Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome (LAVENDER™)

Study Overview
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Brief Summary
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To investigate the efficacy of treatment with oral trofinetide versus placebo in females with Rett syndrome

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome

Conditions
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Rett Syndrome

Intervention / Treatment
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* Drug: Trofinetide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female subjects 5 to 20 years of age, inclusive, at Screening Body weight ≥12 kg at Screening Can swallow the study medication provided as a liquid solution or can take it by gastrostomy tube Has classic/typical Rett syndrome (RTT) Has a documented disease-causing mutation in the MECP2 gene Has a stable pattern of seizures, or has had no seizures, within 8 weeks of Screening Subjects of childbearing potential must abstain from sexual activity for the duration of the study and for at least 30 days thereafter or must agree to use acceptable methods of contraception. Subject must not be pregnant or breastfeeding. The subject's caregiver is English-speaking and has sufficient language skills to complete the caregiver assessments 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 Screening Exclusion Criteria: Has been treated with insulin within 12 weeks of Baseline Has current 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 Has a history of, or current, cerebrovascular disease or brain trauma Has significant, uncorrected visual or uncorrected hearing impairment Has a history of, or current, malignancy Has a known history or symptoms of long QT syndrome Additional inclusion/exclusion criteria apply. Patients will be evaluated at screening to ensure that all criteria for study participation are met. Patients may be excluded from the study based on these assessments (and specifically, if it is determined that their baseline health and condition do not meet all pre-specified entry criteria).

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug - Trofinetide<br>Trofinetide solution of 30-60 mL based on the subject's weight at Baseline, administered twice daily by mouth or gastrostomy tube (G-tube) | Drug: Trofinetide<br>* Trofinetide solution administered based on the subject's weight at Baseline, twice daily for 12 weeks<br>|
| Placebo Comparator: Placebo<br>Trofinetide placebo solution of 30-60 mL based on the subject's weight at Baseline, administered twice daily by mouth or gastrostomy tube (G-tube) | Other: Placebo<br>* Trofinetide placebo solution administered based on the subject's weight at Baseline, twice daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rett Syndrome Behaviour Questionnaire (RSBQ) total score - Change from Baseline to Week 12 | The scale 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 include general mood, breathing problems, hand behavior, face movements, body rocking/expressionless face, night-time behaviors, fear/anxiety, and walking/standing. | 12 Weeks Treatment Duration | 
| Clinical Global Impression-Improvement (CGI-I) Score at Week 12 | 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. | 12 Weeks Treatment Duration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 in Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist - Social Composite Score (CSBS-DP-IT Social) | Standardized screening scale for assessing communication and pre-linguistic skills in young children 12-24 months and can be used with older children with developmental delay. The CSBS-DP includes a suite of three separate measures: The Infant-Toddler Checklist, a follow-up Caregiver Questionnaire and a Behavior Sample. In this study only the Infant-Toddler (CSBS-DP-IT) Checklist will be used. The CSBS-DP-IT Checklist is a 24-item rating scale and each item is scored using a three-level rating of frequency: not yet, sometimes and often. Three composite scores assessing 7 skill areas can be calculated: 1) Social Composite (including Emotion and Eye Gaze, Communication Rate and Function, and Gestures); 2) Speech Composite (including Sounds and Words); 3) Symbolic Composite (including Understanding and Object Use). | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Rett Syndrome Clinician Rating of Hand Function (RTT-HF) | Clinical assessment of the subject's ability to use their hands for functional purposes (such as reaching for and grasping objects, self-feeding, or drawing). The assessment is made on an 8-point Likert scale (0-7) with 0 denoting normal functioning and 7 the most severe impairment. | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Rett Syndrome Clinician Rating of Ambulation and Gross Motor Skills (RTT-AMB) | Clinical assessment of the subject's ability to communicate their 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. | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Clinical Global Impression-Severity (CGI-S) | A 7 point scale that rates 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. 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. | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Rett Syndrome Caregiver Burden Inventory (RTT-CBI) Total Score (items 1-24) | The scale is intended to directly address caregiver burden and indirectly assess the significance of treatment effects on function in the context of activities of daily living. Ratings are on a 5-point Likert scale including: 0-never; 1-rarely; 2-sometimes; 3-frequently and 4-nearly always. As in the original Caregiver Burden Inventory, the RTT-CBI has 24 negatively worded items (items 1 through 24) yielding a total score up to 96. | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Impact of Childhood Neurologic Disability Scale (ICND) Total Score | The scale evaluates the effect of four conditions or health problems on 11 aspects of a child's or family's life as A lot, Some, A little, Not at all, or Does not apply. The four conditions or health problems are 1) inattentiveness, impulsivity, or mood, 2) ability to think and remember, 3) neurologic or physical limitations, and 4) epilepsy. The overall quality of life of the subject is also rated by responding to the following: Please rate your child's overall 'Quality of Life' on the scale below. Choose the number which you feel is best and circle it. The choices range from 1 (Poor) to 6 (Excellent). | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Overall Quality of Life Rating of the Impact of Childhood Neurologic Disability Scale (ICND) | The scale evaluates the effect of four conditions or health problems on 11 aspects of a child's or family's life as A lot, Some, A little, Not at all, or Does not apply. The four conditions or health problems are 1) inattentiveness, impulsivity, or mood, 2) ability to think and remember, 3) neurologic or physical limitations, and 4) epilepsy. The overall quality of life of the subject is also rated by responding to the following: Please rate your child's overall 'Quality of Life' on the scale below. Choose the number which you feel is best and circle it. The choices range from 1 (Poor) to 6 (Excellent). | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC) | Clinical assessment of the subject's ability to communicate their 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. | 12 Weeks Treatment Duration | 
| Change from Baseline to Week 12 in Rett Syndrome Clinician Rating of Verbal Communication (RTT-VCOM) | Clinical assessment of the subject's ability to communicate verbally (e.g. words and phrases). The assessment is made on an 8-point Likert scale (0-7) with 0 denoting normal functioning and 7 the most severe impairment. | 12 Weeks Treatment Duration |