Growth Hormone Treatment for the Prevention of Short Stature in Young Girls With Turner Syndrome Before the Age of 4 Years

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01066052
• Collaborator: (none)
• Enrollment: 115
• Location: 1
• Arms: 2
• Actual Duration (Months): 222
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the efficacy and safety of recombinant human growth hormone (r-hGH) treatment in girls with Turner Syndrome under the age of 4 years. After 4 years of treatment, height in these girls will be compared with an historical control group of untreated girls with Turner Syndrome, matched for age and height at baseline.

Condition or Disease	Intervention/Treatment	Phase
Turner's Syndrome	Drug: r-hGH	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Collaborative Study to Assess the Effects of Treatment With Recombinant Growth Hormone Saizen® in the Prevention of Short Stature in Young Girls Suffering From Turner Syndrome Before the Age of 4 Years. Original French Title: Etude Collaborative Pour apprécier Les Effets du Traitement Par l'Hormone de Croissance Recombinante SAIZEN® Dans le Retard de Croissance de la Fillette Atteinte de Syndrome de Turner Avant l'âge de 4 Ans
• Actual Study Start Date: Feb 29, 1992
• Actual Primary Completion Date: Mar 31, 1999
• Actual Study Completion Date: Aug 31, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: r-hGH Participants (girls) will receive r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received will depend on participants' baseline height standard deviation score (SDS) relative to the general population standard: participants with a height SDS of -2 standard deviation (SD) or lower will receive 0.05 milligrams per kilogram (mg/kg) per day r-hGH and those with a height SDS between -1 and -2 SD will receive 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants will receive a fixed dose of 0.05 mg/kg per day for a further 2 years.	Drug: r-hGH; Subcutaneous administration.; Other Names: Saizen®
No Intervention: Historical Control This arm will include matching (age and height) historical control participants (girls) with turner syndrome, who were born between 1961 and 1990 and were untreated.

Outcome Measures

Primary Outcome Measures

1. Height SDS at Year 4 [Year 4]

   Height SDS was calculated as height minus reference mean height divided by standard deviation of the reference population. Height SDS reflects the height relative to a reference population of the same age and gender.

Secondary Outcome Measures

1. Number of Participants With Abnormal Glycated Hemoglobin (HbA1c) Levels [Baseline up to Year 2]

   HbA1c develops when hemoglobin, a protein within red blood cells that carries oxygen throughout the body, joins with glucose in the blood, becoming glycated. The higher the level of glucose in the blood, the higher the level of HbA1c is detectable on red blood cells. The normal range for HbA1c is 4 percent (%) to 5.9%. Number of participants, who had abnormal HbA1c levels any time during the assessment, were reported.

2. Difference Between Bone Age (BA) and Chronological Age (CA) (BA-CA) [Baseline, Year 1, Year 2]

   BA was determined using left wrist and hand X-ray. CA was determined using the date of birth. Difference of BA and CA (BA-CA) was reported.

3. Number of Participants With Anti r-hGH Antibodies [Baseline up to Year 2]

4. Number of Participants With Abnormal Insulin-Like Growth Factor 1 (IGF1) Levels [Baseline up to Year 2]

   The normal range for IGF1 levels is 45 to 117 nanogram per milliliter (ng/mL) for girls aged less than (<) 3 years and 80 to 236 ng/mL for girls aged 3 to 6 years. Values outside the normal range were considered abnormal. Number of participants, who had abnormal IGF1 levels any time during the assessment, were reported.

5. Number of Participants Who Reached Normal Height at Year 4 [Year 4]

   Participants with normal height were those who attained a height which was within +/- 2 height SDS of reference population standard. Height SDS was calculated as height minus reference mean height divided by standard deviation of the reference population. Height SDS reflects the height relative to a reference population of the same age and gender.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 4 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Young girls with turner syndrome proved by karyotype

• Growth hormone secretion confirmed with ornithin stimulation test

• Normal glucidic metabolism confirmed by assessment of HbA1c

• None associated severe pathology which could have impact on growth (i.e. renal insufficiency, decompensated heart failure)

• No previous or associated treatment with anabolic or sexual steroids

• Known parental height

Exclusion Criteria:

• Severe associated pathology with impact on growth

• Concomitant treatment with impact on growth

• Previous or associated treatment with anabolic steroids

• Associated growth hormone deficiency

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hôpital Robert Debré	Paris		France	75935

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01066052
• Other Study ID Numbers: GF 5834
• First Posted: Feb 10, 2010
• Last Update Posted: Dec 14, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Merck KGaA, Darmstadt, Germany: Growth hormone; Turner syndrome; r-hGH; early treatment
• Additional relevant MeSH terms: Dwarfism; Turner Syndrome; Gonadal Dysgenesis; Syndrome

Study Results

Participant Flow

Arm/Group Title	Recombinant Human Growth Hormone (r-hGH)	Historical Control
Arm/Group Description	Participants (girls) received r-hGH (Saizen®) as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height standard deviation score (SDS) relative to the general population standard: participants with a height SDS of -2 standard deviation (SD) or lower received 0.05 milligrams per kilogram (mg/kg) per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.	This arm included matching (age and height) historical control participants (girls) with turner syndrome, who were born between 1961 and 1990 and were untreated.
Period Title: Overall Study
STARTED	64	51
Treated	61	0
COMPLETED	61	51
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	r-hGH	Historical Control	Total
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.	This arm included matching (age and height) historical control participants (girls) with turner syndrome, who were born between 1961 and 1990 and were untreated.	Total of all reporting groups
Overall Participants	64	51	115
Age (Count of Participants)
<=18 years	64 100%	51 100%	115 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	64 100%	51 100%	115 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Height SDS at Year 4
Description	Height SDS was calculated as height minus reference mean height divided by standard deviation of the reference population. Height SDS reflects the height relative to a reference population of the same age and gender.
Time Frame	Year 4

Outcome Measure Data

Analysis Population Description

All treated participants from r-hGH arm and all participants from Historical Control arm.

Arm/Group Title	r-hGH	Historical Control
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.	This arm included matching (age and height) historical control participants (girls) with turner syndrome, who were born between 1961 and 1990 and were untreated.
Measure Participants	61	51
Mean (Standard Deviation) [standard deviation score]	-1.35 (0.86)	-2.44 (0.73)

2. Secondary Outcome

Title	Number of Participants With Abnormal Glycated Hemoglobin (HbA1c) Levels
Description	HbA1c develops when hemoglobin, a protein within red blood cells that carries oxygen throughout the body, joins with glucose in the blood, becoming glycated. The higher the level of glucose in the blood, the higher the level of HbA1c is detectable on red blood cells. The normal range for HbA1c is 4 percent (%) to 5.9%. Number of participants, who had abnormal HbA1c levels any time during the assessment, were reported.
Time Frame	Baseline up to Year 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-hGH
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.
Measure Participants	61
Number [participants]	1 1.6%

3. Secondary Outcome

Title	Difference Between Bone Age (BA) and Chronological Age (CA) (BA-CA)
Description	BA was determined using left wrist and hand X-ray. CA was determined using the date of birth. Difference of BA and CA (BA-CA) was reported.
Time Frame	Baseline, Year 1, Year 2

Outcome Measure Data

Analysis Population Description

All treated participants from r-hGH arm. This outcome measure was only planned in the r-hGH arm. Overall number of participants analyzed = participants with available data for this outcome; number analyzed = participants with available data for this outcome at specified timepoint.

Arm/Group Title	r-hGH
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.
Measure Participants	60
Baseline	-8.9 (7.5)
Year 1	-8.7 (6.5)
Year 2	-8.1 (7.8)

4. Secondary Outcome

Title	Number of Participants With Anti r-hGH Antibodies
Time Frame	Baseline up to Year 2

Outcome Measure Data

Analysis Population Description

Data for this outcome was not collected from any participant.

Arm/Group Title	r-hGH	Historical Control
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.	This arm included matching (age and height) historical control participants (girls) with turner syndrome, who were born between 1961 and 1990 and were untreated.
Measure Participants	0	0

5. Secondary Outcome

Title	Number of Participants With Abnormal Insulin-Like Growth Factor 1 (IGF1) Levels
Description	The normal range for IGF1 levels is 45 to 117 nanogram per milliliter (ng/mL) for girls aged less than (<) 3 years and 80 to 236 ng/mL for girls aged 3 to 6 years. Values outside the normal range were considered abnormal. Number of participants, who had abnormal IGF1 levels any time during the assessment, were reported.
Time Frame	Baseline up to Year 2

Outcome Measure Data

Analysis Population Description

All treated participants from r-hGH arm. This outcome measure was only planned in the r-hGH arm.

Arm/Group Title	r-hGH
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.
Measure Participants	61
Number [participants]	46 71.9%

6. Secondary Outcome

Title	Number of Participants Who Reached Normal Height at Year 4
Description	Participants with normal height were those who attained a height which was within +/- 2 height SDS of reference population standard. Height SDS was calculated as height minus reference mean height divided by standard deviation of the reference population. Height SDS reflects the height relative to a reference population of the same age and gender.
Time Frame	Year 4

Outcome Measure Data

Analysis Population Description

All treated participants from r-hGH arm. This outcome measure was only planned in the r-hGH arm.

Arm/Group Title	r-hGH
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.
Measure Participants	61
Number [participants]	49 76.6%

Adverse Events

Adverse Event Reporting Description	Adverse events were collected only from participants treated with r-hGH. No adverse event data collection occurred in Historical Control arm.
Arm/Group Title	r-hGH
Arm/Group Description	Participants (girls) received r-hGH as a subcutaneous injection administered by a parent in the evening. During Years 1-2, the dose of r-hGH received depended on participants' baseline height SDS relative to the general population standard: participants with a height SDS of -2 SD or lower received 0.05 mg/kg per day r-hGH and those with a height SDS between -1 and -2 SD received 0.035 mg/kg per day r-hGH. After 2 years of treatment, all participants received a fixed dose of 0.05 mg/kg per day for a further 2 years.
All Cause Mortality
	r-hGH
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	r-hGH
	Affected / at Risk (%)	# Events
Total	8/61 (13.1%)
Congenital, familial and genetic disorders
Chronic persistent cytolysis	1/61 (1.6%)
Immune system disorders
Immunoglobulin G4 deficiency	1/61 (1.6%)
Nervous system disorders
Serious otitis	1/61 (1.6%)
Respiratory, thoracic and mediastinal disorders
Arterial hypertension	1/61 (1.6%)
Skin and subcutaneous tissue disorders
Measles	1/61 (1.6%)
Surgical and medical procedures
Trauma leading to scalp surgery	1/61 (1.6%)
Surgery to remove large mass (meningocele/benign cyst)	1/61 (1.6%)
Transtympanic drainage tube placement	1/61 (1.6%)
Tonsillectomy/adenoidectomy	1/61 (1.6%)
Vascular disorders
Urethral reflux	1/61 (1.6%)
Other (Not Including Serious) Adverse Events
	r-hGH
	Affected / at Risk (%)	# Events
Total	47/61 (77%)
Infections and infestations
Infection	47/61 (77%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.