For women of child bearing potential, the requirements for contraceptives were changed from effective to highly effective and additional pregnancy testing was introduced as a further precautionary measure for all female participants and not only for women of childbearing potential.

The protocol was modified to include 24 months of open-label treatment or until commercial availability of AFQ056, whichever occurred later. In addition, the inclusion criterion describing the requirements for a caregiver was clarified so as to avoid implying only one caregiver was required to oversee study participation for a patient. The criterion excluding patients currently treated with 2 or more psychoactive medications, excluding anti-epileptics, and the requirement prohibiting administration of more than 2 psychoactive medications during the study were removed. The criterion that excluded patients on the basis of a past medical history of clinically significant ECG abnormalities or QTcF >450 msec (males) and >470 msec (females) was modified to clarify that for Group 1 patients, ECGs were assessed at the completion visit of the CAFQ056A2212 study and this served as the ECG baseline for the CAFQ056B2279 study. The protocol was also amended to remove post-baseline assessments of the Clinical Global Impression – Severity (CGI-S). Additionally, instructions were added to the protocol to guide investigators concerning the need to assess patients for the presence of suicidality as part of monitoring of AEs.

The protocol was amended to include new requirements for liver safety monitoring, including an additional blood draw at Month 6 to monitor liver function. The criteria requiring discontinuation of study medication were also revised to include liver function test abnormalities or liver-related adverse events and QTc prolongation. The description and use of the ABC-CFX scoring algorithm were added throughout the protocol. Changes were also made throughout the protocol related to the optional testing to determine the extent of methylation of the FMR1 gene. In addition, the protocol was modified to allow the possibility for eligible subjects from other studies of AFQ056 to be enrolled and the inclusion criteria were modified to reflect that eligible patients had to have been at least 18 years of age at the time of entry into the previous study. An instruction for subjects to avoid drinking grapefruit juice was added to exclusion criterion, and the protocol was modified to state that local anesthetics were specifically allowed for phlebotomy. Criteria excluding patients whose current medications had not been stable for at least 6 weeks prior to baseline and excluding patients planning to initiate or change pharmacologic or non-pharmacologic interventions during the study were removed, and instructions concerning the use of concomitant therapies were clarified.