The Frailty Syndrome
Conditions
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.
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.
Interventions
DRUGGhrelin 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.
DRUGGhrelin 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.
Sponsors
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
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) \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| Insulin Level | 0 and 90 minutes after dosing | Median fasting insulin levels at baseline and 90 minutes after dosing |
| Treatment Emergent Adverse Events | 30 days following the last administration of study treatment. | Number and type of treatment emergent adverse events |
| 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. |
| 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. |
| Growth Hormone | 30 minutes after ghrelin administration | median growth hormone peak 30 minutes after placebo/ghrelin. |
| Cortisol Level | 0, 60 and 120 minutes after dosing | Cortisol response to ghrelin or placebo - levels at 0, 60 and 120 minutes after dosing |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Ghrelin 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. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Ghrelin |
|---|---|
| Age, Continuous | 85 years |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 5 | 0 / 2 | 1 / 5 | 3 / 3 | 1 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 2 | 0 / 5 | 0 / 3 | 0 / 5 |
Outcome results
Primary
Cortisol Level
Cortisol response to ghrelin or placebo - levels at 0, 60 and 120 minutes after dosing
Time frame: 0, 60 and 120 minutes after dosing
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Cortisol Level | 0 minutes, baseline | 26.4 mcg/dL |
| Placebo | Cortisol Level | 120 minutes after dosing | 18.8 mcg/dL |
| Placebo | Cortisol Level | 60 minutes after dosing | 18.6 mcg/dL |
| 2ug/kg | Cortisol Level | 60 minutes after dosing | 22.0 mcg/dL |
| 2ug/kg | Cortisol Level | 0 minutes, baseline | 27.1 mcg/dL |
| 2ug/kg | Cortisol Level | 120 minutes after dosing | 29.7 mcg/dL |
| 5ug/kg | Cortisol Level | 60 minutes after dosing | 35.3 mcg/dL |
| 5ug/kg | Cortisol Level | 0 minutes, baseline | 28.4 mcg/dL |
| 5ug/kg | Cortisol Level | 120 minutes after dosing | 27.5 mcg/dL |
| 7.5ug/kg | Cortisol Level | 0 minutes, baseline | 21.5 mcg/dL |
| 7.5ug/kg | Cortisol Level | 120 minutes after dosing | 32.5 mcg/dL |
| 7.5ug/kg | Cortisol Level | 60 minutes after dosing | 33.7 mcg/dL |
| 10ug/kg | Cortisol Level | 60 minutes after dosing | 31.8 mcg/dL |
| 10ug/kg | Cortisol Level | 0 minutes, baseline | 22.7 mcg/dL |
| 10ug/kg | Cortisol Level | 120 minutes after dosing | 26.4 mcg/dL |
Primary
Free Fatty Acid Level
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Free Fatty Acid Level | 90 minutes | 0.17 mEq/L |
| Placebo | Free Fatty Acid Level | 120 minutes | 0.10 mEq/L |
| 2ug/kg | Free Fatty Acid Level | 120 minutes | 0.08 mEq/L |
| 2ug/kg | Free Fatty Acid Level | 90 minutes | 0.11 mEq/L |
| 5ug/kg | Free Fatty Acid Level | 120 minutes | 0.09 mEq/L |
| 5ug/kg | Free Fatty Acid Level | 90 minutes | 0.22 mEq/L |
| 7.5ug/kg | Free Fatty Acid Level | 90 minutes | 0.35 mEq/L |
| 7.5ug/kg | Free Fatty Acid Level | 120 minutes | 0.14 mEq/L |
| 10ug/kg | Free Fatty Acid Level | 120 minutes | 0.12 mEq/L |
| 10ug/kg | Free Fatty Acid Level | 90 minutes | 0.29 mEq/L |
Primary
Glucose Levels
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Glucose Levels | Fasting (0 minutes) | 93 mg/dL |
| Placebo | Glucose Levels | peak postprandial (60 or 90 minutes after dosing) | 142 mg/dL |
| 2ug/kg | Glucose Levels | Fasting (0 minutes) | 90 mg/dL |
| 2ug/kg | Glucose Levels | peak postprandial (60 or 90 minutes after dosing) | 141 mg/dL |
| 5ug/kg | Glucose Levels | Fasting (0 minutes) | 91 mg/dL |
| 5ug/kg | Glucose Levels | peak postprandial (60 or 90 minutes after dosing) | 162 mg/dL |
| 7.5ug/kg | Glucose Levels | peak postprandial (60 or 90 minutes after dosing) | 167 mg/dL |
| 7.5ug/kg | Glucose Levels | Fasting (0 minutes) | 104 mg/dL |
| 10ug/kg | Glucose Levels | Fasting (0 minutes) | 94 mg/dL |
| 10ug/kg | Glucose Levels | peak postprandial (60 or 90 minutes after dosing) | 164 mg/dL |
Primary
Growth Hormone
median growth hormone peak 30 minutes after placebo/ghrelin.
Time frame: 30 minutes after ghrelin administration
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Growth Hormone | 3.71 ng/mL |
| 2ug/kg | Growth Hormone | 16.87 ng/mL |
| 5ug/kg | Growth Hormone | 31.81 ng/mL |
| 7.5ug/kg | Growth Hormone | 39.20 ng/mL |
| 10ug/kg | Growth Hormone | 33.63 ng/mL |
Primary
Insulin Level
Median fasting insulin levels at baseline and 90 minutes after dosing
Time frame: 0 and 90 minutes after dosing
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Insulin Level | Fasting (0 minutes) | 12.9 uIU/mL |
| Placebo | Insulin Level | 90 minutes after dosing | 82.9 uIU/mL |
| 2ug/kg | Insulin Level | Fasting (0 minutes) | 14.8 uIU/mL |
| 2ug/kg | Insulin Level | 90 minutes after dosing | 115.8 uIU/mL |
| 5ug/kg | Insulin Level | Fasting (0 minutes) | 8.5 uIU/mL |
| 5ug/kg | Insulin Level | 90 minutes after dosing | 109.5 uIU/mL |
| 7.5ug/kg | Insulin Level | 90 minutes after dosing | 77.6 uIU/mL |
| 7.5ug/kg | Insulin Level | Fasting (0 minutes) | 8.7 uIU/mL |
| 10ug/kg | Insulin Level | Fasting (0 minutes) | 9.7 uIU/mL |
| 10ug/kg | Insulin Level | 90 minutes after dosing | 85.8 uIU/mL |
Primary
Median Energy Intake
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Median Energy Intake | 535.16 Kilocalories |
| 2ug/kg | Median Energy Intake | 578 Kilocalories |
| 5ug/kg | Median Energy Intake | 813 Kilocalories |
| 7.5ug/kg | Median Energy Intake | 852 Kilocalories |
| 10ug/kg | Median Energy Intake | 862.04 Kilocalories |
Primary
Percentage of Total Energy Intake Relative to Placebo
% of total energy relative to placebo - breakfast served 30 minutes post-placebo or ghrelin administration.
Time frame: 30 mins post-ghrelin or placebo
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Total Energy Intake Relative to Placebo | 100 percentage of placebo intake |
| 2ug/kg | Percentage of Total Energy Intake Relative to Placebo | 110 percentage of placebo intake |
| 5ug/kg | Percentage of Total Energy Intake Relative to Placebo | 135 percentage of placebo intake |
| 7.5ug/kg | Percentage of Total Energy Intake Relative to Placebo | 139 percentage of placebo intake |
| 10ug/kg | Percentage of Total Energy Intake Relative to Placebo | 129 percentage of placebo intake |
Primary
Treatment Emergent Adverse Events
Number and type of treatment emergent adverse events
Time frame: 30 days following the last administration of study treatment.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Treatment Emergent Adverse Events | euphoria | 0 Events |
| Placebo | Treatment Emergent Adverse Events | burping | 1 Events |
| Placebo | Treatment Emergent Adverse Events | sensation of warmth | 0 Events |
| Placebo | Treatment Emergent Adverse Events | bristley feeling | 1 Events |
| Placebo | Treatment Emergent Adverse Events | dizzy | 0 Events |
| Placebo | Treatment Emergent Adverse Events | awareness of old incision | 0 Events |
| 2ug/kg | Treatment Emergent Adverse Events | dizzy | 0 Events |
| 2ug/kg | Treatment Emergent Adverse Events | awareness of old incision | 0 Events |
| 2ug/kg | Treatment Emergent Adverse Events | euphoria | 0 Events |
| 2ug/kg | Treatment Emergent Adverse Events | sensation of warmth | 0 Events |
| 2ug/kg | Treatment Emergent Adverse Events | bristley feeling | 0 Events |
| 2ug/kg | Treatment Emergent Adverse Events | burping | 0 Events |
| 5ug/kg | Treatment Emergent Adverse Events | bristley feeling | 0 Events |
| 5ug/kg | Treatment Emergent Adverse Events | dizzy | 0 Events |
| 5ug/kg | Treatment Emergent Adverse Events | euphoria | 0 Events |
| 5ug/kg | Treatment Emergent Adverse Events | sensation of warmth | 0 Events |
| 5ug/kg | Treatment Emergent Adverse Events | burping | 1 Events |
| 5ug/kg | Treatment Emergent Adverse Events | awareness of old incision | 0 Events |
| 7.5ug/kg | Treatment Emergent Adverse Events | bristley feeling | 0 Events |
| 7.5ug/kg | Treatment Emergent Adverse Events | burping | 0 Events |
| 7.5ug/kg | Treatment Emergent Adverse Events | sensation of warmth | 2 Events |
| 7.5ug/kg | Treatment Emergent Adverse Events | awareness of old incision | 1 Events |
| 7.5ug/kg | Treatment Emergent Adverse Events | dizzy | 1 Events |
| 7.5ug/kg | Treatment Emergent Adverse Events | euphoria | 0 Events |
| 10ug/kg | Treatment Emergent Adverse Events | dizzy | 0 Events |
| 10ug/kg | Treatment Emergent Adverse Events | sensation of warmth | 1 Events |
| 10ug/kg | Treatment Emergent Adverse Events | burping | 0 Events |
| 10ug/kg | Treatment Emergent Adverse Events | awareness of old incision | 0 Events |
| 10ug/kg | Treatment Emergent Adverse Events | bristley feeling | 0 Events |
| 10ug/kg | Treatment Emergent Adverse Events | euphoria | 1 Events |