GDCT: Somatropin Treatment to Final Height in Turner Syndrome

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00191113
• Collaborator: (none)
• Enrollment: 154
• Locations: 14
• Arms: 2
• Duration (Months): 225.9
• Patients Per Site: 11
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

A randomized, controlled trial in girls with Turner syndrome at least 7 years old and younger than 13 at study entry, to determine the efficacy and safety of Humatrope (somatropin) treatment in promoting linear growth to final height.

Condition or Disease	Intervention/Treatment	Phase
Turner Syndrome	Drug: Somatropin; Drug: Ethinyl estradiol; Drug: Medroxyprogesterone acetate	Phase 3

Detailed Description

A randomized, controlled trial of Humatrope (somatropin) treatment in girls with Turner syndrome at least 7 years old and younger than 13 at study entry.

Core study objectives are to determine the efficacy of Humatrope in promoting linear growth to final height in girls with Turner syndrome, and to assess the safety of this treatment. Core study completion criteria (protocol final height) are that the patient has both a height velocity < 2 cm per year and a bone age of 14 years or greater.

Addendum 1 provides the option of Humatrope treatment to patients who were randomized to the Control arm of the Core study and who discontinued from the study on or after December 19, 1997.

Addendum 2 objectives are: 1) to collect true final height data; 2) to evaluate hearing, tympanic membrane function and other specific areas of interest with respect to the safety of growth hormone therapy in Turner syndrome; 3) to evaluate pancreatic beta cell function (glucose metabolism) in patients previously enrolled in the Core study.

Addendum 3 objective is to determine the parental origin of the retained X chromosome of an appropriate subset of patients currently or previously enrolled in the Core study, and to determine whether this parental origin holds any predictive value for spontaneous growth or for response to growth hormone therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 154 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Humatrope Treatment to Final Height in Turner's Syndrome
• Study Start Date: Feb 1, 1989
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Control Control arm; untreated with Humatrope. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).	Drug: Ethinyl estradiol; escalating doses 2.5-20.0 mcg tablets daily after age 13 and at least one year on study, continuing until Core study completion criteria are met.; Drug: Medroxyprogesterone acetate; 10 mg tablets, ten days monthly, after age 15, continuing until Core study completion criteria are met.
Experimental: Humatrope Humatrope (0.05 mg/kg/dose) by subcutaneous injection 6 times per week. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).	Drug: Somatropin; 0.05 mg/kg/dose by subcutaneous injection 6 times per week, until Core study completion criteria are met (protocol final height).; Other Names: Humatrope Growth hormone ; Drug: Ethinyl estradiol; escalating doses 2.5-20.0 mcg tablets daily after age 13 and at least one year on study, continuing until Core study completion criteria are met.; Drug: Medroxyprogesterone acetate; 10 mg tablets, ten days monthly, after age 15, continuing until Core study completion criteria are met.

Outcome Measures

Primary Outcome Measures

1. Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Change From Baseline to Last Measurement, As Randomized Population [Baseline, and end of 4-year addendum]

   Value analyzed is change from baseline to the most mature height measurement available. The terms Standard Deviation Score (SDS) and National Center for Health Statistics (NCHS) were defined in baseline characteristics. Greater height SDS values indicate greater height; positive values of change from baseline indicate increased height.

2. Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Last Measurement After Attainment of Final Height [at completion of core study, or at end of 4-year addendum]

   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 [NCHS] uses the NCHS US general female population reference height values for age (Kuczmarski RJ et al. 2000) as the population mean and standard deviation. Calculation of Height SDS is provided in Height SDS [Lyon] description (Baseline). Since data reported by Kuczmarski RJ et al provides US general female population standards, values of Height SDS [NCHS] for untreated patients with Turner syndrome tend to be below zero e.g, -2.0 to -4.0 SDS.

Secondary Outcome Measures

1. Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Change From Baseline, As-Treated Population [every 3 months during core study, and at start and end of 4-year addendum]

   Value analyzed is change from baseline to the most mature height measurement available. The terms Standard Deviation Score (SDS) and National Center for Health Statistics (NCHS) were defined in baseline characteristics. Greater height SDS values indicate greater height; positive values of change from baseline indicate increased height.

2. Height (Centimeters [cm]) [every 3 months during core study, and at start and end of 4-year addendum]

   Most mature measurement available, at or after attainment of Final Height.

3. Number of Participants With an Abnormal Pure Tone Audiometry, Audiologist Assessment [at completion of core study or beginning of addendum]

4. Number of Participants With Abnormal Speech Audiometry, Audiologist Assessment [at completion of core study or beginning of addendum]

5. Number of Participants With Abnormal Impedance Tympanometry, Audiologist Assessment [at completion of core study or beginning of addendum]

6. Number of Participants With Hearing Loss, Audiologist Assessment [at completion of core study or beginning of addendum]

   Sensorineural Hearing Loss (SNHL)=air conduction threshold >20 dB HL and air-bone gap ≤10 dB HL; Conductive Hearing Loss (CHL)= air conduction threshold >20 dB HL, bone conduction threshold ≤20 dB HL and air-bone gap >10 dB HL; Mixed Hearing Loss (MHL) = evidence of SNHL as defined above and CHL as defined above, in the same ear; Unspecified Hearing Loss (UHL)= abnormal hearing with none of SNHL, CHL, or MHL present.

7. Fasting Glucose, Change From Baseline [At core study baseline, and at end of 4-year addendum]

   Change from core study baseline to addendum 2 maximum.

8. Maximum Fasting Glucose Value [At start and through end of 4-year addendum (up to an additional 2 years)]

   Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years.

9. Number of Participants With Any Abnormal Fasting Glucose Value [At start and through end of 4-year addendum]

   Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Fasting Glucose=Fasting Glucose >=100 milligrams per deciliter (mg/dL).

10. Maximum Fasting Insulin Values [At start and through end of 4-year addendum (up to an additional 2 years)]

    Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years.

11. Number of Participants With Any Abnormal Fasting Insulin Value [At start and through end of 4-year addendum]

    Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Fasting Insulin = Fasting Insulin >=35 micro International Units per milliliter (uIU/mL).

12. Minimum Fasting Glucose/Insulin Ratio Values [At start and through end of 4-year addendum (up to an additional 2 years)]

    Minimum measured value over addendum. In special cases an additional measurement is taken at 2 years.

13. Number of Participants With Any Abnormal Fasting Glucose/Insulin Ratio Value [At start and through end of 4-year addendum]

    Indicates if patient had any measured value below threshold of normality at any visit during addendum. Abnormal Fasting Glucose/Insulin Ratio = Fasting Glucose/Insulin Ratio <=4.5 milligrams per 10^-4 Units (mg/10^-4U).

14. Glycosylated Hemoglobin, Change From Baseline [At core study baseline, and at end of 4-year addendum]

    Change from core study baseline to addendum 2 maximum.

15. Maximum Glycosylated Hemoglobin [At start and through end of 4-year addendum (up to an additional 2 years)]

    Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years.

16. Number of Participants With Any Abnormal Glycosylated Hemoglobin (HbA1c) Value [At start and through end of 4-year addendum]

    Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Glycosylated Hemoglobin = HbA1c ≥6.8% (up until 11-May-1998); and then HbA1c ≥6.1% (from 19-May-1998 onwards).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 13 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• girl with Turner syndrome

• prepubertal, Tanner stage I breast

• height velocity less than 6 cm/year and height less than or equal to the tenth percentile for sex and age in general population

• at least 6 months (preferably 12 months) of accurate height measurements available for calculation of pre-study height velocity

• if thyroxine deficient, to have received replacement therapy, and for six months prior to enrollment have had normal thyroid function tests

Exclusion Criteria:

• prior treatment with growth hormone

• presence of a Y component in karyotype with gonads in situ

• diabetes mellitus

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 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Calgary	Alberta	Canada	T2T 5C7
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Edmonton	Alberta	Canada	T6G 2B7
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Vancouver	British Columbia	Canada	V6H 3V4
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Winnipeg	Manitoba	Canada	R3E 0Z2
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Halifax	Nova Scotia	Canada	B3J 3G9
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hamilton	Ontario	Canada	L8S 3Z5
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kingston	Ontario	Canada	K7L 3N6
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	London	Ontario	Canada	K7L 3N6
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Ottawa	Ontario	Canada	K1H 8L1
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Toronto	Ontario	Canada	M5G 1X8
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Montreal	Quebec	Canada	H3H 1P3
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Montreal	Quebec	Canada	H3T 1C5
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Sainte-Foy	Quebec	Canada	G1V 4G2
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Sherbrooke	Quebec	Canada	J1G 2E8

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

• Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL. CDC growth charts: United States. Adv Data. 2000 Jun 8;(314):1-27.
• Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child. 1985 Oct;60(10):932-5.

• ClinicalTrials.gov Identifier: NCT00191113
• Other Study ID Numbers: 817/4419; #817 B9R-CA-GDCT Core study; #4419 GDCT/1 Addenda
• First Posted: Sep 19, 2005
• Last Update Posted: Jan 27, 2010
• Last Verified: Dec 1, 2009

• Keywords provided by , ,: syndrome; Turner; Turner's; height; growth; growth hormone; somatropin; short stature; short; hearing; glucose metabolism
• Additional relevant MeSH terms: Turner Syndrome; Gonadal Dysgenesis; Syndrome; Medroxyprogesterone Acetate; Ethinyl Estradiol; Medroxyprogesterone; Estradiol

Study Results

Participant Flow

Recruitment Details	Addenda 1, 2, and 3 are not sequential, and they differ in eligibility criteria. Depending on individual eligibility and choices made, a patient might have participated in none, 1, 2, or all 3 of these addenda.
Pre-assignment Detail	Addendum 1: provided option of Humatrope treatment to patients who had been randomized to control in Core Study. Addendum 2: extended period of follow-up for 5 years after discontinuation from Core Study. Addendum 3: evaluated possible genomic imprinting effects (published: Hamelin et al. 2006).

Arm/Group Title	As-Randomized Control	As-Randomized Humatrope
Arm/Group Description	Control arm; untreated with Humatrope. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).	Humatrope (0.05 mg/kg/dose) by subcutaneous injection 6 times per week. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).
Period Title: Core Study
STARTED	78	76
COMPLETED	43	61
NOT COMPLETED	35	15
Period Title: Core Study
STARTED	2	0
COMPLETED	2	0
NOT COMPLETED	0	0
Period Title: Core Study
STARTED	28	48
COMPLETED	18	31
NOT COMPLETED	10	17
Period Title: Core Study
STARTED	20	37
COMPLETED	20	37
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	As-Randomized Control	As-Randomized Humatrope	Total
Arm/Group Description	Control arm; untreated with Humatrope. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).	Humatrope (0.05 mg/kg/dose) by subcutaneous injection 6 times per week. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).	Total of all reporting groups
Overall Participants	78	76	154
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.46 (1.77)	10.36 (1.80)	10.41 (1.78)
Sex: Female, Male (Count of Participants)
Female	78 100%	76 100%	154 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	78 100%	76 100%	154 100%
Karyotype (participants) [Number]
45,X	48 61.5%	45 59.2%	93 60.4%
45,X/46,XXqi	6 7.7%	2 2.6%	8 5.2%
45,X/46,XXr	1 1.3%	2 2.6%	3 1.9%
45,X/46,XX	3 3.8%	3 3.9%	6 3.9%
46,XXqi	2 2.6%	6 7.9%	8 5.2%
45,X/47,XXX	1 1.3%	2 2.6%	3 1.9%
46,XXp	1 1.3%	0 0%	1 0.6%
45,X/46,XXp	1 1.3%	1 1.3%	2 1.3%
45,X/46,XX/47,XXX	0 0%	0 0%	0 0%
46,XXr	0 0%	0 0%	0 0%
Other	15 19.2%	15 19.7%	30 19.5%
Race/Ethnicity (participants) [Number]
American Indian or Alaska Native	1 1.3%	1 1.3%	2 1.3%
Asian	7 9%	6 7.9%	13 8.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.3%	0 0%	1 0.6%
White	54 69.2%	66 86.8%	120 77.9%
Hispanic	0 0%	2 2.6%	2 1.3%
Other	4 5.1%	0 0%	4 2.6%
Unknown	11 14.1%	1 1.3%	12 7.8%
Bone Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.57 (1.51)	8.79 (1.42)	8.69 (1.46)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	120.06 (8.26)	119.84 (8.45)	119.96 (8.33)
Height Standard Deviation Score (SDS) [Lyon] (Standard Deviation Score (SDS)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Standard Deviation Score (SDS)]	-0.13 (0.86)	-0.10 (0.88)	-0.11 (0.87)
Height Standard Deviation Score (SDS) [National Center for Health Statistics (NCHS)] (Standard Deviation Score (SDS)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Standard Deviation Score (SDS)]	-3.25 (0.82)	-3.21 (0.82)	-3.23 (0.82)

Outcome Measures

1. Primary Outcome

Title	Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Change From Baseline to Last Measurement, As Randomized Population
Description	Value analyzed is change from baseline to the most mature height measurement available. The terms Standard Deviation Score (SDS) and National Center for Health Statistics (NCHS) were defined in baseline characteristics. Greater height SDS values indicate greater height; positive values of change from baseline indicate increased height.
Time Frame	Baseline, and end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Population of all randomized patients. Intent to treat analysis with as-randomized treatment groups, at most mature measurement available.

Arm/Group Title	As-Randomized Control	As-Randomized Humatrope
Arm/Group Description	Control arm; untreated with Humatrope. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).	Humatrope (0.05 mg/kg/dose) by subcutaneous injection 6 times per week. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height).
Measure Participants	78	76
Least Squares Mean (Standard Error) [Standard Deviation Score (SDS) [NCHS]]	0.09 (0.07)	0.97 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments	This component of the primary analysis is inferential i.e. to ascertain definitively whether Humatrope treatment affects change in Height SDS (NCHS). Null hypothesis is no effect of Humatrope treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	Model includes baseline height SDS, baseline age, treatment, and interactions. Age and interaction terms removed when not significant.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Confidence Interval	() 95%; 0.7 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Effect direction is "As-Randomized Humatrope" minus "As-Randomized Control"

2. Primary Outcome

Title	Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Last Measurement After Attainment of Final Height
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 [NCHS] uses the NCHS US general female population reference height values for age (Kuczmarski RJ et al. 2000) as the population mean and standard deviation. Calculation of Height SDS is provided in Height SDS [Lyon] description (Baseline). Since data reported by Kuczmarski RJ et al provides US general female population standards, values of Height SDS [NCHS] for untreated patients with Turner syndrome tend to be below zero e.g, -2.0 to -4.0 SDS.
Time Frame	at completion of core study, or at end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Population of patients for whom Final Height measurements are available. Efficacy analysis with as-treated treatment groups, at most mature measurement available at or after attainment of Final Height.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	48	82
Least Squares Mean (Standard Error) [Standard Deviation Score (SDS) [NCHS]]	-3.30 (0.07)	-2.25 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments	Estimation analysis of the magnitude of effect of treatment with growth hormone upon Final Height. Null hypothesis is no effect of growth hormone upon attained height standard deviation score (National Center for Health Statistics).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	Model includes baseline height SDS, baseline age, treatment, and interactions. Age and interactions terms removed when not significant.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	() 95%; 0.9 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Effect direction is "As-Treated Growth Hormone" minus "As-Treated No Growth Hormone"

3. Secondary Outcome

Title	Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Change From Baseline, As-Treated Population
Description	Value analyzed is change from baseline to the most mature height measurement available. The terms Standard Deviation Score (SDS) and National Center for Health Statistics (NCHS) were defined in baseline characteristics. Greater height SDS values indicate greater height; positive values of change from baseline indicate increased height.
Time Frame	every 3 months during core study, and at start and end of 4-year addendum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Humatrope
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	48	82
Least Squares Mean (Standard Error) [Standard Deviation Score (SDS) [NCHS]]	-0.09 (0.08)	0.99 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.1
	Confidence Interval	() 95%; 0.9 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Height (Centimeters [cm])
Description	Most mature measurement available, at or after attainment of Final Height.
Time Frame	every 3 months during core study, and at start and end of 4-year addendum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Humatrope
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	48	82
Least Squares Mean (Standard Error) [centimeters (cm)]	141.63 (0.47)	148.52 (0.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.9
	Confidence Interval	() 95%; 5.7 to 8.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With an Abnormal Pure Tone Audiometry, Audiologist Assessment
Time Frame	at completion of core study or beginning of addendum

Outcome Measure Data

Analysis Population Description

All Randomized Patients with Hearing Examination

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	19	53
Number [participants]	10 12.8%	29 38.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	Number of Participants With Abnormal Speech Audiometry, Audiologist Assessment
Time Frame	at completion of core study or beginning of addendum

Outcome Measure Data

Analysis Population Description

All Randomized Patients with Hearing Examination

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	19	53
Number [participants]	3 3.8%	12 15.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.744
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Number of Participants With Abnormal Impedance Tympanometry, Audiologist Assessment
Time Frame	at completion of core study or beginning of addendum

Outcome Measure Data

Analysis Population Description

All Randomized Patients with Hearing Examination

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	19	53
Number [participants]	2 2.6%	18 23.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Number of Participants With Hearing Loss, Audiologist Assessment
Description	Sensorineural Hearing Loss (SNHL)=air conduction threshold >20 dB HL and air-bone gap ≤10 dB HL; Conductive Hearing Loss (CHL)= air conduction threshold >20 dB HL, bone conduction threshold ≤20 dB HL and air-bone gap >10 dB HL; Mixed Hearing Loss (MHL) = evidence of SNHL as defined above and CHL as defined above, in the same ear; Unspecified Hearing Loss (UHL)= abnormal hearing with none of SNHL, CHL, or MHL present.
Time Frame	at completion of core study or beginning of addendum

Outcome Measure Data

Analysis Population Description

All Randomized Patients with Hearing Examination for whom Audiologist responded to Hearing Loss question

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	19	52
Conductive Hearing Loss	1 1.3%	7 9.2%
Sensorineural Hearing Loss	8 10.3%	15 19.7%
Mixed Hearing Loss	2 2.6%	9 11.8%
Unspecified Hearing Loss	1 1.3%	1 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments	Comparison of proportion of patients with any category of hearing loss between As-Treated Growth Hormone group and As-Treated No Growth Hormone.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Fasting Glucose, Change From Baseline
Description	Change from core study baseline to addendum 2 maximum.
Time Frame	At core study baseline, and at end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Patients who were followed for at least 4 years without growth hormone treatment or who received growth hormone for at least 4 years, and who were treated as randomized and had core study baseline and addendum glucose metabolism data.

Arm/Group Title	Treated-As-Randomized Control	Treated-As-Randomized Humatrope
Arm/Group Description	Patients in As-Randomized Control group who at each observed time point remained untreated with growth hormone.	Patients in As-Randomized Humatrope group who received Humatrope treatment
Measure Participants	20	36
Least Squares Mean (Standard Error) [mg / dL]	5.495 (2.455)	3.003 (1.830)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.419
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.492
	Confidence Interval	() 95%; -8.631 to 3.646
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of estimated treatment effect is Humatrope minus Control

10. Secondary Outcome

Title	Maximum Fasting Glucose Value
Description	Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years.
Time Frame	At start and through end of 4-year addendum (up to an additional 2 years)

Outcome Measure Data

Analysis Population Description

Patients with addendum data who were followed for at least 4 years without growth hormone treatment (and never received growth hormone) or who received growth hormone for at least 4 years.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	39
Mean (Standard Deviation) [milligrams per deciliter (mg/dL)]	85.2 (6.6)	85.2 (10.4)

11. Secondary Outcome

Title	Number of Participants With Any Abnormal Fasting Glucose Value
Description	Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Fasting Glucose=Fasting Glucose >=100 milligrams per deciliter (mg/dL).
Time Frame	At start and through end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Patients with any Addendum 2 glucose metabolism data

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Humatrope
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	39
Number [participants]	0 0%	3 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.545
	Comments
	Method	Fisher Exact
	Comments

12. Secondary Outcome

Title	Maximum Fasting Insulin Values
Description	Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years.
Time Frame	At start and through end of 4-year addendum (up to an additional 2 years)

Outcome Measure Data

Analysis Population Description

Patients with addendum data who were followed for at least 4 years without growth hormone treatment (and never received growth hormone) or who received growth hormone for at least 4 years.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	40
Mean (Standard Deviation) [micro International Units per milliliter]	9.5 (10.8)	9.7 (9.3)

13. Secondary Outcome

Title	Number of Participants With Any Abnormal Fasting Insulin Value
Description	Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Fasting Insulin = Fasting Insulin >=35 micro International Units per milliliter (uIU/mL).
Time Frame	At start and through end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Patients with any Addendum 2 glucose metabolism data

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Humatrope
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	40
Number [participants]	1 1.3%	2 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

14. Secondary Outcome

Title	Minimum Fasting Glucose/Insulin Ratio Values
Description	Minimum measured value over addendum. In special cases an additional measurement is taken at 2 years.
Time Frame	At start and through end of 4-year addendum (up to an additional 2 years)

Outcome Measure Data

Analysis Population Description

Patients with addendum data who were followed for at least 4 years without growth hormone treatment (and never received growth hormone) or who received growth hormone for at least 4 years.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	38
Mean (Standard Deviation) [milligrams per 10^-4 Units (mg/[10^-4]U)]	12.5 (6.0)	12.2 (5.3)

15. Secondary Outcome

Title	Number of Participants With Any Abnormal Fasting Glucose/Insulin Ratio Value
Description	Indicates if patient had any measured value below threshold of normality at any visit during addendum. Abnormal Fasting Glucose/Insulin Ratio = Fasting Glucose/Insulin Ratio <=4.5 milligrams per 10^-4 Units (mg/10^-4U).
Time Frame	At start and through end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Patients with any Addendum 2 glucose metabolism data. Calculated only for patients with fasting blood <100 mg/dL.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	38
Number [participants]	1 1.3%	3 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

16. Secondary Outcome

Title	Glycosylated Hemoglobin, Change From Baseline
Description	Change from core study baseline to addendum 2 maximum.
Time Frame	At core study baseline, and at end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Patients who were followed for at least 4 years without growth hormone treatment or who received growth hormone for at least 4 years, and who were treated as randomized and had core study baseline and addendum glucose metabolism data.

Arm/Group Title	Treated-As-Randomized Control	Treated-As-Randomized Humatrope
Arm/Group Description	Patients in As-Randomized Control group who at each observed time point remained untreated with growth hormone.	Patients in the As-Randomized Humatrope group who received Humatrope
Measure Participants	20	36
Least Squares Mean (Standard Error) [percent (%)]	0.215 (0.077)	0.208 (0.057)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.945
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.007
	Confidence Interval	() 95%; -0.199 to 0.186
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of estimated treatment effect is Humatrope minus Control

17. Secondary Outcome

Title	Maximum Glycosylated Hemoglobin
Description	Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years.
Time Frame	At start and through end of 4-year addendum (up to an additional 2 years)

Outcome Measure Data

Analysis Population Description

Patients with addendum data who were followed for at least 4 years without growth hormone treatment (and never received growth hormone) or who received growth hormone for at least 4 years.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	40
Mean (Standard Deviation) [percent (%)]	5.0 (0.5)	5.0 (0.4)

18. Secondary Outcome

Title	Number of Participants With Any Abnormal Glycosylated Hemoglobin (HbA1c) Value
Description	Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Glycosylated Hemoglobin = HbA1c ≥6.8% (up until 11-May-1998); and then HbA1c ≥6.1% (from 19-May-1998 onwards).
Time Frame	At start and through end of 4-year addendum

Outcome Measure Data

Analysis Population Description

Patients with any Addendum 2 glucose metabolism data.

Arm/Group Title	As-Treated No Growth Hormone	As-Treated Growth Hormone
Arm/Group Description	Patients who never received growth hormone	Patients who received Humatrope or another brand of growth hormone
Measure Participants	21	40
Number [participants]	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	As-Randomized Control, As-Randomized Humatrope
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Adverse Events

Arm/Group Title	Treated-As-Randomized Control		Treated-As-Randomized Humatrope
Arm/Group Description	Patients in the As-Randomized Control group who at each observed time point remained untreated with growth hormone.		Patients in the As-Randomized Humatrope group who received Humatrope
All Cause Mortality
	Treated-As-Randomized Control		Treated-As-Randomized Humatrope
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Treated-As-Randomized Control		Treated-As-Randomized Humatrope
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/54 (18.5%)		22/74 (29.7%)
Blood and lymphatic system disorders
Anemia iron deficiency	0/54 (0%)		1/74 (1.4%)
Hypochromic microcytic anemia	0/54 (0%)		1/74 (1.4%)
Idiopathic thrombocytopenic purpura	1/54 (1.9%)		0/74 (0%)
Cardiac disorders
Cardiac arrest	1/54 (1.9%)		0/74 (0%)
Infections and infestations
Cellulitis of foot	0/54 (0%)		1/74 (1.4%)
Gastroenteritis	0/54 (0%)		1/74 (1.4%)
Otitis media	0/54 (0%)		1/74 (1.4%)
Pneumonia	1/54 (1.9%)		0/74 (0%)
Pyelonephritis	0/54 (0%)		1/74 (1.4%)
Stomach flu	0/54 (0%)		1/74 (1.4%)
Viral meningitis	0/54 (0%)		1/74 (1.4%)
Injury, poisoning and procedural complications
Arm fracture	0/54 (0%)		2/74 (2.7%)
Wrist fracture	0/54 (0%)		1/74 (1.4%)
Investigations
Colonoscopy	0/54 (0%)		1/74 (1.4%)
Cystoscopy	0/54 (0%)		1/74 (1.4%)
Metabolism and nutrition disorders
Dehydration	0/54 (0%)		1/74 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm benign	0/54 (0%)		1/74 (1.4%)
Skin and subcutaneous tissue disorders
Psoriasis	0/54 (0%)		1/74 (1.4%)
Pustular psoriasis	0/54 (0%)		1/74 (1.4%)
Surgical and medical procedures
Adenoidectomy	0/54 (0%)		1/74 (1.4%)
Aorta coarctation repair	0/54 (0%)		1/74 (1.4%)
Appendectomy	2/54 (3.7%)		0/74 (0%)
Chest wall repair	1/54 (1.9%)		0/74 (0%)
Cholesteatoma removal	0/54 (0%)		1/74 (1.4%)
Dental surgery NOS	0/54 (0%)		1/74 (1.4%)
Eye muscle operation	0/54 (0%)		1/74 (1.4%)
Heart valve operation	0/54 (0%)		1/74 (1.4%)
Mastoid operation	0/54 (0%)		1/74 (1.4%)
Mastoidectomy	0/54 (0%)		1/74 (1.4%)
Orchiectomy	0/54 (0%)		1/74 (1.4%)
Pterygium operation	1/54 (1.9%)		1/74 (1.4%)
Scar removal	1/54 (1.9%)		0/74 (0%)
Surgical procedure	1/54 (1.9%)		0/74 (0%)
Tooth extraction	1/54 (1.9%)		0/74 (0%)
Tympanoplasty	0/54 (0%)		3/74 (4.1%)
Vascular disorders
Aortic aneurysm rupture	1/54 (1.9%)		0/74 (0%)
Thrombophlebitis	1/54 (1.9%)		0/74 (0%)
Other (Not Including Serious) Adverse Events
	Treated-As-Randomized Control		Treated-As-Randomized Humatrope
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/54 (98.1%)		74/74 (100%)
Ear and labyrinth disorders
Ear ache	6/54 (11.1%)		10/74 (13.5%)
Ear discharge	0/54 (0%)		4/74 (5.4%)
Ear pain	3/54 (5.6%)		14/74 (18.9%)
Earache	5/54 (9.3%)		8/74 (10.8%)
Hearing loss	2/54 (3.7%)		7/74 (9.5%)
Sensorineural hearing loss	3/54 (5.6%)		0/74 (0%)
Tympanosclerosis	3/54 (5.6%)		0/74 (0%)
Endocrine disorders
Hypothyroidism	7/54 (13%)		13/74 (17.6%)
Eye disorders
Conjunctivitis	2/54 (3.7%)		4/74 (5.4%)
Myopia	3/54 (5.6%)		4/74 (5.4%)
Gastrointestinal disorders
Abdominal pain	9/54 (16.7%)		9/74 (12.2%)
Ache stomach	0/54 (0%)		4/74 (5.4%)
Diarrhea	11/54 (20.4%)		12/74 (16.2%)
Nausea	5/54 (9.3%)		13/74 (17.6%)
Stomach ache	7/54 (13%)		7/74 (9.5%)
Stomach cramps	4/54 (7.4%)		4/74 (5.4%)
Stomach pain	2/54 (3.7%)		6/74 (8.1%)
Upset stomach	3/54 (5.6%)		5/74 (6.8%)
Vomiting	21/54 (38.9%)		29/74 (39.2%)
General disorders
Chest pain	4/54 (7.4%)		1/74 (1.4%)
Fatigue	4/54 (7.4%)		1/74 (1.4%)
Fever	20/54 (37%)		36/74 (48.6%)
Pain	0/54 (0%)		4/74 (5.4%)
Immune system disorders
Hay fever	1/54 (1.9%)		7/74 (9.5%)
Multiple allergies	1/54 (1.9%)		6/74 (8.1%)
Infections and infestations
Bladder infection	3/54 (5.6%)		4/74 (5.4%)
Bronchitis	5/54 (9.3%)		7/74 (9.5%)
Chest cold	0/54 (0%)		7/74 (9.5%)
Chickenpox	5/54 (9.3%)		8/74 (10.8%)
Cold	39/54 (72.2%)		42/74 (56.8%)
Cold symptoms	4/54 (7.4%)		7/74 (9.5%)
Common cold	4/54 (7.4%)		5/74 (6.8%)
Ear infection	12/54 (22.2%)		27/74 (36.5%)
Eye infection	3/54 (5.6%)		9/74 (12.2%)
Flu	20/54 (37%)		36/74 (48.6%)
Flu syndrome	6/54 (11.1%)		15/74 (20.3%)
Gastroenteritis	2/54 (3.7%)		6/74 (8.1%)
Head cold	9/54 (16.7%)		18/74 (24.3%)
Impetigo	4/54 (7.4%)		6/74 (8.1%)
Otitis externa	6/54 (11.1%)		13/74 (17.6%)
Otitis media	13/54 (24.1%)		31/74 (41.9%)
Pharyngitis	8/54 (14.8%)		11/74 (14.9%)
Rhinitis	11/54 (20.4%)		17/74 (23%)
Sinus infection	1/54 (1.9%)		5/74 (6.8%)
Sinusitis	3/54 (5.6%)		7/74 (9.5%)
Stomach flu	6/54 (11.1%)		6/74 (8.1%)
Streptococcal sore throat	4/54 (7.4%)		9/74 (12.2%)
Throat infection	7/54 (13%)		8/74 (10.8%)
Tonsillitis	5/54 (9.3%)		6/74 (8.1%)
Upper respiratory infection	14/54 (25.9%)		13/74 (17.6%)
Upper respiratory tract infection	9/54 (16.7%)		8/74 (10.8%)
Urinary tract infection	3/54 (5.6%)		5/74 (6.8%)
Injury, poisoning and procedural complications
Accidental overdose	0/54 (0%)		5/74 (6.8%)
Head injury	3/54 (5.6%)		2/74 (2.7%)
Musculoskeletal and connective tissue disorders
Knee pain	1/54 (1.9%)		8/74 (10.8%)
Leg pain	1/54 (1.9%)		4/74 (5.4%)
Low back pain	4/54 (7.4%)		3/74 (4.1%)
Osteopenia	4/54 (7.4%)		2/74 (2.7%)
Scoliosis	8/54 (14.8%)		6/74 (8.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Naevus	2/54 (3.7%)		5/74 (6.8%)
Nervous system disorders
Dizziness	4/54 (7.4%)		7/74 (9.5%)
Headache	25/54 (46.3%)		46/74 (62.2%)
Intermittent headache	3/54 (5.6%)		12/74 (16.2%)
Psychiatric disorders
Depression	4/54 (7.4%)		6/74 (8.1%)
Reproductive system and breast disorders
Cramps menstrual	2/54 (3.7%)		4/74 (5.4%)
Dysmenorrhea	2/54 (3.7%)		4/74 (5.4%)
Menstrual cramps	7/54 (13%)		7/74 (9.5%)
Primary ovarian failure	4/54 (7.4%)		5/74 (6.8%)
Spotting vaginal	4/54 (7.4%)		0/74 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/54 (0%)		4/74 (5.4%)
Congestion nasal	2/54 (3.7%)		5/74 (6.8%)
Cough	14/54 (25.9%)		27/74 (36.5%)
Coughing	2/54 (3.7%)		5/74 (6.8%)
Epistaxis	3/54 (5.6%)		2/74 (2.7%)
Nasal congestion	8/54 (14.8%)		17/74 (23%)
Nasal discharge	3/54 (5.6%)		2/74 (2.7%)
Nose bleed	1/54 (1.9%)		5/74 (6.8%)
Sinus congestion	5/54 (9.3%)		7/74 (9.5%)
Sore throat	28/54 (51.9%)		37/74 (50%)
Throat sore	1/54 (1.9%)		6/74 (8.1%)
Skin and subcutaneous tissue disorders
Dry skin	1/54 (1.9%)		8/74 (10.8%)
Eczema	4/54 (7.4%)		4/74 (5.4%)
Ingrown toe nail	3/54 (5.6%)		2/74 (2.7%)
Rash	8/54 (14.8%)		8/74 (10.8%)
Surgical and medical procedures
Dental surgery NOS	1/54 (1.9%)		4/74 (5.4%)
Dental treatment	8/54 (14.8%)		6/74 (8.1%)
Ear tube insertion	1/54 (1.9%)		4/74 (5.4%)
Mole excision	2/54 (3.7%)		5/74 (6.8%)
Myringotomy	1/54 (1.9%)		8/74 (10.8%)
Tooth extraction	3/54 (5.6%)		3/74 (4.1%)
Tympanoplasty	0/54 (0%)		4/74 (5.4%)
Vascular disorders
Aortic dilatation	3/54 (5.6%)		1/74 (1.4%)
Blood pressure high	3/54 (5.6%)		1/74 (1.4%)
Hypertension	1/54 (1.9%)		7/74 (9.5%)

Limitations/Caveats

[Not Specified]

More Information

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.