Somatropin Treatment to Final Height in Turner Syndrome (GDCT)

• ClinicalTrials.gov Identifier: NCT00191113
• Recruitment Status: Completed
• First Posted: September 19, 2005
• Results First Posted: January 27, 2010
• Last Update Posted: January 27, 2010
• Sponsor: Eli Lilly and Company
• Information provided by: Eli Lilly and Company

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 (Clinical Trial)
• 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: February 1989
• Actual Primary Completion Date: December 2007
• Actual Study Completion Date: December 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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]) [ Time Frame: 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 [ Time Frame: at completion of core study or beginning of addendum ]
4. Number of Participants With Abnormal Speech Audiometry, Audiologist Assessment [ Time Frame: at completion of core study or beginning of addendum ]
5. Number of Participants With Abnormal Impedance Tympanometry, Audiologist Assessment [ Time Frame: at completion of core study or beginning of addendum ]
6. Number of Participants With Hearing Loss, Audiologist Assessment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: At core study baseline, and at end of 4-year addendum ]
    Change from core study baseline to addendum 2 maximum.
15. Maximum Glycosylated Hemoglobin [ Time Frame: 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 [ Time Frame: 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

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

Criteria

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

Canada, Alberta

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

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

Canada, British Columbia

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

Canada, Manitoba

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

Canada, Nova Scotia

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

Canada, Ontario

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

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

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

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

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

Canada, Quebec

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

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

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

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

More Information

Additional Information:

Lilly Clinical Trial Registry 

Publications of Results:

Hamelin CE, Anglin G, Quigley CA, Deal CL. Genomic imprinting in Turner syndrome: effects on response to growth hormone and on risk of sensorineural hearing loss. J Clin Endocrinol Metab. 2006 Aug;91(8):3002-10. Epub 2006 Jun 6.

Stephure DK; Canadian Growth Hormone Advisory Committee. Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab. 2005 Jun;90(6):3360-6. Epub 2005 Mar 22.

Other Publications:

Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child. 1985 Oct;60(10):932-5.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Taback SP, Van Vliet G. Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone. BMC Pediatr. 2011 May 29;11:49. doi: 10.1186/1471-2431-11-49.

• Responsible Party: Chief Medical Officer, Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00191113
• Other Study ID Numbers: 817/4419; #817 B9R-CA-GDCT Core study; #4419 GDCT/1 Addenda
• First Posted: September 19, 2005
• Results First Posted: January 27, 2010
• Last Update Posted: January 27, 2010
• Last Verified: December 2009

Keywords provided by Eli Lilly and Company:

syndrome; Turner; Turner's; height; growth; growth hormone; somatropin; short stature; short; hearing; glucose metabolism

Additional relevant MeSH terms:

Turner Syndrome; Gonadal Dysgenesis; Syndrome; Disease; Pathologic Processes; Disorders of Sex Development; Urogenital Abnormalities; Sex Chromosome Disorders of Sex Development; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases; Medroxyprogesterone Acetate; Medroxyprogesterone; Estradiol; Ethinyl Estradiol; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Estrogens; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic