Clinical Trials Register

Summary
EudraCT Number:	2015-002957-37
Sponsor's Protocol Code Number:	RVT-101-3001
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-02-03
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2015-002957-37

A.3

Full title of the trial

A Phase 3, double-blind, randomized study of RVT-101 versus placebo when added to existing stable donepezil treatment in subjects with mild to moderate Alzheimer’s disease

Фаза 3, двойно-сляпо, рандомизирано изпитване на RVT-101 спрямо плацебо като допълнение към съществуващото постоянно лечение с донепезил при пациенти с лека до умерена форма на болестта на Алцхаймер

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study.
The efficacy and safety of investigated drug RVT-101 at a dose of 35 mg daily when used as an adjunct treatment to stable donepezil therapy will be evaluated over a 24-week treatment period for mild to moderate Alzheimer’s disease in patients on stable therapy with donepezil.

A.4.1

Sponsor's protocol code number

RVT-101-3001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Axovant Sciences Ltd.
B.1.3.4	Country	Bermuda
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Axovant Sciences Ltd.
B.4.2	Country	Bermuda
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Worldwide Clinical Trials
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	2nd Floor, 172 Tottenham Court Road
B.5.3.2	Town/ city	London
B.5.3.3	Post code	W1T 7NS
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44207121 61 61
B.5.5	Fax number	+44 207121 6160

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	RVT-101
D.3.2	Product code	RVT-101
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	607742-69-8
D.3.9.2	Current sponsor code	RVT-101
D.3.9.3	Other descriptive name	3-Phenylsulfonyl-8-(piperazin-1-yl)quinoline
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	35
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	RVT-101 is a nitrogen containing heterocycle also possessing aliphatic amine, aromatic amine and aromatic sulfone functions.

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Alzheimer’s Disease

E.1.1.1

Medical condition in easily understood language

Alzheimer's Disease (AD) is a brain disease that slowly destroys brain cells and has its worst effects on the areas of the brain that control memory, language, and thinking skills.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effects of RVT-101 versus placebo as adjuncts to stable donepezil therapy:
- on cognitive function as measured by the ADAS-Cog-11 after 24 weeks of treatment.
- on activities of daily living as measured by ADCS-ADL scale after 24 weeks of treatment

E.2.2

Secondary objectives of the trial

To assess the effects of RVT-101 versus placebo as adjuncts to stable donepezil therapy;
- on cognition as measured by the ADAS-Cog-13 after 24 weeks of treatment
- on global clinical assessment of change as measured by CIBIC+ after 24 weeks of treatment
- on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) after 24 weeks of treatment
- on an analysis of responders based on prespecified efficacy evaluations
- on subject dependency as measured by the Dependence Scale (DS)

To assess:
- how baseline MMSE score affects efficacy outcome measures after 24 weeks of treatment
- the safety and tolerability of RVT-101 as an adjunct therapy to stable donepezil treatment

To measure RVT-101 plasma concentrations and donepezil plasma concentrations in study subjects

To estimate the PK parameters of RVT-101 and explore relationships to efficacy or safety endpoints, as appropriate

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for enrollment in the study must meet all of the following criteria:
-Male or female subject with a clinical diagnosis of AD in accordance with the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for AD.
- Subject has a documented history of at least 4 months of ongoing donepezil therapy for AD, with stable dosing of 5 or 10 mg/day for at least the last 2 months and with no intent to change for the duration of the study.
- Subject has an MMSE score 12 to 24 inclusive at Screening and a Baseline MMSE score 10 to 26 inclusive. The difference between the Screening and Baseline MMSE score is less than or equal to 3 points. If a greater than 3-point difference between the Screening and Baseline MMSE score is in the opinion of the investigator due to recent changes in AD medication, the Run-in period may be extended for an additional 3 weeks after discussion with the Medical Monitor, during which time MMSE stability, defined as less than or equal to 3-point change over 3 weeks, must be observed.
- Subject has a Hachinski Ischaemia score less than or equal to 4 at Screening.
- Magnetic resonance imaging (MRI) or computed tomography (CT) scan performed within 12 months before screening with findings consistent with the diagnosis of dementia due to AD without any other clinically significant pathologies. If an MRI (preferred) or CT scan is unavailable or was performed longer than 12 months prior to Screening, one must be performed during the Screening Period (prior to Run-In).
- Age greater than or equal to 50 years to less than or equal to 85 years at the time of Screening.
- If female, subject must be:
a. Of non-childbearing potential (i.e., any female who is post-menopausal [greater than 1 year without menstrual period in the absence of hormone replacement therapy]) or surgically sterile; or,
b. If pre-menopausal or menopausal for 1 year or less, must have a negative pregnancy test and must not be lactating at the Screening and Baseline Visits. Female subjects of childbearing potential and who are sexually active are required to practice adequate methods of birth control. Female subjects for whom menopausal status is in doubt in the opinion of the investigator will be required to use an adequate form of birth control. Acceptable, adequate form of birth control is defined as consistent use of combined effective methods of contraception including at least 1 barrier method.
Male subjects who are sexually active will also be required to use an adequate form of birth control as described above.
- Subject has the ability to comply with procedures for cognitive and other testing in the opinion of the investigator.
- Subject must be able to ingest pills (in tablet form) whole.
- Subject lives with a regular caregiver who is willing to attend visits, oversee the subject’s compliance with protocol-specified procedures and study medication, and report on subject’s status, and who has substantial contact with the subject. Substantial contact is defined as a minimum of 10 hours total and at least 3 days contact with the subject per week. Every effort should be made to have the same caregiver throughout the study.
- Subject has provided full written informed consent prior to the performance of any protocol-specified procedure; or if unable to provide informed consent due to cognitive status, subject has provided assent and a legally acceptable representative has provided full written informed consent on behalf of the subject.
- Caregiver has provided full written informed consent on his/her own behalf prior to the performance of any protocol-specified procedure.
- General health status is acceptable for participation in a 24-week study

E.4

Principal exclusion criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

Other Causes for Dementia
- Diagnosis of possible, probable, or definite vascular dementia
- History and/or evidence of any other CNS disorder that could be interpreted as a cause of dementia
- Evidence of the following disorders where this is thought to be the cause of, or to contribute to the severity of, the subject’s dementia: current vitamin B12 deficiency, hypothyroidism, neurosyphilis, or Wernicke’s encephalopathy.
- Focal findings on the neurological exam that are inconsistent with a primary diagnosis of AD.
- History of existing negative amyloid positron emission tomography scan or similar brain amyloid imaging, or Screen Failure from research trial due to negative amyloid imaging within 5 years.
- Atypical clinical features or clinical course of dementia that conclude symptoms are more likely due to an alternate dementia diagnosis.

Confounding Medical Conditions
- History of significant psychiatric illness such as schizophrenia or bipolar affective disorder, or significant suicide risk. Current psychosis that in the opinion of the investigator would interfere with the subject’s ability to participate in this study. History of epilepsy or unexplained seizure in the past 5 years. History of alcohol use disorder or other substance abuse disorder in the past 10 years. History of Down syndrome or Intellectual Development Disorder.
- Any clinically relevant concomitant disease including progressive liver or kidney dysfunction, history of myocardial infarction or unstable angina within 6 months of Screening.

- Concomitant Medications: Participation in another investigational drug or device study in AD during the 60 days prior to the Screening Visit or Treatment with any concomitant medications as detailed in Table 1 of protocol.

Unacceptable Test/Laboratory Values such as:
-Postural hypotension at the time of screening.
- Persistent or recurrent liver enzyme elevations.
- Total bilirubin over 1.5 x ULN
- Calculated creatinine clearance less than 40 mL/min at screening
- Positive hepatitis B surface antigen or hepatitis C antibody test.
- QT interval (QTc) value ≥450 msec for males or ≥470 msec for females

Other
Previous exposure to RVT-101 or SB742457.
Subject non-compliance in taking study medication as prescribed throughout the study
Subject or caregiver is an immediate family member or employee of the participating investigator, any of the participating site staff, or of the sponsor study staff.
Subject was prescribed cognitive tasks for cognitive rehabilitation performed under medical supervision in the 3 months prior to Screening and/or during the study.
Subject has participated in a program of neurostimulation in the past 3 months or plans to participate during the study.

E.5 End points

E.5.1

Primary end point(s)

- ADAS-Cog-11 score change from baseline to Week 24
- ADCS-ADL score change from baseline to Week 24

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24

E.5.2

Secondary end point(s)

- ADAS-Cog-13 score change from baseline to Week 24
- CIBIC+ score at Week 24
- ADAS-Cog score change from baseline
- ADCS-ADL score change from baseline;
- CIBIC+ score; all assessed by MMSE baseline score
- NPI score change from baseline to Week 24
- Analysis of responders defined as improvement of at least 3 points on ADAS-Cog-11 from baseline AND at least no worsening on ADCS-ADL from baseline AND no worsening on CIBIC+ at 24 weeks
- DS score change from baseline to Week 24
- Measurement of concentrations of RVT-101 and donepezil in plasma
- Steady state area under the concentration-time curve (AUCτss), peak concentration (Cmax-ss), and minimum concentration (Cmin-ss) of RVT-101 in plasma
- Occurrence of adverse events (AEs) and changes in physical examinations, vital signs measurements, electrocardiograms (ECGs), routine laboratory assessments, and Columbia Suicide Severity Rating Scale (C-SSRS)

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline to Week 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Bulgaria

Canada

Chile

Croatia

Czech Republic

France

Germany

Italy

Korea, Republic of

Malaysia

Poland

Serbia

Singapore

Slovakia

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS - last visit of the last subject

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

550

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects diagnosed with Alzheimer's Disease who may or may not be able to consent personally. Full, written consent will be
obtained from each subject or his/her legal representative/caregiver where applicable, prior to recruitment.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

410

F.4.2.2

In the whole clinical trial

1150

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subsequent treatments of the study subject will be at the discretion of the investigator in accordance to standard care. The investigator is responsible for ensuring that consideration has been given to the post-study care of the subject’s medical condition.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-04-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-08-31

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