Central laboratory serology testing, including hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV, as well as urine drug testing was added at the screening visit.  Exclusion criteria 26 (chronic active hepatitis) was clarified and distinguished from exclusion criteria 33 (chronic active virus or bacterial infection).  Inclusion of rectal, external genitalia, breast, and pelvic exams in physical exam, if deemed necessary by the Investigator, was clarified.  Temperature was added to the vital sign assessments.

Bimagrumab 70 mg group was added in the study to facilitate an adequate dose selection.  The dosing regimen was changed from weight-based to fixed-dose.  The 24-Week treatment period was extended by a 24-Week follow-up without treatment.  The window of eligibility assessment was extended by 2 weeks.  The age limit was decreased from 65 to 60 years.  Several exclusion criteria of conditions affecting the subject’s mobility were merged into one unique criterion focusing on the potentially confounding symptoms rather than a list of diagnoses.  Stable psychiatric conditions were allowed if they do not affect the ability of the subject to comply with the study procedures.  The restriction pertaining to ischemic heart disease was modified. The criterion was reduced to the exclusion of ongoing unstable angina pectoris and history of myocardial infarction in the past 3 months prior to randomization.  The vitamin D related exclusion criterion was modified to exclude only those vitamin deficient subjects who did not receive adequate vitamin D3 supplementation prior to randomization.  Minimum requirements for physical exercising were modified to minimum 4 weeks with at least 2 sessions and inclusion of strength / resistance components with focus on hip and thigh muscles.  The list of forbidden medication was adjusted and the use of anti-estrogens was allowed.  The tri-axial accelerometer device use was removed from the assessment.  Dedicated monitoring of coagulation parameters was considered as unnecessary and was removed from the assessment schedule.  Some of the exploratory biomarkers were removed from the assessment due to the diminished importance of some of these markers or the delayed/challenged development of some of the assays. The use of electronic (e) -diaries for falls and exercise was removed from the study.

Regular echocardiography was deemed unnecessary to be further included for the monitoring of new subjects while the rest of the cardiac monitoring (vital signs and ECG) remained untouched.  The conservative exclusion criteria with 450 and 460 msec thresholds was considered as unnecessary. Consequently, the threshold was lifted up to 500 msec for both genders.  Closer body weight monitoring was included as a part of assessment.  Serology (HIV, HCV, Hepatitis B surface antigen [HbsAg]) and 25-OH vitamin D measurements were excluded from eligibility criteria, but considered as important baseline characteristics or background information.  The role of the Orthopedic Adjudication Committee (Department of Traumatology, Innsbruck University, Austria) was deemed redundant and reference to the potential operational involvement of this committee was removed from the protocol.  A novel PRO measure called the HIP was included in the study along with the PGIS and PGIC, as well as the PROMIS.

A new safety monitoring guidance for subjects with an increase of lipase and/or amylase was added.  The evaluation of the effects of bimagrumab vs. placebo on the incidence of falls was added as a new secondary endpoint. Falls were also added to the testing strategy and analysis strategy for secondary endpoints (SPPB and gait speed) was amended to increase power of the study.  Evaluation of a new responder (binary) variable was added as one of exploratory objectives. The responder was defined as subjects with physical performance improvement without falls.  The statistical section was updated to include data from the new safety monitoring guidance. Also clarifications were added on the blinding handling at the time of the interim DBL.