Ghrelin in Healthy and Frail Older Women

Phase 1

Completed

Conditions: Frailty

Interventions: Drug: Ghrelin Infusion - Healthy
Drug: Ghrelin Infusion - Frail
Other: Placebo Infusion -Healthy
Other: Placebo Infusion - Frail

Registration Number: NCT00520884

Lead Sponsor: University of Pennsylvania

Brief Summary: The purpose of this research study is to see if giving women a hormone called "ghrelin" will increase levels of growth hormone in the blood and increase appetite. Ghrelin is a naturally occurring hormone that is produced mostly by the stomach and causes secretion of another hormone called growth hormone. It also increases short-term appetite and may lower the amount of inflammation in the body.

Some people lose their appetite as they age and have unintentional weight loss. This may be caused by a break in the communication between the stomach and the brain. We are particularly interested in seeing if there is a difference in the effects of ghrelin in older women who have lost weight recently without wanting to and those who have not.

Detailed Description: Five community-dwelling women aged 70 or over with unintentional weight loss of \>5% in the prior year plus at least 2 of the 4 remaining Fried criteria for frailty and five healthy women without any frailty criteria were enrolled. Women with conditions that can cause weight loss or taking an appetite stimulant or corticosteroids were excluded. Each woman completed two 180 minute infusions, one week apart, assigned randomly: a graded ghrelin infusion of 2.5, 5.0, and 10.0 pmol/kg/min for 60 minutes each and an equivalent placebo (saline) infusion. A meal of standardized composition was provided after each infusion and intake quantified. Samples were collected every 30 minutes for growth hormone (GH), and total and active ghrelin. Additional samples were collected every 60 minutes for glucose, insulin, free fatty acids, leptin, adiponectin, resistin, glucagon-like peptide-1 receptor agonists (GLP-1), and cortisol. Adverse events were collected during the infusion and by telephone 24 hours later. Non-parametric methods were used to compare differences in response to the ghrelin and placebo infusions 1) in all women and 2) between frail and healthy women.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 10

Inclusion Criteria

Frail group:

Women aged 70 or greater
Able to give informed consent
Undiagnosed weight loss (>5% over the previous year)
Two of the following four criteria (from Fried L et al, 2001): low grip strength, slow walking speed, subjective exhaustion, low levels of physical activity

Healthy group:

Women aged 70 or greater
Able to give informed consent
None of the frailty criteria

Exclusion Criteria

Prior diagnosis of Parkinson's Disease
History of cerebrovascular accident with residual hemiparesis
Hospitalization for treatment of vascular disease (including, coronary heart disease, cerebrovascular disease, peripheral vascular disease) in the past 6 months
Congestive heart failure
Rheumatoid arthritis or other inflammatory conditions
Depression (defined as a score of >11 on the Geriatric Depression Questionnaire)
History of cancer requiring treatment in the past 5 years, with the exception of cancers which have been cured, or, in the opinion of the investigator, carry a good prognosis
Cognitive deficit as defined by a Folstein Mini Mental State Exam score < 18/30
Current use of corticosteroids or immune-modulating agents other than topical, ophthalmic, and inhaled preparations, in past 3 months
Diabetes mellitus
Thyroid stimulating hormone (TSH) measured as <0.5 U/L or greater than 10 U/L. If participant is taking replacement thyroid hormone, they should be on a stable dose for at least 2 months
History of liver disease or abnormal liver function tests (LFTs > 2x upper limit of normal)
Renal insufficiency (serum creatinine ≥ 1.4 mg/dL).
Hemoglobin < 11g/dL
History of surgery within the last 30 days.
Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study
Participation in an investigational drug study within 6 weeks prior to screening visit
Self reported history of HIV disease
Hospitalization for chronic obstructive pulmonary disease or asthma in the past 3 months
History of alcohol abuse as defined as any one of the following:
1. average consumption of 3 or more alcohol containing beverages daily; 2) consumption of 7 or more alcoholic beverages within a 24 hr period in the past 12 months; or 3) clinical assessment of alcohol dependence based on two or more positive responses to an alcoholism questionnaire (if confirmed by further probing) or on other evidence available to clinic staff. If any of these exclusion criteria are met, the subject may still be considered eligible if, after an explanation of the importance of limiting alcohol intake during the study, the clinic staff believes that the volunteer can and will limit future alcohol intake to acceptable levels.
History of gastrectomy
Current therapy with an appetite stimulant, i.e. medroxyprogesterone acetate, within the last 6 weeks.
Weight >85 kg

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Healthy 70+ Women Ghrelin Infusion	Ghrelin Infusion - Healthy	Healthy Women 70 and Older are administered a 3 hour graded Ghrelin Infusion (the first hour of the ghrelin infusion a dose of 2.5 pmol/kg/min, increased to a dose of 5.0 pmol/kg/min for one hour, and then increased to the dose of 10 pmol/kg/min for the final hour of the infusion).
Frail 70+ Women Ghrelin Infusion	Ghrelin Infusion - Frail	Frail Women 70 and Older are administered a 3 hour graded Ghrelin Infusion (the first hour of the ghrelin infusion at a dose of 2.5 pmol/kg/min, increased to a dose of 5.0 pmol/kg/min for one hour, and then increased to the dose of 10 pmol/kg/min for the final hour of the infusion).
Healthy 70+ Women Placebo Infusion	Placebo Infusion -Healthy	Healthy and Frail Women 70 and Older Receive a 3 hour Placebo Infusion of Saline administered in a stepwise fashion in amounts equivalent to the ghrelin infusion.
Frail 70+ Women Placebo Infusion	Placebo Infusion - Frail	Frail Women 70 and Older Receive a 3 hour Placebo Infusion of Saline administered in a stepwise fashion in amounts equivalent to the ghrelin infusion.

Primary Outcome Measures

Name	Time	Method
Max Change Total Ghrelin	180 minutes	Maximum total ghrelin change from baseline to 180 minutes
Max Change Growth Hormone	180 minutes	Maximum growth hormone level change from baseline to 180 minutes
Max Change Active Ghrelin	180 minutes	Active ghrelin change from baseline to 180 minutes. Active ghrelin=acylated ghrelin.
Kilocalories Consumed	After infusion	Kilocalorie consumption from meal of standardized composition during the visit when infusion complete