Bimagrumab to improve recovery after hip fracture in older adults: a multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial

Abstract

Summary: Background: Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. Methods: This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15–35 kg/m2 who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. Findings: Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p<0·0001) and in the bimagrumab 700 mg group 2·8 kg [2·2]; p<0·0001) but not in the bimagrumab 70 mg group (0·6 kg [SD 2·2]; significance not assessed). Changes in habitual gait speed and short physical performance battery scores between baseline and week 24 were not significantly different across the treatment groups, suggesting no enhancement of physical recovery with bimagrumab over placebo. Bimagrumab was safe and well tolerated. The most frequently reported treatment-emergent adverse events were falls (six [18%] of 34 participants in the bimagrumab 70 mg group; 12 [17%] of 69 participants in the bimagrumab 210 mg group; 14 [19%] of 75 participants in the bimagrumab 700 mg group; and 13 [18%] of 72 participants in the placebo group), muscle spasms (two [6%] in the bimagrumab 70 mg group; 17 [25%] in the bimagrumab 210 mg group; 12 [16%] in the bimagrumab 700 mg group; and six [8%] in the placebo group), and arthralgia (five [15%] in the bimagrumab 70 mg group; six [9%] in the bimagrumab 210 mg group; nine [12%] in the bimagrumab 700 mg group; and five [7%] in the placebo group). Six deaths were reported during the study, none of which were considered by investigators as related to the study drug. Interpretation: Bimagrumab treatment for 24 weeks led to dose-dependent, significant increases in lean body mass in older patients recovering from hip fracture surgery when compared with placebo. However, no functional benefit was observed in recovery of mobility or lower extremity function following bimagrumab treatment compared with placebo. Funding: Novartis Pharma.