Effect of a Ghrelin Receptor Agonist on Muscle and Bone

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effect of a Ghrelin Receptor Agonist on Muscle and Bone

Conditions
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Sarcopenia, Osteopenia

Intervention / Treatment
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* Drug: Anamorelin Hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to sign informed consent form Community dwelling individuals aged 50 years and older Men (who are sterile or agree to use contraception throughout the study) Postmenopausal women (no menses for 5 years; early postmenopausal women are ineligible because their bone turnover rate is changing rapidly) 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 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 Mini-mental state examination (MMSE) score >21 Exclusion Criteria: BMI > 30 kg/m2 (obese are ineligible because anamorelin may cause weight gain) 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]) Current participation in a fitness program or weight loss program Advanced knee osteoarthritis (OA) or other conditions preventing strength or function testing Lower extremity fracture in the last year Diabetics taking insulin or sulfonylureas and subjects with a fasting blood sugar on screening >150 mg/dl Inadequate hepatic function defined as AST and ALT levels > 2 x upper limit of normal at screening (>74 and >68 MU/ml, respectively) Untreated thyroid or parathyroid disease Significant immune disorder eGFR<30 ml/min Any clinically meaningful electrocardiogram (ECG) abnormality on screening or baseline Crohn's disease Active malignancy or cancer therapy in the last year 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) Allergy to components of the study interventions Other condition or abnormality in screening labs at discretion of the study physician (the PI) Medications: Osteoporosis treatment - teriparatide, abaloparatide, raloxifene, denosumab, or romosozumab in the last 12 mo or a bisphosphonate in the last 2 years Tamoxifen in the last 6 mo Cancer treatment in the last 3 years (except basal cell skin cancer) strong CYP3A4 inhibitors within the previous two weeks (ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin)since anamorelin is mainly metabolized by CYP3A4 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) Drugs with high affinity to alpha-acid glycoprotein (AAG) and therefore with potential to displace anamorelin from binding (e.g., carvedilol, chlorpromazine) Inhibitors of P-glycoprotein (e.g., verapamil, quinidine), and inhibitors of OATP1B3 (e.g., cyclosporine, rifampicin) CYP3A4 inducers (e.g., rifampin) Oral or IV glucocorticoids (>10 days in the last 3 mo) Gonadal hormones (vaginal estrogen okay) Drugs to promote weight loss or gain TNF-α inhibitors (e.g., adalimumab, adalimumab-atto, certolizumab pegol, etanercept, etanercept-szzs, golimumab, infliximab)

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double blind randomized controlled clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: anamorelin<br>one 100 mg tablet daily, taken one hour before breakfast | Drug: Anamorelin Hydrochloride<br>* Ghrelin receptor agonist<br>|
| Placebo Comparator: microcrystaline cellulose<br>one identical appearing tablet daily, taken one hour before breakfast | Drug: Placebo<br>* placebo is a inert substance<br>* Other names: microcrystalline cellulose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| total body muscle mass | to be assessed by D3-creatine dilution | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum procollagen 1 intact N-terminal (P1NP) | a serum biomarker of bone formation | 12 months | 
| fasting plasma glucose | to be assessed by blood drawn after 12 hour fast | 12 months | 
| serum aspartate transaminase (AST) | to be assessed by blood drawn after 12 hour fast | 12 months | 
| alanine transaminase (ALT) | to be assessed by blood drawn after 12 hour fast | 12 months | 
| symptoms and any adverse events | self reported symptoms experienced by study participants | 12 months | 
| appendicular lean mass (ALM) | Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs divided by height squared | 12 months |