This amendment introduced the following changes: The additional safety monitoring of study patients on days 2-6 (period 2) in case when the study medication is administered at patient’s home by the patient’s caregiver. For these days a daily telephone call was recommended to monitor for the potential AEs and safety issues. Initially planned two visits per day in the study center for the study drug administration were considered too stressful for the patients and considering the safety profile of AFQ056 it was judged that the daily telephone call was an appropriate measure to monitor for the safety of the study patients. In addition the meal restriction section was rewritten to provide more flexibility to the patients regarding the meal times on period 2. Further, the b.i.d. dose was introduced for day 1, period 2 (instead of single dose). Originally, it was planned to assess the single-dose pharmacokinetics from 0-24h post dosing. As this was no longer planned to be assessed, the b.i.d. dosing regimen was applied over the entire period 2 (i.e. from day 1-7). This was to ensure a consistent dosing regimen and it would allow for a more appropriate tolerability assessment after an overnight stay of the patients at the site. This assessment was done in the morning of day 2 before patients leave the study site.

This amendment introduced the following changes: In order to further characterize any potential modification of attention after AFQ056 administration to children with FXS, it was decided to perform mental age-appropriate subtests of the Test of Everyday Attention in Childhood (TEA-Ch). In addition, TEA-Ch was included in order to comply with a request by the European Medicines Agency (EMA) received in the course of the PIP review. To minimize the burden for the patients, TEA-Ch subtests were only performed in the multiple-dosing period 2, as after administration of a considerably low, single dose of AFQ056 in period 1 (15 mg), no meaningful modification of behavior was expected. Further, these subtest would only be applied in cohort 1 (5-11 year-old patients), since it was not considered feasible to perform these tests in cohort 2 (3-4 year-old patients) given that these tests have been validated for children ≥6 years of age. The tests were done at baseline, 24 h after first dosing in period 2 and at final visit if possible based on the capabilities of study patients (as judged by Investigator).

This amendment introduced the following changes: In the original study protocol, (a) sequential dosing within cohort 1 beginning with the older (8 to 11 years) followed by the younger patients (5 to 7 years) and (b) an equal number of 5 to 7 year-old and 8-11 year-old patients in cohort 1 was required. This had been implemented due to the absence of any PK data in the pediatric population of FXS patients younger than 12 years. As per this amendment sequential age-dependent dosing as well as an equal age distribution of patients aged 8-11 and 5-7yrs will no longer be required. This was to minimize the burden to the families/caregivers of the FXS patients, since there were often siblings interested in study participation. Therefore, it was expected to improve the recruitment in this study. This amendment would not affect the validity of the statistical analysis as this has originally been planned to be done on the entire cohort 1 without age discrimination. It was also not expected to affect the safety and tolerability of AFQ056 in this study population of pediatric FXS patients.

This amendment introduced the following changes: After a review of Amendment 03, FDA stated via e-mail dated June 29, 2012, that the removal of an equal age distribution in cohort 1 is not acceptable. It was stated that an equal number of 5 to 7 year-old and 8 to11 year-old patients was necessary for the PK trial to be informative given the expected difference in ontogeny among these age groups. Therefore, the requirement for an equal number of six patients aged 5 to 7 years and another six patients aged 8-11 years was re-introduced in this protocol amendment 04.

This amendment introduced the following changes: This study evaluated the pharmacokinetics as well as safety and tolerability of AFQ056 in pediatric patients with FXS aged 5-11 years (cohort 1) and 3-4 years (cohort 2). As of 22- Mar-2013, cohort 1, consisting of 12 children with FXS, has completed the study. This was followed by a pre-planned interim analysis to decide upon continuation of this study with cohort 2. Based on the data obtained in cohort 1, it has been decided to continue with cohort 2 and to implement three key changes to the protocol * An up-titration scheme with a starting dose of 25mg b.i.d. and daily increments of 25mg up to the assigned target dose will be applied in period 2, cohort 2. This up-titration aims at reducing the incidence of AEs (e.g. vomiting) that are considered to be first-dose related, as these occurred primarily on the first day of the multiple-dosing period 2 in cohort 1. * As a consequence of the up-titration, the duration of the treatment in period 2, cohort 2 was extended from 7 to 8 days to assure that the steady state at the target dose is reached (the steady state is known to reach between 48h to 96 h for AFQ056) when the PK samples for AFQ056 measurements are collected. * The sample size required for cohort 2 has been re-evaluated based on the PK data obtained in cohort 1. This has been done in order to minimize the number of patients exposed which appears particularly important given the low age of patients in cohort 2 (3-4 years).