Clinical Trials Register

Summary
EudraCT Number:	2013-000054-22
Sponsor's Protocol Code Number:	ML28641
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-08-07
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

UK - MHRA

A.2

EudraCT number

2013-000054-22

A.3

Full title of the trial

OPEN-LABEL, PHASE IIIB STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SUBCUTANEOUS TOCILIZUMAB (MONOTHERAPY OR COMBINATION THERAPY WITH METHOTREXATE OR OTHER DMARDS) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS WHO HAVE AN INADEQUATE RESPONSE TO CURRENT NON-BIOLOGIC DMARD THERAPY OR THE FIRST ANTI-TNF BIOLOGIC AGENT

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

ACT-MOVE

A.4.1

Sponsor's protocol code number

ML28641

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	Roche Products Limited
B.1.3.4	Country	United Kingdom
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	Roche Products Limited
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	Roche Products Limited
B.5.2	Functional name of contact point	Clinical Projects Group
B.5.3	Address:
B.5.3.1	Street Address	6 Falcon Way, Shire Park
B.5.3.2	Town/ city	Welwyn Garden City
B.5.3.3	Post code	AL7 1TW
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	welwyn.cpg_general@roche.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	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	European Union
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	tocilizumab SC
D.3.2	Product code	Ro 487-7533/F10-04
D.3.4	Pharmaceutical form	Solution for injection
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.3.9.2	Current sponsor code	RO4877533
D.3.9.3	Other descriptive name	Recombinant humanised anti-human monoclonal antibody directed against the IL-6R
D.3.9.4	EV Substance Code	SUB20313
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
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	Yes
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

Rheumatoid Arthritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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 primary objective for this study is to assess the efficacy of switching to subcutaneous (SC) Tocilizumab (as monotherapy or in combination with MTX or other non-biologic DMARDs) in patients who are currently being treated with have an inadequate response to current non-biologic DMARD therapy or the first anti-TNF biologic agent (as monotherapy or in combination with MTX or other non-biologic DMARDs). Inadequate response to anti-TNF treatment is assessed at Week 24 or after a minimum period of 12 weeks of therapy if permitted by local guidance (either defined by the National Institute for Health and Clinical Excellence (NICE) as a Disease Activity Score 28 (DAS28) improvement of less than 1.2, or patients not achieving a DAS28 of ≤ 3.2 according to a treat-to-target strategy). Efficacy will be measured by DAS28-ESR and Clinical Disease Activity Index (CDAI) at every visit up to Week 52.

E.2.2

Secondary objectives of the trial

o To evaluate safety & tolerability of SC Tocilizumab over time (as monotherapy or in combination with MTX or other non-biologic DMARDs) comprising AEs, physical examination, vital signs, clinical laboratory assessments, including immunogenicity, in patients with active RA up to wk 52.
o To assess efficacy of SC TCZ (monotherapy or in combination with MTX or other non-biologic DMARDs) over time using endpoints such as DAS28 ESR, ACR response scores, EULAR response criteria, SDAI or CDAI, TJC/SJC, and patient reported outcomes (PROs) up to wk 52, including onset of action at wk 2.

o Evaluate proportion of patients who achieve low disease activity, defined by DAS28-ESR ≤ 3.2 with SC Tocilizumab (monotherapy or in combination with MTX or other non-biologic DMARDs) at every visit up to wk 52.
o Evaluate the proportion of patients who achieve remission defined by DAS28-ESR < 2.6 with SC TCZ (monotherapy or in combination with DMARDs) at every visit up to wk 52.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet the following criteria for study entry:
1. Able and willing to give written informed consent and comply with the requirements of the study protocol.
2. Patients at least 18 years of age.
3. Patients with a diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria.
4. Oral corticosteroids (≤10 mg/day prednisone or equivalent) and nonsteroidal anti- inflammatory drugs (NSAIDs; up to the maximum recommended dose) are permitted if on a stable dose regimen for ≥4 weeks prior to Baseline.
5. Permitted non-biologic DMARDs are allowed if at a stable dose for at least 4 weeks prior to Baseline.
6. Receiving treatment on an outpatient basis, not including Tocilizumab.
7. Females of childbearing potential and males with female partners of childbearing potential may participate in this study only if using a reliable means of contraception (e.g., physical barrier [patient or partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) during the study. Females of childbearing potential and males with female partners of childbearing potential must use a reliable means of contraception for at least 3 months following the last dose of TCZ.
8. If female of childbearing potential, the patient must have a negative pregnancy test at Screening and Baseline visits.
9.Patients who have an inadequate response to current non-biologic DMARD therapy or the first anti-TNF agent (in monotherapy or in combination with MTX or other non-biologic DMARDs). Inadequate response to anti-TNF treatment is defined as not achieving an adequate response to treatment at 24 weeks or after a minimum period of 12 weeks therapy if permitted by local guidance (timing of assessment according to local clinical practice and no more than 8 weeks post-Week 24) defined by NICE as a DAS28 score improvement of less than 1.2 or patients achieving a 1.2 reduction in DAS28 but not achieving low disease activity (current DAS28 ESR above 3.2) and have not been previously exposed to treatment with tocilizumab.

E.4

Principal exclusion criteria

A patient will be excluded if the answer to any of the following statements is “yes”.
General:
1. Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 6 months following baseline.
2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosis, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty’s syndrome). Secondary Sjögren’s syndrome with RA is permitted.
3. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis (Appendix 2).
4. Diagnosis of juvenile idiopathic arthritis or juvenile RA, and/or RA before the age of 16.
5. Prior history of or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, and arthropathy of inflammatory bowel disease).

Excluded Previous or Concomitant Therapy:
6. Exposure to Tocilizumab (either IV or SC) at any time prior to Baseline.
7. Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening.
8. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti CD4, anti-CD5, anti CD3, anti CD19, and anti CD20.
9. Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline.
10. Intraarticular (IA) or parenteral corticosteroids within 4 weeks prior to Baseline.
11. Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline.
12. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.

Exclusions for General Safety:
13. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies.
14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or GI disease.
15. History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforation.
16. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
17. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening.
18. Active TB requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating Tocilizumab. However, if local practice or guidelines allow reference to test results that were obtained prior to the screening period as part of routine clinical practice, this is allowed. Patients treated for TB with no recurrence in 3 years are permitted.
19. Current liver disease as determined by the investigator.
20. Positive hepatitis B surface antigen (HbsAg) or hepatitis C antibody.
21. Primary or secondary immunodeficiency (history of or currently active).
22. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumours, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years.
23. Pregnant women or nursing (breast feeding) mothers.
24. Patients with reproductive potential not willing to use an effective method of contraception.
25. History of alcohol, drug, or chemical abuse within 1 year prior to Screening.
26. Neuropathies or other conditions that might interfere with pain evaluation.

Laboratory Exclusion Criteria (at Screening):
27. Serum creatinine >1.4 mg/dL (124 μmol/L) in female patients and >1.6 mg/dL (141 μmol/L) in male patients.
28. ALT or AST >1.5 times ULN
29. Total bilirubin >ULN.
30. Platelet count <100 x 109/L (100,000/mm3).
31. Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L).
32. White blood cells <3.0 x 109/L (3000/mm3).
33. Absolute neutrophil count (ANC) <2.0 x 109/L (2000/mm3)
34. Absolute lymphocyte count <0.5 x 109/L (500/mm3).

E.5 End points

E.5.1

Primary end point(s)

• Change in DAS28-ESR at every visit up to Week 52

E.5.1.1

Timepoint(s) of evaluation of this end point

At every visit up to Week 52

E.5.2

Secondary end point(s)

· ACR response scores at every visit up to Week 52.
· EULAR response criteria at every visit up to Week 52.
· Change in SDAI or CDAI at every visit up to Week 52.
· Change in total TJC and total SJC over time.
· Proportion of patients and reasons for non-biologic DMARD/ corticosteroid dose reductions and/or discontinuation over time.

MTX adherence in patients being prescribed the biologic DMARD (bDMARD) in combination with a non-biologic DMARD, by using a special designed “Methotrexate adherence questionnaire” at Baseline, W12, W24, W36 and W52.

E.5.2.1

Timepoint(s) of evaluation of this end point

· ACR response scores at every visit up to Week 52.
· EULAR response criteria at every visit up to Week 52.
· Change in SDAI or CDAI at every visit up to Week 52.
· Change in total TJC and total SJC over time.
· Proportion of patients and reasons for non-biologic DMARD/ corticosteroid dose reductions and/or discontinuation over time.

MTX adherence in patients being prescribed the biologic DMARD (bDMARD) in combination with a non-biologic DMARD, by using a “Methotrexate adherence questionnaire” at baseline (week 0), week 12, week 24, week 36 and week 52

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

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

E.8.1.1

Randomised

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

LPLV

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.1.3

Elderly (>=65 years)

Yes

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

160

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)

The Sponsor does not intend to provide Tocilizumab or other study interventions to patients after conclusion of the study or any earlier patient withdrawal.

For patients who wish to remain on TCZ treatment, and for whom the investigator considers continued treatment would be beneficial, they should be able to receive TCZ, following approval of subcutaneous TCZ, via the NHS or NICE/ SMC guidance by the time the study completes.

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

2013-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-08-04

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