Clinical Trials Register

Summary
EudraCT Number:	2016-003682-26
Sponsor's Protocol Code Number:	CF101-301RA
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-05-17
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2016-003682-26

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Active- and Placebo controlled, Parallel-group Trial to Evaluate the Efficacy and Safety of CF101 Compared to Methotrexate in the Treatment of Early Rheumatoid Arthritis

A.3.1

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

Phase 3 trial to Evaluate the Efficacy and Safety of CF101 Compared to Methotrexate in the Treatment of patients suffering of Early Rheumatoid Arthritis

A.4.1

Sponsor's protocol code number

CF101-301RA

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	Can-Fite BioPharma, Ltd.
B.1.3.4	Country	Israel
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	CanFite BioPharma Ltd.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CanFite BioPharma Ltd.
B.5.2	Functional name of contact point	Director Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	10 Bareket Street, Kiryat Matalon
B.5.3.2	Town/ city	Petach Tikva
B.5.3.3	Post code	49170
B.5.3.4	Country	Israel
B.5.4	Telephone number	+972-3-924 1114
B.5.5	Fax number	+972-3-924 9378
B.5.6	E-mail	zivit@canfite.co.il

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	CF101
D.3.2	Product code	CF101
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	Piclidenoson
D.3.9.1	CAS number	152918-18-8
D.3.9.2	Current sponsor code	CF101
D.3.9.3	Other descriptive name	IB-MECA
D.3.9.4	EV Substance Code	SUB26816
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.IMP: 2
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	CF101
D.3.2	Product code	CF101
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	Piclidenoson
D.3.9.1	CAS number	152918-18-8
D.3.9.2	Current sponsor code	CF101
D.3.9.3	Other descriptive name	IB-MECA
D.3.9.4	EV Substance Code	SUB26816
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	2
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	METHOTREXATE
D.3.2	Product code	METHOTREXATE
D.3.4	Pharmaceutical form	Capsule
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	METHOTREXATE
D.3.9.1	CAS number	133073-73-1
D.3.9.2	Current sponsor code	METHOTREXATE
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
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	5
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
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
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

Early Rheumatoid Arthritis

E.1.1.1

Medical condition in easily understood language

Early Rheumatoid Arthritis

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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

Determine the efficacy of oral CF101 when administered daily for 12 weeks to subjects with active rheumatoid arthritis (RA) relative to oral methotrexate (MTX), as assessed by the proportion of subjects achieving a Disease Activity Score (DAS) of Low Disease Activity (LDA);

E.2.2

Secondary objectives of the trial

- Determine the efficacy of oral CF101 when administered daily for 24 weeks to subjects with active RA relative to oral MTX, as assessed by the proportion of subjects achieving DAS remission; and
- Explore the relationship between whole blood adenosine A3 receptor (A3AR) expression and treatment response

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacokinetics in selected sites

E.3

Principal inclusion criteria

1. Males and females ages 18-75 years.
2. Meet the ACR/EULAR criteria for RA (Aletaha, 2010) (Appendix 1).
3. Not bed- or wheelchair-bound.
4. Active RA, as indicated by EULAR Disease Activity Score (DAS28) >3.2 (Fransen, 2005; DAS28, 2015; Appendix 3).
5. Demonstrate at least 6 swollen and at least 6 tender joints.
6. If taking an NSAID, dose has been stable for at least 1 month prior to the Screening Visit, and will remain unchanged during protocol participation.
7. If taking an oral corticosteroid, dose is ≤10 mg/day prednisone or equivalent, has been stable for at least 1 month prior to the Screening Visit, and will remain unchanged during protocol participation.
8. Willing to take oral folate (minimum dose of 5 mg/week) or folinic acid (up to 10 mg/week) for the duration of the study.
9. In the Investigator’s opinion, the ability to understand the nature of the study and any hazards of participation, and to communicate satisfactorily with the Investigator and to participate in, and to comply with, the requirements of the entire protocol.
10. Negative Screening serum pregnancy test for female subjects of childbearing potential.
11. Female subjects of childbearing potential must use highly effective contraception throughout
the course of the trial and for 3 months after. Highly effective methods include hormonal contraception (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants; each method must be used with a barrier method, preferably male condom), intrauterine device or system, tubal ligation, partner vasectomy, or dual (male plus female) barrier methods (each barrier method must be used with a hormonal method). Female subjects who use a hormonally based method must agree to use it in conjunction with a barrier method. Female partners of male study subjects should consider using one of the above methods of contraception as well. Post-menopausal status is defined as menopause for at least 1 year prior to the Screening Visit and must be confirmed by an elevated serum FSH level.
12. Male subjects must refrain from sperm donation during treatment and until at least 90 days
after the end of study drug dosing. Male subjects with fertile or pregnant partners must agree
to use condoms throughout the course of the trial and for 3 months after.
13. All aspects of the protocol explained and written informed consent obtained.

E.4

Principal exclusion criteria

1. Prior receipt of MTX.
2. Prior receipt of >1 regimen of synthetic small-molecule DMARDs.
3. Receipt of any non-MTX synthetic small-molecule DMARDs (including but not limited to sulfasalazine, chloroquine/hydroxychloroquine, azathioprine, and/or leflunomide) for at least 1 month prior to the Screening Visitor concomitantly during the trial.
4. Receipt of tofacitinib at any time during the 4-week period prior to the Screening Visit or concomitantly during the trial.
5. Receipt of a biologic anti-rheumatic agent (including, but not limited to, etanercept, abatacept, infliximab, golimumab, adalimumab, tocilizumab, certolizumab, and rituximab) at any time prior to or concomitantly during the trial.
6. Receipt of parenteral or intra-articular corticosteroids during the 1 month prior to the Screening Visit.
7. Participation in a previous trial CF101 trial.
8. Presence or history of uncontrolled arterial hypertension or symptomatic hypotension.
9. QTcF interval on Screening Visit ECG or on average of triplicate Baseline Visit ECGs > 450 milliseconds (msec) for males or >470 msec for females (except when QT prolongation is associated with right or left bundle branch block, in which case enrollment is allowed).
10. A condition which increases proarrhythmic risk, including hypokalemia, hypomagnesemia, congenital Long QT Syndrome.
11. Heart disease which is, in the Investigator’s judgment, clinically unstable.
12. Ongoing or planned use of a concomitant medication that is on the CredibleMedsTM list of drugs known to cause Torsades de Pointes (Appendix 5).
13. Clinical laboratory abnormalities at the Screening Visit as follows:
a. Hemoglobin level <9.0 gm/dL
b. Platelet count <125,000/mm3
c. White blood cell (WBC) count <3000/mm3
d. Serum creatinine level >1.25 times above the central laboratory’s normal limits
e. Liver aminotransferase (ALT and/or AST) levels greater than 2 times the central
laboratory’s upper limit of normal
14. Known or suspected immunodeficiency or human immunodeficiency virus positivity.
15. Active or chronic viral hepatitis (B and/or C).
16. Active or known latent tuberculosis requiring therapy.
17. Anticipated need for live-organism vaccine.
18. Pregnancy, lactation, or inadequate contraception as judged by the Investigator.
19. Participation in another investigational drug or vaccine trial concurrently or within 30 days
prior to Screening.
20. Active drug or alcohol dependence.
21. History of malignancy within the past 2 years (excluding excised basal or squamous cell
carcinoma of the skin).
22. Significant acute or chronic medical or psychiatric illness that, in the judgment of the
Investigator, could compromise subject safety, limit the subject’s ability to complete the
study, and/or compromise the objectives of the study.

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects achieving DAS(ESR) LDA (<3.2) at Week 12, with all-cause
dropouts considered as non-responders

E.5.1.1

Timepoint(s) of evaluation of this end point

Endpoint is evaluated at 12 weeks

E.5.2

Secondary end point(s)

- Proportion of subjects achieving DAS remission (<2.6) at Week 24
- ACR20/50/70 response rates by visit
- EULAR Good and Moderate Response rates by visit
- Change from Baseline (CFB) and percent change from Baseline (PCFB) for each of the components of the DAS/ACR responses at each visit

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints are evaluated at each visit up to and including 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

Yes

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)

Yes

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

Bosnia and Herzegovina

Bulgaria

Canada

Israel

Moldova, Republic of

Poland

Romania

Serbia

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

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.1.1.1

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:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

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

360

F.4.2.2

In the whole clinical trial

500

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)

None

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

2019-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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