Muscle Wasting (Atrophy) After Hip Fracture Surgery
Conditions
Keywords
bimagrumab, BYM338, hip fracture, elderly, controlled clinical trial, randomized, muscle wasting, atrophy
Brief summary
The purpose of this study was to assess if bimagrumab is safe and effective in patients with muscle wasting (atrophy) after hip fracture surgery.
Interventions
DRUGbimagrumab
Bimagrumab was administered as intravenous infusion starting on Day 1 until week 20.
OTHERplacebo
Matching placebo was administered as intravenous infusion starting on Day 1 until week 20.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
randomized, interventional, multicenter, placebo-controlled, phase IIa/IIb trial in patients
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Must have X-ray confirmed successful hip fracture repair; Must have completed surgical wound healing; Ability to walk a specified distance with or without a walking aid; Must weigh at least 35 kg.
Exclusion criteria
Must not have history of any other lower limb fractures in the past 6 months; Must not have certain cardiovascular conditions; Must not have a chronic active infection (e.g. HIV, hepatitis B or C, etc); Must not have used high-dose corticosteroid medications for at least 3 months in the past year;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | baseline, weeks 12 and 24 | Mixed Model for Repeated Measures (MMRM) of change from baseline in total LBM (kg) by treatment and visit To assess dose-response relationship of bimagrumab and facilitate an adequate dose selection for future phase III studies, without the need for supportive data from another dose-response finding study, at least three doses were required, ranging from a non-effective or minimally effective dose to a dose where maximal efficacy is expected. Original study was initiated with only two doses of bimagrumab, therefore, a lower dose arm of 70mg has been added to this study with Amendment 2, changing the randomization ratio from 1:1:1 to 2:1:2:2 to either placebo, bimagrumab 70mg, bimagrumab 210mg, or bimagrumab 700mg. Since the 70mg dose was expected to show suboptimal efficacy and fewer patients were randomized to this group, it was used only for dose response modelling and not for hypothesis testing. Consequently, no efficacy evaluations for the bimagrumab 70mg Arm were performed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Gait Speed at Week 24 (Meters/Sec) | Baseline, Week 24 | Mixed Model for Repeated Measures (MMRM) of change from baseline in derived gait speed (m/sec) by treatment and visit To assess dose-response relationship of bimagrumab and facilitate an adequate dose selection for future phase III studies, without the need for supportive data from another dose-response finding study, at least 3 doses were required, ranging from a non-effective or minimally effective dose to a dose where maximal efficacy is expected. Original study was initiated with only two doses of bimagrumab, therefore, a lower dose arm of 70mg was added to this study with Amendment 2, changing the randomization ratio from 1:1:1 to 2:1:2:2 to either placebo, bimagrumab 70mg, bimagrumab 210mg, or bimagrumab 700mg. Since the 70mg dose was expected to show suboptimal efficacy and fewer patients were randomized to this group, it was used only for dose response modelling and not for hypothesis testing. Consequently, no efficacy evaluations for the bimagrumab 70mg Arm were performed |
| Change From Baseline in Short Physical Performance Battery at Weeks 24 | Week 24 | MMRM change from baseline in total score by treatment & visit to Week 24 in physical performance measured by Short Physical Performance Battery (SPPB) that evaluates lower extremity function. Score range is 0 (worst performance) to 12 (best) to assess dose-response relationship of bimagrumab & facilitate adequate dose selection for future phase III studies, without need for supportive data from another dose-response finding study, at least 3 doses were required, ranging from non- or minimally effective dose to a dose where maximal efficacy was expected. Original study was initiated with only 2 doses, therefore, lower 70mg arm was added to this study, changing randomization ratio from 1:1:1 to 2:1:2:2 to either placebo, bimagrumab 70mg, 210mg, or 700mg. Since 70mg dose was expected to show suboptimal efficacy, fewer patients were randomized to this group & it was used only for dose response modelling & not hypothesis testing. Consequently, no efficacy evaluation for 70mg were performed |
| Incidence of Falls up to Week 48 | Up to Week 48 | Group falls rate The frequency of having at least one fall up to Week 48 was summarized by treatment groups Incidence of falls was calculated for each arm up to Week 48. The ratio of these fall rates versus Placebo were calculated and presented as the Falls Rate Ratio. As mentioned in comment 5.1 above, the Falls Rate Ratio for Placebo does not apply because it would entail comparing the group to itself |
Countries
Argentina, Australia, Austria, Belgium, Chile, Colombia, Czechia, France, Germany, Hungary, Japan, Mexico, Russia, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
384 subjects were screened, and 252 subjects completed Screening period. One was lost to follow-up after screening and did not attend any visits for treatment epoch therefore, 251 were recruited to study. 2 subjects died during Screening epoch (1 was reported as discontinued and 1 was reported as a screen failure)
Pre-assignment details
251 subjects entered treatment epoch and were randomized to one of the three bimagrumab dose groups (70 mg, 210 mg and 700 mg) or the placebo group. 1 from the 210 mg group was randomized in error and did not receive study drug. Of the 250 subjects who were randomized and treated, 207 completed the 24 weeks treatment epoch.
Participants by arm
| Arm | Count |
|---|---|
| Bimagrumab 700 mg bimagrumab 700mg administered via intravenous infusion from Day 1 until Week 20 | 75 |
| Bimagrumab 210 mg bimagrumab 210 mg administered via intravenous infusion from Day 1 until Week 20 | 69 |
| Bimagrumab 70 mg bimagrumad 70 mg administered via intravenous infusion starting Day 1 until Week 20 | 34 |
| Placebo placbo administered via intravenous infusion from Day 1 until Week 20 | 72 |
| Total | 250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Epoch: Post-treatment Follow-up Epoch | Adverse Event | 1 | 0 | 0 | 0 |
| Epoch: Post-treatment Follow-up Epoch | Death | 1 | 0 | 0 | 1 |
| Epoch: Post-treatment Follow-up Epoch | Lost to Follow-up | 1 | 4 | 0 | 0 |
| Epoch: Post-treatment Follow-up Epoch | Withdrawal by Subject | 1 | 3 | 0 | 1 |
| Epoch: Treatment Epoch | Adverse Event | 3 | 6 | 1 | 2 |
| Epoch: Treatment Epoch | Death | 0 | 3 | 1 | 0 |
| Epoch: Treatment Epoch | Lost to Follow-up | 0 | 2 | 0 | 0 |
| Epoch: Treatment Epoch | Non-compliance with treatment | 1 | 1 | 0 | 0 |
| Epoch: Treatment Epoch | Technical problems | 0 | 0 | 0 | 1 |
| Epoch: Treatment Epoch | Withdrawal by Subject | 7 | 8 | 3 | 5 |
Baseline characteristics
| Characteristic | Bimagrumab 70 mg | Bimagrumab 700 mg | Bimagrumab 210 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 76.1 years STANDARD_DEVIATION 8.59 | 76.1 years STANDARD_DEVIATION 8.58 | 74.8 years STANDARD_DEVIATION 8.94 | 76.4 years STANDARD_DEVIATION 7.88 | 75.8 years STANDARD_DEVIATION 8.46 |
| Age, Customized 65 - 74 years | 10 Participants | 22 Participants | 23 Participants | 27 Participants | 82 Participants |
| Age, Customized < 65 years | 4 Participants | 9 Participants | 9 Participants | 3 Participants | 25 Participants |
| Age, Customized 75 - 84 years | 16 Participants | 30 Participants | 26 Participants | 32 Participants | 104 Participants |
| Age, Customized =>85 years | 4 Participants | 14 Participants | 11 Participants | 10 Participants | 39 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 13 Participants | 8 Participants | 17 Participants | 44 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 26 Participants | 57 Participants | 58 Participants | 53 Participants | 194 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 4 Participants | 3 Participants | 2 Participants | 11 Participants |
| Sex: Female, Male Female | 21 Participants | 54 Participants | 48 Participants | 53 Participants | 176 Participants |
| Sex: Female, Male Male | 13 Participants | 21 Participants | 21 Participants | 19 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 75 | 3 / 69 | 1 / 34 | 5 / 178 | 1 / 72 |
| other Total, other adverse events | 47 / 75 | 34 / 69 | 15 / 34 | 96 / 178 | 30 / 72 |
| serious Total, serious adverse events | 15 / 75 | 17 / 69 | 9 / 34 | 41 / 178 | 9 / 72 |
Outcome results
Primary
Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24
Mixed Model for Repeated Measures (MMRM) of change from baseline in total LBM (kg) by treatment and visit To assess dose-response relationship of bimagrumab and facilitate an adequate dose selection for future phase III studies, without the need for supportive data from another dose-response finding study, at least three doses were required, ranging from a non-effective or minimally effective dose to a dose where maximal efficacy is expected. Original study was initiated with only two doses of bimagrumab, therefore, a lower dose arm of 70mg has been added to this study with Amendment 2, changing the randomization ratio from 1:1:1 to 2:1:2:2 to either placebo, bimagrumab 70mg, bimagrumab 210mg, or bimagrumab 700mg. Since the 70mg dose was expected to show suboptimal efficacy and fewer patients were randomized to this group, it was used only for dose response modelling and not for hypothesis testing. Consequently, no efficacy evaluations for the bimagrumab 70mg Arm were performed
Time frame: baseline, weeks 12 and 24
Population: The Full Analysis Set (FAS) used for all efficacy analyses consists of all randomized patients who received at least one dose of treatment after randomization and had at least one post-dose efficacy assessment. Patients who were randomized in error were excluded. Patients were analyzed according to treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Bimagrumab 700 mg | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 12 | 1.066 kg | Standard Error 0.0107 |
| Bimagrumab 700 mg | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 24 | 1.064 kg | Standard Error 0.0113 |
| Bimagrumab 210 mg | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 24 | 1.042 kg | Standard Error 0.0115 |
| Bimagrumab 210 mg | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 12 | 1.052 kg | Standard Error 0.0109 |
| Active Total Efficacy (AT:E) | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 12 | 1.059 kg | Standard Error 0.0096 |
| Active Total Efficacy (AT:E) | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 24 | 1.053 kg | Standard Error 0.0101 |
| Placebo | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 12 | 1.009 kg | Standard Error 0.0103 |
| Placebo | Change From Baseline in Total Lean Body Mass Measured by DXA (Dual-energy X-ray Absorptiometry) at Weeks 12 and 24 | week 24 | 0.996 kg | Standard Error 0.0109 |
Comparison: week 12p-value: <0.000195% CI: [1.037, 1.076]Mixed Models Analysis
Comparison: week 12p-value: <0.000195% CI: [1.024, 1.064]Mixed Models Analysis
Secondary
Change From Baseline in Gait Speed at Week 24 (Meters/Sec)
Mixed Model for Repeated Measures (MMRM) of change from baseline in derived gait speed (m/sec) by treatment and visit To assess dose-response relationship of bimagrumab and facilitate an adequate dose selection for future phase III studies, without the need for supportive data from another dose-response finding study, at least 3 doses were required, ranging from a non-effective or minimally effective dose to a dose where maximal efficacy is expected. Original study was initiated with only two doses of bimagrumab, therefore, a lower dose arm of 70mg was added to this study with Amendment 2, changing the randomization ratio from 1:1:1 to 2:1:2:2 to either placebo, bimagrumab 70mg, bimagrumab 210mg, or bimagrumab 700mg. Since the 70mg dose was expected to show suboptimal efficacy and fewer patients were randomized to this group, it was used only for dose response modelling and not for hypothesis testing. Consequently, no efficacy evaluations for the bimagrumab 70mg Arm were performed
Time frame: Baseline, Week 24
Population: The Full Analysis Set (FAS) used for all efficacy analyses consisted of all randomized subjects who received at least 1 dose of investigational drug. Subjects were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bimagrumab 700 mg | Change From Baseline in Gait Speed at Week 24 (Meters/Sec) | 0.268 meters per second | Standard Error 0.0599 |
| Bimagrumab 210 mg | Change From Baseline in Gait Speed at Week 24 (Meters/Sec) | 0.350 meters per second | Standard Error 0.0617 |
| Active Total Efficacy (AT:E) | Change From Baseline in Gait Speed at Week 24 (Meters/Sec) | 0.339 meters per second | Standard Error 0.0607 |
Comparison: week 24p-value: 0.182995% CI: [-0.175, 0.034]Mixed Models Analysis
Comparison: week 24p-value: 0.836595% CI: [-0.096, 0.119]Mixed Models Analysis
Secondary
Change From Baseline in Short Physical Performance Battery at Weeks 24
MMRM change from baseline in total score by treatment & visit to Week 24 in physical performance measured by Short Physical Performance Battery (SPPB) that evaluates lower extremity function. Score range is 0 (worst performance) to 12 (best) to assess dose-response relationship of bimagrumab & facilitate adequate dose selection for future phase III studies, without need for supportive data from another dose-response finding study, at least 3 doses were required, ranging from non- or minimally effective dose to a dose where maximal efficacy was expected. Original study was initiated with only 2 doses, therefore, lower 70mg arm was added to this study, changing randomization ratio from 1:1:1 to 2:1:2:2 to either placebo, bimagrumab 70mg, 210mg, or 700mg. Since 70mg dose was expected to show suboptimal efficacy, fewer patients were randomized to this group & it was used only for dose response modelling & not hypothesis testing. Consequently, no efficacy evaluation for 70mg were performed
Time frame: Week 24
Population: The Full Analysis Set (FAS) used for all efficacy analyses consists of all randomized patients who received at least one dose of treatment after randomization and had at least one post-dose efficacy assessment. Patients who were randomized in error were excluded. Patients were analyzed according to treatment they were assigned to at randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bimagrumab 700 mg | Change From Baseline in Short Physical Performance Battery at Weeks 24 | 2.331 scores on a scale | Standard Error 0.5436 |
| Bimagrumab 210 mg | Change From Baseline in Short Physical Performance Battery at Weeks 24 | 3.535 scores on a scale | Standard Error 0.5623 |
| Active Total Efficacy (AT:E) | Change From Baseline in Short Physical Performance Battery at Weeks 24 | 2.702 scores on a scale | Standard Error 0.5516 |
Comparison: week 24p-value: 0.580295% CI: [-1.311, 1.053]Mixed Models Analysis
Comparison: week 24p-value: 0.091395% CI: [-0.135, 1.801]Mixed Models Analysis
Secondary
Incidence of Falls up to Week 48
Group falls rate The frequency of having at least one fall up to Week 48 was summarized by treatment groups Incidence of falls was calculated for each arm up to Week 48. The ratio of these fall rates versus Placebo were calculated and presented as the Falls Rate Ratio. As mentioned in comment 5.1 above, the Falls Rate Ratio for Placebo does not apply because it would entail comparing the group to itself
Time frame: Up to Week 48
Population: The Full Analysis Set (FAS) used for all efficacy analyses consisted of all randomized subjects who received at least one dose of investigational drug. Subjects were analyzed according to the treatment they were assigned to at randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Bimagrumab 700 mg | Incidence of Falls up to Week 48 | 0.31 Number of Falls per week |
| Bimagrumab 210 mg | Incidence of Falls up to Week 48 | 0.45 Number of Falls per week |
| Active Total Efficacy (AT:E) | Incidence of Falls up to Week 48 | 0.36 Number of Falls per week |
| Placebo | Incidence of Falls up to Week 48 | 0.29 Number of Falls per week |
p-value: 0.835395% CI: [0.53, 2.21]Negative binomial regression
p-value: 0.201595% CI: [0.78, 3.18]Negative binomial regression
Comparison: week 24p-value: 0.399995% CI: [0.52, 3]Negative binomial regression