Effect of a Ghrelin Receptor Agonist on Muscle and Bone

• ClinicalTrials.gov Identifier: NCT04021706
• Recruitment Status: Completed
• First Posted: July 16, 2019
• Last Update Posted: March 9, 2023
• Sponsor: Tufts University
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Information provided by (Responsible Party): Bess Dawson-Hughes, Tufts University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Sarcopenia; Osteopenia	Drug: Anamorelin Hydrochloride; Drug: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: double blind randomized controlled clinical trial
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of a Ghrelin Receptor Agonist on Muscle and Bone
• Actual Study Start Date: December 5, 2019
• Actual Primary Completion Date: January 26, 2023
• Actual Study Completion Date: January 26, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: anamorelin; one 100 mg tablet daily, taken one hour before breakfast	Drug: Anamorelin Hydrochloride; Ghrelin receptor agonist
Placebo Comparator: microcrystaline cellulose; one identical appearing tablet daily, taken one hour before breakfast	Drug: Placebo; placebo is a inert substance; Other Name: microcrystalline cellulose

Outcome Measures

Primary Outcome Measures :

1. total body muscle mass [ Time Frame: 12 months ]
   to be assessed by D3-creatine dilution

Secondary Outcome Measures :

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

Other Outcome Measures:

1. handgrip strength [ Time Frame: 12 months ]
   measure muscle strength and performance using grip strength dynamometer
2. isokinetic leg strength [ Time Frame: 12 months ]
   measure muscle strength and performance using Biodex Isokinetic Dynamometer
3. Health Aging and Body Composition-Physical Performance Battery [ Time Frame: 12 months ]
   measure muscle strength and performance of lower extremity function
4. serum insulin like growth factor-1 (IGF-1) [ Time Frame: 12 months ]
   anabolic intermediary of growth hormone
5. serum C-telopeptide (CTX) [ Time Frame: 12 months ]
   bone resorption marker
6. bone mineral density of the spine and hip [ Time Frame: 12 months ]
   assessed by DXA

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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)

Contacts and Locations

Locations

United States, Massachusetts

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University

Boston, Massachusetts, United States, 02111

Sponsors and Collaborators

Tufts University

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: Bess Dawson-Hughes, MD; Tufts University

More Information

• Responsible Party: Bess Dawson-Hughes, Director Bone Metabolism Lab and Professor of Medicine, Tufts University
• ClinicalTrials.gov Identifier: NCT04021706
• Other Study ID Numbers: 3035; 1R21AR074138-01A1 ( U.S. NIH Grant/Contract )
• First Posted: July 16, 2019
• Last Update Posted: March 9, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Bone Diseases, Metabolic; Sarcopenia; Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases