary Outcome

Title	Percent Changes From Baseline in Serum Concentrations of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) at One Year
Description	Blood sample was collected while subject is in a fasting state for measuring the level of IGFBP-3 in the growth factor panel.
Time Frame	Measured at baseline and at one year

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with baseline measurement and Month 12 measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	18	0	34	42
Mean (Standard Deviation) [Percent change]	13 (33)	-19 (22)	-19 (28)

8. Secondary Outcome

Title	IGF Generation Test: Change of Serum IGF-1 After 7 Days Exposure to Recombinant Human Growth Hormone (rhGH)
Description	Blood drawn at Study Day 1, followed by 7 days of rhGH daily dosing at 0.05 mg/kg of body weight. Additional blood draw at Study Day 7.
Time Frame	Study Day 1 and Day 7

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with measurements both pre and post exposure to rhGH. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	18	0	34	42
Mean (Standard Deviation) [ng/mL]	40 (49)	53 (49)	48 (43)

9. Secondary Outcome

Title	IGF Generation Test: Change of Serum IGFBP-3 After 7 Days Exposure to Recombinant Human Growth Hormone (rhGH)
Description	Blood drawn at Study Day 1, followed by 7 days of rhGH daily dosing at 0.05 mg/kg of body weight. Additional blood draw at Study Day 7.
Time Frame	Study Day 1 and Day 7

Outcome Measure Data

Analysis Population Description

All randomized subjects in the untreated control, 80 and 120 µg/kg BID groups with measurements both pre and post exposure to rhGH. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	18	0	34	42
Mean (Standard Deviation) [mg/dL]	744 (459)	800 (1095)	681 (568)

10. Post-Hoc Outcome

Title	Height Velocity During the First Year for Subjects - Completers
Description	Height to be measured standing without shoes as the average of three measurements by the same observer using identical technique with a Harpenden or other wall mounted stadiometer. Reposition subject between each measurement.
Time Frame	One Year

Outcome Measure Data

Analysis Population Description

All randomized subjects who completed 12 months of treatment in the untreated control, 80 and 120 µg/kg BID groups with a baseline height measurement and at least one on-treatment height measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	21	0	39	43
Mean (Standard Deviation) [cm/year]	5.2 (1.0)	7.0 (1.0)	7.9 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Untreated, 80 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.83
	Confidence Interval	() 95%; 1.26 to 2.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.29
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Untreated, 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.83
	Confidence Interval	() 95%; 2.26 to 3.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.29
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	80 μg/kg BID (Twice Daily Dosing), 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares the 80 and 120 µg/kg BID groups using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.01
	Confidence Interval	() 95%; 0.50 to 1.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.25
	Estimation Comments

11. Post-Hoc Outcome

Title	Change From Baseline in Height Standard Deviation (SD) Score at One Year - Completers
Description	Height to be measured standing without shoes as the average of three measurements by the same observer using identical technique with a Harpenden or other wall mounted stadiometer. Reposition subject between each measurement. Please note that Standard Deviation (SD) Score is a term used in growth studies. The SD Score is calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child.
Time Frame	One Year

Outcome Measure Data

Analysis Population Description

All randomized subjects who completed 12 months of treatment in the untreated control, 80 and 120 µg/kg BID groups with a baseline height measurement and at least one on-treatment height measurement. Subjects assigned to 40 μg/kg BID arm were excluded from the analysis due to the dose change to 120 μg/kg BID.

Arm/Group Title	Untreated	40 μg/kg BID (Twice Daily Dosing)	80 μg/kg BID (Twice Daily Dosing)	120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group	Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.	Injection of rhIGF-1 80 μg/kg BID	Injection of rhIGF-1 120 μg/kg BID
Measure Participants	21	0	39	43
Mean (Standard Deviation) [SD/year]	0.02 (0.24)	0.39 (0.17)	0.53 (0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Untreated, 80 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.37
	Confidence Interval	() 95%; 0.25 to 0.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Untreated, 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares each of the 80 and 120 µg/kg BID groups with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett's method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.52
	Confidence Interval	() 95%; 0.39 to 0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	80 μg/kg BID (Twice Daily Dosing), 120 μg/kg BID (Twice Daily Dosing)
	Comments	The analysis compares the 80 and 120 µg/kg BID groups using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomization, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0071
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.15
	Confidence Interval	() 95%; 0.04 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected until 30 days after last subject visit or until resolution. Adverse event collection for an individual subject was 1 year 1 month. Across study adverse event reporting continued for a total of 4 years 5 months.
Arm/Group Title	Untreated		40 μg/kg BID (Twice Daily Dosing)		80 μg/kg BID (Twice Daily Dosing)		120 μg/kg BID (Twice Daily Dosing)
Arm/Group Description	Observational Group		Injection of rhIGF-1 40 μg/kg BID. Per protocol amendment these subjects were reassigned to receive 120 μg/kg BID. Due to the dose change, the efficacy results for these subjects were analysed in a separate subanalysis. For all outcome measures, mean and standard deviations were not calculated for this arm.		Injection of rhIGF-1 80 μg/kg BID		Injection of rhIGF-1 120 μg/kg BID
All Cause Mortality
	Untreated		40 μg/kg BID (Twice Daily Dosing)		80 μg/kg BID (Twice Daily Dosing)		120 μg/kg BID (Twice Daily Dosing)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Untreated		40 μg/kg BID (Twice Daily Dosing)		80 μg/kg BID (Twice Daily Dosing)		120 μg/kg BID (Twice Daily Dosing)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		1/16 (6.3%)		2/44 (4.5%)		5/51 (9.8%)
Congenital, familial and genetic disorders
Cor Triatriatum	0/25 (0%)	0	0/16 (0%)	0	0/44 (0%)	0	1/51 (2%)	1
Endocrine disorders
Hypoglycemic seizure	0/25 (0%)	0	0/16 (0%)	0	0/44 (0%)	0	1/51 (2%)	1
Gastrointestinal disorders
Gastroenteritis	0/25 (0%)	0	1/16 (6.3%)	1	0/44 (0%)	0	0/51 (0%)	0
Gastroenteritis escherichia coli	0/25 (0%)	0	0/16 (0%)	0	1/44 (2.3%)	1	0/51 (0%)	0
Vomiting	0/25 (0%)	0	1/16 (6.3%)	1	0/44 (0%)	0	0/51 (0%)	0
Infections and infestations
Cellulitis	1/25 (4%)	1	0/16 (0%)	0	0/44 (0%)	0	0/51 (0%)	0
Gastroenteritis viral	0/25 (0%)	0	0/16 (0%)	0	0/44 (0%)	0	1/51 (2%)	1
Pneumonia	0/25 (0%)	0	0/16 (0%)	0	0/44 (0%)	0	1/51 (2%)	1
Metabolism and nutrition disorders
Dehydration	0/25 (0%)	0	0/16 (0%)	0	0/44 (0%)	0	1/51 (2%)	1
Nervous system disorders
Benign Itracranial Hypertension	0/25 (0%)	0	0/16 (0%)	0	0/44 (0%)	0	1/51 (2%)	1
Intracranial pressure increased	0/25 (0%)	0	0/16 (0%)	0	1/44 (2.3%)	1	0/51 (0%)	0
Other (Not Including Serious) Adverse Events
	Untreated		40 μg/kg BID (Twice Daily Dosing)		80 μg/kg BID (Twice Daily Dosing)		120 μg/kg BID (Twice Daily Dosing)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/25 (72%)		16/16 (100%)		37/44 (84.1%)		43/51 (84.3%)
Ear and labyrinth disorders
Ear infection	0/25 (0%)	0	1/16 (6.3%)	3	1/44 (2.3%)	1	6/51 (11.8%)	8
Ear pain	2/25 (8%)	2	1/16 (6.3%)	1	3/44 (6.8%)	3	1/51 (2%)	2
Gastrointestinal disorders
Nausea	0/25 (0%)	0	4/16 (25%)	5	6/44 (13.6%)	7	2/51 (3.9%)	2
Gastroenteritis	0/25 (0%)	0	3/16 (18.8%)	4	4/44 (9.1%)	7	3/51 (5.9%)	4
General disorders
Injection site bruising	0/25 (0%)	0	3/16 (18.8%)	3	6/44 (13.6%)	10	4/51 (7.8%)	7
Injection site pain	0/25 (0%)	0	2/16 (12.5%)	2	7/44 (15.9%)	7	4/51 (7.8%)	6
Infections and infestations
Upper respiratory tract infection	6/25 (24%)	7	3/16 (18.8%)	5	10/44 (22.7%)	17	12/51 (23.5%)	13
Nasopharyngitis	2/25 (8%)	3	2/16 (12.5%)	3	5/44 (11.4%)	5	7/51 (13.7%)	12
Gastroenteritis viral	0/25 (0%)	0	3/16 (18.8%)	4	8/44 (18.2%)	10	3/51 (5.9%)	3
Pharyngitis streptococcal	2/25 (8%)	2	1/16 (6.3%)	1	4/44 (9.1%)	6	7/51 (13.7%)	9
Influenza	1/25 (4%)	1	1/16 (6.3%)	1	4/44 (9.1%)	7	7/51 (13.7%)	10
Otitis media	3/25 (12%)	3	3/16 (18.8%)	3	2/44 (4.5%)	3	4/51 (7.8%)	6
Sinusitis	3/25 (12%)	4	0/16 (0%)	0	1/44 (2.3%)	1	4/51 (7.8%)	8
Metabolism and nutrition disorders
Hypoglycemia	1/25 (4%)	1	2/16 (12.5%)	4	3/44 (6.8%)	3	9/51 (17.6%)	10
Musculoskeletal and connective tissue disorders
Pain in extremity	1/25 (4%)	1	1/16 (6.3%)	1	3/44 (6.8%)	5	6/51 (11.8%)	7
Nervous system disorders
Headache	4/25 (16%)	9	8/16 (50%)	16	13/44 (29.5%)	30	21/51 (41.2%)	35
Respiratory, thoracic and mediastinal disorders
Cough	4/25 (16%)	7	4/16 (25%)	6	10/44 (22.7%)	17	7/51 (13.7%)	7
Nasal congestion	0/25 (0%)	0	4/16 (25%)	5	5/44 (11.4%)	6	5/51 (9.8%)	7
Pharyngolaryngeal pain	0/25 (0%)	0	3/16 (18.8%)	3	4/44 (9.1%)	4	4/51 (7.8%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Each investigator may publish or report data from their own subjects. The trial data in aggregate are the property of Tercica, Inc. and may not be published without permission of Tercica, Inc. Tercica, Inc. will be the final arbitrator of issues relating to the publication or presentation of the aggregate data.