Osteopenia, Sarcopenia
Conditions
Brief summary
Adults with low muscle mass also usually have low bone mass, making them vulnerable to falls, fractures and other injuries. This project will determine the effectiveness of treatment with a ghrelin receptor agonist in improving short term indicators of muscle and bone health in adults with low bone and muscle mass. The results of this trial will inform the design of a larger, definitive randomized trial designed to establish efficacy.
Detailed description
Adults with both osteopenia and sarcopenia (osteosarcopenia) have greater risk of falls and fractures than those with osteopenia or sarcopenia alone. Drugs are available to reduce fracture risk but currently exercise is the only effective strategy to combat muscle loss. Unfortunately, the majority of adults who start a self-monitored exercise program drop out after 6 months and other options are needed. Ghrelin receptor agonists have been under development to treat anorexia and weight loss in patients with cancer cachexia. The agonist anamorelin has significantly increased weight and lean tissue mass in these patients. Anamorelin mimics the hormone ghrelin which not only increases appetite, but also acts on the pituitary to increase pulsatile growth hormone (GH) secretion. Pulsatile GH stimulates the production of insulin-like growth factor 1 which is anabolic to both muscle and bone. GH levels decline with age and this is thought to contribute to the age-related muscle and bone losses in adults. The central hypothesis is that anamorelin will increase muscle mass, improve muscle function, and increase bone formation in adults with osteosarcopenia. To test this hypothesis, the investigators will conduct a randomized, double-blind, 2-armed, parallel-group intervention trial in 32 osteosarcopenic men and postmenopausal women age 50 and older. Participants will be randomized to anamorelin (100 mg per day) or placebo and treated for 12 months. The primary endpoint is change from baseline in muscle mass by D3-creatine dilution. Secondary endpoints are:appendicular lean tissue mass/ht2 (ALM/ht2) measured by dual-energy x-ray absorptiometry (DXA); the bone formation biomarker, amino-terminal propeptide (P1NP), total body lean mass by DXA. Exploratory outcomes are changes in isokinetic leg strength, grip strength, and muscle performance (Health ABC-Physical Performance Battery (HABC-PPB), serum IGF-1 and C-telopeptide (CTX), and spine and hip bone mineral density (BMD). The proposed treatment supplies the anabolic stimulus to build both muscle and bone. Anamorelin has not been tested in adults with osteosarcopenia. The investigators propose to evaluate this treatment in osteosarcopenic adults who are most in need of treatment and who are also most likely to benefit. Data obtained from this pilot study are critical to determine the feasibility and guide the design of a definitive trial to evaluate this ghrelin receptor agonist as potential therapy to mitigate the dual hazards of osteopenia and sarcopenia.
Interventions
Ghrelin receptor agonist
DRUGPlacebo
placebo is a inert substance
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Tufts University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
double blind randomized controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Ability to sign informed consent form 2. Community dwelling individuals aged 50 years and older 1. Men (who are sterile or agree to use contraception throughout the study) 2. Postmenopausal women (no menses for 5 years; early postmenopausal women are ineligible because their bone turnover rate is changing rapidly) 3. Sarcopenia defined as maximum grip strength \<35.5 kg (men) and \<20 kg (women) in either hand (excluding hands with severe pain or recent surgery) and/or gait speed \<0.8 m/sec 4. Osteopenia defined as spine (at L1, L2, L3, or L4) or total hip or femoral neck BMD T-score between -1.0 and -2.5 5. Mini-mental state examination (MMSE) score \>21
Exclusion criteria
1. BMI \> 30 kg/m2 (obese are ineligible because anamorelin may cause weight gain) 2. Osteoporosis of the spine or hip by DXA scan (specifically, T-score ≤ -2.5 at two lumbar vertebrae or at the total hip or femoral neck, as recommended by the International Society for Clinical Densitometry \[ISCD\]) 3. Current participation in a fitness program or weight loss program 4. Advanced knee osteoarthritis (OA) or other conditions preventing strength or function testing 5. Lower extremity fracture in the last year 6. Diabetics taking insulin or sulfonylureas and subjects with a fasting blood sugar on screening \>150 mg/dl 7. Inadequate hepatic function defined as AST and ALT levels \> 2 x upper limit of normal at screening (\>74 and \>68 MU/ml, respectively) 8. Untreated thyroid or parathyroid disease 9. Significant immune disorder 10. eGFR\<30 ml/min 11. Any clinically meaningful electrocardiogram (ECG) abnormality on screening or baseline 12. Crohn's disease 13. Active malignancy or cancer therapy in the last year 14. Non-English speaking subjects (the investigators can't be confident that non-English speaking subjects could accurately complete the diet assessments which are critical to the integrity of the study) 15. Allergy to components of the study interventions 16. Other condition or abnormality in screening labs at discretion of the study physician (the PI) 17. Medications: 1. Osteoporosis treatment - teriparatide, abaloparatide, raloxifene, denosumab, or romosozumab in the last 12 mo or a bisphosphonate in the last 2 years 2. Tamoxifen in the last 6 mo 3. Cancer treatment in the last 3 years (except basal cell skin cancer) 4. strong CYP3A4 inhibitors within the previous two weeks (ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin)since anamorelin is mainly metabolized by CYP3A4 5. Use of drugs that may prolong the PR or QRS interval durations, such as any of the Class I/Sodium (Na+) Channel blocking antiarrhythmic medications (e.g. flecainide, procainamide, propafenone, quinidine) 6. Drugs with high affinity to alpha-acid glycoprotein (AAG) and therefore with potential to displace anamorelin from binding (e.g., carvedilol, chlorpromazine) 7. Inhibitors of P-glycoprotein (e.g., verapamil, quinidine), and inhibitors of OATP1B3 (e.g., cyclosporine, rifampicin) 8. CYP3A4 inducers (e.g., rifampin) 9. Oral or IV glucocorticoids (\>10 days in the last 3 mo) 10. Gonadal hormones (vaginal estrogen okay) 11. Drugs to promote weight loss or gain 12. TNF-α inhibitors (e.g., adalimumab, adalimumab-atto, certolizumab pegol, etanercept, etanercept-szzs, golimumab, infliximab)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Body Muscle Mass | baseline and 12 months | to be assessed by D3-creatine dilution |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Procollagen 1 Intact N-terminal (P1NP) | baseline and 12 months | a serum biomarker of bone formation |
| Fasting Plasma Glucose | baseline and 12 months | to be assessed by fasting blood drawn after 12 hour fast |
| Serum Aspartate Transaminase (AST) | baseline and 12 months | to be assessed by blood drawn after 12 hour fast |
| Alanine Transaminase (ALT) | baseline and 12 months | to be assessed by blood drawn after 12 hour fast |
| Number of Participants With Symptoms and Any Adverse Events | between baseline and 12 months | Number of participants with symptoms and any adverse events |
| Appendicular Lean Mass (ALM) | baseline and 12 months | Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs |
Other
| Measure | Time frame | Description |
|---|---|---|
| Isokinetic Leg Strength | baseline and 12 months | measure muscle strength and performance using Biodex Isokinetic Dynamometer |
| Health Aging and Body Composition-Physical Performance Battery | baseline and 12 months | lower extremity performance score, scale from 0 (worst performance) to 4 (best performance) |
| Serum Insulin Like Growth Factor-1 (IGF-1) | baseline and 12 months | anabolic intermediary of growth hormone |
| Serum C-telopeptide (CTX) | baseline and 12 months | bone resorption marker |
| Bone Mineral Density of the Spine and Hip | baseline and 12 months | assessed by DXA |
| Handgrip Strength | baseline and 12 months | measure muscle strength and performance using grip strength dynamometer |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anamorelin one 100 mg tablet daily, taken one hour before breakfast
Anamorelin Hydrochloride: Ghrelin receptor agonist | 13 |
| Microcrystaline Cellulose one identical appearing tablet daily, taken one hour before breakfast
Placebo: placebo is a inert substance | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Anamorelin | Total | Microcrystaline Cellulose |
|---|---|---|---|
| Age, Continuous | 73.2 years STANDARD_DEVIATION 5.8 | 74.5 years STANDARD_DEVIATION 6 | 75.7 years STANDARD_DEVIATION 6.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 22 Participants | 11 Participants |
| Region of Enrollment United States | 13 participants | 26 participants | 13 participants |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 17 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 15 |
| other Total, other adverse events | 3 / 17 | 1 / 15 |
| serious Total, serious adverse events | 1 / 17 | 1 / 15 |
Outcome results
Primary
Total Body Muscle Mass
to be assessed by D3-creatine dilution
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Total Body Muscle Mass | Baseline | 21.8 kg units on a scale | Standard Deviation 4.8 |
| Anamorelin | Total Body Muscle Mass | 12 month visit | 22.2 kg units on a scale | Standard Deviation 5.6 |
| Microcrystaline Cellulose | Total Body Muscle Mass | Baseline | 20.8 kg units on a scale | Standard Deviation 6 |
| Microcrystaline Cellulose | Total Body Muscle Mass | 12 month visit | 20.8 kg units on a scale | Standard Deviation 7.4 |
Secondary
Alanine Transaminase (ALT)
to be assessed by blood drawn after 12 hour fast
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Alanine Transaminase (ALT) | baseline | 16.8 U/L | Standard Deviation 6.9 |
| Anamorelin | Alanine Transaminase (ALT) | 12 month visit | 15.8 U/L | Standard Deviation 5.9 |
| Microcrystaline Cellulose | Alanine Transaminase (ALT) | baseline | 17.8 U/L | Standard Deviation 7.9 |
| Microcrystaline Cellulose | Alanine Transaminase (ALT) | 12 month visit | 15.9 U/L | Standard Deviation 6.3 |
Secondary
Appendicular Lean Mass (ALM)
Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Appendicular Lean Mass (ALM) | 12 month visit | 20.8 kg | Standard Deviation 4.4 |
| Anamorelin | Appendicular Lean Mass (ALM) | baseline | 20.8 kg | Standard Deviation 4.4 |
| Microcrystaline Cellulose | Appendicular Lean Mass (ALM) | baseline | 18.3 kg | Standard Deviation 3.8 |
| Microcrystaline Cellulose | Appendicular Lean Mass (ALM) | 12 month visit | 18.0 kg | Standard Deviation 4 |
Secondary
Fasting Plasma Glucose
to be assessed by fasting blood drawn after 12 hour fast
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Fasting Plasma Glucose | baseline | 95 mg/dL | Standard Deviation 8 |
| Anamorelin | Fasting Plasma Glucose | 12 month visit | 102 mg/dL | Standard Deviation 16 |
| Microcrystaline Cellulose | Fasting Plasma Glucose | baseline | 100 mg/dL | Standard Deviation 8 |
| Microcrystaline Cellulose | Fasting Plasma Glucose | 12 month visit | 97 mg/dL | Standard Deviation 8 |
Secondary
Number of Participants With Symptoms and Any Adverse Events
Number of participants with symptoms and any adverse events
Time frame: between baseline and 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Anamorelin | Number of Participants With Symptoms and Any Adverse Events | Myalgia | 1 Participants |
| Anamorelin | Number of Participants With Symptoms and Any Adverse Events | Mild GI complaints | 2 Participants |
| Microcrystaline Cellulose | Number of Participants With Symptoms and Any Adverse Events | Myalgia | 0 Participants |
| Microcrystaline Cellulose | Number of Participants With Symptoms and Any Adverse Events | Mild GI complaints | 0 Participants |
Secondary
Serum Aspartate Transaminase (AST)
to be assessed by blood drawn after 12 hour fast
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Serum Aspartate Transaminase (AST) | baseline | 23.2 U/L | Standard Deviation 9.6 |
| Anamorelin | Serum Aspartate Transaminase (AST) | 12 month visit | 21.8 U/L | Standard Deviation 8.4 |
| Microcrystaline Cellulose | Serum Aspartate Transaminase (AST) | baseline | 17.9 U/L | Standard Deviation 3.8 |
| Microcrystaline Cellulose | Serum Aspartate Transaminase (AST) | 12 month visit | 17.8 U/L | Standard Deviation 3.7 |
Secondary
Serum Procollagen 1 Intact N-terminal (P1NP)
a serum biomarker of bone formation
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Serum Procollagen 1 Intact N-terminal (P1NP) | baseline | 42.0 micrograms/L | Standard Deviation 16.5 |
| Anamorelin | Serum Procollagen 1 Intact N-terminal (P1NP) | 12 month visit | 74.1 micrograms/L | Standard Deviation 45.4 |
| Microcrystaline Cellulose | Serum Procollagen 1 Intact N-terminal (P1NP) | baseline | 45.9 micrograms/L | Standard Deviation 33.7 |
| Microcrystaline Cellulose | Serum Procollagen 1 Intact N-terminal (P1NP) | 12 month visit | 46.2 micrograms/L | Standard Deviation 31.9 |
Other Pre-specified
Bone Mineral Density of the Spine and Hip
assessed by DXA
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Bone Mineral Density of the Spine and Hip | Femoral neck BMD at baseline | 0.73 g/cm^2 | Standard Deviation 0.06 |
| Anamorelin | Bone Mineral Density of the Spine and Hip | Spine BMD at baseline | 1.03 g/cm^2 | Standard Deviation 0.16 |
| Anamorelin | Bone Mineral Density of the Spine and Hip | Femoral neck BMD at 12 months | 0.72 g/cm^2 | Standard Deviation 0.06 |
| Anamorelin | Bone Mineral Density of the Spine and Hip | Spine BMD at 12 months | 1.04 g/cm^2 | Standard Deviation 0.16 |
| Microcrystaline Cellulose | Bone Mineral Density of the Spine and Hip | Femoral neck BMD at 12 months | 0.71 g/cm^2 | Standard Deviation 0.07 |
| Microcrystaline Cellulose | Bone Mineral Density of the Spine and Hip | Femoral neck BMD at baseline | 0.73 g/cm^2 | Standard Deviation 0.08 |
| Microcrystaline Cellulose | Bone Mineral Density of the Spine and Hip | Spine BMD at 12 months | 1.09 g/cm^2 | Standard Deviation 0.17 |
| Microcrystaline Cellulose | Bone Mineral Density of the Spine and Hip | Spine BMD at baseline | 1.08 g/cm^2 | Standard Deviation 0.17 |
Other Pre-specified
Handgrip Strength
measure muscle strength and performance using grip strength dynamometer
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Handgrip Strength | baseline | 28.1 kg | Standard Deviation 8.3 |
| Anamorelin | Handgrip Strength | 12 month visit | 28.4 kg | Standard Deviation 8.4 |
| Microcrystaline Cellulose | Handgrip Strength | baseline | 25.0 kg | Standard Deviation 6.7 |
| Microcrystaline Cellulose | Handgrip Strength | 12 month visit | 26.3 kg | Standard Deviation 7.3 |
Other Pre-specified
Health Aging and Body Composition-Physical Performance Battery
lower extremity performance score, scale from 0 (worst performance) to 4 (best performance)
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Health Aging and Body Composition-Physical Performance Battery | baseline | 2.25 score on a scale of 0 to 4 | Standard Deviation 0.4 |
| Anamorelin | Health Aging and Body Composition-Physical Performance Battery | 12 month visit | 2.43 score on a scale of 0 to 4 | Standard Deviation 0.4 |
| Microcrystaline Cellulose | Health Aging and Body Composition-Physical Performance Battery | baseline | 2.22 score on a scale of 0 to 4 | Standard Deviation 0.4 |
| Microcrystaline Cellulose | Health Aging and Body Composition-Physical Performance Battery | 12 month visit | 2.35 score on a scale of 0 to 4 | Standard Deviation 0.5 |
Other Pre-specified
Isokinetic Leg Strength
measure muscle strength and performance using Biodex Isokinetic Dynamometer
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Isokinetic Leg Strength | knee flexion at 240 degrees/sec - baseline | 27.5 Nm | Standard Deviation 11.4 |
| Anamorelin | Isokinetic Leg Strength | knee extension at 240 degrees/sec - baseline | 61.0 Nm | Standard Deviation 18.5 |
| Anamorelin | Isokinetic Leg Strength | knee extension at 240 degrees/sec, 12 month visit | 65.2 Nm | Standard Deviation 18.9 |
| Anamorelin | Isokinetic Leg Strength | knee flexion at 240 degrees/s, 12 month visit | 34.0 Nm | Standard Deviation 11.2 |
| Microcrystaline Cellulose | Isokinetic Leg Strength | knee flexion at 240 degrees/s, 12 month visit | 27.8 Nm | Standard Deviation 8.2 |
| Microcrystaline Cellulose | Isokinetic Leg Strength | knee flexion at 240 degrees/sec - baseline | 27.2 Nm | Standard Deviation 9 |
| Microcrystaline Cellulose | Isokinetic Leg Strength | knee extension at 240 degrees/sec, 12 month visit | 55.9 Nm | Standard Deviation 18.1 |
| Microcrystaline Cellulose | Isokinetic Leg Strength | knee extension at 240 degrees/sec - baseline | 56.1 Nm | Standard Deviation 18.6 |
Other Pre-specified
Serum C-telopeptide (CTX)
bone resorption marker
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Serum C-telopeptide (CTX) | baseline | 0.69 ng/mL | Standard Deviation 0.2 |
| Anamorelin | Serum C-telopeptide (CTX) | 12 month visit | 0.73 ng/mL | Standard Deviation 0.3 |
| Microcrystaline Cellulose | Serum C-telopeptide (CTX) | baseline | 0.72 ng/mL | Standard Deviation 0.3 |
| Microcrystaline Cellulose | Serum C-telopeptide (CTX) | 12 month visit | 0.64 ng/mL | Standard Deviation 0.3 |
Other Pre-specified
Serum Insulin Like Growth Factor-1 (IGF-1)
anabolic intermediary of growth hormone
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anamorelin | Serum Insulin Like Growth Factor-1 (IGF-1) | baseline | 108 ng/mL | Standard Deviation 14 |
| Anamorelin | Serum Insulin Like Growth Factor-1 (IGF-1) | 12 month visit | 162 ng/mL | Standard Deviation 47 |
| Microcrystaline Cellulose | Serum Insulin Like Growth Factor-1 (IGF-1) | baseline | 110 ng/mL | Standard Deviation 22 |
| Microcrystaline Cellulose | Serum Insulin Like Growth Factor-1 (IGF-1) | 12 month visit | 107 ng/mL | Standard Deviation 38 |