Clinical Trials Register

Summary
EudraCT Number:	2013-003493-27
Sponsor's Protocol Code Number:	CQAL964B2201
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-01-30
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2013-003493-27

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled study to
investigate the safety, tolerability and efficacy of orally
administered QAL964 in patients with active rheumatoid
arthritis on stable doses of methotrexate and with
inadequate response to methotrexate

A.3.1

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

Study with the aim to evaluate the safety, tolerability and efficacy of QAL964 in patients with Rheumatoid Arthritis who are treated with anti-rheumatic drug methotrexate but where the treatment does not sufficiently work.

A.3.2

Name or abbreviated title of the trial where available

CQAL964B2201

A.4.1

Sponsor's protocol code number

CQAL964B2201

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Hungary Kft. Pharma
B.5.2	Functional name of contact point	Public Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Bartók Béla út 43-47.
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1114
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+361457-6500
B.5.5	Fax number	+361457-6600
B.5.6	E-mail	infoph.hungary@novartis.com

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.3.2	Product code	QAL964
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.3.9.2	Current sponsor code	QAL964
D.3.9.3	Other descriptive name	QAL964
D.3.9.4	EV Substance Code	SUB129746
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 25
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	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

Rheumatoid Arthritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	HLT
E.1.2	Classification code	10039075
E.1.2	Term	Rheumatoid arthritis and associated conditions
E.1.2	System Organ Class	100000004870

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 primary objective is to demonstrate that the efficacy of 50 mg or 25 mg bid QAL964 at
week 12 is superior to placebo in patients with active RA on a stable dose of MTX, based on
the proportion of patients achieving an ACR20 response.

E.2.2

Secondary objectives of the trial

The key secondary objective is to evaluate the safety and tolerability of QAL964 in
comparison to placebo in terms of incidences of AEs, laboratory abnormalities, vital signs and
ECG.
Further secondary objectives are
1. To evaluate the ACR20, ACR50 and ACR70 responses at Week 2, 4, 8 and 12 during
QAL964 dosing versus placebo.
2. To evaluate the HAQ-

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for inclusion in this study have to fulfill all of the following criteria.
1. Patient must be able to understand and communicate with the Investigator and comply with the requirements
of the study and must give a written, signed and dated informed consent before any study assessment is performed.
2. Male or non-pregnant, non-lactating female patients at least 18 years of age.
3. Presence of RA classified by ACR 2010 revised criteria for at least 3 months before screening.
4. At Baseline: Disease activity criteria defined by ≥ 6 tender joints out of 28 and ≥ 6 swollen joints out of 28 with:
a. At least 1 of the following at screening:
1. Anti-CCP antibodies positive or
2. Rheumatoid Factor positive
b. AND hsCRP ≥ 8 mg/L.
5. Patients must be taking MTX for at least 3 months before randomization and have to be on a stable dose of
at least 10 mg/week for at least 6 weeks before randomization.
6. Patients must be taking folic acid (or equivalent, e.g., folinic acid) supplementation before randomization.
7. Patients who were taking other DMARDs (in combination with MTX) will be allowed entry into study after appropriate
washout period (except for MTX) prior to baseline of 28 days, except for leflunomide, which has to be discontinued
for 8 weeks prior to baseline unless a cholestyramine washout has been performed.
8. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/d prednisone or equivalent for at
least 4 weeks before randomization.
9. Patients who are regularly taking NSAIDs (e.g., COX-1 or COX-2 inhibitors) are required to be on a stable dose for
at least 2 weeks before randomization.

E.4

Principal exclusion criteria

Subjects fulfilling any of the following criteria are not eligible for inclusion in this study.
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment.
2. Patients who have ever received biologic immunomodulating agents, e.g., anti-TNFα or anti-IL-6 therapeutic
antibodies, or any cell-depleting therapies including but not limited to anti-CD20, or investigational agents (e.g.,
CAMPATH, anti-CD4, anti-CD3, anti-CD19).
3. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
4. RA patients functional status class IV according to the ACR 1991 revised criteria.
5. Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone, or morphine).
6. Any therapy by intra-articular injections (e.g., corticosteroid, hyaluronan) required for treatment of arthritis
within 4 weeks before randomization.
7. Any intramuscular corticosteroid injection within 4 weeks before randomization.
8. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and
until the termination of gestation, confirmed by a positive hCG serumtest.
9. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they
are using highly effective methods of contraception (excluding systemic hormonal contraceptives) during dosing of
study treatment and for additional 2 days (≥ 5 times the terminal half-life) of study medication.
10. History of malignancy, < 5 years, except for basal cell carcinoma or actinic keratoses treated with no evidence of recurrence > 3 months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed.
11. Significant medical problems or diseases, including but not limited to: uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure [NYHA class III or IV], renal trauma, glomerulonephritis, one kidney only, a serum creatinine level exceeding 1.5 mg/dL (132.6 μmol/L).
12. Uncontrolled diabetes mellitus (IDDM or NIDDM) or a high risk for diabetes, as guided by following criteria:
a. Clinically significant elevations of overnight fasted morning glucose levels
b. HbA1c > 7.5%
13. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as AST,
ALT, alkaline phosphatase, or serum bilirubin, guided by the following criteria.
a. Any single parameter may not exceed 2 x ULN. A single parameter > 2 x ULN should be re-checked once,
to rule out lab error.
b. If the total bilirubin is > 2 x ULN, total bilirubin to be differentiated into direct/indirect reacting bilirubin.
In any case, serum bilirubin should not exceed 1.6 mg/dL .
14. History of ongoing, chronic or recurrent infectious disease
15. History or evidence of active or latent tuberculosis at screening:
a. PPD tuberculin skin test reaction of 10 mm diameter at screening or < 6-month prior to screening visit.
Patients who have a positive PPD skin test with a documentation of BCG vaccination, who are at low
environmental risk for tuberculosis (TB) infection or reactivation, and have a negative chest X-ray not older
than 6 month can be included.
b. For sites using QuantiFeron test, a positive test at screening or within 6 month prior to the
screening visit will exclude the subject from the participation in the study.
16. Known infection with HIV, hepatitis B or hepatitis C at screening or randomization.
17. Current severe progressive or uncontrolled disease which in the judgment of the clinical Investigator renders the
patient unsuitable for the trial.
18. Any medical or psychiatric condition which, in the Investigator’s opinion, would preclude the participant from
adhering to the protocol or completing the study per protocol.
19. Donation or loss of 400 mL or more of blood within 8 weeks before randomization.
20. History or evidence of ongoing alcohol or drug abuse, within the last six months before randomization.
21. During treatment with QAL964 vaccination may be less effective. Any subjects receiving live vaccines (this includes
nasal-spray flu vaccine) starting from 6 weeks before study entry, during the study, and up to 7 day after the last
dose of QAL964 should be excluded.
22. Receiving treatment with CYP1A2 substrates with a narrow therapeutic index:
namely (but not limited to) theophylline and tizanidine.
23. Overt or laboratory evidence of immunodeficiency syndromes, blood dyscrasias (e.g., bone marrow hypoplasia,
leukopenia, thrombocytopenia, significant anemia), known hypersensitivity to methotrexate, or any other
contraindication to methotrexate as per local regulation.

E.5 End points

E.5.1

Primary end point(s)

ACR20 response.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

E.5.2

Secondary end point(s)

safety and tolerability of QAL964 in
comparison to placebo in terms of incidences of AEs, laboratory abnormalities, vital signs and
ECG.
Further secondary objectives are
1. To evaluate the ACR20, ACR50 and ACR70 responses at Week 2, 4, 8 and 12 during
QAL964 dosing versus placebo.
2. To evaluate the HAQ-DI at Week 2, 4, 8 and 12 in patients receiving QAL964 versus
placebo treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 2, 4, 8, 12

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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

Russian Federation

Ukraine

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

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

F.4.2.2

In the whole clinical trial

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

2014-04-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-10

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

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