Muscular Atrophy
Conditions
Keywords
Disuse Atrophy, Muscle, Strength, Arthroplasty, Hip, Joint Replacement
Brief summary
The primary objective of this study is to test the hypothesis that appendicular lean body mass (aLBM) will increase after 12 weeks of LY2495655 treatment versus placebo in older participants undergoing elective total hip arthroplasty (eTHA).
Interventions
DRUGLY2495655
Administered subcutaneously
DRUGPlacebo
Administered subcutaneously
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males with a female partner of childbearing potential should use contraception during the treatment period of the trial and up to 15 weeks after the last dose of investigational product. * Females should be of non-child bearing potential. * Elective total hip arthroplasty (eTHA) is scheduled. * Have a body mass index of \<40 kilograms per square meter (kg/m\^2) and a weight \<136.4 kilograms (kg). * Can climb at least 6 stairs with or without holding the handrail (but without human assistance), according to the participant at screening. * Can stand up from a chair and walk more than 10 meters without human assistance. * Takes at least 12 seconds to perform the Timed Up and Go (TUG) test at screening.
Exclusion criteria
* Another inpatient surgical procedure is planned in the 6 months following randomization. * Lower extremity amputation. * Lower-limb fracture within 6 months prior to screening or any major lower-limb surgery within 3 months prior to randomization. * Simultaneous bilateral eTHA. * The planned surgical procedure will preclude weight bearing for at least 4 weeks postoperatively (for instance, the planned procedure will involve extensive bone grafting). Partial weight-bearing and weight-bearing as tolerated are acceptable, but non weight-bearing, touch weight-bearing, or feather weight-bearing are exclusive. * Underlying muscle disease (for example, polymyositis or muscular dystrophy) or a history of muscle disease other than age-associated muscle waste or disuse atrophy. * Recent neurologic injury (\<6 months prior to randomization) such as stroke or spinal cord injury, or unstable neurologic disorders that are likely to confound physical performance tests during the course of the study (such as unstable Parkinson disease or hemiplegia). * History of positive testing for human immunodeficiency virus (HIV). * Current use or previous use of any drugs known to influence muscle mass or performance within 6 months prior to randomization (this includes anabolic steroids, replacement therapy for gonadal deficiency, anti-androgens, luteinizing hormone-releasing hormone \[LHRH\] agonist and antagonists, growth hormone, Insulin-Like Growth Factor 1 \[IGF1\], or creatinine supplements) or systemic corticosteroid use for at least 3 months (in the last year) prior to randomization at a daily dose greater than or equal to a 10 mg prednisone equivalent. * Severe Vitamin D deficiency defined as 25-hydroxy-vitamin D levels \<9.2 nanograms per milliliter (ng/mL) or \<23 nanomoles per milliliter (nmol/mL) at screening. * History of a malignant neoplasm in the 5 years prior to screening, with the exception of superficial basal cell carcinoma or squamous cell carcinoma of the skin that has been definitively treated. Participants with carcinoma in situ of the uterine cervix treated definitively for more than 1 year prior to screening may enter the study. * History of any of the following conditions within 90 days of screening: unstable angina, myocardial infarction, coronary artery bypass graft surgery, or percutaneous coronary intervention (such as, angioplasty or stent placement). * Any current supraventricular arrhythmia with an uncontrolled ventricular response (mean heart rate \>100 beats per minute \[bpm\]) at rest despite medical or device therapy, any history of spontaneous or induced sustained ventricular tachycardia (heart rate \>100 bpm for 30 seconds) despite medical or device therapy, or any history of resuscitated cardiac arrest or the presence of an automatic internal cardioverter-defibrillator. * Any history of congestive heart failure within 6 months of screening. * Systolic blood pressure \>160 or \<90 millimeters of mercury (mmHg) or diastolic blood pressure \>100 or \<50 mmHg at screening, or malignant hypertension. * An abnormality in the locally read 12-lead electrocardiogram (ECG) that in the opinion of the investigator increases the risk of participating in the study. * Have either or both of the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT) \>2 times the upper limit of normal (ULN), or alkaline phosphatase \>1.5 times ULN, or total bilirubin \>1.5 times ULN. * Known history or presence of severe acute or chronic liver disease. * History of significant renal insufficiency, defined as receiving renal dialysis or having an estimated creatinine clearance \<30 milliliters per minute (mL/minute) at screening. * Current evidence or recent history of significant psychiatric disease such as dementia/Alzheimer's disease, schizophrenia, or bipolar disorder. * Are currently enrolled in, or discontinued within the last 30 days (or 5 half-lives whichever is longer) from a clinical trial involving an investigational drug or off-label use of a drug, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. * Regularly uses known drugs of abuse and/or shows positive findings on urinary drug screening (physician prescribed narcotics are allowed). * Have a positive fecal occult blood (FOB) test at screening or cannot provide a stool sample for FOB testing prior to randomization. * Have uncontrolled diabetes mellitus. * Have had ocular trauma, ophthalmologic surgery, or eye laser treatment within 6 months prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Appendicular Lean Body Mass (aLBM) at Week 12 | Baseline, 12 Weeks | The percentage change in aLBM of 3 limbs (excluding the operated limb) was measured by dual energy x-ray absorptiometry (DEXA). Least squares (LS) means of the aLBM change from baseline to the 12 week endpoint was adjusted by baseline aLBM values as a covariate and treatment, visit, and the treatment-by-visit interaction were included as fixed effect via a mixed-effects model for repeated measured (MMRM) analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Baseline, 4 Weeks, 8 Weeks, and 16 Weeks | The percentage change in aLBM of 3 limbs (excluding the operated limb) was measured by DEXA. LS means of the aLBM change from baseline to the 12 week endpoint was adjusted by baseline aLBM values as a covariate and treatment, visit, and the treatment-by-visit interaction were included as fixed effect via an MMRM analysis. |
Countries
Austria, Belgium, Canada, Denmark, Estonia, Finland, France, Japan, Spain, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Administered subcutaneously every 4 weeks for 12 weeks (administered 4 times) | 98 |
| 35 mg LY2495655 LY2495655: 35 mg administered subcutaneously every 4 weeks for 12 weeks (administered 4 times) | 104 |
| 105 mg LY2495666 LY2495655: 105 mg administered subcutaneously every 4 weeks for 12 weeks (administered 4 times) | 98 |
| 315 mg LY2495655 LY2495655: 315 mg administered subcutaneously every 4 weeks for 12 weeks (administered 4 times) | 100 |
| Total | 400 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 5 | 0 |
| Overall Study | Entry criteria not met | 2 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 2 |
| Overall Study | Physician Decision | 3 | 4 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 2 |
| Overall Study | Sponsor decision | 2 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 6 | 4 | 6 |
Baseline characteristics
| Characteristic | 105 mg LY2495666 | 315 mg LY2495655 | Placebo | Total | 35 mg LY2495655 |
|---|---|---|---|---|---|
| Age, Continuous | 67.85 years STANDARD_DEVIATION 8.14 | 68.71 years STANDARD_DEVIATION 7.95 | 69.38 years STANDARD_DEVIATION 8.9 | 68.65 years STANDARD_DEVIATION 8.26 | 68.66 years STANDARD_DEVIATION 8.09 |
| Body Mass Index (BMI) | 28.14 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.31 | 28.51 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.47 | 28.58 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.82 | 28.51 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.63 | 28.78 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 55 Participants | 52 Participants | 214 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 42 Participants | 45 Participants | 45 Participants | 184 Participants | 52 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 11 Participants | 12 Participants | 46 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 87 Participants | 88 Participants | 85 Participants | 349 Participants | 89 Participants |
| Region of Enrollment Austria | 3 Participants | 5 Participants | 4 Participants | 17 Participants | 5 Participants |
| Region of Enrollment Belgium | 7 Participants | 5 Participants | 4 Participants | 20 Participants | 4 Participants |
| Region of Enrollment Canada | 19 Participants | 19 Participants | 16 Participants | 74 Participants | 20 Participants |
| Region of Enrollment Denmark | 6 Participants | 6 Participants | 11 Participants | 34 Participants | 11 Participants |
| Region of Enrollment Estonia | 13 Participants | 12 Participants | 11 Participants | 41 Participants | 5 Participants |
| Region of Enrollment Finland | 7 Participants | 4 Participants | 7 Participants | 22 Participants | 4 Participants |
| Region of Enrollment France | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 3 Participants |
| Region of Enrollment Japan | 9 Participants | 11 Participants | 11 Participants | 45 Participants | 14 Participants |
| Region of Enrollment Spain | 7 Participants | 5 Participants | 7 Participants | 26 Participants | 7 Participants |
| Region of Enrollment Sweden | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 2 Participants |
| Region of Enrollment United States | 26 Participants | 31 Participants | 27 Participants | 113 Participants | 29 Participants |
| Sex: Female, Male Female | 51 Participants | 54 Participants | 59 Participants | 234 Participants | 70 Participants |
| Sex: Female, Male Male | 47 Participants | 46 Participants | 39 Participants | 166 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 72 / 98 | 76 / 104 | 66 / 98 | 68 / 100 |
| serious Total, serious adverse events | 14 / 98 | 8 / 104 | 16 / 98 | 3 / 100 |
Outcome results
Primary
Change From Baseline in Appendicular Lean Body Mass (aLBM) at Week 12
The percentage change in aLBM of 3 limbs (excluding the operated limb) was measured by dual energy x-ray absorptiometry (DEXA). Least squares (LS) means of the aLBM change from baseline to the 12 week endpoint was adjusted by baseline aLBM values as a covariate and treatment, visit, and the treatment-by-visit interaction were included as fixed effect via a mixed-effects model for repeated measured (MMRM) analysis.
Time frame: Baseline, 12 Weeks
Population: Randomized participants with non-missing baseline and at least 1 post-baseline aLBM measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Week 12 | 0.297 percentage change in aLBM (3 limbs) | Standard Error 0.492 |
| 35 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Week 12 | 0.741 percentage change in aLBM (3 limbs) | Standard Error 0.5 |
| 105 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Week 12 | 1.018 percentage change in aLBM (3 limbs) | Standard Error 0.471 |
| 315 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Week 12 | 1.357 percentage change in aLBM (3 limbs) | Standard Error 0.494 |
Comparison: at Week 12p-value: 0.527Mixed Models Analysis
Comparison: at Week 12p-value: 0.291Mixed Models Analysis
Comparison: at Week 12p-value: 0.129Mixed Models Analysis
Secondary
Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16
The percentage change in aLBM of 3 limbs (excluding the operated limb) was measured by DEXA. LS means of the aLBM change from baseline to the 12 week endpoint was adjusted by baseline aLBM values as a covariate and treatment, visit, and the treatment-by-visit interaction were included as fixed effect via an MMRM analysis.
Time frame: Baseline, 4 Weeks, 8 Weeks, and 16 Weeks
Population: Randomized participants with non-missing baseline and at least 1 post-baseline aLBM measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 4 | NA percentage change in aLBM (3 limbs) | — |
| Placebo | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 16 | -0.102 percentage change in aLBM (3 limbs) | Standard Error 0.494 |
| Placebo | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 8 | -0.900 percentage change in aLBM (3 limbs) | Standard Error 0.485 |
| 35 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 8 | -0.680 percentage change in aLBM (3 limbs) | Standard Error 0.498 |
| 35 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 16 | 0.606 percentage change in aLBM (3 limbs) | Standard Error 0.502 |
| 35 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 4 | NA percentage change in aLBM (3 limbs) | — |
| 105 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 4 | NA percentage change in aLBM (3 limbs) | — |
| 105 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 8 | 0.340 percentage change in aLBM (3 limbs) | Standard Error 0.466 |
| 105 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 16 | 2.058 percentage change in aLBM (3 limbs) | Standard Error 0.467 |
| 315 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 4 | NA percentage change in aLBM (3 limbs) | — |
| 315 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 16 | 1.784 percentage change in aLBM (3 limbs) | Standard Error 0.494 |
| 315 mg LY2495655 | Change From Baseline in Appendicular Lean Body Mass (aLBM) at Weeks 4, 8, and 16 | Week 8 | 0.585 percentage change in aLBM (3 limbs) | Standard Error 0.488 |
Comparison: at Week 8p-value: 0.751Mixed Models Analysis
Comparison: at Week 8p-value: 0.066Mixed Models Analysis
Comparison: at Week 8p-value: 0.031Mixed Models Analysis
Comparison: at Week 16p-value: 0.315Mixed Models Analysis
Comparison: at Week 16p-value: 0.002Mixed Models Analysis
Comparison: at Week 16p-value: 0.007Mixed Models Analysis