| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult Rheumatoid Arthritis (RA) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| 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 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the proportion of patients who maintain good/ moderate European League Against Rheumatism (EULAR) response between weeks 24 and week 56: in patients receiving RoActemra in combination with a tapering dose of MTX versus patients receiving RoActemra in combination with a stable dose of MTX. |
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| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of RoActemra with tapering MTX dosage versus RoActemra in combination with stable MTX dosage using EULAR and patient reported health assessments.
To compare the incidence of anaemia in patients receiving RoActemra with tapering MTX dosage versus RoActemra in combination with stable MTX dosage.
To compare change in work/productivity, as assessed by quality of life changes in patients receiving RoActemra with tapering MTX dosage versus RoActemra in combination with stable MTX dosage.
To compare the safety of RoActemra with tapering MTX dosage versus RoActemra in combination with stable MTX dosage, with regards to adverse events and laboratory assessments.
To assess the proportion of patients able to discontinue MTX.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or non-pregnant, non-nursing female.
2.≥ 18 years of age.
3.Patients currently experiencing active severe RA (DAS28 >5.1) according to the EULAR/ACR criteria for the diagnosis of RA at start of treatment (week 0).
4.Patients should have inadequately responded to a trial of 2 DMARDs, including MTX (as defined by NICE) and have not been previously treated with a biologic agent, such as a TNF inhibitor. NICE define a trial of DMARDs (including MTX) as being normally of 6 months, with 2 months at standard dose.
5.Patients with a history of parenteral (subcutaneous or intramuscular) MTX prior to start of treatment (week 0) are eligible. However, prior to treatment (day 1) these patients must have been on a stable dose of oral MTX of at least 10 mg/week.
6.If patients are receiving an oral corticosteroid, the dose must have been ≤ 10 mg/day prednisone (or equivalent) and stable for at least 25 out of 28 days prior to start of treatment (day 1).
7.Patients receiving treatment on an outpatient basis.
8.Patients able and willing to give written informed consent and comply with the requirements of the study protocol.
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| E.4 | Principal exclusion criteria |
Disease
1.Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomisation
2.Rheumatic autoimmune disease other than RA. Patients with interstitial pulmonary fibrosis and Sjögren’s Syndrome with RA are permitted.
3.Functional class IV as defined by ACR Classification of Functional Status in RA
4.Prior history of/current inflammatory joint disease other than RA
Drug-specific
5.Treatment with leflunomide, or cholestyramine washout within 3 months prior to enrolment.
6.Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening
7.Previous treatment with RoActemra
8.Previous treatment with any biologic drug that is used in the treatment of RA
9.Any previous treatment with alkylating agents eg as cyclophosphamide or chlorambucil, or with total lymphoid irradiation
10.Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 6 months before enrolment
11.Intra-articular/parenteral corticosteroids within 6 weeks prior to enrolment
12.Immunisation with a live/attenuated vaccine within 4 weeks prior to enrolment
Laboratory analyses (at screening)
13.Serum creatinine > 142 μmol/L (1.6 mg/dL) in female patients and > 168 μmol/L (1.9 mg/dL) in male patients
14.ALT (SGPT) or AST (SGOT)> 2 x ULN
15.Platelets< 100 x 109/L (100,000/mm3)
16. Haemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
17.White blood cells< 1.0 x 109/L (1000/mm3), ANC< 1.0 x 109/L (1000/mm3)
18. Absolute lymphocyte count< 0.5 x 109/L (500/mm3)
19.Positive hepatitis B virus surface antibody (HBsAg) or Hepatitis C virus (HCV) antibody
20.Total bilirubin> ULN
21.Triglycerides> 10 mmol/L (>900 mg/dL) at screening (non-fasting or fasting)
General medical
22.Pregnant women or breastfeeding mothers
23.Females of child-bearing potential not using reliable means of contraception
24.History of severe allergic/anaphylactic reactions to human, humanised, or murine monoclonal antibodies
25.Chest X-Ray (CXR) evidence of any clinically significant abnormality
26.Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease
27.In patients with a history of diverticulitis or diverticulosis requiring antibiotic treatment, the treating physician needs to consider the benefit-risk ratio
28. History of chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforations
29.Uncontrolled disease states, eg asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with oral/parenteral corticosteroids
30.Current liver disease as determined by investigator. Patients with prior history of ALT (SGPT) elevation are not excluded
31.Known active current/history of recurrent bacterial, viral, fungal mycobacterial, or other infections (including but not limited to tuberculosis (TB) and atypical mycobacterial disease, clinically significant abnormalities on CXR as determined by the investigator, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening (does not apply to the treatment of latent TB)
32.History of, or currently active, primary or secondary immunodeficiency
33.Evidence of active malignant disease, malignancies active or diagnosed within the previous 5 years (including haematological malignancies and solid tumours, except non-melanoma skin cancer that has been cured and treated cervical carcinoma in situ)
34.Active TB requiring treatment within the previous 3 years. Patients treated for TB with no recurrence in 3 years are permitted
35. Latent TB: Patients with latent TB are not eligible, unless having started treatment with standard anti-mycobacterial therapy before initiating RoActemra and have a negative CXR for active TB at screening. Therefore, patients should be screened for latent TB, prior to biologics use, as per local guidelines or clinical practice. The assessment of the presence or absence of latent TB will take place during the screening period. 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
36.HIV positive patient
37.History of alcohol, drug, or chemical abuse within the 6 months prior to screening
38.Neuropathies or other painful conditions that might interfere with pain evaluation
39. Patients with lack of peripheral venous access.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients maintaining previous disease activity (EULAR response) from week 24 (time of randomisation) to week 56. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Change in DAS28 score from week 24 (time of randomisation) to week 56, between the 2 randomisation arms.
Proportion of patients who achieve score of ≤1 in TJC, SJC at week 56.
Proportion of patients who achieve a DAS28 ≤3.2 at week 56.
Proportion of patients who achieve DAS28 remission (DAS28 < 2.6) at week 56.
Proportion of patients who achieve cDAS ≥ 1.2 at week 56.
Proportion of patients who achieve CDAI remission (CDAI< 2.8) at week 56.
Proportion of patients who achieve SDAI remission (SDAI < 3.3) at week 56.
Improvement in physical function (HAQ, FACIT, SF 12) at week 56.
Change in work/productivity (WPAI-SHP score) at week 56.
Safety outcome measures:
Incidence, nature and severity of adverse events.
Incidence of MTX related side effects prior to (week 0 to 24) and after (week 28 to 56) randomisation and between randomisation arms.
Change in haemoglobin from week 0 to weeks 24 and 56.
Incidence of AEs of special interest:
1.Infections including all opportunistic infections and non-serious infections as defined by those treated with IV anti-infectives
2.Myocardial infarction/acute coronary syndrome
3.Gastrointestinal perforations and related events
4.Malignancies
5.Anaphylaxis/Hypersensitivity reactions
6.Demyelinating disorders
7.Stroke
8.Bleeding events
9.Hepatic events
Incidence of anti-TCZ antibodies (immunogenicity testing).
Patient reported outcome measures:
Improvement in physical function (HAQ scire, FACIT, SF-12), WPAI-SHP score. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, Immunogenicity testing |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 65 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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