The second amendment (INT-2) was considered substantial and included specification that for all non-responders at Week 24, the treatment code would be broken after the Week 28 assessments. For responders at Week 48, the treatment code would be broken after Week 48, following assessment of response. It was also clarified that blinded study treatment would be administered to all subjects at Week 24, and that blood samples for erythropoietin antibody testing in Week 24 non-responders would be obtained after Week 24 response assessments. Additionally, study inclusion criterion 4 was modified: a maximum hemoglobin concentration of 10.5 gram per deciliter (g/dL) at baseline was deemed acceptable for subjects undergoing Red blood cells (RBC) transfusion between screening and baseline. For inclusion criterion 6, a transfusion requirement of less than or equal to (≤) 4 RBC units over the 8 weeks before randomization was defined.

The third amendment (INT-3; 24 January 2013) was considered substantial and included a number of changes to the inclusion/exclusion criteria to reduce the burden on subjects and to provide clarifications. Inclusion criteria 2 and 3 were modified to include diagnosis of myelodysplastic syndromes (MDS) and documentation of International Prognostic Scoring System (IPSS) during the screening phase as well as within the 12 weeks previously, but in case of signs of possible disease progression, a bone marrow aspirate/biopsy for diagnosis of primary MDS and an IPSS score were to be obtained during the screening period. In addition, the possibilities for retesting or rescreening were extended for potential subjects who were suitable for the study but temporarily ineligible due to either factors at screening that could be corrected or that were potentially due to fluctuations in laboratory tests. Inclusion criterion 5 was amended to clarify that erythropoietin could be retested. Additional changes allowed the resupply of vitamin B12 and/or folate to potential subjects who had confirmed MDS diagnosis but had B12/folate deficiency at screening. Such subjects could be eligible for study if adequate retested B12/folate levels were demonstrable before randomization. Inclusion criterion 4 was modified further such that the maximum allowable hemoglobin concentration of 10.5 g/dL was also applied to potential subjects who had received RBC transfusions within 2 weeks before screening. Changes to exclusion criteria included clarifications regarding: prior use of approved or experimental agents for the treatment of MDS ; history of uncontrolled hypertension; androgen or corticosteroid use; 2-week period before screening for prior treatment for neutropenia; and history of heart disease before screening. A new criterion was added to exclude patients who were receiving iron chelation therapy for greater than or equal (≥) 6 months at screening for iron overload caused by blood transfusion.

The local Country-specific protocol amendments that were considered were implemented in Germany (12th Feb 2013), Bulgaria (19th Feb 2014), and Greece (15th Feb 2013). The amendments provided an optional open-label treatment phase and were implemented in Germany, Bulgaria, and Greece. Non-responders at Week 24 who received placebo in the double-blind phase and responders at Week 48 who received epoetin alfa in the treatment extension phase could receive open-label epoetin alfa for up to 6 months after the end of the main double-blind study phase (Germany and Greece) or until up to 1 year after the last subject had enrolled in the open-label treatment phase (Bulgaria). The key aspects and results of the open-label treatment phase will be reported separately. Additionally, a local protocol amendment indicated that measurement of iron-binding capacity was optional in Germany, consistent with local clinical practice.