Clinical Trials Register

Summary
EudraCT Number:	2017-003037-28
Sponsor's Protocol Code Number:	TOPIRA
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-07-22
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-003037-28

A.3

Full title of the trial

Efficacy of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease modifying anti-rheumatic drugs.

A.3.1

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

Efficacy of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease modifying anti-rheumatic drugs.

A.3.2

Name or abbreviated title of the trial where available

TOPIRA

A.4.1

Sponsor's protocol code number

TOPIRA

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 Medical Center Utrecht
B.1.3.4	Country	Netherlands
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	University Medical Center Utrecht
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Roche
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Utrecht
B.5.2	Functional name of contact point	Rheumatology & Clinical Immunology
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 100
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3508GA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31887550459
B.5.6	E-mail	reumatologie-research@umcutrecht.nl

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	RoActemra
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Solution for injection/infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOCILIZUMAB
D.3.9.1	CAS number	375823-41-9
D.3.9.3	Other descriptive name	TOCILIZUMAB
D.3.9.4	EV Substance Code	SUB20313
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	162
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	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	Yes
D.2.1.1.1	Trade name	Prednisone
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Prednisone
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	Prednisone
D.3.9.2	Current sponsor code	Prednisone
D.3.9.3	Other descriptive name	PREDNISONE
D.3.9.4	EV Substance Code	SUB10020MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PREDNISOLONE
D.3.9.1	CAS number	50-24-8
D.3.9.2	Current sponsor code	Prednisolone
D.3.9.3	Other descriptive name	Prednisolone
D.3.9.4	EV Substance Code	SUB10018MIG
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	5 to 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

RA patients with active RA despite treatment with DMARDs.

Reumatoïde artritis

E.1.1.1

Medical condition in easily understood language

RA patients with active RA despite treatment with DMARDs.

Reuma (reumatoïde artritis)

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	23.1
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

To assess whether adding TCZ (subcutaneously 162 mg/week) to current csDMARD therapy is more effective in reducing disease activity than adding prednisone (orally 10 mg/day) in a usual care treat-to-target strategy in patients with insufficient response to DMARD therapy (DMARD-IR).

E.2.2

Secondary objectives of the trial

Secondary Efficacy Objective(s):
-To compare treatment strategies on drug retention (TCZ vs prednisone), as surrogate measure of drug efficacy and tolerability, and on drug treatment over time.
-To assess whether TCZ is more effective than prednisone in reaching different criteria for response, clinical remission, and low disease activity; and on reduction of radiographic progression.
-To compare treatments on costs and effects in a cost-effectiveness analysis

Secondary Patient-Reported Outcome Objectives:
-To assess whether TCZ is more effective than prednisone with regard to quality of life, functional ability, fatigue, sleep quality, and anxiety and depression.
-To compare treatments on costs and quality of life (utility) in a cost-utility analysis

Secondary Safety Objectives:
-To assess the occurrence of serious adverse events (SAEs), glucocorticoid-associated AEs and TCZ-associated AEs

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

HandScan substudy:
Primary Objective: to assess whether adding TCZ is more effective than adding prednisone using the HandScan score as endpoint.
Secondary Objective: To assess the clinical utility of the HandScan in comparison with the clinically used disease activity measures to monitor response to prednisone or TCZ treatment.

E.3

Principal inclusion criteria

• • Able and willing to give written informed consent.
• Have sufficient knowledge of the Dutch language to be able to comply with the requirements of the study protocol.
• At least 18 years of age.
• Diagnosed as having RA and meeting the 2010 ACR/EULAR criteria for RA (Appendix A).
• Active RA defined by CDAI>10 and at least 1 swollen joint of the 28 joint count.
• For patients < 65 years of age: On stable treatment with csDMARDs for ≥ 8 weeks prior to the screening visit.
• Eligible to start with a biological according to the 2019 EULAR guidelines for management of RA (see appendix L): previous treatment with ≥2 csDMARDs OR previous treatment with ≥1 csDMARD with presence of a prognostically unfavorable factor.

E.4

Principal exclusion criteria

• Having a contraindication for treatment with systemic GCs (as determined by the treating rheumatologist, in line with regular care).
• Having a contraindication for treatment with TCZ, as determined by the treating rheumatologist or as described in the Summary of Product Characteristics (SPC) Paragraph 4.3, page 33. ‘Special warnings and precautions for use’ as described in the SPC Paragraph 4.4, page 33, should be strictly followed.
• Use of systemic GCs (including i.a. GCs) within 4 weeks before the screening visit.
• Current use of a bDMARD or tsDMARD; i.e. these need to be discontinued before start of study medication. Wash out periods for bDMARDs and tsDMARDs should follow routine care.
• Treatment with any investigational agent within 4 weeks prior to the screening visit.
• Having any other inflammatory rheumatic disease than RA., except for secondary Sjögren’s syndrome will be allowed, as well as RA-overlap syndromes that are primarily treated as RA at the time of screening.
• Female who is pregnant (by anamnesis) or breast feeding, or considering becoming pregnant during the study period.

E.5 End points

E.5.1

Primary end point(s)

Change in CDAI from baseline to 6, 9, and 12 months

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to 6, 9, and 12 months

E.5.2

Secondary end point(s)

SECONDARY EFFICACY ENDPOINTS:
- Change in CDAI from baseline to 6 months
- Change in SDAI and change in DAS28 from baseline to 12 months.
- Drug retention rate, defined as the proportion of patients at 12 months on the treatment (TCZ/prednisone) to which they were allocated.
- Switch rate, defined as the proportion of patients who switched during the study period to treatment of the other arm.
- Average dose of TCZ or prednisone from baseline up to 12 months.
- ACR20, ACR50, and ACR70 response (using 28 joint counts), EULAR good or moderate response.
- Proportion of patients reaching a state of clinical remission at any time during the study defined by different criteria: CDAI≤2.8 AND max 1 swollen joint of the 28 joint count, CDAI≤2.8, SDAI≤3, DAS28<2.6, and ACR-EULAR Boolean remission (defined by a tender joint count ≤1, a swollen joint count ≤1, a C-reactive protein ≤1mg/dL, and a patient global assessment ≤1 on a 0-10 scale).
- Time to reach a state of clinical remission defined by the criteria mentioned before.
- Proportion of patients reaching at least a state of low disease activity (defined by 2.8<CDAI≤10, 3.3<SDAI≤11, 2.6≤DAS28<3.2,) during the study.
- Change in Sharp/van der Heijde (SvH) score from baseline to 12 months
- Change in quality of life from baseline to 12 months (using the EQ5D)
- Change in functional ability from baseline to 12 months (using the Dutch consensus HAQ)
- Change in fatigue (using the FACIT-F), sleep quality (using the PSQI) and anxiety and depression (using the HADS) from baseline to 12 months.
- Direct medical (e.g. GP visits) and non-medical (e.g. travel expenses) costs as well as indirect costs (e.g. productivity loss) using the Health Care Utilisation and Work Productivity Questionnaire, and observed drug use and visits to the rheumatology clinic.
- Quality Adjusted Life Years (based on EQ5-D utility scores over time).

SECONDARY SAFETY ENDPOINTS:
- GC Toxicity Index (GTI) score at 6, 9 and 12 months
- The proportion of patients reaching ≥1 of the following categories of the GTI:
o Major increase in BMI
o Worsening of glucose tolerance despite treatment
o Worsening hypertension despite treatment
o Worsening hyperlipidemia despite treatment
o Decrease in bone density
o Moderate steroid myopathy or greater
o Moderate skin toxicity or greater
o Moderate neuropsychiatric symptoms or greater
o Grade 3 infection or greater
o Any category of the Specific List
- The proportion of patients experiencing ≥1 TCZ-associated AE
- The proportion of patients experiencing ≥1 SAE
- The number of AEs of the GTI, of TCZ-associated AE and of SAE per patient

E.5.2.1

Timepoint(s) of evaluation of this end point

As described in E.5.2.

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

Yes

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

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

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:

100

F.1.3

Elderly (>=65 years)

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

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

120

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)

Patients will be treated in regular clinical care.

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

2019-07-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-02

P. End of Trial
P.	End of Trial Status	Ongoing

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