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出境医 / 临床实验 / Effect of a Ghrelin Receptor Agonist on Muscle and Bone

Effect of a Ghrelin Receptor Agonist on Muscle and Bone

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
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021
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
Layout table for eligibility information
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
Layout table for location information
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
Layout table for investigator information
Principal Investigator: Bess Dawson-Hughes, MD Tufts University
Tracking Information
First Submitted Date  ICMJE July 9, 2019
First Posted Date  ICMJE July 16, 2019
Last Update Posted Date April 26, 2021
Actual Study Start Date  ICMJE December 5, 2019
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 22, 2021) 		total body muscle mass [ Time Frame: 12 months ]
to be assessed by D3-creatine dilution
Original Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019) 		appendicular lean mass (ALM) [ Time Frame: 12 months ]
Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs divided by height squared
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2021)
  • serum procollagen 1 intact N-terminal (P1NP) [ Time Frame: 12 months ]
    a serum biomarker of bone formation
  • fasting plasma glucose [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast
  • serum aspartate transaminase (AST) [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast
  • alanine transaminase (ALT) [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast
  • symptoms and any adverse events [ Time Frame: 12 months ]
    self reported symptoms experienced by study participants
  • appendicular lean mass (ALM) [ Time Frame: 12 months ]
    Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs divided by height squared
Original Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • serum procollagen 1 intact N-terminal (P1NP) [ Time Frame: 12 months ]
    a serum biomarker of bone formation
  • total body muscle mass [ Time Frame: 12 months ]
    to be assessed by D3-creatine dilution
  • fasting plasma glucose [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast
  • serum aspartate transaminase (AST) [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast
  • alanine transaminase (ALT) [ Time Frame: 12 months ]
    to be assessed by blood drawn after 12 hour fast
  • symptoms and any adverse events [ Time Frame: 12 months ]
    self reported symptoms experienced by study participants
Current Other Pre-specified Outcome Measures
 (submitted: July 15, 2019)
  • handgrip strength [ Time Frame: 12 months ]
    measure muscle strength and performance using grip strength dynamometer
  • isokinetic leg strength [ Time Frame: 12 months ]
    measure muscle strength and performance using Biodex Isokinetic Dynamometer
  • Health Aging and Body Composition-Physical Performance Battery [ Time Frame: 12 months ]
    measure muscle strength and performance of lower extremity function
  • serum insulin like growth factor-1 (IGF-1) [ Time Frame: 12 months ]
    anabolic intermediary of growth hormone
  • serum C-telopeptide (CTX) [ Time Frame: 12 months ]
    bone resorption marker
  • bone mineral density of the spine and hip [ Time Frame: 12 months ]
    assessed by DXA
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Effect of a Ghrelin Receptor Agonist on Muscle and Bone
Official Title  ICMJE Effect of a Ghrelin Receptor Agonist on Muscle and Bone
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
double blind randomized controlled clinical trial
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Sarcopenia
  • Osteopenia
Intervention  ICMJE
  • Drug: Anamorelin Hydrochloride
    Ghrelin receptor agonist
  • Drug: Placebo
    placebo is a inert substance
    Other Name: microcrystalline cellulose
Study Arms  ICMJE
  • Active Comparator: anamorelin
    one 100 mg tablet daily, taken one hour before breakfast
    Intervention: Drug: Anamorelin Hydrochloride
  • Placebo Comparator: microcrystaline cellulose
    one identical appearing tablet daily, taken one hour before breakfast
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: April 22, 2021) 		32
Original Estimated Enrollment  ICMJE
 (submitted: July 15, 2019) 		40
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04021706
Other Study ID Numbers  ICMJE 3035
1R21AR074138-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Bess Dawson-Hughes, Tufts University
Study Sponsor  ICMJE Tufts University
Collaborators  ICMJE National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators  ICMJE
Principal Investigator: Bess Dawson-Hughes, MD Tufts University
PRS Account Tufts University
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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