The primary purpose of this amendment was to eliminate unnecessary delays in qualifying patients caused by the use of a single instrument. The exclusion criterion for minimum protein/calorie intake was revised to provide a choice of well accepted, valid methods for diet evaluation. In addition, the exclusion criteria were amended to identify a minimum body weight. Both of these changes could assist Investigators in identifying potential study patients and reduced the burden on patients who could not be enrolled. Because this amendment was necessary, an opportunity was taken to improve the clarity of certain text, correct a typographical error and update the risks section from data that became available after submission of the original protocol. These data were included in the the Investigator’s Brochure (Edition 3). In addition, two lab parameters were added, but this did not require extra blood sampling. No patients was screened or enrolled in this study at the time of this amendment

The primary purpose of this amendment was to address comments from the IRB, requesting additional exclusion criteria added relating to the optional muscle biopsies. The additional text clarified patient eligibility for this procedure to assist in patient safety and recruitment. A muscle symptoms log was added, to allow patients to record any symptoms related to their muscle throughout the study. To try to clarify and detail adverse events, a detailed dermatology assessment was added to the physical examination

The purpose of this amendment was to update the blood log to adjust the blood volumes taken for safety and PK assessments. Some assessments listed in the biomarkers sections of the protocol, after this amendment, were done together with the safety lab samples, and other volumes adjusted to ensure a sufficient volume for the assay used. There were no changes to the safety, PK, or biomarker parameters being assessed

The purpose of this amendment was to include the addition of an internal DMC separate from the BYM338 project team, which was being implemented in all new and ongoing phase I and IIa studies with BYM338. This DMC was introduced at the request of the US Food and Drug Administration (FDA) because of the new mode of action of BYM338, for which the safety profile was not fully characterized and because of safety concerns observed by FDA with a non-Novartis molecule with a similar mode of action. This amendment also added a second 30 mg/kg iv dose of BYM338 at Week 8 to the study design. Therefore, patients received two doses of BYM338 (Days 1 and 57) during the study period. This additional dosing was to provide drug exposure at a certain serum level over 16 continuous weeks rather than 8 weeks seen with a single dose. This additional exposure extended the treatment time to cover the estimated 16 weeks needed to see a measurable change in physical function, i.e., 6-MWD. Text was modified to clarify the NIRS assessment.

Following a review of the protocol by Health Authorities and ECs, it was requested that an additional exclusion criteria be added, to specifically exclude immunocompromised patients. While most immunodeficient patients were excluded by their primary pathology or medication, i.e. rheumatoid arthritis, it was specified their exclusion to eliminate the possible risk of acquiring from or transmitting infections to other study patients. It was also requested that text included in the ICF section of the protocol regarding pregnancy was removed, as this study excluded women of child bearing potential

The primary purpose of this amendment was to change the number of patients required for the second interim analysis. Following the first interim analysis, the protocol was updated to reflect the need for 50 patients at Week 16 for the second planned interim analysis. This was supported by simulations that showed that this sample size would provide sufficient power to declare that BYM338 significantly improves TMV at Week 8 compared to placebo. Minor administrative changes to the protocol were also included in this amendment.