E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Muscle wasting which includes shrinking of the muscle and weakness. This can occur when a muscle is no longer as active as usual. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013521 |
E.1.2 | Term | Disuse muscle atrophy |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 patients undergoing elective total hip arthroplasty (eTHA). |
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E.2.2 | Secondary objectives of the trial |
Not applicable. In Section E.5.2. exploratory objectives defined. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum I1Q-MC-JDDE(2) approved 22Feb2011
A Phase 2 Randomized Study to Investigate the Efficacy and Safety of LY2495655 Versus Placebo in Older Patients Undergoing Elective Total Hip Arthroplasty (eTHA) – Six Minute Walk Addendum.
Planned in Denmark, Estonia and Finland. |
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E.3 | Principal inclusion criteria |
Males or females age 50 years or older.
Elective total hip arthroplasty (eTHA) is scheduled.
Have a body mass index of <40 kg/ m² and a weight <136.4 kg.
Can climb at least 6 stairs with or without holding the handrail (but without human assistance), according to the patient at the screening visit.
Can stand up from a chair and walk more than 10 meters without human assistance
Take at least 12 seconds to perform the Timed Up and Go (TUG) test at the screening visit. |
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E.4 | Principal exclusion criteria |
1. Another inpatient surgical procedure is planned in the 6 months following the randomization visit.
2. Lower extremity amputation.
3. Lower limb fracture within 6 months prior to the screening visit or any major lower limb surgery within 3 months prior to randomisation.
4. Simultaneous bilateral eTHA.
5. 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.
6. Underlying muscle disease (for example, polymyositis or muscular dystrophy) or a history of muscle disease other than age-associated muscle waste or disuse atrophy.
7. 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).
8. History of positive testing for human immunodeficiency virus (HIV).
9. 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) agonists and antagonists, growth hormone, IGF1, or creatine supplements), or systemic corticosteroid use for at least 3 months (in the last year) prior to randomization at a daily dose ≥10 mg prednisone equivalent.
10. Severe Vitamin D deficiency defined as 25-hydroxy-vitamin D levels <9.2 ng/mL or <23 nmol/L at the screening visit.
11. History of a malignant neoplasm in the 5 years prior to the screening visit, with the exception of superficial basal cell carcinoma or squamous cell carcinoma of the skin that has been definitively treated. Patients with carcinoma in situ of the uterine cervix treated definitively more than 1 year prior to screening may enter the study.
12. History of any of the following conditions within 90 days of the screening visit: Unstable angina, myocardial infarction, coronary artery bypass graft surgery, or percutaneous coronary intervention (eg, angioplasty or stent placement).
13. Any current supraventricular arrhythmia with an uncontrolled ventricular response (mean heart rate >100 beats per minute) at rest despite medical or device therapy, or 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.
14. Any history of congestive heart failure within 6 months of the screening visit.
15. Systolic blood pressure >160 or <90 mm Hg or diastolic blood pressure >100 or <50 mm Hg at randomisation visit (if stress is suspected, retest under basal conditions), or malignant hypertension.
16. 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.
17. Have either or both of the following: Aspartate aminotransferase (AST) or 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. The liver tests above may be repeated once within a week if the initial response exceeds this limit, and the lesser value accepted if it meets this criterion; Known history or presence of severe acute or chronic liver disease.
18. History of significant renal insufficiency, defined as receiving renal dialysis or having an estimated creatinine clearance 30 mL/minute at the screening visit.
19. Current evidence or recent history of significant psychiatric disease such as dementia/Alzheimer’s disease, schizophrenia, or bipolar disorder.
20. 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.
21. Regularly uses known drugs of abuse and/or shows positive findings on urinary drug screening (physician prescribed narcotics are allowed).
22. Have a positive fecal occult blood (FOB) test at screening or the patient cannot provide a stool sample for FOB testing within the visit window prior to randomization.
23. Have uncontrolled diabetes mellitus.
24. Have had ocular trauma, ophthalmologic surgery, or eye laser treatment within 6 months prior to randomisation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in appendicular lean body mass. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after the first injection |
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E.5.2 | Secondary end point(s) |
Exploratory objectives:
To explore changes in aLBM, fat mass, and whole body bone mineral density (BMD) over the course of the study.
To explore the effect of LY2495655 versus placebo on the following efficacy
measures:
o Leg extension strength as assessed with a leg press
o Timed Up and Go Test (TUG)
o Stair climbing time and power
o Hand grip strength
o Use of walking aids
o The Lower Extremity Functional Scale (LEFS) questionnaire
o Number of days hospitalized including surgery and inpatient
rehabilitation
o Number of rehabilitation sessions since last visit
o Falls and fall-related injuries
o Hip pain as assessed by Numeric Rating Scale (NRS).
To explore the population PK of LY2495655 after repeated SC
administration.
To explore the relationship between LY2495655 plasma concentrations and
selected efficacy endpoints including aLBM and physical performance
measures.
To explore the effect of several covariates (such as age and surgical approach,
to be further defined in the Statistical Analysis Plan [SAP]) on LY2495655
efficacy as assessed by aLBM, muscle strength, and physical function.
May explore if genetic variants in myostatin, or genes in the myostatin
pathway are associated with variable efficacy or safety of LY2495655. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Denmark |
Estonia |
Finland |
Japan |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |