Ghrelin Dose Finding In Frail Elderly

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01605435
• Collaborator: (none)
• Enrollment: 5
• Location: 1
• Arms: 2
• Duration (Months): 7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Frailty is a geriatric syndrome leading to physical deterioration including muscle wasting (sarcopenia) and unintentional weight loss. There are currently no approved therapies for frailty. Ghrelin is a hormone produced by the stomach that stimulates appetite centers in the brain. The purpose of this study is to determine the optimal subcutaneous ghrelin dose as a potential intervention for frail elderly individuals. We will examine food intake and metabolic parameters after placebo and ghrelin administration at three escalating subcutaneously administered doses.

Condition or Disease	Intervention/Treatment	Phase
The Frailty Syndrome	Drug: Ghrelin Group 1; Drug: Ghrelin Group 2	Phase 2

Detailed Description

This study is to determine the optimal ghrelin dose for use in a daily subcutaneous dosing study in frail individuals. Using data from our previous study and the published literature, we have designed a single blind, single dose administration study in which we will examine food intake after ghrelin administration and metabolic parameters (plasma glucose, insulin, free fatty acids, and cortisol) pre and post ghrelin administration.We have selected a dose range using our own and previously published studies from which we will determine subcutaneous doses to use in subsequent studies. The selection criteria for subsequent studies will be the dose that maximizes food intake by more than 30% without inducing hyperglycemia or raising cortisol levels. Participants must meet all inclusion criteria and have no exclusion criteria. Data will be analyzed after the first three participants have completed the protocol and used to inform dose modifications for the next three participants. Data from this portion of the study will be analyzed immediately after its completion, to allow updates to the design of the next study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Other
• Official Title: Ghrelin In Frail Elderly Subcutaneous Dose Finding Study
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ghrelin Group 1 Dose finding with each of the first two participant coming to the CTRC for four visits greater than or equal to 72 hours apart and on each receiving subcutaneous injection of - placebo (first visit) and three escalating doses of ghrelin 2ug/kg (second visit) , 5 ug/kg (third visit), and 10 ug/kg (fourth visit).	Drug: Ghrelin Group 1; The first two participants received placebo at baseline visit, 2 mcg/kg as a single subcutaneous dose at Visit 2, 5 mcg/kg as a single subcutaneous dose at Visit 3, and 10 mcg/Kg as a single subcutaneous dose at visit 4. There was 3-10 days between visits.; Other Names: First dose escalation group
Experimental: Ghrelin Group 2 Dose finding with each of the final three participant coming to the CTRC for four visits greater than or equal to 72 hours apart and on each receiving subcutaneous injection of - placebo (first visit) and three escalating doses of ghrelin 5ug/kg (second visit) , 7.5 ug/kg (third visit), and 10 ug/kg (fourth visit).	Drug: Ghrelin Group 2; The next three participants received placebo at baseline visit, 5 mcg/kg as a single subcutaneous dose at Visit 2, 7.5 mcg/kg as a single subcutaneous dose at Visit 3, and 10 mcg/Kg as a single subcutaneous dose at visit 4.; Other Names: Second dose escalation group

Outcome Measures

Primary Outcome Measures

1. Treatment Emergent Adverse Events [30 days following the last administration of study treatment.]

   Number and type of treatment emergent adverse events

2. Median Energy Intake [30 mins post-ghrelin or placebo]

   Median energy intake at breakfast, which was served 30 minutes post-placebo or ghrelin administration demonstrated at each dose level.

3. Percentage of Total Energy Intake Relative to Placebo [30 mins post-ghrelin or placebo]

   % of total energy relative to placebo - breakfast served 30 minutes post-placebo or ghrelin administration.

4. Growth Hormone [30 minutes after ghrelin administration]

   median growth hormone peak 30 minutes after placebo/ghrelin.

5. Cortisol Level [0, 60 and 120 minutes after dosing]

   Cortisol response to ghrelin or placebo - levels at 0, 60 and 120 minutes after dosing

6. Glucose Levels [0 minutes (baseline) and 60 or 90 minutes from dosing]

   Median fasting and peak postprandial Glucose levels (60 or 90 minutes from dosing) at placebo and at each ghrelin dose.

7. Insulin Level [0 and 90 minutes after dosing]

   Median fasting insulin levels at baseline and 90 minutes after dosing

8. Free Fatty Acid Level [90 and 120 minutes after dosing]

   Free Fatty Acid levels (mEq/L) at 60 and 90 minutes after meal (90 and 120 minutes)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• We will include men and women aged 70 or older who are able to provide informed consent and are frail by the Fried criteria (Table 1).

• Table 1. Frailty criteria. Individuals with three, four, or all five criteria are frail.

• Weight loss: Unintentional weight loss of >5% over the previous year

Exhaustion: Two statements are read:

• I felt that everything I did was an effort

• I could not get going. The question is asked "How often in the last week did you feel this way?" 0 = rarely or none of the time (<1 day), 1 = some or a little of the time (1-2 days), 2 = a moderate amount of the time (3-4 days), or 3 = most of the time. A "2" or "3" response to either question is a positive response.

• Low physical activity: Kcal/week of physical activity calculated from the short version of the Minnesota Leisure Time Activity questionnaire.40 < 383 kcals in men or < 270 kcals/wk in women is positive for this criterion.

• Slow walking speed: A usual pace, 15-ft walk timed from a defined standing start. For men ≤173 cm tall and women ≤159 cm, ≥7 sec, and for men >173 cm and women > 159 cm, ≥ 6 sec is positive for this criterion.

• Weakness: Hand grip strength measured with a dynamometer. The average of three measurements performed in the dominant hand is used. For men with BMI ≤ 24 kg/m2, the cutoff is ≤ 29 kg, for BMI 24.1 to 26 the cutoff is ≤ 30 kg, for BMI 26.1 to 28 the cutoff is ≤30 kg, and for BMI > 28 the cutoff is ≤ 32 kg. For women with BMI ≤ 23 kg/m2, the cutoff is ≤ 17 kg, for BMI 23.1 to 26 the cutoff is ≤ 17.3 kg, for BMI 26.1 to 29 the cutoff is ≤ 18 kg, and for BMI > 29 the cutoff is ≤ 21 kg for a positive criterion.

Exclusion Criteria:

1. Diabetes mellitus or fasting glucose ≥ 126 mg/dL

2. Hospitalization for stroke, myocardial infarction, coronary artery bypass graft surgery, vascular surgery in the past six months.

3. NYHA Class III or IV congestive heart failure

4. Therapy for cancer in the past 12 months, except non-melanoma skin cancer

5. BMI≥ 30 kg/m2

6. Current use of corticosteroids other than topical, ophthalmic, and inhaled preparations

7. Therapy with megestrol acetate or dronabinol within the last 6 weeks

8. TSH measured as <0.4 mU/L or greater than 10mU/L

9. Abnormal liver function tests (LFTs > 2x upper limit of normal)

10. Hemoglobin < 11g/dL

11. Insulin-like growth factor-I (IGF-I) above the age-specific reference range

12. History of surgery within the last 30 days

13. Unstable medical or psychological conditions or unstable home or food environment

14. Cognitive deficit as defined by a Folstein Mini Mental State Exam score < 18/30

15. Depression (defined as a score of >11 on the Geriatric Depression Questionnaire)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical and Translational Research Center, University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Anne R. Cappola, M.D., Sc.M., University Of Pennsylvania, Perelman School of Medicine, Department of Endocrinology, Diabetes and Metabolism

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Anne Cappola, Associate Professor of Medicine, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01605435
• Other Study ID Numbers: IRB 814309
• First Posted: May 24, 2012
• Last Update Posted: Dec 12, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Frailty

Study Results

Participant Flow

Recruitment Details	Study participants were recruited from community dwelling adults meeting study criteria expressing interest in participating in research studies at University of Pennsylvania.
Pre-assignment Detail	Dose finding with each participant receiving placebo at their first study visits and three escalating doses of ghrelin, separated by 3-7 days in visits 2,3 and 4.

Arm/Group Title	Initial Dosing Group	Second Dosing Group
Arm/Group Description	Visit 1: Placebo Visit 2: 2 ug/kg ghrelin Visit 3: 5 ug/kg ghrelin Visit 4: 10 ug/kg ghrelin	Visit 1: Placebo Visit 2: 5 ug/kg ghrelin Visit 3: 7.5 ug/kg ghrelin Visit 4: 10 ug/kg ghrelin
Period Title: Overall Study
STARTED	2	3
COMPLETED	2	3
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ghrelin
Arm/Group Description	Dose finding with each participant receiving placebo and three doses of ghrelin, separated by 3-7 days Ghrelin: The first three participants will receive 2 mcg/kg as a single subcutaneous dose at Visit 3, 5 mcg/kg as a single subcutaneous dose at Visit 4, and 10 mcg/Kg as a single subcutaneous dose at visit 5. There will be 3-10 days between visits. The next three participants will receive either the same dosing at the first three, a regimen that includes an intermediate dose (e.g., 7.5 mcg/kg), or higher (e.g., 12, 15, and 18 mcg/kg) doses.
Overall Participants	5
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	85
Sex: Female, Male (Count of Participants)
Female	3 60%
Male	2 40%
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Treatment Emergent Adverse Events
Description	Number and type of treatment emergent adverse events
Time Frame	30 days following the last administration of study treatment.

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2ug/kg	5ug/kg	7.5ug/kg	10ug/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
burping	1	0	1	0	0
sensation of warmth	0	0	0	2	1
bristley feeling	1	0	0	0	0
dizzy	0	0	0	1	0
awareness of old incision	0	0	0	1	0
euphoria	0	0	0	0	1

2. Primary Outcome

Title	Median Energy Intake
Description	Median energy intake at breakfast, which was served 30 minutes post-placebo or ghrelin administration demonstrated at each dose level.
Time Frame	30 mins post-ghrelin or placebo

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2, 3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2 mcg/kg	5mcg/kg	7.5mcg/kg	10mcg/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
Median (Full Range) [Kilocalories]	535.16	578	813	852	862.04

3. Primary Outcome

Title	Percentage of Total Energy Intake Relative to Placebo
Description	% of total energy relative to placebo - breakfast served 30 minutes post-placebo or ghrelin administration.
Time Frame	30 mins post-ghrelin or placebo

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2 mcg/kg	5mcg/kg	7.5mcg/kg	10mcg/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
Number [percentage of placebo intake]	100	110	135	139	129

4. Primary Outcome

Title	Growth Hormone
Description	median growth hormone peak 30 minutes after placebo/ghrelin.
Time Frame	30 minutes after ghrelin administration

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2mcg/kg	5mcg/kg	7.5mcg/kg	10mcg/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
Median (Full Range) [ng/mL]	3.71	16.87	31.81	39.20	33.63

5. Primary Outcome

Title	Cortisol Level
Description	Cortisol response to ghrelin or placebo - levels at 0, 60 and 120 minutes after dosing
Time Frame	0, 60 and 120 minutes after dosing

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2ug/kg	5ug/kg	7.5ug/kg	10ug/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
0 minutes, baseline	26.4	27.1	28.4	21.5	22.7
60 minutes after dosing	18.6	22.0	35.3	33.7	31.8
120 minutes after dosing	18.8	29.7	27.5	32.5	26.4

6. Primary Outcome

Title	Glucose Levels
Description	Median fasting and peak postprandial Glucose levels (60 or 90 minutes from dosing) at placebo and at each ghrelin dose.
Time Frame	0 minutes (baseline) and 60 or 90 minutes from dosing

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2mcg/kg	5mcg/kg	7.5mcg/kg	10mcg/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
Fasting (0 minutes)	93	90	91	104	94
peak postprandial (60 or 90 minutes after dosing)	142	141	162	167	164

7. Primary Outcome

Title	Insulin Level
Description	Median fasting insulin levels at baseline and 90 minutes after dosing
Time Frame	0 and 90 minutes after dosing

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2ug/kg	5ug/kg	7.5ug/kg	10ug/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
Fasting (0 minutes)	12.9	14.8	8.5	8.7	9.7
90 minutes after dosing	82.9	115.8	109.5	77.6	85.8

8. Primary Outcome

Title	Free Fatty Acid Level
Description	Free Fatty Acid levels (mEq/L) at 60 and 90 minutes after meal (90 and 120 minutes)
Time Frame	90 and 120 minutes after dosing

Outcome Measure Data

Analysis Population Description

At the first visit all participants received s.c. placebo. The first two participants received 2 ,5, and 10ug/kg of ghrelin at visit 2,3 and 4 consecutively. The final three participants received 5,7.5, and 10ug/kg of s.c. ghrelin at visits 2,3 and 4 consecutively.

Arm/Group Title	Placebo	2mcg/kg	5mcg/kg	7.5mcg/kg	10mcg/kg
Arm/Group Description	All 5 subjects received s.c. placebo at visit 1.	The first two participants received 2ug/kg of s.c. ghrelin at visit 2.	The first two participants received 5ug/kg of s.c. ghrelin at visit 3. The final three participants received 5ug/kg of s.c. ghrelin at visits 2.	The final three participants received 7.5ug/kg of s.c. ghrelin at visit 3.	The first two participants received 10ug/kg of s.c. ghrelin at visit 4. The final three participants received 10ug/kg of s.c. ghrelin at visit 4.
Measure Participants	5	2	5	3	5
90 minutes	0.17	0.11	0.22	0.35	0.29
120 minutes	0.10	0.08	0.09	0.14	0.12

Adverse Events

Time Frame	Recorded from study screen through 30 days after the final study visit. Assessed systematically during study visits at time 0, 15, 30, 45, 60, 90 120, and 150 minutes after dosing and 1 day after all study visits by telephone call to subject.
Arm/Group Title	Placebo		2mcg/kg		5mcg/kg		7.5mcg/kg		10mcg/kg
Arm/Group Description	Visit 1 for all five subjects placebo injected s.c. at time 0		Visit 2 for the first two subjects 2mcg/kg ghrelin injected s.c at time 0		Visit 3 for the first two subjects Visit 2 for the last three subjects 5mcg/kg ghrelin injected s.c. at time 0		Visit 3 for the last three subjects 7.5mcg/kg ghrelin injected at time 0		Visit 4 for all five subjects
All Cause Mortality
	Placebo		2mcg/kg		5mcg/kg		7.5mcg/kg		10mcg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		2mcg/kg		5mcg/kg		7.5mcg/kg		10mcg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)		0/5 (0%)		0/3 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		2mcg/kg		5mcg/kg		7.5mcg/kg		10mcg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		0/2 (0%)		1/5 (20%)		3/3 (100%)		1/5 (20%)
Gastrointestinal disorders
burping	1/5 (20%)	1	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0	0/5 (0%)	0
General disorders
bristley feeling in chest	1/5 (20%)	1	0/2 (0%)	0	0/5 (0%)	0	0/3 (0%)	0	0/5 (0%)	0
warmth	0/5 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/3 (66.7%)	2	1/5 (20%)	1
euphoria	0/5 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/3 (0%)	0	1/5 (20%)	1
Nervous system disorders
dizziness	0/5 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1	0/5 (0%)	0
Skin and subcutaneous tissue disorders
awareness of sternotomy incision	0/5 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1	0/5 (0%)	0

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.