Open-Label Extension Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome (LILAC™)

Percentage of subjects with treatment-emergent adverse events (TEAEs), percentage of subjects with serious adverse events (SAEs), and percentage of subjects with withdrawals due to AEs

Potentially clinically important ECG changes were defined in the study protocol as absolute QTcF interval >500 ms or QTcF interval change from the baseline value of previous study ACP-2566-003 of >60 ms

Potentially clinically important changes in vital signs were defined in the study protocol as:

systolic blood pressure (SBP) ≥180 mmHg and increased ≥20 mmHg from baseline; SBP ≤90 mmHg and decreased ≥20 mmHg from baseline; diastolic blood pressure (DBP) ≥ 105 mmHg and increased ≥15 mmHg from baseline; DBP ≤50 mmHg and decreased ≥15 mmHg from baseline; Pulse ≥120 bpm and increased ≥15 bpm from baseline; Pulse ≤50 bpm and decreased ≥15 bpm from baseline

Potentially clinically important changes in body weight were defined in the study protocol as:

Weight increase ≥7% from baseline; Weight decrease ≥7% from baseline

Potentially clinically important changes in laboratory parameters were defined in the study protocol as:

Sodium ≤125 mmol/L; Sodium ≥155 mmol/L; Potassium ≤3.0 mmol/L; Potassium ≥5.5 mmol/L; Chloride ≤85 mmol/L; Chloride ≥120 mmol/L; Calcium <2.0 mmol/L; Calcium >2.0 mmol/L; Blood urea nitrogen ≥10.71 mmol/L; Creatinine >1.5 x upper limit of normal (ULN); Uric acid ≥505.75 μmol/L; Lactate dehydrogenase ≥3 x ULN; Glucose ≤2.48 mmol/L; Glucose ≥11 mmol/L; Albumin ≤26 g/L; Albumin ≥60 g/L; Protein ≤50 g/L; Protein ≥100 g/L; Alanine aminotransferase ≥3 x ULN; Aspartate aminotransferase ≥3 x ULN; Gamma glutamyl transpeptidase ≥3 x ULN; Alkaline phosphatase ≥3 x ULN; Bilirubin ≥1.5 x ULN

The RSBQ is a 45-item caregiver-completed rating scalescale includes 45 items, 39 of them grouped into 8 subscales, whose ratings reflect the severity and frequency of symptoms. Items are rated as 0 (not true), 1 (somewhat or sometimes true), or 2 (very true). The 8 subscales are general mood, breathing problems, hand behavior, face movements, body rocking/expressionless face, night-time behaviors, fear/anxiety, and walking/standing. Scores for item 31 are reversed in the calculation of the total score. The total score ranges from 0 to 90 and is calculated as the sum of the item scores. Higher scores mean worse behaviour.

To rate how much the subject's illness has improved or worsened relative to a baseline state, a 7-point scale is used from 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Higher CGI-I scores denote more severe illness and less improvement in the illness.

Scale to assess communication and pre-linguistic skills in children 12-24 months (or older children with developmental delay). The Checklist consists of 24 questions ranging from 0 to 4 points within each of 7 Clusters. 0 points are given for"Not Yet", 1 point for "Sometimes", or 2 points for "Often". For items describing a series of numbers or ranges, 0 points are given for "None" and 1 to 4 points for items containing numbered choices.

The Social Composite score is one of 3 composite scores. It comprises 13 items in skill areas "Emotion and Eye Gaze" (items 1 to 4), "Communication" (items 5 to 8), and "Gestures" (items 9 to 13). The Social Composite raw score (items 1 to 13), ranging from 0 to 26, is calculated as the sum of the item scores. Higher Social Composite raw scores indicate better social communication development.

The overall quality of life score rating of the ICND ranges from 1 ("Poor") to 6 ("Excellent"); lower overall quality of life scores indicate lower quality of life.

The RTT-HF is a clinician completed clinical assessment of the subject's ability to use her hands for functional purposes. The assessment is made on an 8-point Likert scale (0-7) with 0 denoting normal functioning and 7 the most severe impairment

The RTT-AMB is a clinician completed clinical assessment of the subject's ability to sit, stand, and ambulate. The assessment is made on an 8-point Likert scale (0-7) with 0 denoting normal functioning and 7 the most severe impairment.

The RTT-COMC is a clinician completed clinical assessment of the subject's ability to communicate her choices or preferences, which can include the use of nonverbal means such as eye contact or gestures. The assessment is made on an 8-point Likert scale (0-7) with 0 denoting normal functioning and 7 the most severe impairment.

The RTT-VCOM is a clinician completed clinical assessment of the subject's ability to communicate verbally. The assessment is made on an 8-point Likert scale (0-7) with 0 denoting normal functioning and 7 the most severe impairment.

The CGI-S is a 7-point scale that requires the clinician to rate the severity of the subject's illness at the time of assessment, relative to the clinician's experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on severity of illness at the time of rating: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4= moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill. Higher CGI-S scores denote more severe illness and less improvement in the illness.

The RTT-CBI consists of 24 negatively worded items (Items 1 through 24). Frequency ratings are on a 5-point Likert scale including: 0-never; 1-rarely; 2-sometimes; 3-frequently and 4-nearly always. The RTT-CBI also includes 2 positively worded items (items 25 and 26) that comprise the Optimism Index; this index will not be used for analysis. The total score ranging from 0 to 96 is calculated as the sum of the scores for Items 1-24.Higher scores signify higher caregiver burden.

The ICND scale evaluates the effect of 4 health problems on 11 aspects of the child's or the family's life scored 0 ("Not at all"), 1 ("A little"), 2 ("Some"), 3 ("A lot"), or "Does not apply". The 4 health problems are 1) inattentiveness, impulsivity, or mood, 2) ability to think and remember, 3) neurologic or physical limitations, and 4) epilepsy. For each health problem, the score is calculated as the sum of the item scores. The ICND total score will be calculated as the sum of the average of each problem score multiplied by 11. The ICND total score ranges from 0 to 132. Higher ICND total scores indicate worse health problems. The ICND total score does not include the Overall Quality of Life Rating.