Ghrelin Dose Finding In Frail Elderly

Study Description

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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	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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	6 participants
Intervention Model:	Single Group Assignment
Masking:	Single (Participant)
Official Title:	Ghrelin In Frail Elderly Subcutaneous Dose Finding Study
Study Start Date :	May 2012
Actual Primary Completion Date :	December 2012
Actual Study Completion Date :	December 2012

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Ghrelin; Dose finding with each participant receiving placebo and three doses of ghrelin, separated by 3-7 days

Drug: 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.

Outcome Measures

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Primary Outcome Measures :

1. Safety [ Time Frame: 0, 15, 30, 45, 60, 90, 120 minutes ]
   laboratory measurements compared to placebo (pre- and post-prandial glucose, insulin, free fatty acids, and cortisol).
2. Safety [ Time Frame: 0, 15, 30, 45, 60, 90, 120 minutes, 1 day later and through 30 days following the last administration of study treatment. ]
   Treatment emergent adverse events
3. Efficacy [ Time Frame: 2 hours, 30 minutes post injection ]
   A standardized nutritionally balanced meal provided 30 minutes post injection ) and assessed for caloric intake two hours later based upon returned uneaten portion.

Secondary Outcome Measures :

1. Growth hormone, total ghrelin and active ghrelin profiles [ Time Frame: 0, 15, 30, 45, 60, 90 and 120 minutes ]
2. Food Intake [ Time Frame: Day-1 and Day-2 ]
   Assessed via self reported food intake record on day 1 and day 2 post injection.

Eligibility Criteria

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Ages Eligible for Study:	70 Years and older (Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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 Jamar dynamometer (Fred Sammons, Inc., Burr Ridge, IL). 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

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Locations

United States, Pennsylvania
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

More Information

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Responsible Party:	Anne Cappola, Associate Professor of Medicine, University of Pennsylvania
ClinicalTrials.gov Identifier:	NCT01605435 History of Changes
Other Study ID Numbers:	IRB 814309
First Posted:	May 24, 2012
Last Update Posted:	January 16, 2013
Last Verified:	January 2013