| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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 |
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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 efficacy of etanercept to placebo in inadequate responders to infliximab or adalimumab plus methotrexate (MTX) in all subjects and in subjects who are anti-drug antibody positive (ADA+) to one of these monoclonal antibodies (mAbs). |
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| E.2.2 | Secondary objectives of the trial |
• To assess the effect of ADA status on the efficacy of etanercept in inadequate responders to infliximab or adalimumab plus MTX
• To evaluate the safety of etanercept in inadequate responders to infliximab or adalimumab plus MTX.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Subject is literate and able to complete the protocol-specified questionnaires.
Period 1 Inclusion Criteria
In addition to the criteria in Section 4.1, subjects must meet all of the following inclusion criteria to be eligible for enrollment into Period 1 of the study:
1. Male or female ≥ 18 years and <80 years of age at the time of consent.
2. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 12 weeks after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active (see Section 4.5 Life Style Guidelines)..
3. Met the 1987 ACR Revised Criteria for RA (see Appendix 1).
4. A history of inadequate efficacy response to at least a 6-month course of either infliximab or adalimumab with at least the last 4 weeks before the screening visit receiving a combination of either infliximab plus MTX or adalimumab plus MTX.
5. For subjects receiving infliximab, the last dose of infliximab must have been received ≥ 6 weeks before the screening mAb ADA test.
6. For subjects receiving adalimumab, the last dose of adalimumab must have been taken ≥ 11 days before the screening mAb ADA test.
7. Stable dose of oral MTX (10 mg QW to 25 mg QW) for ≥6 weeks before the baseline visit.
8. Active RA at the screening visit, defined as all of the following:
a. high-sensitivity C-reactive protein (hs-CRP) ≥ 1.0 mg/L
b. ≥ 6 tender joints based on the 28 joint assessment (see Section 7.1.5)
c. ≥ 6 swollen joints based on the 28 joint assessment (see Section 7.1.5)
9. Active RA at the baseline visit, defined as all of the following:
a. ≥ 6 tender joints based on the 28 joint assessment (see Section 7.1.5)
b. ≥ 6 swollen joints based on the 28 joint assessment (see Section 7.1.5)
10.In the opinion of the investigator, subject is a reasonable candidate for treatment with etanercept plus MTX.
11.Either the subject or a designee must be capable (according to the investigator’s judgment) of administering the SC investigational product and must be able to store all investigational product under required storage conditions or must be able to come to the study site for administrations where the investigational product may be stored on behalf of the subject.
12.Active and latent tuberculosis (TB) must be ruled out by screening for TB in accordance with local country guidelines; subjects with recent exposure to active TB must be evaluated by a qualified physician to rule out TB (see Period 1 Exclusion Criteria 20).
13.Female subjects of childbearing potential per the investigator’s opinion must have negative urine pregnancy test results based on the screening visit and baseline visit tests (see Section 7.4.1 Pregnancy Testing). This includes subjects who are menstruating at the time of the visit and/or who are not sexually active.
Escape Arm Inclusion Criteria
The subject must meet all of the following criteria to be included in the Escape Arm of the study:
1. The subject has completed the week 8 visit of the study.
2. Less than 10% improvement in either the tender/painful joint count or the swollen joint count at the week 8 visit as compared to the baseline joint counts (see Appendix 1 for examples).
Subject must be willing to continue stable dose of all RA medications that the subject is using at Week 8 through Week 24 (except when dose adjustment is allowed according to Section 5.5 Concomitant Medications).
Period 2 Inclusion Criteria
The subject must meet all of the following criteria to be included in Period 2 of the study:
1. Subject has completed Period 1 (ie, the week 12 visit) of the study.
2. Subject must be willing to continue stable dose of all RA medications that the subject is using at Week 12 through Week 24 (except when dose adjustment is allowed according to Section 5.5 Concomitant Medications).
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| E.4 | Principal exclusion criteria |
Period 1:
1.Subjects who are investigational site staff members directly involved in conduct of trial and their family members, site staff members otherwise supervised by Investigator or subjects who are Pfizer employees directly involved in conduct of trial
2.ACR functional class IV
3.Prior treatment with etanercept any immunosuppressive biologic agent other than infliximab or adalimumab or both infliximab and adalimumab
4.Discontinuation of infliximab or adalimumab for primary reason other than inadequate efficacy response
5.Subjects receiving infliximab, dose >10 mg/kg every 4 weeks within 12 weeks before baseline
6.Subjects receiving adalimumab, dose >40 mg every other week within 12 weeks before baseline
7.Subject with known or suspected allergy, hypersensitivity or contraindication to MTX or its components or to etanercept, its excipients or other compounds related to this class of medication including biopharmaceutical proteins
8.Receipt >1 permitted non-biologic DMARD other than MTX or change in total daily dose of the additional permitted non-biologic DMARD within 4 weeks before baseline
9.Cyclophosphamide, cyclosporine or azathioprine within 6 months before baseline
10.Leflunomide without elimination procedure within 8 weeks before baseline or within 4 weeks of baseline if protocol-specified elimination procedure is followed.
11.Any invest. non-biologic drugs or devices within 12 weeks before baseline and/or during study B1801355
12.Non-biologic DMARDs other than those permitted during study or which are not listed under other excl. criteria within 8 weeks before baseline
13.Receipt >10 mg/day of oral prednisone (or equivalent) or change in dose within 2 weeks before baseline
14.IA or soft tissue corticosteroid injection or bolus IM or IV corticosteroids within 4 weeks before baseline
15.Receipt >1 NSAID or change in dose or type of NSAID within 2 weeks before baseline
16.Any live (attenuated) vaccines within 4 weeks before baseline
17.Any of following hematology or chemistry lab.abnormalities based on screening test results
a.WBC count ≤3.5 x 109/L
b.Hemoglobin level ≤85 g/L or ≤5.3 mmol/L
c.Hematocrit ≤27%
d.Platelet count ≤125 x 109/L
e.Serum creatinine level ≥175 µmol/L or ≥1.98 mg/dL
f.AST or ALT level ≥2 times upper limit of normal (X ULN)
18.Any other clinically significant lab. results or vital sign measurements
19.Active TB or evidence of untreated latent or active TB
20.Received TB chemoprophylaxis between the screening and baseline visits and has had ALT≥2X ULN and/or AST≥2X ULN during this period
21.Any infection assoc. with hospitalization and/or parenteral anti-infective agents within 4 weeks before baseline
22.Active infection at screening and/or baseline including systemic fungal infections
23.Any clinically relevant concurrent medical conditions, incl.:
a.Uncompensated congestive heart failure, Class III or IV heart failure or any episode of acute congestive heart failure within 6 months before screening
b.Uncontrolled hypertension
c.Myocardial infarction within 12 months before screening
d.Coronary artery bypass graft or percutaneous transluminal coronary angioplasty within 12 months before screening
e.Unstable angina pectoris within 6 months before screening
f.Presence or history of severe pulmonary disease requiring recurrent hospitalizations or supplemental oxygen
g.Presence or history of confirmed blood dyscrasias
h.Diagnosis of multiple sclerosis or other central or peripheral nervous system demyelinating diseases
i.Malignancy or history of malignancy (except non metastatic basal cell or squamous cell skin carcinoma; or cervical carcinoma in situ)
j.Uncontrolled diabetes mellitus
k.Diagnosis of systemic lupus erythematosus, scleroderma or polymyositis
l.Open cutaneous ulcers
m.History of clinically significant drug induced liver injury, cirrhosis or fibrosis
n.Known history or presence of hepatitis C or chronic hepatitis B infection; or positive test result at screening for hepatitis C virus or chronic hepatitis B
o.Known history, presence of, or positive test result history for HIV
24.Other severe acute or chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation or invest. product administration or may interfere with interpretation of study results and, in the investigator’s judgment, would make subject inappropriate for entry into this study.
25.Any anticipated or planned surgical procedure during study period
26.Pregnant or breastfeeding females
27.Sexually active males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 12 weeks after last dose of invest. product
Escape Arm:
1.Discontinuation of invest. product for any reason prior to completion of week 8 visit
Period 2:
1.Discontinuation of invest. product for any reason prior to completion of week 12 visit |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline in the disease activity score based on a 28 joint count (DAS28-CRP) at week 12
The primary study comparison is between etanercept 50 mg QW and placebo in all subjects, as determined by the change from baseline in DAS28-CRP scores at week 12.
The conditional primary study comparison is between etanercept 50 mg QW and placebo in subjects who are mAb ADA+, as determined by the change from baseline in DAS28-CRP scores at week 12.
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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) |
Key Secondary Efficacy Endpoint
Change from baseline in the DAS28-CRP at week 24
The key secondary study comparison will be between subjects who are mAb ADA+ and mAb ADA- and are randomized to etanercept, as determined by the change from baseline in DAS28-CRP scores at week 24.
Additional Secondary Efficacy Endpoints
The following endpoints will be assessed at all timepoints unless otherwise noted:
• Change from baseline in DAS28-CRP
• DAS28-CRP < 3.2 and DAS28-CRP < 2.6
• American College of Rheumatology (ACR) 20, ACR50, ACR70, and ACR90
• European League Against Rheumatism (EULAR) good response and EULAR good/moderate response
• Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)
• Individual components of the ACR and DAS
• Etanercept ADA status (at week 12 and week 24, or upon early withdrawal). Samples which are positive for etanercept ADAs will also be tested for etanercept neutralizing antibodies.
• Vectra disease activity (DA) levels (at baseline, week 4, week 12, and week 24, or upon early withdrawal)
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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 | No |
| 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.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 | No |
| 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 | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 | No |
| 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 |
| Belgium |
| France |
| Netherlands |
| Australia |
| Chile |
| Colombia |
| Hong Kong |
| Spain |
| Israel |
| Russian Federation |
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| 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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| End of Trial in all participating countries is defined as the Last Subject Last Visit. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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