Chronic Obstructive Pulmonary Disease (COPD) With Cachexia
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD; cachexia; muscle wasting
Brief summary
This study will assess the pharmacodynamics, pharmacokinetics, safety and tolerability of BYM338 in patients with COPD and cachexia. The primary outcome will be a change in thigh muscle volume compared to placebo. The study will last for approximately 24 weeks.
Interventions
DRUGPlacebo
DRUGBYM338
BYM338
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * Males and females ages 40 to 80 years * Smoking history of at least 10 pack-years * Diagnosis of COPD according to GOLD guidelines (GOLD, 2010), with a post-bronchodilator FEV¬1 \< 80% predicted and FEV1/FVC ratio \< 0.70 * BMI \<20 kg/m2 or skeletal muscle mass index by DXA \< 7.25 kg/m2 for men or \<5.45 kg/m2 for women. * In general stable health, including managed COPD, by past medical history, physical examination, vital signs at baseline as determined by the investigator.
Exclusion criteria
* Patients with MRC dyspnoea grade 5 (i.e. patients too breathless to leave the house or breathless when dressing) * Plans for lung transplantation or lung reduction surgery within four months of enrollment * Patients participating in a formal pulmonary rehabilitation program within 3 months of dosing * History of malignancy of any organ system (other than excised non-melanomatous carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. * Diseases other than cancer known to cause cachexia or muscle atrophy, including but not limited to congestive heart failure of any stage, chronic kidney disease (estimated GFR \< 30 mL/min using the MDRD equation), rheumatoid arthritis, primary myopathy, stroke, HIV infection, tuberculosis or other chronic infection, uncontrolled diabetes mellitus, etc. * Inflammatory bowel disease, celiac disease, short bowel syndrome, pancreatic insufficiency * Use of any prescription drugs known to affect muscle mass, including androgen supplements, anti-androgens (such as LHRH agonists), anti-estrogens (tamoxifen, etc.) recombinant human growth hormone (rhGH), insulin, oral beta agonists, megestrol acetate, dronabinol, metformin, etc. * Hemoglobin concentration below 11.0 g/dL at screening. * Liver disease or liver injury. * Use of other investigational drugs at the time of enrollment, or within 30 days and for any other limitation of participation in an investigational trial based on local regulations. * Women of child-bearing potential. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Baseline, Weeks 4, 8, 16, 24 | Thigh Muscle Volume (TMV) change was evaluated by a responder analysis. Patients whose loss of muscle TMV by MRI was no more than or equal to 2% at Week 4,8,16 and 24 was considered responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6 Minute Walk Distance Compared to Placebo | Baseline, Weeks 4, 8, 16, 24 | Practical simple test that requires a 100-ft hallway but no exercise quipment or advanced training for technicians. Walking is an activity performed daily by all but the most severely impaired patients. This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD) |
| Maximum Observed Serum Concentration (Cmax) | 0 hour, 2 hour, Day 8, 15, 29, 57, 71, 85, 99, 113, 127, 168 post dose | The observed maximum plasma concentration following drug administration |
| Time to Reach the Maximum Concentration After Drug Administration (Tmax) | 24 weeks | The time to reach the maximum concentration after drug administration |
| AUC0-56 and AUClast | 0 hour, 2 hour, Day 8, 15, 29, 57, 71, 85, 99, 113, 127, 168 post dose | AUC0-56, the area under the serum concentration-time curve from the time zero to the end of the dosing interval, day 56. AUC0-56 was analyzed for dose 1 and 2. AUClast is from time zero to the last quantifiable concentration. AUClast was analyzed for dose 2 only. |
Countries
Netherlands, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BYM338 30 mg/kg | 33 |
| Placebo Placebo to BYM338 30mg/kg | 34 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 1 | 2 |
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Subject withdrew consent | 2 | 2 |
Baseline characteristics
| Characteristic | BYM338 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.5 Years STANDARD_DEVIATION 5.93 | 63.1 Years STANDARD_DEVIATION 7.51 | 63.7 Years STANDARD_DEVIATION 6.76 |
| Sex: Female, Male Female | 16 Participants | 18 Participants | 34 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 33 | 30 / 34 |
| serious Total, serious adverse events | 4 / 33 | 3 / 34 |
Outcome results
Primary
Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24
Thigh Muscle Volume (TMV) change was evaluated by a responder analysis. Patients whose loss of muscle TMV by MRI was no more than or equal to 2% at Week 4,8,16 and 24 was considered responders.
Time frame: Baseline, Weeks 4, 8, 16, 24
Population: Pharmacodynamics (PD) analysis set: Patients with evaluable PD parameter data. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BYM338 | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Week 4 Day 29 (n=30,31) | 5.87 Percentage Change of TMV | Standard Deviation 3.413 |
| BYM338 | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Week 8 Day 57 (n=27,27) | 7.01 Percentage Change of TMV | Standard Deviation 3.707 |
| BYM338 | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Week 16 Day 113 (27,28) | 7.84 Percentage Change of TMV | Standard Deviation 5.052 |
| BYM338 | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | End of Study, week 24 (n=27,28) | 5.04 Percentage Change of TMV | Standard Deviation 4.872 |
| Placebo | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | End of Study, week 24 (n=27,28) | -1.31 Percentage Change of TMV | Standard Deviation 4.282 |
| Placebo | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Week 4 Day 29 (n=30,31) | 0.02 Percentage Change of TMV | Standard Deviation 3.261 |
| Placebo | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Week 16 Day 113 (27,28) | -0.88 Percentage Change of TMV | Standard Deviation 4.471 |
| Placebo | Percentage Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan at Week 4, 8, 16, and 24 | Week 8 Day 57 (n=27,27) | -0.65 Percentage Change of TMV | Standard Deviation 2.752 |
Comparison: Week 4p-value: <0.00190% CI: [104.64, 107.58]ANCOVA
Comparison: Week 8p-value: <0.00190% CI: [106.18, 109.35]ANCOVA
Comparison: Week 16p-value: <0.00190% CI: [106.31, 111]ANCOVA
Comparison: Week 24p-value: <0.00190% CI: [104.39, 108.93]ANCOVA
Secondary
AUC0-56 and AUClast
AUC0-56, the area under the serum concentration-time curve from the time zero to the end of the dosing interval, day 56. AUC0-56 was analyzed for dose 1 and 2. AUClast is from time zero to the last quantifiable concentration. AUClast was analyzed for dose 2 only.
Time frame: 0 hour, 2 hour, Day 8, 15, 29, 57, 71, 85, 99, 113, 127, 168 post dose
Population: Pharmacokinetics (PK) analysis set: Patients with evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BYM338 | AUC0-56 and AUClast | AUC0-56 dose 1 (n=26) | 4540 day*ug/mL | Standard Deviation 897 |
| BYM338 | AUC0-56 and AUClast | AUC0-56 dose 2 (n=25) | 5790 day*ug/mL | Standard Deviation 1300 |
| BYM338 | AUC0-56 and AUClast | AUClast dose 2 (n=25) | 7480 day*ug/mL | Standard Deviation 2080 |
Secondary
Change in 6 Minute Walk Distance Compared to Placebo
Practical simple test that requires a 100-ft hallway but no exercise quipment or advanced training for technicians. Walking is an activity performed daily by all but the most severely impaired patients. This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD)
Time frame: Baseline, Weeks 4, 8, 16, 24
Population: Pharmacodynamics (PD) analysis set: Patients with evaluable PD parameter data. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BYM338 | Change in 6 Minute Walk Distance Compared to Placebo | Week 8 Day 57 (n=27,29) | 373.9 meter | Standard Deviation 101.42 |
| BYM338 | Change in 6 Minute Walk Distance Compared to Placebo | Week 16 Day 113 (n=25,28) | 379.7 meter | Standard Deviation 83.78 |
| BYM338 | Change in 6 Minute Walk Distance Compared to Placebo | Week 12 Day 85 (n=27,28) | 383.0 meter | Standard Deviation 84.63 |
| BYM338 | Change in 6 Minute Walk Distance Compared to Placebo | End of Study week 24 (n=27, 28) | 374.9 meter | Standard Deviation 98.29 |
| BYM338 | Change in 6 Minute Walk Distance Compared to Placebo | Week 4 Day 29 (n=30,32) | 364.6 meter | Standard Deviation 85.45 |
| Placebo | Change in 6 Minute Walk Distance Compared to Placebo | End of Study week 24 (n=27, 28) | 378.8 meter | Standard Deviation 81.5 |
| Placebo | Change in 6 Minute Walk Distance Compared to Placebo | Week 4 Day 29 (n=30,32) | 388.5 meter | Standard Deviation 100.22 |
| Placebo | Change in 6 Minute Walk Distance Compared to Placebo | Week 8 Day 57 (n=27,29) | 387.4 meter | Standard Deviation 99.73 |
| Placebo | Change in 6 Minute Walk Distance Compared to Placebo | Week 12 Day 85 (n=27,28) | 385.6 meter | Standard Deviation 107.62 |
| Placebo | Change in 6 Minute Walk Distance Compared to Placebo | Week 16 Day 113 (n=25,28) | 352.9 meter | Standard Deviation 104.01 |
Secondary
Maximum Observed Serum Concentration (Cmax)
The observed maximum plasma concentration following drug administration
Time frame: 0 hour, 2 hour, Day 8, 15, 29, 57, 71, 85, 99, 113, 127, 168 post dose
Population: Pharmacokinetics (PK) analysis set: Patients with evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BYM338 | Maximum Observed Serum Concentration (Cmax) | Cmax dose 1 (n=31) | 614 ug/mL | Standard Deviation 143 |
| BYM338 | Maximum Observed Serum Concentration (Cmax) | Cmax dose 2 (n=26) | 580 ug/mL | Standard Deviation 121 |
Secondary
Time to Reach the Maximum Concentration After Drug Administration (Tmax)
The time to reach the maximum concentration after drug administration
Time frame: 24 weeks
Population: Pharmacokinetics (PK) analysis set: Patients with evaluable PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BYM338 | Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Tmax dose 1 (n=31) | 2.22 hr |
| BYM338 | Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Tmax dose 2 (n=26) | 2.23 hr |