Healthy Volunteer
Conditions
Brief summary
The purpose of this study is to evaluate the safety and tolerability of single and multiple doses of LY2495655 administered subcutaneously and intravenously in Japanese subjects.
Interventions
DRUGLY2495655
administered intravenously or subcutaneously
DRUGPlacebo
administered intravenously or subcutaneously
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
24 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Single dose cohort * Overtly healthy males or females, as determined by medical history and physical examination * Between the ages of 24 and 50 years * Multiple dose cohorts * Sedentary males and females with stable medical problems, if any, that, in the investigator's opinion, will not place the subject at increased risk by participating in the study and will not interfere with interpretation of the data * Between the ages of 50 and 85 years * Score \<600 Metabolic Equivalent Tasks (METs) per week based on International Physical Activity Questionnaire (IPAQ) * All subjects * Male subjects: agree to use a reliable method of birth control * Female subjects: women not of child-bearing potential due to surgical sterilization (at least 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history, or menopause * Up to third generation Japanese, that is defined as all of the subject's biological grandparents are of exclusive Japanese descent and have been born in Japan * Are ambulatory and able to perform a stair climb test * Have clinical laboratory tests within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator * Have venous access sufficient to allow for blood sampling and/or administration of investigational product for intravenous administration
Exclusion criteria
* Single dose cohort * Intend to use over the counter or prescription medication within 14 days prior to dosing through 2 months after dosing except for thyroid replacement hormones or non-absorbed topical preparations per investigator instructions * Abnormal supine blood pressure defined as diastolic blood pressure \> 90 millimeters of mercury (mmHg) and/or systolic blood pressure \>140 mmHg * Multiple dose cohort * If taking medications, subjects who have not been stable for at least 3 months, or the time required to produce stable effects of the drug * Abnormal supine blood pressure defined as \>100 mmHg and/or systolic blood pressure \>160 mmHg * All subjects * Have known allergies to LY2495655, related compounds or any components of the formulation * Have a history or presence of cardiovascular, respiratory (including moderate to severe restrictive lung disease and obstructive disease, chronic bronchitis, and those with symptomatic asthma), hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of constituting a risk when taking the study medication or of interfering with the interpretation of data * Have a history of seizures or convulsions, excluding febrile convulsions in childhood * Subjects with underlying muscle disease or a history of muscle disease (for example, polymyositis or rhabdomyolysis) * Evidence or recent history of significant active psychiatric disease such as schizophrenia, depression, or bipolar disorder * Recent immobilization or major trauma to the legs within 6 months * Knee or hip replacement or lower extremity amputation * Participate in, or have participated within 3 months of study drug administration, a regular resistance training program or plan to participate in an exercise program during the study * Actively working in a physically demanding profession * Have contraindications for the Magnetic Resonance Imaging (MRI) scan * Tattoos on the right leg if the tattoos are at least 20 years old and may have iron-containing pigments * Electrocardiogram (ECG) considered outside the normal limits for the study population by the investigator and relevant for interpretation or indicating cardiac disease * Clinically significant abnormality in neurologic or neurocognitive examinations at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Effects | Baseline to study completion (up to 135 days) | Clinically significant effects are defined as treatment emergent adverse events (TEAEs) which in the opinion of the investigator are thought to be possibly related to study drug. A summary of serious and all other non-serious adverse events (whether or not related to study drug) is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics, Maximum Concentration (Cmax) | Single Dose:Day 1:Predose,10 minutes before end,2,6,12,24,48,192,360,528,696,1032,1368and2040 hours(hrs)Postdose;Multiple Dose:Day 1:Predose,24,48,96,168,264,360,528,696,1032hrs Postdose; Day57:Predose,24,48,96,168,336,672and1680hrs Postdose | — |
| Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Single Dose:Day 1:Predose,10 minutes before end,2,6,12,24,48,192,360,528,696,1032,1368and2040 hours(hrs)Postdose;Multiple Dose:Day 1:Predose,24,48,96,168,264,360,528,696,1032hrs Postdose; Day57:Predose,24,48,96,168,336,672and1680hrs Postdose | Area under the concentration curve (AUC) time zero to infinity (0-inf) was calculated for single dose administration and AUCtau (AUCτ) at steady state was calculated for multiple dose administration. |
| Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Single Dose:Day 1:Predose,10 minutes before end,2,6,12,24,48,192,360,528,696,1032,1368and2040 hours(hrs)Postdose;Multiple Dose:Day 1:Predose,24,48,96,168,264,360,528,696,1032hrs Postdose; Day57:Predose,24,48,96,168,336,672and1680hrs Postdose | — |
| Percentage Change in Thigh Muscle Volume | Baseline, Day 22 for a single dose arm/ baseline, Days 22 and 71 for multiple dose arms | Thigh muscle volume was determined by Magnetic Resonance Imaging (MRI) scan of the right leg thigh muscle. Percentage change in thigh muscle volume=(time point value-baseline value)\*100. Change from baseline for muscle volume was analyzed using mixed model repeated measures (MMRM) model with fixed effects of treatment, time and treatment\*time interaction and a random effect of subject where baseline values were included as a covariate. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single IV Dose 70 mg LY2495655 Single 70 milligram (mg) dose LY2495655 administered intravenously (IV) | 6 |
| Multiple SC Dose 17.5 mg LY2495655 17.5 mg of LY2495655 administered subcutaneously (SC) every 2 weeks for 8 weeks (total of 5 doses) | 9 |
| Multiple SC Dose 140 mg LY2495655 140 mg of LY2495655 administered subcutaneously (SC) every 2 weeks for 8 weeks (total 5 of doses) | 10 |
| Multiple SC Dose 420 mg LY2495655 420 mg dose of LY2495655 administered subcutaneously (SC) every 2 weeks for 8 weeks (total 5 of doses) | 10 |
| Single IV Dose Placebo Single placebo dose administered intravenously (IV) | 2 |
| Multiple SC Dose Placebo Placebo dose administered subcutaneously (SC) every 2 weeks for 8 weeks (total of 5 doses) | 10 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Sponsor decision | 0 | 0 | 1 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Single IV Dose 70 mg LY2495655 | Multiple SC Dose 17.5 mg LY2495655 | Multiple SC Dose 140 mg LY2495655 | Multiple SC Dose 420 mg LY2495655 | Single IV Dose Placebo | Multiple SC Dose Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.7 years STANDARD_DEVIATION 4.2 | 64.6 years STANDARD_DEVIATION 7.2 | 61.2 years STANDARD_DEVIATION 6.9 | 60.3 years STANDARD_DEVIATION 3.3 | 48.0 years STANDARD_DEVIATION 11.3 | 65.0 years STANDARD_DEVIATION 9.2 | 60.4 years STANDARD_DEVIATION 8.5 |
| Height | 167.83 centimeters (cm) STANDARD_DEVIATION 6.81 | 163.57 centimeters (cm) STANDARD_DEVIATION 4.97 | 162.01 centimeters (cm) STANDARD_DEVIATION 8.11 | 162.70 centimeters (cm) STANDARD_DEVIATION 6.2 | 165.65 centimeters (cm) STANDARD_DEVIATION 15.06 | 164.52 centimeters (cm) STANDARD_DEVIATION 6.57 | 163.89 centimeters (cm) STANDARD_DEVIATION 6.82 |
| International Physical Activity Questionnaire (IPAQ) | 1829.25 MET-minutes per week STANDARD_DEVIATION 1619.29 | 278.11 MET-minutes per week STANDARD_DEVIATION 341.65 | 130.80 MET-minutes per week STANDARD_DEVIATION 214.24 | 331.50 MET-minutes per week STANDARD_DEVIATION 301.53 | NA MET-minutes per week | 108.40 MET-minutes per week STANDARD_DEVIATION 198.18 | 436.10 MET-minutes per week STANDARD_DEVIATION 803.71 |
| Race/Ethnicity, Customized Asian/Japanese | 6 Participants | 9 Participants | 10 Participants | 10 Participants | 2 Participants | 10 Participants | 47 Participants |
| Region of Enrollment United States | 6 Participants | 9 Participants | 10 Participants | 10 Participants | 2 Participants | 10 Participants | 47 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants | 4 Participants | 17 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 6 Participants | 7 Participants | 1 Participants | 6 Participants | 30 Participants |
| Weight | 66.48 kilograms (kg) STANDARD_DEVIATION 8.55 | 62.04 kilograms (kg) STANDARD_DEVIATION 7.31 | 63.29 kilograms (kg) STANDARD_DEVIATION 12.56 | 64.05 kilograms (kg) STANDARD_DEVIATION 9.08 | 57.15 kilograms (kg) STANDARD_DEVIATION 12.66 | 62.90 kilograms (kg) STANDARD_DEVIATION 12.36 | 63.28 kilograms (kg) STANDARD_DEVIATION 10.05 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 9 / 9 | 10 / 10 | 10 / 10 | 2 / 2 | 7 / 10 |
| serious Total, serious adverse events | 0 / 6 | 0 / 9 | 0 / 10 | 0 / 10 | 0 / 2 | 0 / 10 |
Outcome results
Primary
Number of Participants With Clinically Significant Effects
Clinically significant effects are defined as treatment emergent adverse events (TEAEs) which in the opinion of the investigator are thought to be possibly related to study drug. A summary of serious and all other non-serious adverse events (whether or not related to study drug) is located in the Reported Adverse Events module.
Time frame: Baseline to study completion (up to 135 days)
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single IV Dose 70 mg LY2495655 | Number of Participants With Clinically Significant Effects | 0 Participants |
| Multiple SC Dose 17.5 mg LY2495655 | Number of Participants With Clinically Significant Effects | 0 Participants |
| Multiple SC Dose 140 mg LY2495655 | Number of Participants With Clinically Significant Effects | 7 Participants |
| Multiple SC Dose 420 mg LY2495655 | Number of Participants With Clinically Significant Effects | 4 Participants |
| Single IV Dose Placebo | Number of Participants With Clinically Significant Effects | 0 Participants |
| Multiple SC Dose Placebo | Number of Participants With Clinically Significant Effects | 2 Participants |
Secondary
Percentage Change in Thigh Muscle Volume
Thigh muscle volume was determined by Magnetic Resonance Imaging (MRI) scan of the right leg thigh muscle. Percentage change in thigh muscle volume=(time point value-baseline value)\*100. Change from baseline for muscle volume was analyzed using mixed model repeated measures (MMRM) model with fixed effects of treatment, time and treatment\*time interaction and a random effect of subject where baseline values were included as a covariate.
Time frame: Baseline, Day 22 for a single dose arm/ baseline, Days 22 and 71 for multiple dose arms
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single IV Dose 70 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 22 | 0.30 percentage change | Standard Deviation 2.33 |
| Multiple SC Dose 17.5 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 22 | 0.40 percentage change | Standard Deviation 1.4 |
| Multiple SC Dose 17.5 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 71 | 1.33 percentage change | Standard Deviation 2.47 |
| Multiple SC Dose 140 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 22 | 1.51 percentage change | Standard Deviation 2.48 |
| Multiple SC Dose 140 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 71 | 2.88 percentage change | Standard Deviation 2.39 |
| Multiple SC Dose 420 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 22 | 1.80 percentage change | Standard Deviation 1.46 |
| Multiple SC Dose 420 mg LY2495655 | Percentage Change in Thigh Muscle Volume | Day 71 | 3.48 percentage change | Standard Deviation 2.84 |
| Single IV Dose Placebo | Percentage Change in Thigh Muscle Volume | Day 22 | NA percentage change | — |
| Multiple SC Dose Placebo | Percentage Change in Thigh Muscle Volume | Day 71 | -1.22 percentage change | Standard Deviation 2.97 |
| Multiple SC Dose Placebo | Percentage Change in Thigh Muscle Volume | Day 22 | -1.15 percentage change | Standard Deviation 1.81 |
Secondary
Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC)
Area under the concentration curve (AUC) time zero to infinity (0-inf) was calculated for single dose administration and AUCtau (AUCτ) at steady state was calculated for multiple dose administration.
Time frame: Single Dose:Day 1:Predose,10 minutes before end,2,6,12,24,48,192,360,528,696,1032,1368and2040 hours(hrs)Postdose;Multiple Dose:Day 1:Predose,24,48,96,168,264,360,528,696,1032hrs Postdose; Day57:Predose,24,48,96,168,336,672and1680hrs Postdose
Population: All participants who received study drug and had evaluable AUC data were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single IV Dose 70 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 1 | 50.5 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 11 |
| Multiple SC Dose 17.5 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 57 | 6.82 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 39 |
| Multiple SC Dose 17.5 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 1 | 2.32 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 34 |
| Multiple SC Dose 140 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 1 | 24.0 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 59 |
| Multiple SC Dose 140 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 57 | 88.7 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 32 |
| Multiple SC Dose 420 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 1 | 79.8 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 40 |
| Multiple SC Dose 420 mg LY2495655 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC) | Day 57 | 319 nanomoles*hour per milliliter(nmol*h/mL) | Geometric Coefficient of Variation 23 |
Secondary
Pharmacokinetics, Maximum Concentration (Cmax)
Time frame: Single Dose:Day 1:Predose,10 minutes before end,2,6,12,24,48,192,360,528,696,1032,1368and2040 hours(hrs)Postdose;Multiple Dose:Day 1:Predose,24,48,96,168,264,360,528,696,1032hrs Postdose; Day57:Predose,24,48,96,168,336,672and1680hrs Postdose
Population: All participants who received study drug and had evaluable Cmax data were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single IV Dose 70 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 1 | 192 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 7 |
| Multiple SC Dose 17.5 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 1 | 8.11 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 41 |
| Multiple SC Dose 17.5 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 57 | 23.8 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 36 |
| Multiple SC Dose 140 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 57 | 304 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 32 |
| Multiple SC Dose 140 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 1 | 102 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 80 |
| Multiple SC Dose 420 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 1 | 303 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 42 |
| Multiple SC Dose 420 mg LY2495655 | Pharmacokinetics, Maximum Concentration (Cmax) | Day 57 | 1060 picomoles per milliliter (pmol/mL) | Geometric Coefficient of Variation 24 |
Secondary
Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax)
Time frame: Single Dose:Day 1:Predose,10 minutes before end,2,6,12,24,48,192,360,528,696,1032,1368and2040 hours(hrs)Postdose;Multiple Dose:Day 1:Predose,24,48,96,168,264,360,528,696,1032hrs Postdose; Day57:Predose,24,48,96,168,336,672and1680hrs Postdose
Population: All participants who received study drug and had evaluable Tmax data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Single IV Dose 70 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 1 | 0.58 hours (h) |
| Multiple SC Dose 17.5 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 1 | 168 hours (h) |
| Multiple SC Dose 17.5 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 57 | 48.0 hours (h) |
| Multiple SC Dose 140 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 57 | 96.0 hours (h) |
| Multiple SC Dose 140 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 1 | 168 hours (h) |
| Multiple SC Dose 420 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 1 | 167 hours (h) |
| Multiple SC Dose 420 mg LY2495655 | Pharmacokinetics, Time of Maximum Observed Drug Concentration (Tmax) | Day 57 | 96.0 hours (h) |