E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus |
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E.1.1.1 | Medical condition in easily understood language |
Lupus, a disease of the immune system |
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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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
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 |
The primary objective of this study is to evaluate the efficacy of sifalimumab compared to placebo in subjects with chronic, moderately-to-severely active SLE with an inadequate response to SOC SLE at Day 365 (Week 52). |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate the effect of sifalimumab compared to placebo in reducing background oral corticosteroids dosage.
2) To evaluate the effect of sifalimumab compared to placebo in improving inflammatory cutaneous lupus lesions.
3) To evaluate the effect of sifalimumab compared to placebo in improving fatigue.
4) To evaluate the safety profile of sifalimumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Able tocomprehend and complete the informed consent, and all protocol-related subject assessments.
2) Age 18-75 years.
3) Written informed consent.
4) Fulfils at least 4 of the 11 American College of Rheumatology (ACR) classification criteria for SLE, one of which must be: a) Significantly positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at central lab; OR b) Elevated anti-dsDNA or Sm antibody at screening as determined by central lab
5) Weight ≥ 40.0 kg.
6) Diagnosis of pediatric or adult SLE with chronic disease activity requiring ongoing treatment or observation for ≥ 24 weeks prior to screening.
7) Receiving at least one of the following (at stable doses) prior to signing ICF through Day 1: a) prednisone (or equivalent) ≤ 20 mg/day for at least 2 weeks; b) one of the following for at least 8 weeks: azathioprine, an antimalarial, mycophenolate mofetil/ mycophenolic acid, weekly administrations of oral or SC methotrexate.
8) External Adjudication Group confirmation of both: a) SLEDAI-2K score ≥ 6 points or ‘Clinical’ SLEDAI-2K score ≥ 6 points; b) At least one of the following: i) BILAG-2004 Index level A disease in ≥ 1 body/organ system ii) BILAG-2004 Index level B disease in ≥ 2 body/organ systems.
9) Day 1 ‘Clinical’ SLEDAI-2K score ≥ screening “Clinical” SLEDAI-2K score.
10) Physicians Global assessment (MDGA) ≥ 1.0 on a 0-3 scale at screening.
11) Females of childbearing potential must use 2 effective methods of avoiding pregnancy from screening through 180 days after the final dose of investigational product unless surgically sterile, has a sterile male partner, is 1 year postmenopausal, or practices abstinence.
12) Non-sterilized males must practice two effective contraceptive measures with a female of childbearing potential from Day 1 through at least 180 days after the last dose of investigational product has been administered.
13) Females with an intact cervix must have documentation of a Pap smear and HPV
testing with no documented malignancy within 24 weeks prior to Day 1.
14) Willing to forego other forms of experimental treatment for SLE during the study.
15) Meets various criteria for freedom from tuberculosis.
16) Adequate peripheral venous access. |
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E.4 | Principal exclusion criteria |
1) Any condition that would interfere with evaluation of the IMP or interpretation of subject safety or study results.
2) Concurrent enrollment in any other study with an IMP within 4 weeks prior to Day 1 or within 5 half-lives of the IMP used in that study, whichever is longer.
3) Employees of the study site or any other individuals involved with the study or immediate family members.
4) Receipt of any of: a) any new oral prednisone therapy (or equivalent) or any change in current oral prednisone dose (or equivalent) from 2 weeks prior to signing of the ICF through Day 1; b) any new dose or change in current dose of any of the following anytime in the 8 weeks prior to signing of the ICF through Day 1: azathioprine; any antimalarial; mycophenolate mofetil/mycophenolic acid; oral methotrexate; or SC methotrexate.
5) Receipt of any of the following: a) azathioprine > 150 mg/day; b) mycophenolate mofetil/mycophenolic acid > 3.0 grams/day; c) oral or SC methotrexate > 20 mg/week; d) any change in route of administration of oral or SC methotrexate anytime within the 8 weeks prior to signing of the ICF.
6) Receipt of more than one dose of sifalimumab prior to screening.
7) Receipt of a biologic agent within 5 half-lives or prior to loss of PD and/or clinical effect, whichever is longer, prior to signing of the ICF.
8) A known history of allergy or reaction to any component of the IMP formulation or history of anaphylaxis to any human gamma globulin therapy.
9) Receipt of more than one prescribed NSAID at an anti-inflammatory dose within 2 weeks (14 days) prior to Day 1; OR receipt of fluctuating doses of a prescribed NSAID within 2 weeks (14 days) prior to Day 1;.
10) Receipt of any of the following: a) any live vaccine within 4 weeks prior to signing the ICF; b) oral anti-infectives (including antivirals) for active infection within 2 weeks prior to Day 1; c) BCG vaccine within 1 year of signing the ICF; d) any restricted medication (as listed in Appendix 3 of the protocol).
11) Receipt of any of the following: a) etanercept ≤ 4 weeks prior to signing the ICF; b) adalimumab, infliximab, or golimumab ≤ 12 weeks prior to signing the ICF; c) rituximab or certolizumab pegol < 24 weeks prior to signing the ICF.
12) Any fluctuation in hormone replacement therapy dose within 8 weeks of signing the ICF.
13) Active severe or unstable neuropsychiatric SLE that would make the subject unsuitable for the study or unable to fully understand the ICF.
14) Within 8 weeks prior to screening, active severe SLE-driven renal disease or unstable renal disease.
15) A diagnosis (within 1 year) of mixed connective tissue disease or any history of overlap syndromes of SLE with rheumatoid arthritis, erosive arthritis, or scleroderma.
16) History of, or current, inflammatory joint or skin disease other than SLE that could interfere with the inflammatory arthritis or skin assessments and confound the disease activity assessments.
17) History of asthma that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to randomization.
18) Known history of a primary immunodeficiency or an underlying condition such as HIV infection or splenectomy that predisposes to infection.
19) Confirmed positive tests for hepatitis B surface antigen serology.
20) Positive test for hepatitis C serology as confirmed by central laboratory.
21) Any serious herpes infection at any time prior to randomization, including but not limited to disseminated herpes, herpes encephalitis, or ophthalmic herpes.
22) Any herpes zoster infection that has not completely resolved within 12 weeks prior to signing of the ICF.
23) Any of the following within 4 weeks prior to signing the ICF: a) clinically significant active infection; b) any infection requiring hospitalization or treatment with IV anti-infectives.
24) Lactating or pregnant females or females who intend to become pregnant from initiation of screening through the 180-day safety follow-up period following last dose of IMP.
25) Current evidence of alcohol, drug or chemical abuse, or a recent history of such abuse within 1 year of randomization.
26) History of cancer, apart from basal cell carcinoma or cervical cancer treated with apparent success with curative therapy within 1 year of randomization.
27) Major surgery within 8 weeks before signing the ICF or elective major surgery planned during the study period.
28) Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to signing the ICF.
29) At screening, any of the following: AST or ALT > 2.0 × ULN unless caused by myositis (with elevated CPK) associated with SLE; total bilirubin > ULN (unless due to Gilbert’s syndrome); serum creatinine > 2.0 mg/dL; protein/creatinine ratio > 2.0; neutrophil count < 1,000/μL; platelet count < 25,000/μL; hemoglobin < 8 g/dL; hemoglobin A1c > 8% at screening (diabetic subjects only). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is the proportion of subjects achieving a response in an SLE responder index [SRI (4)] at Day 365 in subjects with chronic moderately-to-severely active SLE.
An SRI(4) Responder is defined as 1) a reduction in baseline SLEDAI-2K disease activity score of ≥ 4 points; and 2) no worsening of disease from baseline as measured by the MDGA (defined as an increase of ≥ 10% on a 0-3.0 VAS); and 3) no new BILAG-2004 Index A organ system score and no more than one new or worsening BILAG-2004 Index B organ system scores.
There will be 6 primary comparisons for the primary endpoint. Sifalimumab 200 mg versus placebo, sifalimumab 600 mg versus placebo, and sifalimumab 1200 mg versus placebo will be compared for the overall population. The same 3 dose comparisons will also be performed for the subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening. The primary endpoint will be analyzed using a logistic regression model. The independent variables in the model will include treatment groups and stratification factors. The multiplicity adjustment for 3 dose comparisons within each of the 2 study populations, the overall population and the baseline gene signature positive subpopulation, will be done by performing a global test of all treatments prior to performing pairwise comparisons. No multiplicity adjustment for the 2 study populations is planned. An additional analysis with a more rigorous multiplicity adjustment approach may also be performed. The details of the multiplicity adjustments will be documented in the SAP that will be finalized prior to unblinding.
Unless otherwise specified, the stratification factors will include geographic region (Latin America, Eastern Europe, and Asia vs. North America, Western Europe, and South Africa), SLEDAI-2K score at screening (< 10 points vs. ≥ 10 points), and the results of a diagnostic test for type I IFN signature in whole blood at screening using a 4-gene diagnostic test (positive vs. negative) for the overall population, and include geographic region and SLEDAI-2K score at screening only for subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening.
The primary endpoint analysis will be conducted using the mITT Population. This analysis will also be conducted on the PP population as a sensitivity analysis.
The dose-response trend based on SRI (4) at Day 365 will be tested using a Cochran-Armitage trend test. Other dose-response models may be evaluated. The details of the dose-response analysis will be described in the SAP. |
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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) |
The following secondary efficacy endpoints will be evaluated in the overall population of subjects with chronic, moderately-to-severely active SLE; and a subpopulation of subjects with a positive diagnostic test for type I IFN signature at screening.
1) The proportion of subjects on ≥ 10 mg oral prednisone (or equivalent) at baseline who are able to taper ≤ 7.5mg/ day at Day 365 will be compared between treatment groups using logistic regression model.
2) The proportion of subjects with an active CLASI score ≥ 10 at baseline who achieve a ≥ 4-point reduction at Day 365 will be compared between treatment groups using logistic regression model.
3) The proportion of subjects who achieve a > 3-point reduction in the FACIT-FATIGUE Scale at Day 365 will be compared between treatment groups using logistic regression model.
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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 | 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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 4 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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 |
Brazil |
Canada |
Chile |
France |
Germany |
Hungary |
India |
Italy |
Mexico |
Netherlands |
Peru |
Philippines |
Poland |
Romania |
South Africa |
Spain |
Thailand |
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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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |