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Effect of a Ghrelin Receptor Agonist on Muscle and Bone

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ClinicalTrials.gov Identifier: NCT04021706
Recruitment Status : Not yet recruiting
First Posted : July 16, 2019
Last Update Posted : July 16, 2019
Sponsor:
Collaborator:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
Bess Dawson-Hughes, Tufts University

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 40 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 increase in appendicular lean tissue mass measured by dual-energy x-ray absorptiometry. Secondary endpoints are: increases in muscle strength (isometric leg strength) and function (6-minute walk and modified short physical performance battery), an increase in total body muscle mass, an increase in the bone formation biomarker, amino-terminal propeptide (P1NP), and an increase in total lean (non-fat, non-bone) tissue mass. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 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
Estimated Study Start Date : August 2019
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. appendicular lean mass (ALM) [ Time Frame: 12 months ]
    Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs divided by height squared


Secondary Outcome Measures :
  1. serum procollagen 1 intact N-terminal (P1NP) [ Time Frame: 12 months ]
    a serum biomarker of bone formation

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

  3. fasting plasma glucose [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast

  4. serum aspartate transaminase (AST) [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast

  5. alanine transaminase (ALT) [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast

  6. symptoms and any adverse events [ Time Frame: 12 months ]
    self reported symptoms experienced by study participants


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



Information from the National Library of Medicine

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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 ALM/ht2 of ≤7.26 kg/m2 (men) and ≤5.45 kg/m2 (women) based on screening total body DXA scan
  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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04021706


Contacts
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Contact: Bess Dawson-Hughes, MD 6175563066 bess.dawson-hughes@tufts.edu
Contact: Elise Reitshamer, MS, RD 6175563265 elise.reitshamer@tufts.edu

Locations
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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
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Principal Investigator: Bess Dawson-Hughes, MD Tufts University

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Responsible Party: Bess Dawson-Hughes, Director Bone Metabolism Lab and Professor of Medicine, Tufts University
ClinicalTrials.gov Identifier: NCT04021706     History of Changes
Other Study ID Numbers: 3035
1R21AR074138-01A1 ( U.S. NIH Grant/Contract )
First Posted: July 16, 2019    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
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Sarcopenia
Bone Diseases, Metabolic
Muscular Atrophy
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Atrophy
Pathological Conditions, Anatomical
Signs and Symptoms
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases