E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active rheumatoid arthritis |
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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 | 14.1 |
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 |
Determine whether baricitinib 4 mg QD is superior to placebo in the treatment of patients with moderately to severely active RA who have had an inadequate response to a TNF inhibitor, despite ongoing treatment with cDMARDs, as assessed by the proportion of patients achieving ACR20 at Week 12. |
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E.2.2 | Secondary objectives of the trial |
to evaluate the efficacy of baricitinib 4 mg QD versus placebo as assessed by:
-change from baseline to Week 12 in Health Assessment Questionnaire-Disability Index (HAQ-DI) score
-change from baseline to Week 12 in DAS28-high-sensitivity C-reactive protein(hsCRP)
to evaluate the efficacy of baricitinib 2 mg QD versus placebo as assessed by:
-proportion of patients achieving ACR20 at Week 12
-change from baseline to Week 12 in HAQ-DI score
-change from baseline to Week 12 in DAS28-hsCRP |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Entry Criteria-Inclusion Criteria:
•are at least 18 years of age
•have a diagnosis of adult-onset RA as defined by the ACR/EULAR 2010 Criteria for the Classification of RA
•have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints
a. If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC for entry or enrollment purposes.
•have a C-reactive protein (or hsCRP) measurement ≥1 times the ULN based on the most recent data (if available)
•have been treated at approved doses with at least 1 biologic TNF-α inhibitor for at least 3 months and in the opinion of the investigator either:
a. experienced insufficient efficacy or loss of efficacy at a dose that, in accordance with local clinical practice, is considered acceptable to adequately assess clinical response or
b. experienced intolerance of such treatment
•have had regular use of at least 1 cDMARD for at least the 12 weeks prior to study entry at a dose that, in accordance with local clinical practice, is considered acceptable to adequately assess clinical response, as specified below:
a. The dose of MTX must have been a stable, unchanging oral dose of 7.5 to 25 mg/week (or the equivalent injectable dose) for at least the 8 weeks prior to study entry. The dose of MTX is expected to remain stable throughout the study and may be adjusted only for safety reasons.
b. For patients entering the trial on MTX doses <15 mg/week, there must be clear documentation in the medical record that higher doses of MTX were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines.
c. Local standard of care should be followed for concomitant
administration of folic acid.
d. For patients entering the trial while receiving the following
DMARDs, the dose must be stable for at least 8 weeks prior to study entry and not exceed the dose listed: hydroxychloroquine up to 400 mg/day; sulfasalazine up to 3000 mg/day; leflunomide up to 20 mg/day; and azathioprine up to 150 mg/day or 2 mg/kg/day.
•are able to read, understand, and give written informed consent
Enrollment Criteria-Inclusion Criteria:
•have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints assessed at Visit 1 and Visit 2 at the time of randomization
•have an hsCRP measurement ≥1 times the ULN based on Visit 1 laboratory results by central laboratory testing |
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E.4 | Principal exclusion criteria |
Entry Criteria-Exclusion Criteria:
•have received a biologic treatment for RA within 28 days of randomization
•are currently receiving corticosteroids at doses>10mg per day of prednisone or have been receiving an unstable dosing regimen of
corticosteroids within 2 weeks of study entry or within 6 weeks of planned randomization
•have started treatment with NSAIDs within 2 weeks of study entry or within 6 weeks of planned randomization or have been receiving an unstable dosing regimen of NSAIDs within 2 weeks of study entry or within 6 weeks of randomization
•are currently receiving concomitant treatment with MTX,
hydroxychloroquine,sulfasalazine
•have started a new physiotherapy treatment for RA in the 2 weeks prior to study entry
•have received any parenteral corticosteroid administered by IM or
IV injection within 2 weeks prior to study entry
•have had 3 or more joints injected with intraarticular corticosteroids within 2 weeks prior to study entry or within 6 weeks prior to randomization
•have active fibromyalgia, that would make it difficult to assess RA activity
•have a diagnosis of any systemic inflammatory condition other than RA
•have a diagnosis of Felty’s syndrome
•have had any major surgery within 8 weeks prior to study entry
•have experienced within 12 weeks of study entry:myocardial infarction,unstable ischemic heart disease,stroke,NYHA IV heart failure
•have a history or presence of disorders or other serious illness that, could constitute a risk when taking IP
•are largely or wholly incapacitated permitting little or no self care
•have an eGFR based on serum creatinine<40 mL/min/1.73 m2
•have a history of chronic liver disease with ASTor ALT>1.5ULN
•have lymphoproliferative disease
•have been exposed to a live vaccine within 12 weeks prior to
randomization
•have serious viral,bacterial,fungal,parasitic infection
•have had symptomatic herpes zoster infection within 12 weeks prior to study entry
•have a history of disseminated/complicated herpes zoster
•are immunocompromised and are at an risk for participating
•have a history of active HBV,HCV,HIV
•have had household contact with a person with active TB and
did not receive prophylaxis
•have evidence of active TB and did not receive treatment
•are pregnant/nursing
•are females of childbearing potential who do not agree to use 2 forms of highly effective birth control when engaging in sexual intercourse
•are males who do not agree to use 2 forms of highly effective birth control while engaging in sexual intercourse with female partners
•have donated >500 mL of blood
•have a history of chronic alcohol,IV drug or other illicit drug
abuse within the 2 years prior to study entry
•have previously been randomized in this study
•are unable or unwilling to make themselves available for the duration of the study
•have received prior treatment with an oral JAK inhibitor
•are investigator site personnel directly affiliated with this study and/or their immediate families
•are Lilly employees
•are currently enrolled in, or discontinued within the 30 days of study entry
Enrollment Criteria-Exclusion Criteria:
•have screening laboratory test values outside the reference range
•have any of the following specific abnormalities on screening laboratory tests:AST or ALT >1.5 times the ULN, total bilirubin ≥1.5 times the ULN,hemoglobin<10.0 g/dL,total white blood cell count <2500 cells/L,neutropenia,lymphopenia,thrombocytopenia, eGFR<40 mL/min/1.73 m2
•have screening ECG abnormalities that are clinically significant and indicate a risk for the patient’s participation in the study
•have symptomatic herpes simplex at the time of study enrollment
•have evidence of active or latent TB
•have a positive test for HBV
•have HCV
•have evidence of HIV infection and/or positive HIV antibodies
•are women ≥40 and <60 years of age who have had a cessation of menses for at least 12 months, have a follicle-stimulating hormone value <40 mIU/mL,and do not agree to use 2 forms of highly effective methods of birth control |
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Proportion of patients achieving ACR20 response (baricitinib 4mg compared to placebo) |
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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) |
2.change in HAQ-DI score (baricitinib 4mg QD versus placebo)
3.change in DAS28-hsCRP (baricitinib 4mg QD versus placebo)
4.proportion of patients achieving ACR20 (baricitinib 2mg QD versus placebo)
5.change in HAQ-DI score (baricitinib 2mg QD versus placebo)
6.change in DAS28-hsCRP(baricitinib 2mg QD versus placebo)
7.proportion of patients achieving ACR20(baricitinib 2mg and 4mg QD versus placebo)
8.proportion of patients achieving ACR50(baricitinib 2mg and 4mg QD versus placebo)
9.proportion of patients achieving a 70% improvement in ACR70(baricitinib 2mg and 4mg QD versus placebo)
10.percentage change in individual components of the ACR Core Set(baricitinib 2mg and 4mg QD versus placebo)
11.change in DAS28-hsCRP (baricitinib 2mg and 4mg QD versus placebo)
12.change in DAS28-ESR(baricitinib 2mg and 4mg QD versus placebo)
13.proportion of patients achieving DAS28-hsCRP ≤3.2 and DAS28-hsCRP <2.6(baricitinib 2mg and 4mg QD versus placebo)
14.proportion of patients achieving DAS28-ESR ≤3.2 and DAS28-ESR <2.6(baricitinib 2mg and 4mg QD versus placebo)
15.change in HAQ-DI score(baricitinib 2mg and 4mg QD versus placebo)
16.proportion of patients achieving HAQ-DI improvement of ≥0.22 and ≥0.3(baricitinib 2mg and 4mg QD versus placebo)
17.change in CDAI score(baricitinib 2mg and 4mg QD versus placebo)
18.change in SDAI score(baricitinib 2mg and 4mg QD versus placebo)
19.proportion of patients achieving CDAI score ≤2.8(baricitinib 2mg and 4mg QD versus placebo)
20.proportion of patients achieving SDAI score ≤3.3(baricitinib 2mg and 4mg QD versus placebo)
21.proportion of patients achieving EULAR Responder Index based on the EULAR28(baricitinib 2mg and 4mg QD versus placebo)
22.change in duration of morning joint stiffness(baricitinib 2mg and 4mg QD versus placebo)
23.change in severity of tiredness using the scale NRS(baricitinib 2mg and 4mg QD versus placebo)
24.change in severity of pain using the Worst Pain NRS(baricitinib 2mg and 4mg QD versus placebo)
25.change in FACIT-F scale scores(baricitinib 2mg and 4mg QD versus placebo)
26.change in each scale and the summary scores for
the MCS and PCS of the SF-36v2 Acute(baricitinib 2mg and 4mg QD versus placebo)
27.change in EQ-5D-5L scores(baricitinib 2mg and 4mg QD versus placebo)
28.change in WAPI scores(baricitinib 2mg and 4mg QD versus placebo)
29.change in healthcare resource utilization(baricitinib 2mg and 4mg QD versus placebo) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
2.baseline to Week 12
3.baseline to Week 12
4.Week 12
5.baseline to Week 12
6.baseline to Week 12
7.Week 24
8.Week 12 and Week 24
9.Week 12 and Week 24
10.baseline to Week 12 and Week 24
11.baseline to Week 24
12.baseline to Week 12 and Week 24
13.Week 12 and Week 24
14.Week 12 and Week 24
15.baseline to Week 24
16.baseline to Week 12 and Week 24
17.baseline to Week 12 and Week 24
18.baseline to Week 12 and Week 24
19.Week 12 and Week 24
20.Week 12 and Week 24
21.Week 12 and Week 24
22.baseline through Week 24
23.baseline through Week 24
24.baseline through Week 24
25.baseline to Week 12 and Week 24
26.baseline to Week 24
27.baseline to Week 24
28.baseline to Week 24
29.baseline to Week 24 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | 3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Canada |
Croatia |
Denmark |
France |
Germany |
Greece |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
Spain |
Switzerland |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 1 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |