The use of ANAVEX2-73 as a new therapeutic treatment for Patients with Rett Syndrome

• Register: EUCTR
• Last refreshed on: 30 November 2020
• Main ID: EUCTR2019-004345-32-GB
• Date of registration: 07/02/2020
• Prospective Registration: Yes
• Primary sponsor: Anavex Germany GmbH
• Public title: The use of ANAVEX2-73 as a new therapeutic treatment for Patients with Rett Syndrome
• Scientific title: A Double-Blind, Randomised, Placebo-Controlled, Safety and Efficacy Study of ANAVEX2-73 in Patients with Rett Syndrome - The Safety and Efficacy of ANAVEX2-73 in Patients with Rett Syndrome
• Date of first enrolment: 26/05/2020
• Target sample size: 30
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-004345-32
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, United Kingdom

Contacts

• Name: Stephan Toutain
• Affiliation: Anavex Germany GmbH

• Name: Stephan Toutain
• Affiliation: Anavex Germany GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
1.Aged = 18 years, inclusive.
2. Diagnosis of classic Rett Syndrome, according to 2010 criteria (Neul et al., 2010), and a MECP2 mutation.
3. Rett Syndrome Behaviour Questionnaire (RSBQ) total score =40.
4. Patients with a Clinical Global Impression – Severity (CGI-S) score of 4 or greater at Screening.
5. Current pharmacological treatment regimen, including supplements, has been stable for at least 4 weeks.
6. If on antiepileptic drugs (AEDs), 1-4 AEDs allowed. Treatment must be stable (drug, dose, interval of administration) for 30 days prior to enrollment.
7. 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/legally authorized representative (LAR) will not electively initiate new or modify ongoing interventions for the duration of the study. ‘Study duration’ is defined as lasting from the screening visit until the treatment is terminated. For participants in the 18-21 years range, typical school vacations are not considered modifications of stable programming.
8. Ability to keep accurate seizure diaries or have caregiver who can keep accurate seizure diaries.
9.If participant is a woman of childbearing potential, a negative urine or serum pregnancy test is required to confirm she is not pregnant.
Female patients of childbearing potential are to use adequate contraception as recommended by their health care provider. For participants that are sexually active, highly effective contraception may be used as recommended by their health care provider.Highly effective methods of contraception may include:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral, intravaginal or transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, injectable, implantable
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
10. 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.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
1. Patients who have a progressive medical or neurological condition that in the opinion of the Investigator would interfere with the conduct of the study.
2. Patients with a 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.
3. History of clinically evident stroke or clinically significant carotid or vertebrobasilar stenosis or plaque or other history of neurologic (e.g., head trauma with loss of consciousness) or psychiatric condition that the Investigator deems may interfere with interpretability of data.
4. 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.
5. 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.
6. Other clinically significant abnormality on physical, neurological, laboratory, or electrocardiogram (ECG) examination (e.g., atrial fibrillation) that could compromise the study or be detrimental to the participant.
7. Any known hypersensitivity to any of the excipients contained in the study drug or placebo formulation.
8. Other co-morbid or chronic illness beyond that known to be associated with Rett Syndrome.
9. Subjects who plan to initiate or change pharmacologic or nonpharmacologic intervention during the course of the study.
10. Subjects taking another investigational drug currently or within the last 30 days.
11. 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.
12. 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.
13. Patients with hepatic and renal impairment.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Rett Syndrome
MedDRA version: 20.0 Level: PT Classification code 10077709 Term: Rett syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: ANAVEX2-73
Pharmaceutical Form: Oral liquid
INN or Proposed INN: ANAVEX2-73 (blarcamesine)
Current Sponsor code: ANAVEX2-73
Other descriptive name: ANA001XHCl (Syntagon) or VEXA-04 (Patheon)
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 55 week study period

Main Objective: The main objective of PART B will be to evaluate the safety, tolerability, and efficacy of ANAVEX2-73 in RTT, as well as to determine the most appropriate dose.

Secondary Objective: Secondary outcome measures include a measure of the change or proposed improvement in daily functioning and the quality of life measures of participants with Rett Syndrome and the change or proposed improvement in caregiver burden

The following assessments will be completed at end of the 48 week Open Label Extension (OLE) treatment period:

1. Physical examination, including body weight,
2. Neurological examination
3. Vital signs measurement (heart rate, SBP and DBP, respiratory rate, oxygen saturation [pulse oximetry], and body temperature).
4. Safety laboratory assessments
5. Glutamate Plasma Concentration
6. GABA Plasma Concentration
7. RNA profiles (sample collection)
8. 12-Lead ECG
9. Adverse Events
10. Concurrent Medications, including supplements

Primary end point(s): Include safety and tolerability measures:
• Physical and neurological examination.
• Vital signs (heart rate, respiratory rate, systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse oximetry, and oral body temperature).
• Recording of adverse events (AEs).
• 12-lead ECG; three consecutive ECGs where participants should be in a resting position for =5 minutes prior to each ECG evaluation.
• Clinical laboratory tests
• Concomitant medication log.
• PK of ANAVEX2-73 and ANAVEX19-144.

Secondary Outcome(s)

Secondary end point(s): Efficacy:
Include two clinical tests, which consist of change from baseline to end of treatment in the modified intent-to-treat (mITT) population in the:
• RSBQ total score; and
• the CGI-I score, with anchors specifically designed for RTT, at EOT, in the mITT population.

Safety and tolerability:
The objective is to characterize the population PK of ANAVEX2-73 and its active metabolite, ANAVEX19-144, in patients with RTT. Details will be provided in the Pharmacometrics Analysis Plan (PAP).

AUC of ANAVEX2-73 and ANAVEX19-144 will be estimated using PK modeling approach.

Timepoint(s) of evaluation of this end point: 55 weeks

Secondary ID(s)

NCT03941444

ANAVEX2-73-RS-002

Source(s) of Monetary Support

Anavex Germany GmbH

Ethics review

Status: Approved
Approval date: 26/05/2020
Contact: