| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Lupus Erythematosus (SLE) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus ( SLE) also known as Lupus |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025139 |
| E.1.2 | Term | Lupus erythematosus systemic |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 evaluate the effect of baricitinib 4-mg QD and background standard-of-care therapy compared with placebo and background standard-of-care therapy on SLE disease activity. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
-the effect of baricitinib 4mg QD compared to placebo on: SLE disease activity; SLE flares; PROs
-the corticosteroid sparing effect of baricitinib 4mg QD or 2mg QD compared to placebo
-the effect of baricitinib 2mg QD compared to placebo on SLE disease activity; SLE flares; PROs
To evaluate:
-the effect of baricitinib 4mg or 2mg QD compared to placebo on SLE disease activity
-the corticosteroid sparing effect of baricitinib 4mg or 2mg QD compared to placebo
-the effect of baricitinib 4mg or 2mg QD compared to placebo on SLE flares
-the effect of baricitinib 4mg QD or 2mg QD compared to placebo on: mucocutaneous and musculoskeletal manifestations of SLE; individual organ system disease activity; PROs
To measure baricitinib PK exposure and assess the relationship between exposure and efficacy
To evaluate the effect of baricitinib 4mg QD or 2mg QD compared to placebo on: damage; on serologic markers of SLE; on SLE disease activity in subgroups of interest
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Type of Patient and Disease Characteristics
[1] Are at least 18 years of age.
[2] Have a clinical diagnosis of SLE at least 24 weeks prior to screening.
[3] Have documentation of having met at least 4 of 11 Revised Criteria for Classification of Systemic Lupus Erythematosus according to the 1997 Update of the 1982 ACR criteria for classification of SLE (Tan et al. 1982; Hochberg et al. 1997) prior to randomization.
[4] Have 1 or more of the following as assessed by the central lab during
screening: a positive antinuclear antibody (ANA; titer ≥1:80), and/or a positive antidsDNA,
and/or a positive anti-Smith (anti-Sm). Patients with an ANA <1:80 at
screening with documentation of a historical ANA ≥1:80 may be eligible, as
assessed by the eligibility review committee.
Note: The ANA, anti-dsDNA, and anti-Smith measurements may be Repeated by the central lab once during the screening period, and the value resulting from repeat testing may be accepted for enrollment eligibility if it meets the eligibility criterion.
[5] Have a total SLEDAI-2K score ≥6 during screening, with at least 4 points attributed to clinical items (not including items requiring laboratory value assessment). SLEDAI-2K items requiring laboratory values should be assessed based on the results from the labs drawn during the screening period.
[6] Have a clinical SLEDAI-2K score ≥4 at Baseline (Visit 2); not including any items requiring laboratory value assessment.
[7] Have at least 1 BILAG A score or 2 BILAG B scores during the screening period.
BILAG items requiring laboratory values should be assessed based on the results from the labs drawn during the screening period.
Prior/Concomitant Therapy
[8 ]Are receiving at least one of the following SoC medications for SLE:
a. A single antimalarial (such as hydroxychloroquine, chloroquine, quinacrine)
At a stable therapeutic dose for at least 8 weeks prior to screening (Visit 1).
b. A single immunosuppressant (such as methotrexate [MTX], azathioprine,
mycophenolate, tacrolimus) at a stable therapeutic dose for at least 8 weeks
prior to screening (Visit 1).
|
|
| E.4 | Principal exclusion criteria |
-Have severe active lupus nephritis defined clinically and/or by histologic evidence of proliferative glomerulonephritis on renal biopsy (if available) within the 24 weeks prior to screening, or urine protein/creatinine ratio >200 mg/mmol (as an estimate of approximate proteinuria >2 g/day) or eGFR (Modification of Diet in Renal Disease [MDRD]) <40 mL/min/1.73 m2 at screening, or as determined by the eligibility review committee.
-Have active CNS lupus as defined by ACR nomenclature for neuropsychiatric lupus syndromes and as captured by SLEDAI-2K
-Have active fibromyalgia that, in the investigator's opinion, would make it difficult to appropriately assess SLE activity for the purposes of this study.
-Have been treated for or had an active occurrence of a systemic inflammatory condition other than SLE such as, but not limited to, RA, juvenile chronic arthritis, spondyloarthropathy, Crohn's disease,
ulcerative colitis, or psoriatic arthritis within the 12 weeks prior to screening. Patients with secondary Sjögren's syndrome are not excluded.
-Have had any major surgery within 8 weeks prior to screening or will require major surgery during the study
-Have screening ECG abnormalities
-Have experienced any of the following within 12 weeks of screening: VTE, MI, unstable ischemic heart disease, stroke, or New York Heart Association Stage III/IV heart failure.
- Have a history of: recurrent (≥ 2) VTE (DVT/PE); cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/orunstable illness; lymphoproliferative disease; have signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly (other than primarily due to SLE); have active primary or recurrent malignant disease; or have been in remission from clinically significant malignancy for <5 years prior to randomization.
- Have a current or recent (<4 weeks prior to randomization) clinically serious viral, bacterial, fungal, or parasitic infection or any other active or recent infection that in the opinion of the investigator, would pose an unacceptable risk to the patient if participating in the study
- Have symptomatic herpes simplex at the time of randomization - Have had symptomatic herpes zoster infection within 12 weeks prior to randomization
- Have a history of disseminated/complicated herpes zoster
- Have a positive test for HBV, hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV ribonucleic acid [RNA]-positive)
- Have evidence of HIV infection and/or positive HIV antibodies
- Have had household contact with a person with active TB and did not receive appropriate and documented prophylaxis for TB
- Have evidence of active TB or latent TB
- Have received parenteral corticosteroids within 6 weeks of screening (Visit 1), or are expected to require parenteral corticosteroids during the study
- Have received any of the following medications:
a. Biologic treatments for immunologic disease within 4 weeks of screening
b. Cyclophosphamide (or any other cytotoxic agent), belimumab, or anifrolumab (or another anti-IFN therapy) within 12 weeks of screening
c. Rituximab, any other B cell depleting therapies, or intravenous immunoglobulin (IVIg) within 24 weeks of screening
- Have received a JAK inhibitor or TYK-2 inhibitor
- Have been treated with probenecid that cannot be discontinued for the duration of the study
- Have received plasmapheresis within 12 weeks of screening.
- Have been exposed to a live vaccine within 12 weeks of randomization
- Are currently enrolled in or have discontinued within 4 weeks of screening from, any other clinical trial involving an investigational product or nonapproved use of a drug or device or any other type of
medical research
-Have previously completed or been randomized and withdrawn from this study or any other study investigating baricitinib.
- Have screening laboratory test values, including TSH
- Patients who are receiving thyroxine as replacement therapy may participate in the study, provided stable therapy has been administered for ≥12 weeks and TSH is within the laboratory's reference range. Patients who have TSH marginally outside the laboratory's normal reference range and are receiving stable thyroxine replacement therapy may participate if the treating physician has documented that the thyroxine replacement therapy is adequate for the patient. Have any of the following specific abnormalities on screening lab tests: ALT or AST >2 x ULN, ALP ≥2 x ULN, Total bilirubin ≥1.5 x ULN, Hemoglobin <9 g/dL (90.0 g/L), Total white blood cell count <2500 cells/μL (<2.50 x 103/μL or <2.50, GI/L), Neutropenia (absolute neutrophil count [ANC] <1200 cells/μL), (<1.20 x 103/μL or <1.20 GI/L), lymphopenia (lymphocyte count <500 cells/μL) (<0.50 x 103/μL or
<0.50 GI/L), thrombocytopenia (platelets <50,000 cells/μL) (<50 x 103/μL or <50 GI/L)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of patients achieving an SRI-4 response at
Week 52, defined as:
- Reduction of ≥4 points from baseline in SLEDAI-2K score; and
- No new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B disease activity score; and
- No worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician’s Global Assessment of Disease Activity.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The change will be evaluated from the baseline time point to the study week 52 time point. |
|
| E.5.2 | Secondary end point(s) |
- Proportion of patients achieving an SRI-4 response at Week 24.
- Proportion of patients achieving a lupus low disease activity state (LLDAS) response at Week 52
- Proportion of patients receiving >7.5 mg prednisone (or equivalent) at baseline able to decrease dose by ≥25% to a prednisone equivalent dose of ≤7.5 mg/day maintained between Week 40 and Week 52.
- Time to first severe flare over 52 weeks.
- Change from baseline in Worst Pain NRS at Week 52.
- Change from baseline in FACIT-Fatigue total score at Week 52.
- Proportion of patients achieving an SRI-4 response at Week 52.
- Proportion of patients achieving an SRI-4 response at Week 24.
- Proportion of patients achieving a lupus low disease activity state (LLDAS) response at Week 52
- Proportion of patients receiving >7.5 mg prednisone (or equivalent) at baseline able to decrease dose by ≥25% to a prednisone equivalent dose of ≤7.5 mg/day maintained between Week 40 and Week 52.
- Time to first severe flare over 52 weeks.
- Change from baseline in Worst Pain NRS at Week 52. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The change will be evaluated from the baseline time point to the study week 52 time point. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| China |
| Czech Republic |
| Germany |
| Hungary |
| Mexico |
| Russian Federation |
| Switzerland |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
End of the trial is the date of the last visit, last scheduled procedure
shown in the Schedule of Activities, or date of discontinued
participation for the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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