Study Description

Adults with both osteopenia and sarcopenia (osteosarcopenia) have a 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 apatite 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. Our 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 study team 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 the bone formation biomarker, amino-terminal propeptide (P1NP), and an increase in total lean 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 study proposes 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 a potential therapy to mitigate the dual hazards of osteopenia and sarcopenia.

ELIGIBILITY CRITERIA:

Ages Eligible for Study:           50 Years and older (Adult, Older Adult)

Sexes Eligible for Study:          All

Accepts Healthy Volunteers:  Yes

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

Study Design:

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Study Location(s):

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States, 02111

Study Website:

https://clinicaltrials.gov/ct2/show/NCT04021706?term=NCT04021706&draw=2&rank=1