Clinical Trials Register

Summary
EudraCT Number:	2018-001756-35
Sponsor's Protocol Code Number:	16/0163
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-05-13
Trial 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

UK - MHRA

A.2

EudraCT number

2018-001756-35

A.3

Full title of the trial

A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Trial to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

ReCOVER V1.3 June 2019

A.4.1

Sponsor's protocol code number

16/0163

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02521311

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	University of California, San Francisco
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UCL
B.5.2	Functional name of contact point	Nimrita Verma
B.5.3	Address:
B.5.3.1	Street Address	UCL, Joint Research Office
B.5.3.2	Town/ city	London
B.5.3.3	Post code	W1T 7DN
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02031086839
B.5.6	E-mail	n.verma@ucl.ac.uk

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	Yes
D.2.1.1.1	Trade name	TAVEGIL TABLETS
D.2.1.1.2	Name of the Marketing Authorisation holder	GSK
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	TAVEGIL TABLETS
D.3.4	Pharmaceutical form	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	Clemastine Hydrogen Fumarate
D.3.9.1	CAS number	14976-57-9
D.3.9.4	EV Substance Code	AS1
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	1
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	No

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	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

acute optic neuritis

E.1.1.1

Medical condition in easily understood language

Optic neuritis is an inflammatory, demyelinating disease of the optic nerve. It is most often characterized by visual loss or blurred vision along with dyschromotopsia accompanied by pain.

E.1.1.2

Therapeutic area

Body processes [G] - Cell Physiological Phenomena [G04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10030942
E.1.2	Term	Optic neuritis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This study is about helping patients to recover from visual loss by restoration of the key structure affected, the "insulation" (myelin) around the "electric wire" (axon). This is achieved by using a hayfever drug which has been on the market for many years.

The drug is called Clemastine fumarate, an FDA- and EMA-approved antihistamine, restores nervous system function in patients with chronic multiple sclerosis. This has been shown in a Phase II clinical trial led by UC San Francisco scientists which was published in The Lancet.

Extending on the intended to assess for clinical evidence of remyelination (improving the "insulation around the electric wire") and associated preservation of axonal integrity (the "electric wire") using clemastine fumarate (the "hayfever drug") as a treatment for patients with acute optic neuritis (the cause for "loss of vision"). The study is designed to assess tolerability and clinical efficacy of clemastine using outcomes intended to assess for (a) adv

E.2.2

Secondary objectives of the trial

The key secondary study objectives address how well the treatment helps to keep the damaged "electric wire" (axon) intact and well "insulated" (myelinated) such that there is a real chance for patients to recover their vision.

- The first key secondary objective is to evaluate the efficacy of Clemastine ("heyfever drug") relative to placebo at preventing loss of retinal nerve fiber layer thickness (loss of the damaged "electric wire") and total macular volume (another measure for the "damaged electric wire") on optical coherence tomography (the method which permits us to accurately assess the "eliectric wires" and their "switches"). This will be assessed at every study visit.
- The second key secondary study objective is to evaluate how well patients recover their vision. This is done by assessing the efficacy of clemastine relative to placebo at improving patient performance on ETDRS low contrast visual acuity chart testing (2.5% black on white). This will be assessed at ever

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients diagnosed or suspected to have an acute demyelinating optic neuritis within 2 weeks from the onset of any visual symptom other than pain.
2. Male and females patients aged 18-55 years (inclusive).
3. Use of disease modifying therapies is not a contraindication.
4. Use of appropriate contraception during period of trial (women). Before entry womenfemales of child-bearing potential as defined in Section 6.4.4 must be:
a. Post-menopausal for at least 1 year OR
b. Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation or otherwise incapable of pregnancy) OR
c. Practicing a highly effective method of birth control if sexually active, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g., condoms, diaphragm or cervical cap with spermicidal foam, cream or gel), or male partner sterilization consistent with local regulations regarding use of birth control methods for patients participating in clinical trials, for the duration of their participation in the study OR
d. Not heterosexually active (patients who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study) OR
e.Practicing true abstinence (when this is in line with the preferred and usal lifestyle of the subject) Period abstinence (e.g. calendar, ovulation, symptothermal, post ovulation methods) is not an acceptable method.
5.Written informed consent must be obtained prior to any assessment being performed.

E.4

Principal exclusion criteria

1. Major ophthalmologic disease /Concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma (narrow-angle glaucoma), severe myopia, peptic ulcer, pyloroduodenal obstruction, or prostatic hypertrophy with urinary retention and bladder neck obstruction, etc.), severe myopia, etc).
2. Hypersensitivity to clemastine or other arylalkylamine antihistamines, or any of the excipients.
3. Treatment with corticosteroids within 30 days prior to screening.
4. Myopia > -7 Diopters (Severe myopia).
5. Disc hemorrhages in qualifying eye.
6. No light perception in qualifying eye.
7. Simultaneous bilateral optic neuritis.
8. Cotton wool spots in qualifying eye.
9. Macular star in qualifying eye.
10. History of significant cardiac conduction block.
11. History of cancer.
12. Suicidal ideation or behaviour in 6 months prior to baseline.
13. Pregnancy, breastfeeding, or planning to become pregnant.
14. Involved with other study protocol simultaneously without prior approval.
15. Concomitant use of any other putative remyelinating therapy as determined by investigator.
16. Concomitant use of Dalfamprdine or any other formulation of 4AP or diamino4ap.
17. Prior treatment with total lymphoid irradiation, T cell or T cell receptor vaccination.
18. Prior treatment with alemtuzamab, mitoxantrone, or cyclophosphamide.
19. Serum creatinine > 1.5 mg/dL; AST, ALT, or alkaline phosphatase > 2 times the upper limit of normal. (Reported within 72 hours)
20. History of drug or alcohol abuse within the past year.
21. Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid [MMA] and homocysteine) or untreated hypothyroidism.
22. Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal or other major diseases that in the PI’s judgment may affect interpretation of study results or patient safety.
23. History of or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is the efficacy of clemastine relative to placebo for reducing P100 latencies on full field transient pattern reversal visual evoked potentials. This will be assessed at every visit.

E.5.2

Secondary end point(s)

The first key secondary objective is to evaluate the efficacy of clemastine relative to placebo at preventing loss of retinal nerve fiber layer thickness and total macular volume on optical coherence tomography. This will be assessed at every study visit.
The second key secondary study objective is to evaluate the efficacy of clemastine relative to placebo at improving patient performance on ETDRS low contrast visual acuity chart testing (2.5% black on white). This will be assessed at every visit.
The third key secondary objective is to demonstrate the tolerability of Clemastine in this population. This will include special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis.
The fourth key secondary objective is to document the safety of Clemastine in this population of patients.
The fifth key secondary objective of this study is to help assess which secondary and tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

Yes

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

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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 across the study

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1