ERG/5-HTP in Fragile X Syndrome (FXS)

Adverse Events (AEs), including clinically meaningful laboratory abnormalities and significant behavioral changes will be recorded from the time of the subject's first dose of study drug to the end of the study (Week 17) or longer if needed. Adverse events will be assessed at each visit as well as during each phone call and will be tabulated for each treatment period.

Adverse Events (AEs), including clinically meaningful laboratory abnormalities and significant behavioral changes will be tabulated for each treatment period.

The Investigator is responsible for assessing the severity (intensity) of each adverse event as mild, moderate, or severe according to the following definitions:

Mild - An event that is easily tolerated and generally not interfering with normal daily activities. Moderate - An event that is sufficiently discomforting to interfere with normal daily activities. Severe - An event that is incapacitating with inability to work or perform normal daily activities.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The alertness subtest requires subjects to tap a button every time a stimulus appears on the screen. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean reaction time was measured over 90 seconds and change from baseline was calculated. A lower reaction time (net decrease in reaction time) indicates better performance.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The distractibility subtest measures how easily the subject is distracted by extraneous stimuli. This subtest requires subjects to tap a button when a target stimulus appears on the screen while ignoring distracters that appear shortly before the stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the distractability subtest, a higher mean number of correct responses and lower mean number of errors over the 3 minutes indicates better performance.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The distractibility subtest measures how easily the subject is distracted by extraneous stimuli. This subtest requires subjects to tap a button when a target stimulus appears on the screen while ignoring distracters that appear shortly before the stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the distractability subtest, a higher mean number of correct responses and lower mean number of errors over the 3 minutes indicates better performance.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The flexibility subtest measures the subject's ability to be flexible about shifting from one response type to another. This subtest is 2 minutes long and requires subjects to alternate between identifying blue and green dragons which seem on random sides of the screen by tapping one of two buttons. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded and change from baseline was calculated. For the flexibility subtest, a higher mean number of correct responses and lower mean number of errors indicates better performance.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The flexibility subtest measures the subject's ability to be flexible about shifting from one response type to another. This subtest is 2 minutes long and requires subjects to alternate between identifying blue and green dragons which seem on random sides of the screen by tapping one of two buttons. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded and change from baseline was calculated. For the flexibility subtest, a higher mean number of correct responses and lower mean number of errors indicates better performance.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The Go-NoGo subtest measures a subject's impulsivity by requiring subjects to tap a button when the target stimulus is presented, while refraining from hitting the button for the non-target stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). This subtest takes place over 2 minutes 30 seconds. Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the Go-NoGo subtest, a higher mean number of correct responses and a lower mean number of errors indicates better performance.

The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The Go-NoGo subtest measures a subject's impulsivity by requiring subjects to tap a button when the target stimulus is presented, while refraining from hitting the button for the non-target stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). This subtest takes place over 2 minutes 30 seconds. Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the Go-NoGo subtest, a higher mean number of correct responses and a lower mean number of errors indicates better performance.

The Clinical Global Impression-Severity (CGI-S) is a global measure to provide a clinical judgment of a participant's overall condition based on a trained clinician's assessment of cognition, behavior and activities of daily living. The clinician compares the subject with individuals of the same age and sex. The assessment of severity is with a 7-point scale: 1, not ill; 2, very mild; 3, mild; 4, moderate; 5, marked; 6, severe; 7, extremely severe. A net decrease in severity score over time indicates a positive outcome.

This assessment is a parent/caregiver-rated scale with six subscales to assess irritability, stereotypes, lethargy, hyperactivity, inappropriate speech, and social avoidance, using ABC-FX factoring system. The ABC was was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean score for each subscale was measured and change from baseline was calculated. Lower mean scores on each subscale indicate fewer aberrant behaviors (better functioning).The range of possible scores on each subscale are irritability (0-54), lethargy (0-39), stereotypes (0-18), hyperactivity (0-30), inappropriate speech (0-12), and social avoidance (0-12).

The ADAMS is a parent/caregiver rated scale with five subscores to assess manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, and obsessive/compulsive behavior. The ADAMs was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean score for each subscale was recorded, and change from baseline was calculated for each subscore. The range of possible scores for each subscale is 0-21. Lower mean scores on each subscale indicate better functioning.

VABS-3 is a clinician-administered standardized interview. For this study, we collected data in domains of communication (receptive & written language), daily living skills (domestic & community skills), & socialization (interpersonal relationships, play & leisure time, & coping abilities). This assessment was administered at Baseline as well as at Week 4, Week 8, Week 12, and Week 16 (end of each treatment period). Mean growth scale value (GSV) for each subdomain was recorded at each time point and change from baseline was calculated. The possible GSVs for each subdomain are receptive (10-162), written (10-163), domestic (10-110), community (10-136), interpersonal (10-152), play and leisure (10-164), & coping skills (10-120). Higher GSVs for each subdomain indicate better functioning.

The NIH-TCB is a battery of extensively validated computer-administered cognitive tests. The NIH-TCB includes 7 evaluations measuring cognitive flexibility, inhibition & visual attention, episodic memory, immediate recall & sequencing of different visually & orally presented stimuli, processing speed, recognition of letters and words, & receptive vocabulary. This assessment was administered at Baseline as well as at Week 4, Week 8, Week 12, and Week 16 (end of each treatment period). This battery produces fluid and crystallized cognition composite scores. The Total Cognition Composite Score is found by converting raw fluid and crystallized scores to standard scores, averaging these two scores, then deriving standard scores based on this new distribution. Scores range from 0-140. The normative mean of the uncorrected standard score is 100 and the standard deviation is 15. A higher mean total cognition composite score indicates better performance.

IIn an attempt to measure the level of behavioral difficulty experienced by the parent/caregiver with respect to the child with FXS, the VAS allows parents to mark on a visual line measuring 10 cm with one side marked "worst behavior" and the other side marked "best behavior." The caregiver rated the participant's behavior with respect to three domains: daily functioning, anxiety/irritability and language. Distances closer to 10 cm are considered worse behavior and distances closer to 0 cm are considered better behavior. Average distance of the mark was recorded for each domain at Baseline then again at Week 4, Week 8, Week 12, and Week 16 (end of each treatment period). Change from baseline was calculated for each domain. Lower scores indicate a better outcome (closer distance to best behavior side).

Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific sensory, cognitive, or motor events from an overall EEG. Gamma 1 and gamma 2 waves were measured for various parts of the brain at a resting state. ERP was performed at Baseline as well as at Week 4, Week 8, Week 12, Week 16 (at the end of each treatment period). Mean power of gamma 1 and gamma 2 bands, measured by frontal EEG leads, was recorded for each time point and change from baseline was calculated. FXS patients have typically been found to exhibit greater gamma frequency band power than typically developing controls, which may be related to social and sensory processing difficulties. Therefore, lower gamma band power would indicate better functioning.

Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific sensory, cognitive, or motor events from an overall EEG. Auditory stimuli are presented and EEG events are assessed in relation to timing of the stimuli. ERP was performed at Baseline as well as at week Week 4, Week 8, Week 12, Week 16 (end of each treatment period). The area under the curve was measured for different components of the ERP including P1 and P2 (positive components) and N1 and N2 (negative components). The average area under the curve was recorded for each component at each time point and change from baseline was calculated. Individuals with FXS are thought to have excessive ERP response, so a decrease in area under each curve compared to baseline would indicate a favorable outcome.

Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific sensory, cognitive, or motor events from an overall EEG. EEG data was collected when the subject was in a resting state. Frontal alpha asymmetry measures differences in alpha activity level of the right and left hemisphere of the frontal lobe of the brain. ERP was performed at Baseline as well as at Week 4, Week 8, Week 12, Week 16 (end of each treatment period). Mean alpha asymmetry at resting state was recorded and change from baseline was calculated for each time point. Higher alpha asymmetry scores indicate greater alpha power in the right hemisphere, which corresponds to increased neural activity of the left hemisphere. High activity of the left frontal lobe is hypothesized to correspond with approach behaviors, and high activity of the right frontal lobe is thought to correspond to withdrawal behaviors. In this study, higher alpha asymmetry scores indicate a better outcome.