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

A 40-Week, Open-label Extension Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04279314

Acronym

LILAC™

Enrollment

154

Registered

2020-02-21

Start date

2020-01-29

Completion date

2022-08-19

Last updated

2024-04-11

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rett Syndrome

Brief summary

To investigate the safety and tolerability of long-term treatment with oral trofinetide in girls and women with Rett syndrome

Interventions

DRUGTrofinetide

Trofinetide solution of 30-60 mL based on subject's weight at Baseline, administered twice daily by mouth or gastrostomy tube (G-tube)

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

5 Years to 21 Years

Healthy volunteers

Inclusion criteria

1. Has completed the Week 12/End-of-treatment visit of the antecedent study, Study ACP-2566-003 2. Met all entry criteria for the antecedent study 3. May benefit from long-term treatment with open-label trofinetide in the judgment of the Investigator 4. Can still swallow the study medication provided as a liquid solution or can take it by gastrostomy tube 5. The subject's caregiver is English-speaking and has sufficient language skills to complete the caregiver assessments 6. Subject and caregiver(s) must reside at a location to which study drug can be delivered and have been at their present residence for at least 3 months prior to Baseline

Exclusion criteria

1. Began treatment with growth hormone during the antecedent study 2. Began treatment with IGF-1 during the antecedent study 3. Began treatment with insulin during the antecedent study 4. Has developed a clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, Type 1 diabetes mellitus, or uncontrolled Type 2 diabetes mellitus), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease) or has major surgery planned during the study 5. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for the study due to AEs, medical condition, or noncompliance with investigational product or study procedures in the antecedent study 6. Has a clinically significant abnormality in vital signs at Baseline 7. Has a QTcF interval of \>450 ms on the Baseline ECG performed before the first dose of trofinetide is given in the present study 8. Has developed a clinically significant ECG finding during the antecedent study Additional inclusion/

Design outcomes

Primary

Measure	Time frame	Description
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	40 Weeks Treatment Duration	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
Subjects (N, %) With Post-baseline Potentially Clinically Important Changes in ECG	40 Weeks Treatment Duration	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
Subjects (N, %) With Post-baseline Potentially Clinically Important Changes in Vital Signs	40 Weeks Treatment Duration	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
Subjects (N, %) With Post-baseline Potentially Clinically Important Changes in Body Weight	40 Weeks Treatment Duration	Potentially clinically important changes in body weight were defined in the study protocol as: Weight increase ≥7% from baseline; Weight decrease ≥7% from baseline
Subjects (N, %) With Post-baseline Potentially Clinically Important Changes	40 Weeks Treatment Duration	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

Secondary

Measure	Time frame	Description
Rett Syndrome Clinician Rating of Ambulation and Gross Motor Skills (RTT-AMB) Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC) Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Rett Syndrome Clinician Rating of Verbal Communication (RTT-VCOM) Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Rett Syndrome Behaviour Questionnaire (RSBQ) Total Score Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Rett Syndrome Caregiver Burden Inventory (RTT-CBI) Total Score (Items 1-24) Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Impact of Childhood Neurologic Disability Scale (ICND) Total Score Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Change From Baseline to Week 40 in Clinical Global Impression-Severity (CGI-S)	40 Weeks Treatment Duration	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.
Clinical Global Impression-Improvement (CGI-I) Score at Week 40	40 Weeks Treatment Duration	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.
Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist - Social Composite Score (CSBS-DP-IT Social) Change From Baseline to Week 40	40 Weeks Treatment Duration	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 forNot 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.
Overall Quality of Life Rating of the Impact of Childhood Neurologic Disability Scale (ICND) Change From Baseline to Week 40	40 Weeks Treatment Duration	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.
Rett Syndrome Clinician Rating of Hand Function (RTT-HF) Change From Baseline to Week 40	40 Weeks Treatment Duration	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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Trofinetide All subjects enrolled and treated with trofinetide	154
Total	154

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	55
Overall Study	Lack of Efficacy	5
Overall Study	Other (not COVID-19 related)	2
Overall Study	Protocol Violation	3
Overall Study	Withdrawal by Subject	5

Baseline characteristics

Characteristic	Trofinetide
Age, Continuous	11.0 years STANDARD_DEVIATION 4.55
Body Mass Index	17.03 kg/m2 STANDARD_DEVIATION 0.285
Height	128.60 cm STANDARD_DEVIATION 1.229
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	5 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants
Race (NIH/OMB) White	143 Participants
Sex: Female, Male Female	154 Participants
Sex: Female, Male Male	0 Participants
Weight	29.28 kg STANDARD_DEVIATION 0.869

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 154
other Total, other adverse events	114 / 154
serious Total, serious adverse events	19 / 154

Outcome results

Primary

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

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