Phoenix: Somatropin + Leuprorelin vs Somatropin Alone in Pubertal Children With Idiopathic Short Stature

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00355030
• Collaborator: (none)
• Enrollment: 91
• Locations: 19
• Arms: 2
• Duration (Months): 109
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The present randomized trial was initially intended to study the benefits of a combined treatment with growth hormone (GH) and a gonadotropin-releasing hormone (GnRH) agonist for pubertal children with idiopathic short stature. However, treatments were stopped in January 2012 at the request of the French drug agency. Therefore, a protocol amendment divided the study in two study periods.

Study Period 1 involved combined treatment with somatropin and leuprorelin or treatment with somatropin alone. Participants from France who participated in this Period 1 of the study were asked to participate in a long term safety follow up defined as a Period 2 of the study. Participants from the Netherlands were offered participation in Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS, clinicaltrials.gov Identifier: NCT01088412) for long term safety follow up independent of this study.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Short Stature (ISS)	Drug: somatropin; Drug: leuprorelin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Somatropin in Combination With Leuprorelin Compared to Somatropin Alone in Pubertal Children With Idiopathic Short Stature
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: somatropin; 0.05 mg/kg/day; Other Names: LY137998 Humatrope ; Drug: leuprorelin; 11.25 mg/3 months
Experimental: 2	Drug: somatropin; 0.05 mg/kg/day; Other Names: LY137998 Humatrope

Outcome Measures

Primary Outcome Measures

1. Number of Participants With One or More Drug-related Adverse Events [Baseline through End of Study (up to 9 years)]

   A drug-related AE was an AE that occurred postdose or was present predose and became more severe postdose and was considered to be related to study treatment. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.

2. Adult Height Standard Deviation Score (SDS) [Baseline through End of Study (up to 9 years)]

   The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.

Secondary Outcome Measures

1. Height Velocity [Baseline through End of Study (up to 9 years)]

   Height velocity is the difference between 2 height measurements, divided by years elapsed between measurements.

2. Height SDS [Baseline through End of Study (up to 9 years)]

   SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.

3. Difference Between Adult Height SDS and Target Height SDS [Baseline through End of Study (up to 9 years)]

   This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of target height [calculated as (mother's height (SDS) + father's height (SDS))/2] for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.

4. Difference Between Adult Height SDS and Baseline Predicted Height SDS [Baseline through End up Study (up to 9 years)]

   This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of baseline predicted height [calculated using the Bayley-Pinneau method based on height and bone age] for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.

5. Difference Between Adult Height SDS and Baseline Height SDS [Baseline through End up Study (up to 9 years)]

   This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of baseline height for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.

6. Percentage of Children With Normal Adult Height SDS [Baseline through End of Study (up to 9 years)]

   Percentage of children with normal adult height SDS (greater than -2 SDS and less than +2 SDS)

7. Bone Age [Baseline through End of Study (up to 9 years)]

   Bone age measured using the X-Ray of left hand and wrist.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 171 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• male or female children with ISS

• age greater than or equal to 8 years and less than or equal to 12 years and 3 months for girls and greater than or equal to 9 years and less than or equal to 14 years and 3 months for boys

• bone age less than or equal to 12.0 years for girls and less than or equal to 14.0 years for boys based on a central reading of an X-ray of the left hand and wrist

• Pubertal stage B2 and B3 for girls based on the Tanner method

• Pubertal stage G2 and G3 for boys based on the Tanner method

Exclusion Criteria:

• Growth hormone deficiency (GHD)

• Insulin-like growth factor-I levels greater than 3 SDS

• Chromosomal abnormality diagnosed locally on a karyotype. For girls, the karyotype to eliminate a Turner syndrome, is mandatory

• Small for gestational age (SGA)

• Has reached menarche (had her first menstrual period)

• Have any significant concomitant disease that is likely to interfere with growth or with the study, or is a known contraindication to Growth Hormone treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Amiens		France	80084
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Besancon		France	25030
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bordeaux		France	33076
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Boulogne		France	92100
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Le Havre		France	76083
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lille		France	59037
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lyon		France	69322
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Marseille		France	13385
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Nice		France	06200
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Paris		France	75743
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Reims		France	51092
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rennes		France	35056
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rouen		France	76036
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Saint-Etienne		France	42055
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Strasbourg		France	67 098
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tarbes		France	65000
17	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Toulouse		France	31026
18	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Nijmegen		Netherlands	6525 GM
19	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rotterdam		Netherlands	3015 GD

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00355030
• Other Study ID Numbers: 9861; B9R-FP-GDGI
• First Posted: Jul 20, 2006
• Last Update Posted: Sep 30, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Dwarfism; Leuprolide

Study Results

Participant Flow

Arm/Group Title	Somatropin and Leuprorelin: Experimental Arm 1	Somatropin: Experimental Arm 2
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Period Title: Study Period 1 Treatment
STARTED	46	45
Received At Least One Dose of Study Drug	45	43
COMPLETED	1	1
NOT COMPLETED	45	44
Period Title: Study Period 1 Treatment
STARTED	20	19
COMPLETED	19	17
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Somatropin and Leuprorelin	Somatropin	Total
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only	Total of all reporting groups
Overall Participants	45	43	88
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.1 (1.41)	12.1 (1.33)	12.1 (1.36)
Sex: Female, Male (Count of Participants)
Female	26 57.8%	20 46.5%	46 52.3%
Male	19 42.2%	23 53.5%	42 47.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	4 8.9%	2 4.7%	6 6.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2.2%	0 0%	1 1.1%
White	38 84.4%	40 93%	78 88.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 4.4%	1 2.3%	3 3.4%
Region of Enrollment (participants) [Number]
Netherlands	6 13.3%	5 11.6%	11 12.5%
France	39 86.7%	38 88.4%	77 87.5%
Standing Height SDS (Standard Deviation Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Standard Deviation Score]	-2.5 (0.45)	-2.5 (0.46)	-2.5 (.045)
Standing Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	131.6 (6.72)	131.6 (5.78)	131.6 (6.24)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With One or More Drug-related Adverse Events
Description	A drug-related AE was an AE that occurred postdose or was present predose and became more severe postdose and was considered to be related to study treatment. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug in Period 1 and all participants who entered Period 2 (safety population).

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	46	45
Study Period 1 (n=46, 45)	42 93.3%	38 88.4%
Study Period 2 (n=20, 19)	11 24.4%	9 20.9%

2. Primary Outcome

Title	Adult Height Standard Deviation Score (SDS)
Description	The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug with at least one follow up visit.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	19	16
Mean (Standard Deviation) [standard deviation score]	-1.8 (0.53)	-1.9 (0.77)

3. Secondary Outcome

Title	Height Velocity
Description	Height velocity is the difference between 2 height measurements, divided by years elapsed between measurements.
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug with at least one follow up visit. The safety follow up participants did not reach final height at end of Period 1 unless final height is noted for participants that reached final height at the end of Period 1.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	45	43
Randomization (n=45, 43)	7.8 (6.92)	7.4 (6.03)
Month 3 (n=45, 43)	9.9 (3.94)	10.6 (3.53)
Month 6 (n=45, 42)	8.1 (2.31)	9.7 (2.80)
Month 12 (n=44, 42)	7.0 (1.64)	8.8 (2.33)
Month 18 (n=42, 42)	6.6 (1.68)	8.4 (2.64)
Month 24 (n=37, 41)	4.9 (1.33)	7.8 (3.36)
Month 30 (n=25, 25)	6.2 (2.09)	5.8 (2.93)
Month 36 (n=18, 19)	6.6 (3.25)	3.5 (2.71)
Month 42 (n=13, 14)	5.7 (1.94)	3.7 (2.17)
Month 48 (n=7, 8)	5.4 (2.27)	2.9 (2.73)
Month 54 (n=1, 1)	6.3 (0)	7.1 (0)
Safety follow up 6 months (n=16, 9)	4.6 (2.08)	4.5 (2.45)
Safety follow up 12 months(n=15, 8)	2.9 (2.37)	2.3 (1.43)
Safety follow up 18 months (n=12, 4)	3.3 (1.69)	1.2 (1.20)
Safety follow up 24 months (n=9, 1)	2.0 (1.32)	2.5 (0)
Safety follow up 36 months (n=5, 0)	1.3 (0.53)	0 (0)
Safety follow up 42 months (n=2, 0)	2.1 (2.45)	0 (0)
Safety follow up 12 months (final height)(n=18,14)	0.5 (0.86)	0.8 (1.59)
Safety follow up 24 months (final height) (n=7,10)	0.3 (0.77)	0.3 (0.97)
Safety follow up 36 months (final height) (n=3,7)	0.9 (0.78)	0.3 (0.60)

4. Secondary Outcome

Title	Height SDS
Description	SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug with at least one follow up visit. The safety follow up participants did not reach final height at end of Period 1 unless final height is noted for participants that reached final height at the end of Period 1.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	45	43
Randomization (n=45, 43)	-2.5 (0.45)	-2.5 (0.46)
Month 3 (n=45, 43)	-2.4 (0.42)	-2.4 (0.47)
Month 6 (n=45, 42)	-2.3 (0.48)	-2.2 (0.52)
Month 12 (n=44, 42)	-2.2 (0.50)	-2.0 (0.57)
Month 18 (n=42, 42)	-2.2 (0.53)	-1.9 (0.63)
Month 24 (n=37, 41)	-2.3 (0.58)	-1.8 (0.67)
Month 30 (n=25, 25)	-2.2 (0.63)	-2.0 (0.58)
Month 36 (n=18, 19)	-2.0 (0.65)	-2.0 (0.68)
Month 42 (n=13, 14)	-1.8 (0.68)	-1.9 (0.66)
Month 48 (n=7, 8)	-1.6 (0.52)	-1.9 (0.65)
Month 54 (n=1, 1)	-1.0 (0)	-1.7 (0)
Safety follow up 6 months (n=16, 9)	-2.1 (0.65)	-1.7 (0.77)
Safety follow up 12 months(n=15, 8)	-1.9 (0.55)	-1.7 (0.77)
Safety follow up 18 months (n=12, 4)	-1.9 (0.63)	-1.9 (0.78)
Safety follow up 24 months (n=9, 1)	-1.9 (0.46)	-1.2 (0)
Safety follow up 36 months (n=5, 0)	-1.9 (0.67)	0 (0)
Safety follow up 42 months (n=2, 0)	-2.4 (0.18)	0 (0)
Safety follow up 12 months (final height)(n=18,14)	-1.9 (0.46)	-1.8 (0.71)
Safety follow up 24 months (final height) (n=7,10)	-1.6 (0.56)	-2.0 (0.79)
Safety follow up 36 months (final height) (n=3,7)	-1.2 (0.90)	-2.2 (0.94)

5. Secondary Outcome

Title	Difference Between Adult Height SDS and Target Height SDS
Description	This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of target height [calculated as (mother's height (SDS) + father's height (SDS))/2] for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received who reached final height.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	16	15
Mean (Standard Deviation) [standard deviation score]	-0.6 (0.89)	-1.2 (0.80)

6. Secondary Outcome

Title	Difference Between Adult Height SDS and Baseline Predicted Height SDS
Description	This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of baseline predicted height [calculated using the Bayley-Pinneau method based on height and bone age] for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.
Time Frame	Baseline through End up Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received who reached final height.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	18	16
Mean (Standard Deviation) [standard deviation score]	1.1 (0.96)	1.2 (0.70)

7. Secondary Outcome

Title	Difference Between Adult Height SDS and Baseline Height SDS
Description	This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of baseline height for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height.
Time Frame	Baseline through End up Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received who reached final height.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	19	16
Mean (Standard Deviation) [standard deviation score]	0.6 (0.59)	0.6 (0.67)

8. Secondary Outcome

Title	Percentage of Children With Normal Adult Height SDS
Description	Percentage of children with normal adult height SDS (greater than -2 SDS and less than +2 SDS)
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug with at least one follow up visit.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	45	43
Number [percentage of participants]	26.7 59.3%	25.6 59.5%

9. Secondary Outcome

Title	Bone Age
Description	Bone age measured using the X-Ray of left hand and wrist.
Time Frame	Baseline through End of Study (up to 9 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug with at least one follow up visit. The safety follow up participants did not reach final height at end of Period 1 unless final height is noted for participants that reached final height at the end of Period 1.

Arm/Group Title	Somatropin and Leuprorelin	Somatropin
Arm/Group Description	0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first).	0.05mg/kg/day subcutaneous somatropin only
Measure Participants	45	43
Randomization (n=45, 43)	10.8 (1.58)	11.0 (1.45)
Month 12 (n=40, 41)	11.7 (1.59)	12.1 (1.12)
Month 24 (n=34, 37)	12.4 (1.32)	13.4 (1.09)
Month 36 (n=18, 18)	13.3 (1.49)	14.5 (1.64)
Month 48 (n=7, 8)	14.8 (1.33)	15.4 (1.27)
Safety follow up 6 months (n=16, 7)	14.1 (1.11)	14.9 (0.81)
Safety follow up 18 months (n=12, 3)	15.2 (1.25)	17.0 (1.00)
Safety follow up 36 months (n=5, 0)	15.7 (1.04)	0 (0)
Safety follow up 12 months (final height)(n=18,14)	19.6 (14.53)	16.3 (1.27)

Adverse Events

Arm/Group Title	Somatropin and Leuprorelin		Somatropin
Arm/Group Description	Somatropin and leuprorelin n=46		Somatropin n=45
All Cause Mortality
	Somatropin and Leuprorelin		Somatropin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Somatropin and Leuprorelin		Somatropin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/46 (26.1%)		7/45 (15.6%)
Congenital, familial and genetic disorders
Congenital genital malformation	0/46 (0%)	0	1/45 (2.2%)	1
Thyroglossal cyst	1/46 (2.2%)	1	0/45 (0%)	0
General disorders
Complication of device removal	1/46 (2.2%)	1	0/45 (0%)	0
Infections and infestations
Appendiceal abscess	1/46 (2.2%)	1	0/45 (0%)	0
Appendicitis	2/46 (4.3%)	2	2/45 (4.4%)	2
Gastroenteritis	0/46 (0%)	0	1/45 (2.2%)	1
Peritonitis	1/46 (2.2%)	1	0/45 (0%)	0
Viral infection	0/46 (0%)	0	1/45 (2.2%)	1
Injury, poisoning and procedural complications
Fall	1/46 (2.2%)	1	0/45 (0%)	0
Fracture	1/46 (2.2%)	1	0/45 (0%)	0
Joint dislocation	1/46 (2.2%)	1	0/45 (0%)	0
Radius fracture	1/46 (2.2%)	1	0/45 (0%)	0
Road traffic accident	1/46 (2.2%)	1	0/45 (0%)	0
Upper limb fracture	1/46 (2.2%)	1	0/45 (0%)	0
Wrist fracture	1/46 (2.2%)	1	0/45 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Histiocytosis	1/46 (2.2%)	1	0/45 (0%)	0
Nervous system disorders
Migraine	1/46 (2.2%)	1	0/45 (0%)	0
Psychiatric disorders
Agitation	0/46 (0%)	0	1/45 (2.2%)	1
Intentional self-injury	0/46 (0%)	0	1/45 (2.2%)	1
Mental disorder	0/46 (0%)	0	1/45 (2.2%)	1
Suicidal ideation	0/46 (0%)	0	1/45 (2.2%)	1
Renal and urinary disorders
Nephrolithiasis	0/46 (0%)	0	1/45 (2.2%)	1
Renal colic	1/46 (2.2%)	1	0/45 (0%)	0
Other (Not Including Serious) Adverse Events
	Somatropin and Leuprorelin		Somatropin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/46 (89.1%)		36/45 (80%)
Ear and labyrinth disorders
Ear pain	1/46 (2.2%)	5	3/45 (6.7%)	4
Endocrine disorders
Hypothyroidism	1/46 (2.2%)	1	3/45 (6.7%)	3
Gastrointestinal disorders
Abdominal pain	4/46 (8.7%)	4	7/45 (15.6%)	18
Abdominal pain upper	3/46 (6.5%)	11	4/45 (8.9%)	10
Diarrhoea	3/46 (6.5%)	14	3/45 (6.7%)	3
Nausea	3/46 (6.5%)	7	2/45 (4.4%)	3
Toothache	3/46 (6.5%)	7	0/45 (0%)	0
Vomiting	3/46 (6.5%)	5	3/45 (6.7%)	5
General disorders
Injection site pain	8/46 (17.4%)	22	0/45 (0%)	0
Pyrexia	4/46 (8.7%)	4	5/45 (11.1%)	6
Immune system disorders
Hypersensitivity	3/46 (6.5%)	3	0/45 (0%)	0
Infections and infestations
Bronchitis	3/46 (6.5%)	4	2/45 (4.4%)	2
Cystitis	3/46 (6.5%)	3	0/45 (0%)	0
Ear infection	4/46 (8.7%)	4	5/45 (11.1%)	8
Gastroenteritis	11/46 (23.9%)	15	6/45 (13.3%)	9
Influenza	15/46 (32.6%)	17	9/45 (20%)	16
Nasopharyngitis	19/46 (41.3%)	36	8/45 (17.8%)	10
Rhinitis	5/46 (10.9%)	5	3/45 (6.7%)	11
Tonsillitis	6/46 (13%)	9	5/45 (11.1%)	12
Tracheitis	2/46 (4.3%)	2	3/45 (6.7%)	3
Injury, poisoning and procedural complications
Ligament sprain	3/46 (6.5%)	3	1/45 (2.2%)	1
Metabolism and nutrition disorders
Vitamin d deficiency	3/46 (6.5%)	3	0/45 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	7/46 (15.2%)	11	4/45 (8.9%)	6
Pain in extremity	4/46 (8.7%)	4	1/45 (2.2%)	1
Scoliosis	4/46 (8.7%)	4	1/45 (2.2%)	1
Nervous system disorders
Headache	21/46 (45.7%)	51	16/45 (35.6%)	37
Respiratory, thoracic and mediastinal disorders
Cough	3/46 (6.5%)	4	6/45 (13.3%)	15
Epistaxis	3/46 (6.5%)	4	2/45 (4.4%)	2
Oropharyngeal pain	5/46 (10.9%)	6	4/45 (8.9%)	6
Skin and subcutaneous tissue disorders
Acne	2/46 (4.3%)	2	5/45 (11.1%)	7

Limitations/Caveats

No statistical analyses was performed after the early treatment termination. All data represented is descriptive statistics only and no confirmatory conclusions can be drawn from this study.

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Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.