Frailty
Conditions
Keywords
frailty, ghrelin, appetite, weight loss
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.
Interventions
DRUGGhrelin Infusion - Healthy
At time 0, a graded infusion of Ghrelin of 2.5, 5.0, and 10.0 pmol/kg/min infused in one of the IV sites for 60 minutes each, totalling 180 minutes when the infusion will be stopped.
DRUGGhrelin Infusion - Frail
At time 0, a graded infusion of Ghrelin of 2.5, 5.0, and 10.0 pmol/kg/min will be infused in one of the IV sites for 60 minutes each, totalling 180 minutes when the infusion will be stopped.
OTHERPlacebo Infusion -Healthy
At time 0, an infusion of saline will be started in one of the IV sites (an equivalent amount to compare to the Ghrelin infusion) and will be infused in a stepwise fashion continued until 180 minutes, when the infusion will be stopped.
OTHERPlacebo Infusion - Frail
At time 0, an infusion of saline will be started in one of the IV sites (an equivalent amount to compare to the Ghrelin infusion) and will be infused in a stepwise fashion continued until 180 minutes, when the infusion will be stopped.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
70 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kilocalories Consumed | After infusion | Kilocalorie consumption from meal of standardized composition during the visit when infusion complete |
| Max Change Growth Hormone | 180 minutes | Maximum growth hormone level change from baseline to 180 minutes |
| Max Change Total Ghrelin | 180 minutes | Maximum total ghrelin change from baseline to 180 minutes |
| Max Change Active Ghrelin | 180 minutes | Active ghrelin change from baseline to 180 minutes. Active ghrelin=acylated ghrelin. |
Countries
United States
Participant flow
Pre-assignment details
Seventeen women were screened. Ten qualified - five had unintentional weight loss of \>5% in the prior year plus at least 2 out of the 4 remaining Fried criteria for frailty and five healthy women without any frailty criteria. Women with conditions that can cause weight loss or taking an appetite stimulant or corticosteroids were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Receiving Placebo at one visit/Ghrelin at other visit | 5 |
| Frail Receiving Placebo at one visit/Ghrelin at other visit | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Healthy | Frail | Total |
|---|---|---|---|
| Age, Continuous | 80.6 years | 80.0 years | 80.3 years |
| Sex/Gender, Customized | 5 participants | 5 participants | 10 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 4 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Kilocalories Consumed
Kilocalorie consumption from meal of standardized composition during the visit when infusion complete
Time frame: After infusion
Population: Per protocol, primary analysis combined healthy and frail groups. The study was not powered to make statistical comparisons between the healthy and frail groups. Therefore, we are providing combined data per our protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saline Infusion | Kilocalories Consumed | 412 Kilocalorie | Standard Deviation 151 |
| Ghrelin Infusion | Kilocalories Consumed | 553 Kilocalorie | Standard Deviation 151 |
Primary
Max Change Active Ghrelin
Active ghrelin change from baseline to 180 minutes. Active ghrelin=acylated ghrelin.
Time frame: 180 minutes
Population: Per protocol, primary analysis combined healthy and frail groups. The study was not powered to make statistical comparisons between the healthy and frail groups. Therefore, we are providing combined data per our protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saline Infusion | Max Change Active Ghrelin | -9.1 pg/mL | Standard Deviation 20.4 |
| Ghrelin Infusion | Max Change Active Ghrelin | 845.4 pg/mL | Standard Deviation 448.3 |
Primary
Max Change Growth Hormone
Maximum growth hormone level change from baseline to 180 minutes
Time frame: 180 minutes
Population: Per protocol, primary analysis combined healthy and frail groups. The study was not powered to make statistical comparisons between the healthy and frail groups. Therefore, we are providing combined data per our protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saline Infusion | Max Change Growth Hormone | 0.33 ng/mL | Standard Deviation 1.44 |
| Ghrelin Infusion | Max Change Growth Hormone | 14.24 ng/mL | Standard Deviation 8.49 |
Primary
Max Change Total Ghrelin
Maximum total ghrelin change from baseline to 180 minutes
Time frame: 180 minutes
Population: Per protocol, primary analysis combined healthy and frail groups. The study was not powered to make statistical comparisons between the healthy and frail groups. Therefore, we are providing combined data per our protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saline Infusion | Max Change Total Ghrelin | -68.6 pg/mL | Standard Deviation 90.6 |
| Ghrelin Infusion | Max Change Total Ghrelin | 1803.2 pg/mL | Standard Deviation 714.8 |