Clinical Trials Register

Summary
EudraCT Number:	2020-002952-18
Sponsor's Protocol Code Number:	Protocol
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:	2020-07-09
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

2020-002952-18

A.3

Full title of the trial

Targeting de novo Pyrimidine Biosynthesis by leflunomide as a Novel Concept for the Treatment of Corona Virus Disease 2019 (COVID-19)

A.3.1

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

DEFEAT-COVID Study

A.3.2

Name or abbreviated title of the trial where available

DEFEAT- Covid Study

A.4.1

Sponsor's protocol code number

Protocol

A.5.4

Other Identifiers

Name:

Clinical Trials.gov

Number:

TBC

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	Ashford and St Peter's Hospitals NHS Foundation Trust
B.1.3.4	Country	United Kingdom
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	LifeArc
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Freda Gomes
B.5.2	Functional name of contact point	St Peter's Hospital
B.5.3	Address:
B.5.3.1	Street Address	Guildford Road
B.5.3.2	Town/ city	Chertsey, Surrey
B.5.3.3	Post code	KT16 0PZ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01932723534
B.5.6	E-mail	Freda.Gomes@nhs.net

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.2.1.1.1	Trade name	Leflunomide
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Deutshland GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Leflunomide
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	leflunomide
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	10
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Confirmed Covid-19 infection by RT-PCR

E.1.1.1

Medical condition in easily understood language

Typical symptoms of Coronavirus infection such as high temperature, cough, sore throat, headaches etc

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The overall objective of the trial is to evaluate the efficacy and safety of oral leflunomide in COVID-19 patients with moderate to critical complications.

The primary focus will be on clinical progression (speed of recovery and complications, i.e. time to clinical improvement, TTCI) and on kinetics of viral clearance. This means

1. how many days it takes for patient to make clinical improvement after treatment.
2. how quickly for the the virus to clear from infected patients.

E.2.2

Secondary objectives of the trial

The secondary outcome measures are
1. Overall outcome measures (time to Hospital Discharge, All cause mortality, Duration of Intensive Care Stay)
2. Organ and multiorgan function: degree of acute Lung Injury , cardiac function, low blood pressure and acute kidney Injury
3. Physiological and biochemical markers include P/F ratio, i.e. arterial pO2 divided by the FIO2) and clinical bimolecular characterisation (biomarkers including high specificity CRP, ferritin, procalcitonin, troponin, BNP, creatinine and kidney biomarkers.
4. Cytokine profile including pro and anti-inflammatory cytokines (China only)
5. Exploratory outcome: Clinical predictors based on computer modelling and artificial intelligence data
analysis [Time Frame: up to 28 days]
6. Adverse events due to Leflunomide therapy such as stress and strain on liver function

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

1. Age ≥18 years
2. Patients with onset of symptoms 15 days of onset
3. Laboratory (RT-PCR) confirmed infection with 2019-nCoV.

E.4

Principal exclusion criteria

1. Pregnant or breast-feeding women;

2. Individuals already receiving specific antiviral medications (such as lopinavir/lidonavir, ribavirin), monoclonal antibodies, or other drug trial treatment for COVID-19 within one week prior to study enrolment;

3. Liver function tests>2 fold of upper limits of normal (ULN).
Advisory:
If the attending clinician considers that there exists a specific contra-indication to leflunomide (such as severe hypoproteinaemia, severe immunodeficiency) to Leflunomide, then the patient would be considered ineligible for the study

E.5 End points

E.5.1

Primary end point(s)

1.Time to Clinical Improvement (TTCI) [Censored atDay 28] [ Time Frame: up to 28 days ]
2.Viral clearance by time to 2019-nCoV RT-PCR negativity and change in viral load in upper respiratory tract specimens

TTCI is defined as the time (in days) from initiation of study treatment (active or placebo) until a decline of two categories from status at randomisation on a 7 category ordinal scale of clinical status which ranges
from 1 (discharged) to 7 (death) as per WHO R&D Blueprint expert group. The 7-category ordinal scale
include:
1. not hospitalised with resumption of normal activities;2. not hospitalized, but unable to resume normal activities;
3. hospitalised, not requiring supplemental oxygen;
4. hospitalised, requiring supplemental oxygen;
5. hospitalised, requiring nasal high-flow oxygen HFNC therapy, non-invasive mechanical ventilation NIV, or both;
6. hospitalized, requiring ECMO, invasive mechanical ventilation IMV, or both;
7. death.
Abbreviation: IMV: invasive mechanical ventilation; NIV: non-invasive mechanical ventilation; HFNC: High-flow nasal cannula.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days after initiation of treatment (a course of 10 days oral administrations)

E.5.2

Secondary end point(s)

1. Overall outcome measures (time to Hospital Discharge, All cause mortality, Duration of Intensive Care Stay.
2. Organ and multiorgan function: degree of Acute Lung Injury by Berlin definition, cardiac function, vasoplegia
and Acute Kidney Injury by the KDIGO criteria including the need and duration of invasive and non-invasive ventilation, incidence of re-intubation, tracheostomy, CXR scores, echocardiography, inotropic/vasoactive support, need for RRT
3. Physiological (P/F ratio, i.e. arterial pO2 divided by the FIO2) and clinical bimolecular characterisation(biomarkers including high specificity CRP, ferritin, procalcitonin, troponin, BNP, creatinine and kidney biomarkers.
4. Cytokine profile including pro and anti-inflammatory cytokines (China only)
5. Exploratory outcome: Clinical predictors based on AI data analysis
6. Adverse events due to leflunomide therapy such as
hepatotoxicity.

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days after initiation of treatment (a course of 10 days oral administrations)

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

Yes

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)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

All randomised participants are to be followed up until death, discharge from hospital or 28 days post-randomisation (whichever is sooner).

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