GHD: Effects of Growth Hormone on Cognition and Cerebral Metabolism in Adults With Growth Hormone Deficiency

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01007071
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 11
• Location: 1
• Arms: 2
• Actual Duration (Months): 37.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Patients with Growth hormone (GH) deficiency often report impaired quality of life and difficulty with mental functioning. It has been suggested that GH replacement in such patients leads to improvement in cognitive function. The aim of this study is to elucidate the effects of GH replacement in patients with GH deficiency on cognitive function using structural and functional neuroimaging and cognitive testing.

Condition or Disease	Intervention/Treatment	Phase
Hypopituitarism	Drug: Human Growth Hormone (1-134); Drug: Placebo	Phase 3

Detailed Description

Eligibility screening: Diagnosis of GHD will be based on standard testing, including a blunted GH response to stimulation with glucagon provocation, defined as GH <3 microgram/l. Subjects with adult-onset GH deficiency will be included if they are age 18-65 years old, naive to GH replacement therapy, in good general health, and on stable thyroid, glucocorticoid (at replacement doses) and gonadal replacement therapy for at least 6 weeks prior to study initiation. Patients with history a Major Depression will be excluded.

Baseline: Qualifying subjects will be admitted to the CTRU for the following: Weight, body mass index, waist/hip ratio, menstrual cycle history on female subjects and vital signs. Initial clinical laboratory assessments will include IGF-1, a complete blood count, liver function tests, free T4, and a serum pregnancy test for women. Subjects will undergo 3 hours of neuropsychological testing when attention, working memory, executive function and verbal memory will be assessed with the Wechsler Adult Intelligence Scale III and Wechsler Memory Scale (WMS III). Quality of life and mood will be quantified through the Quality of Life Scale, Hamilton Rating Scale for Depression and the Quality of Life Assessment of Growth Hormone Deficiency in Adults (Qol AGHDA). After a lunch break, the patients will undergo a 1 hour MRI scan. Resting images will be obtained, and thereafter simple letters, words or pictures will be projected to subjects while in the scanner. The subjects will be asked simple questions relating to these stimuli.

Randomization and treatment: Following completion of the baseline measurements, study participants will be randomized in a double blind fashion to receive either active treatment with GH or placebo for a period of 16 weeks. GH dosages will be increased incrementally over the first 6 weeks. At 16 weeks, all subjects randomized to placebo will be switched to GH in an open label fashion with dose schedules based on the above titration. Subjects initially randomized to GH will continue to receive GH with their endocrinologist without further follow up for the study.

For efficacy measures, neuropsychological testing and fMRI will be performed at baseline and at 16 weeks, and, for subjects initially randomized to placebo, repeat studies will be performed at 32 weeks.

Safety monitoring will include assessment of changes in thyroid and adrenal status, as well as changes in liver function.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effects of Growth Hormone on Cognition and Cerebral Metabolism in Adults
• Actual Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Dec 12, 2012
• Actual Study Completion Date: Dec 12, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Growth hormone Subjects randomized to growth hormone (1-134) for 16 weeks. In this arm, growth hormone is dosed sc on a daily basis and increased over first 6 weeks (Men: start at 0.2 mg sc/d, increase to 0.6 mg sc/d after 4 weeks. Women, postmenopausal: start at 0.3 mg sc/d, increase to 0.9 mg sc/d after 4 weeks. Dose adjustments based on serum insulin-like growth factor-1 (IGF-1) levels at 6 and 12 weeks, with final IGF-1 measurement for efficacy performed at 16 weeks, with goal in range of -0.5 standard deviation (SD) to +2SD. An elevated serum IGF-1 value will result in a 20% dose reduction in GH in an active and random placebo patient. Similarly, a low serum IGF-1 will result in a 20% dose increase in an active and random placebo subject.	Drug: Human Growth Hormone (1-134); Subjects randomized to human growth hormone (1-134) for 16 weeks. In this arm, growth hormone is dosed sc on a daily basis and increased over first 6 weeks (Men: start at 0.2 mg sc/d, increase to 0.6 mg sc/d after 4 weeks. Women, postmenopausal: start at 0.3 mg sc/d, increase to 0.9 mg sc/d after 4 weeks. Women premenopausal or on estrogen: start at 0.6 mg sc/d, increase to 1.3 mg sc/d after 4 weeks.) Dose adjustments based on serum IGF-1 levels at 6 and 12 weeks, with final IGF-1 measurement for efficacy performed at 16 weeks, with goal in range of -0.5 SD to +2SD. An elevated serum IGF-1 value will result in a 20% dose reduction in GH in an active and random placebo patient. Similarly, a low serum IGF-1 will result in a 20% dose increase in an active and random placebo subject.; Other Names: Nutropin (brand name)
Placebo Comparator: Placebo Subjects randomized to placebo for 16 weeks. As noted above, placebo subjects will be initiated on a daily subcutaneous injection, with dose changes based on changes in active drug subjects.	Drug: Placebo; Subjects randomized to placebo

Outcome Measures

Primary Outcome Measures

1. BOLD Signal Measured by Functional MRI Scan to Functional Connectivity Measured by fMRI [Baseline and 16 weeks]

   Functional MRI scans were to be performed at baseline and at 16 weeks. Changes in functional connectivity before and after 16 weeks of treatment were analyzed. The analysis involved approximately 40,000 paired sample t-tests. The dependent variable here for each subject is the correlation between the BOLD timeseries in the seed region (posterior cingulate cortex) and the BOLD timeseries in a given, standard space, brain voxel. This paired-sample t-test is run, separately, for every voxel in the brain. The pre-specified Outcome Measure intended to report the number of voxels that showed significant changes with active treatment. A preliminary analysis was conducted using a paired-sample t-test at each of the 40,000+ voxels, however, none of the voxels reached the level of significance. Since no significant voxels were detected, subsequent planned analyses were not performed, and summary level data cannot be reported for this Outcome Measure.

Secondary Outcome Measures

1. Neuropsychological Testing of Executive Function [16 weeks]

   Executive function was assessed in part B of the 2-part Trail Making Test. In Part A, 25 circles are distributed over a sheet of paper, numbered 1 - 25, and the patient draws lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1-13) and letters (A-L); as in Part A, the patient draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the numbers and letters (i.e., 1-A-2-B-3-C, etc.). The patient is instructed to connect the circles as quickly as possible. The amount of time the patient takes to connect the circles is recorded as their score. If patients make an error, they are corrected then continue from the last correct circle. The number of seconds for completion of part B is reported, therefore higher scores reveal greater impairment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ability to provide written informed consent and comply with study assessments for the full duration of the study

• Age 18-65 years old

• Both men and women

• Naive to GH replacement therapy

• Diagnosis of Growth Hormone deficiency, adult onset

• Good general health

• Normal thyroid, adrenal or gonadal function, or stable thyroid, glucocorticoid (at replacement doses) and gonadal replacement therapy for at least 3 months prior to study initiation. If subjects are receiving transdermal testosterone, attainment of mid-normal serum values will be considered adequate. If subjects are on intramuscular testosterone, attainment of mid-normal serum testosterone at mid-injection cycle will be considered adequate

Exclusion Criteria:

• Pregnancy (positive pregnancy test) prior to enrollment in the study

• Any other condition that the investigator believes would pose a significant hazard to the subject if Growth Hormone therapy was initiated

• Idiopathic Growth Hormone Deficiency

• DSM IV diagnosis of Major Depressive Disorder with or without psychotic features, Bipolar II Disorder with or without psychotic features in a major depressive episode

• Current use of psychotropic medications

• History of moderate to severe brain injury

• Clinically significant cardiovascular disease

• Anemia with hct<30

• Renal insufficiency with creatinine >2.0

• Recent history of excessive alcohol use

• Participation in another simultaneous medical investigation or trial

• Active neoplasm

• Prader Willi Syndrome

• History of brain radiation

• Chemotherapy, past or present use

• History of head or eye injury involving persistent metal fragments, and implanted electrical device (such as a heart pacemaker)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University
• Genentech, Inc.

Investigators

• Sub-Investigator: Era Sidhaye Shah, Stanford University
• Principal Investigator: Laurence Katznelson, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Laurence Katznelson, Professor of Neurosurgery and Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT01007071
• Other Study ID Numbers: SU-10022009-4140; IRB eprotocol # 15129
• First Posted: Nov 3, 2009
• Last Update Posted: Nov 17, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Hypopituitarism; Hormones

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the neuroendocrine center at Stanford Hospital
Pre-assignment Detail	All patients were naïve to study drug, per protocol and eligibility criteria. Therefore, no washouts or other required delays were part of the study.

Arm/Group Title	Growth Hormone	Placebo
Arm/Group Description	Subjects were randomized to receive growth Human Growth Hormone (1-134) (Nutropin) for 16 weeks	Subjects were randomized to receive placebo for 16 weeks, and then were immediately crossed over to receive active study drug for 16 weeks
Period Title: Overall Study
STARTED	6	5
COMPLETED	6	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Growth Hormone	Placebo	Total
Arm/Group Description	Subjects were randomized to receive growth Human Growth Hormone (1-134) (Nutropin) for 16 weeks All subjects were diagnosed with growth hormone deficiency using standard testing.	Subjects were randomized to receive placebo for 16 weeks, and then were immediately crossed over to receive active study drug for 16 weeks All subjects were diagnosed with growth hormone deficiency using standard testing.	Total of all reporting groups
Overall Participants	6	5	11
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	3 60%	9 81.8%
>=65 years	0 0%	2 40%	2 18.2%
Sex: Female, Male (Count of Participants)
Female	1 16.7%	1 20%	2 18.2%
Male	5 83.3%	4 80%	9 81.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 33.3%	1 20%	3 27.3%
Not Hispanic or Latino	1 16.7%	3 60%	4 36.4%
Unknown or Not Reported	3 50%	1 20%	4 36.4%
Region of Enrollment (Count of Participants)
United States	6 100%	5 100%	11 100%

Outcome Measures

1. Primary Outcome

Title	BOLD Signal Measured by Functional MRI Scan to Functional Connectivity Measured by fMRI
Description	Functional MRI scans were to be performed at baseline and at 16 weeks. Changes in functional connectivity before and after 16 weeks of treatment were analyzed. The analysis involved approximately 40,000 paired sample t-tests. The dependent variable here for each subject is the correlation between the BOLD timeseries in the seed region (posterior cingulate cortex) and the BOLD timeseries in a given, standard space, brain voxel. This paired-sample t-test is run, separately, for every voxel in the brain. The pre-specified Outcome Measure intended to report the number of voxels that showed significant changes with active treatment. A preliminary analysis was conducted using a paired-sample t-test at each of the 40,000+ voxels, however, none of the voxels reached the level of significance. Since no significant voxels were detected, subsequent planned analyses were not performed, and summary level data cannot be reported for this Outcome Measure.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

Preliminary analysis did not work as intended and subsequent data were not collected from any participants (please see the detailed explanation in the Measure Description).

Arm/Group Title	Growth Hormone	Placebo
Arm/Group Description	Subjects randomized to growth hormone for 16 weeks Human Growth Hormone (1-134): Subjects to receive growth hormone	Subjects randomized to placebo for 16 weeks Placebo: Subjects randomized to placebo
Measure Participants	0	0

2. Secondary Outcome

Title	Neuropsychological Testing of Executive Function
Description	Executive function was assessed in part B of the 2-part Trail Making Test. In Part A, 25 circles are distributed over a sheet of paper, numbered 1 - 25, and the patient draws lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1-13) and letters (A-L); as in Part A, the patient draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the numbers and letters (i.e., 1-A-2-B-3-C, etc.). The patient is instructed to connect the circles as quickly as possible. The amount of time the patient takes to connect the circles is recorded as their score. If patients make an error, they are corrected then continue from the last correct circle. The number of seconds for completion of part B is reported, therefore higher scores reveal greater impairment.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Growth Hormone	Placebo
Arm/Group Description	Subjects randomized to growth hormone for 16 weeks Human Growth Hormone (1-134): Subjects to receive growth hormone	Subjects randomized to placebo for 16 weeks Placebo: Subjects randomized to placebo
Measure Participants	5	5
Mean (Standard Deviation) [seconds]	69.4 (4.5)	77.6 (25.5)

Adverse Events

Time Frame	Data were collected during study (16 weeks) and for subsequent 4 months.
Adverse Event Reporting Description	No difference in definition.
Arm/Group Title	Human Growth Hormone (1-134)		Placebo
Arm/Group Description	This arm received study drug for 16 weeks. There were no serious adverse events.		This arm received placebo for 16 weeks. There were no serious adverse evens in this group.
All Cause Mortality
	Human Growth Hormone (1-134)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/5 (0%)
Serious Adverse Events
	Human Growth Hormone (1-134)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Human Growth Hormone (1-134)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/5 (20%)
Cardiac disorders
chest pain	0/6 (0%)	0	1/5 (20%)	1

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.