This protocol amendment was implemented to provide contact details for the study pharmacovigilance representative at the CRO, and to add the name of the Study Medical Expert to the Investigator’s Approval page. In addition, typographical errors were corrected, including an incorrect mathematical symbol in the description of the null hypothesis.

This protocol amendment was implemented in order to implement changes requested by Ethics Committees and Health Authorities during the approval phase, and to increase compliance with the SmPC. Changes were made to the eligibility criteria, including exclusion of patients using CYP3A4 inducers and patients who were hypersensitive to ranolazine (or its excipients), modification of the definition of alcoholism, and introduction of mandatory GFR calculation as part of the assessment of renal impairment. The parameters to be assessed during clinical laboratory assessment were clarified. Prohibition of grapefruit juice and CYP3A4 inducers was added due to their capacity to affect ranolazine metabolism. The severity of newly developed renal sufficiency requiring dose reduction was changed from mild severe to mild-moderate. The description of adverse reactions was updated to reflect the description provided in the updated SmPC. Verification of eligibility criteria (including laboratory tests) within 3 days of screening was introduced prior to provision of the patients’ drug supply. The description of the efficacy variables was clarified to indicate that efficacy variables should be assessed at the maximum dosage reached. The description of the Modified Bruce exercise treadmill test protocol was amended to clarify that testing was to be carried out by suitably qualified individuals with training in basic life support, and with the requirement of a written emergency plan. In addition, changes were made to reflect changes in the study team, to clarify text and correct typographical errors.

This protocol amendment was implemented following the availability of new data on ranolazine drug interactions, and to change the cardiopulmonary assessment from a treadmill test to a cycle ergometer. In addition, the title of the study was modified to include the “RESTYLE-HCM” name. Based on recent data showing that ranolazine can increase plasma concentrations of metformin by 1.8-fold, a maximum daily dose of 1000 mg metformin was introduced. In addition, the dose of simvastatin was limited to 20 mg once daily, due to the involvement of CYP3A4 in its metabolism. Eligibility criteria were modified accordingly. The description of the procedure for unblinding was clarified. The schedule of events was modified to clarify that physical examinations, ECGs, and assessments of E/E’ ratio and pro-BNP were to take place before the VO2 peak evaluation, and to add recording of concomitant diseases and medications to Visits 2 and 3. The cardiopulmonary test to be employed was changed from the Treadmill test (Bruce modified) to the Cyclo ergometer test, based on the majority of study sites being more familiar with this test; both techniques were considered to be equally appropriate and comparable with regard to the determination of VO2 peak. In addition, changes were made to clarify text and correct typographical errors.

This PA was implemented in order to add details to text describing certain evaluations (Holter ECG monitoring, pro-BNP analysis, etc), to extend the enrolment period further, to update the protocol according to the updated ranolazine SmPC, and to describe administrative changes. The enrolment period was increased from 18 months to 24 months. Clarification was made in the exclusion criteria that QTc would be calculated according to the Bazets method (...). A central review was introduced for ECG parameters (...), whilst clarifying that local evaluations should also be maintained. Details were provided on the data to be collected during the cardiopulmonary exercise test and VO2 peak evaluation. The definition of SAE was amended to include medically important conditions, and clarification was made that hospitalizations planned at the time of obtaining informed consent would not be reported as SAEs. It was also clarified that assessments of expectedness of AEs were to be made based on the ranolazine SmPC rather than the IB, as the SmPC is updated more frequently. The definition of SUSAR was also updated to reflect the definition provided in CT3. Clarification was made that clinically significant abnormal laboratory findings were to be considered as AEs. In addition, the text describing SAE reporting and AE management was updated. Descriptions of 24-h Holter ECG monitoring and proBNP evaluation were added (...). (...)Text describing AR was updated according to the most recent version of the ranolazine SmPC. (...) In addition, atorvastatin was added to the list of drugs metabolised by CYP3A4 that could undergo a dose reduction when co-administered with ranolazine. (...) Details of the study team were updated. (...) The appendices were updated with the most recent version of the Declaration of Helsinki, and with a list of CROs and Consultants involved in the study conduct. Changes were made to clarify text and correct typographical errors.