Ghrelin Dose Finding In Frail Elderly

Ghrelin In Frail Elderly Subcutaneous Dose Finding Study

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.

Study Overview

• Status: Completed
• Conditions: The Frailty Syndrome
• Intervention / Treatment: Drug: Ghrelin Group 1; Drug: Ghrelin Group 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 Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Clinical and Translational Research Center, University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

    -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Emergent Adverse Events	Number and type of treatment emergent adverse events	30 days following the last administration of study treatment.
Median Energy Intake	Median energy intake at breakfast, which was served 30 minutes post-placebo or ghrelin administration demonstrated at each dose level.	30 mins post-ghrelin or placebo
Percentage of Total Energy Intake Relative to Placebo	% of total energy relative to placebo - breakfast served 30 minutes post-placebo or ghrelin administration.	30 mins post-ghrelin or placebo
Growth Hormone	median growth hormone peak 30 minutes after placebo/ghrelin.	30 minutes after ghrelin administration
Cortisol Level	Cortisol response to ghrelin or placebo - levels at 0, 60 and 120 minutes after dosing	0, 60 and 120 minutes after dosing
Glucose Levels	Median fasting and peak postprandial Glucose levels (60 or 90 minutes from dosing) at placebo and at each ghrelin dose.	0 minutes (baseline) and 60 or 90 minutes from dosing
Insulin Level	Median fasting insulin levels at baseline and 90 minutes after dosing	0 and 90 minutes after dosing
Free Fatty Acid Level	Free Fatty Acid levels (mEq/L) at 60 and 90 minutes after meal (90 and 120 minutes)	90 and 120 minutes after dosing

Collaborators and Investigators

• Sponsor: 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 record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: May 22, 2012
• First Submitted That Met QC Criteria: May 23, 2012
• First Posted (Estimate): May 24, 2012

Study Record Updates

• Last Update Posted (Actual): December 12, 2019
• Last Update Submitted That Met QC Criteria: November 26, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Frailty
• Other Study ID Numbers: IRB 814309