ANAVEX2-73 Study in Pediatric Patients With Rett Syndrome (EXCELLENCE)

• ClinicalTrials.gov Identifier: NCT04304482
• Recruitment Status: Completed
• First Posted: March 11, 2020
• Last Update Posted: August 21, 2023
• Sponsor: Anavex Life Sciences Corp.
• Collaborators: Anavex Australia Pty Ltd.; Anavex Germany GmbH
• Information provided by (Responsible Party): Anavex Life Sciences Corp.

Study Description

Brief Summary:

ANAVEX2-73-RS-003 is a Phase 2/3, double-blind, randomized, placebo-controlled dose escalation safety, tolerability and efficacy study in patients 5-17 years of age with RTT using endpoints including multiple clinical and exploratory molecular and biochemical measures.

Condition or disease	Intervention/treatment	Phase
Rett Syndrome	Drug: ANAVEX2-73 oral liquid; Drug: Placebo oral liquid	Phase 2; Phase 3

Detailed Description:

This Phase 2/3 efficacy study is designed as a double-blind, randomized, placebo-controlled study.

This is a 12-week placebo-controlled study of ANAVEX2-73 oral solution for the treatment of patients with RTT 5-17 years of age. A voluntary option will be offered for all patients who meet the exposure criteria for ANAVEX2-73 to continue a 48-week open label extension.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: ANAVEX2-73-RS-003 is a Phase 2/3, Double-blind, Randomized, Placebo-controlled Safety and Efficacy Study in Pediatric Patients With RTT
• Actual Study Start Date: July 1, 2020
• Actual Primary Completion Date: June 1, 2023
• Actual Study Completion Date: June 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: ANAVEX2-73 Active; ANAVEX2-73 liquid oral solution	Drug: ANAVEX2-73 oral liquid; Liquid oral solution; Other Name: Blarcamesine
Placebo Comparator: ANAVEX2-73 Placebo; Placebo liquid oral solution	Drug: Placebo oral liquid; Liquid oral solution

Outcome Measures

Primary Outcome Measures :

1. RSBQ [ Time Frame: 12 weeks ]
   Change from baseline to End of Treatment (EOT) in the Rett Syndrome Behaviour Questionnaire (RSBQ) Total score
2. Incidents of Adverse Events [ Time Frame: 12 weeks ]
   Change from baseline to End of Treatment (EOT)

Secondary Outcome Measures :

1. CGI-I [ Time Frame: 12 weeks ]
   Change from baseline to End of Treatment (EOT) in the Clinical Global Impression Improvement Scale (CGI-I) score
2. Anxiety, Depression, and Mood Scale (ADAMS) [ Time Frame: 12 weeks ]
   Anxiety, Depression, and Mood Scale (ADAMS)
3. Motor Behavioral Assessment-7 dynamic pediatric items (MBA-Ped7) [ Time Frame: 12 weeks ]
   Motor Behavioral Assessment-7 dynamic pediatric items (MBA-Ped7)
4. Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: 12 weeks ]
   Children's Sleep Habits Questionnaire (CSHQ)
5. Seizure Frequency via seizure diary [ Time Frame: 12 weeks ]
   Seizure Frequency via seizure diary
6. Incidence of Adverse Events [ Time Frame: 12 weeks ]
   Incidence of Adverse Events
7. RSBQ Emotional Factor-Pediatric (subset of the RSBQ) [ Time Frame: 12 weeks ]
   RSBQ Emotional Factor-Pediatric (subset of the RSBQ)
8. Rett Syndrome Caregiver Inventory Assessment (RTT CIA) [ Time Frame: 12 weeks ]
   Rett Syndrome Caregiver Inventory Assessment (RTT CIA)
9. Child Health Questionnaire-Parent Form 50 (CHQ-PF50) [ Time Frame: 12 weeks ]
   Child Health Questionnaire-Parent Form 50 (CHQ-PF50)

Other Outcome Measures:

1. Glutamate Plasma Concentration [ Time Frame: 12 weeks ]
   Glutamate Plasma Concentration
2. GABA Plasma Concentration [ Time Frame: 12 weeks ]
   GABA Plasma Concentration
3. Genetic variant SIGMAR1, COMT [ Time Frame: 12 weeks ]
   Genetic variant SIGMAR1, COMT
4. Maximum Plasma Concentration [Cmax] [ Time Frame: 12 weeks ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
5. Maximum Plasma Concentration [Cmax] relationship with RSBQ [ Time Frame: 12 weeks ]
   Number of participants with positive Maximum Plasma Concentration [Cmax] relationship with RSBQ
6. Other Amino Acid Plasma concentrations [ Time Frame: 12 weeks ]
   Other Amino Acid Plasma concentrations
7. Measure of gene DNA variants and gene RNA expressions [ Time Frame: 12 weeks ]
   Number of participants with active dose compared gene DNA variants and gene RNA expressions

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 17 Years (Child)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Aged ≥ 5 years to 17 (inclusive).
• Diagnosis of classic RTT, according to 2010 criteria, and a MECP2 mutation.
• Post-regression stage, defined as ≥ 6 months since last loss of spoken language or motor (fine or gross) skills.
• Clinical Global Impression - Severity (CGI-S) score of 4 or greater at Screening.
• Current pharmacological treatment regimen, including supplements, has been stable for at least 4 weeks.
• If on AEDs, 1-4 AEDs allowed. Treatment must be stable (drug, dose, interval of administration) for 30 days prior to enrollment.
• If the subject is already receiving stable non-pharmacologic educational, behavioral, and/or dietary interventions, participation in these programs must have been continuous during the 90 days prior to the screening visit and subjects or their parent/caregiver/LAR will not electively initiate new or modify ongoing interventions for the duration of the study.
• The subject's caregiver/LAR is English-speaking and has sufficient language skills to complete the caregiver assessments and has the ability to keep accurate seizure diaries.
• If participant is a woman of childbearing potential (WOCBP#), a negative urine or serum pregnancy test is required to confirm she is not pregnant.
• Prior to the conduct of study-specific procedures, the subject's parent/caregiver/LAR must provide written informed consent. If applicable, the research team must attempt to obtain consent from both parents.

Exclusion Criteria:

• Patients who have a progressive medical or neurological condition that in the opinion of the Investigator would interfere with the conduct of the study.
• Current clinically significant systemic illness that is likely to result in deterioration of the patient's condition or affect the patient's safety during the study.
• History or clinically evident neurologic (e.g., head trauma with loss of consciousness) or psychiatric condition that the Investigator deems may interfere with interpretability of data.
• Indication of liver disease, defined by serum levels of ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3x upper limit of normal (ULN) as determined during screening.
• Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
• Other clinically significant abnormality on physical, neurological, laboratory, or electrocardiogram (ECG) examination (e.g., long QT) that could compromise the study or be detrimental to the participant.
• Any known hypersensitivity to any of the excipients contained in the study drug or placebo formulation.
• Other co-morbid or chronic illness beyond that known to be associated with RTT.
• Subjects who plan to initiate or change pharmacologic or nonpharmacologic intervention during the course of the study.
• Subjects taking another investigational drug currently or within the last 30 days.
• Any other criteria (such as a clinically significant screening blood test result), which in the opinion of the Investigator could interfere with the study conduct or outcome.
• Treatment with strong inhibitors or inducers of CYP3A4 or CYP2C19 is not stable (drug, dose) for 30 days prior to screening. Although these medications are not excluded, caution is advised when enrolling participants on potent CYP3A4 or CYP2C19 inducers or inhibitors (see respective section).
• Patients with hepatic and renal impairment.

Contacts and Locations

Locations

Australia, New South Wales

The Children's Hospital at Westmead

Sydney, New South Wales, Australia, 2145

Australia, Queensland

Queensland Children's Hospital

Brisbane, Queensland, Australia, 4101

Australia, Victoria

Austin Health

Melbourne, Victoria, Australia, 3084

Canada, Alberta

Alberta Children's Hospital

Calgary, Alberta, Canada, T3B 6A8

Canada, British Columbia

British Columbia Children's Hospital

Vancouver, British Columbia, Canada, V6H 3V4

Canada, Ontario

Children's Hospital LHSC

London, Ontario, Canada, N6A 5W9

Holland Bloorview Kids Hospital

Toronto, Ontario, Canada, M5H 3W4

United Kingdom

Royal Hospital for Children

Edinburgh, United Kingdom, EH16 4TJ

Evelina London Children's Hospital

London, United Kingdom, SE1 7EH

King's College of London

London, United Kingdom, SE5 8AF

Manchester CGM, St Mary's Hospital

Manchester, United Kingdom, M13 9WL

Nottingham University Hospital NHS Trust

Nottingham, United Kingdom, NG7 2UH

Sponsors and Collaborators

Anavex Life Sciences Corp.

Anavex Australia Pty Ltd.

Anavex Germany GmbH

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Heussler HS. Emerging Therapies and challenges for individuals with Angelman syndrome. Curr Opin Psychiatry. 2021 Mar 1;34(2):123-128. doi: 10.1097/YCO.0000000000000674. Erratum In: Curr Opin Psychiatry. 2021 Sep 1;34(5):514.

• Responsible Party: Anavex Life Sciences Corp.
• ClinicalTrials.gov Identifier: NCT04304482
• Other Study ID Numbers: ANAVEX2-73-RS-003
• First Posted: March 11, 2020
• Last Update Posted: August 21, 2023
• Last Verified: August 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Rett Syndrome; Syndrome; Disease; Pathologic Processes; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System