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, an autoimmune disease |
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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 | 20.0 |
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 |
- To evaluate the effect of anifrolumab 300 mg compared to placebo on disease activity as
measured by the difference in the proportion of subjects who achieve an SLE Responder Index of ≥4 (SRI[4]) at Week 52
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of anifrolumab 300mg compared to placebo on:
a. The proportion of subjects with SRI(4) at Week 52 in the IFN test-high sub-group
b. The proportion of subjects who achieve an OCS dose ≤7.5 mg/day at Week 40, which is maintained through Week 52 in the sub-group of subjects with baseline OCS ≥10 mg/day
c. The proportion of subjects with a ≥50% reduction in CLASI activity score at Week 12 in the sub-group of subjects with baseline CLASI activity score ≥10
d. The proportion of subjects with SRI(4) at Week 24
e. The annualised flare rate through 52 weeks
2. To evaluate the effect of anifrolumab 150 mg compared to placebo on disease activity as
measured by the difference in the proportion of subjects who achieve SRI(4) at Week 52
3. To evaluate the safety and tolerability of anifrolumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Aged 18 through 70 years at the time of screening
2. Completion of all screening procedures needed to determine subject eligibility and stratification within 30 days after signing the Informed Consent Form (ICF)
3. Diagnosis of paediatric or adult SLE with a diagnosis of SLE according to the ACR 1982 revised criteria ≥24 weeks prior to signing the ICF
4. Currently receiving at least 1 of the following:
(a) Where prednisone is the single standard of care medication, a dose of oral prednisone ≥7.5 mg/day but ≤40 mg/day (or prednisone equivalent) for a minimum of 8 weeks prior to Day 1. In addition, the dose of oral prednisone or prednisone equivalent the subject is taking must be stable for a minimum of 2 weeks prior to randomisation.
(b) Where prednisone is not the single standard of care medication, a dose of oral prednisone ≤40 mg/day (or prednisone equivalent) for a minimum of 2 weeks prior to signing of the ICF. In addition, the dose of oral prednisone or prednisone equivalent the subject is taking must be stable for a minimum of 2 weeks prior to randomisation.
(c) Any of the following medications administered for a minimum of 12 weeks prior to signing the informed consent, and at a stable dose for a minimum of 8 weeks prior to signing the informed consent through Day 1:
(i) Azathioprine ≤200 mg/day
(ii) Antimalarial (eg, chloroquine, hydroxychloroquine, quinacrine)
(iii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day
(iv) Oral, subcutaneous (SC), or intramuscular methotrexate ≤25 mg/week
(v) Mizoribine ≤150 mg/day
5. Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE, at least 1 of which must be:
(a) Positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at the central laboratory with titre ≥1:80; OR
(b) Anti-dsDNA antibodies at screening elevated to above normal (including indeterminate), as per the central laboratory; OR
(c) Anti-Smith (anti-Sm) antibody at screening elevated to above normal as per the central laboratory
6. At Screening, Disease Activity Adjudication Group confirmation of:
- SLEDAI-2K Criteria: SLEDAI-2K score ≥6 points and “Clinical” SLEDAI-2K score ≥4 points. The “Clinical” SLEDAI-2K is the SLEDAI-2K assessment score without the inclusion of points attributable to any urine or laboratory results including immunologic measures.
7. Meets all of the following TB criteria:
(i) No history of active TB prior to any Screening visit
(ii) No history of latent TB prior to initial Screening visit, with the exception of latent TB with documented completion of appropriate treatment. Subjects with no history of latent TB prior to the initial Screening visit, but who are diagnosed with latent TB during screening, may be considered eligible if appropriate treatment is initiated prior to randomisation. Such subjects may be re-screened if necessary to allow for local guidelines on latent TB treatment initiation.
8. Day 1 “Clinical” SLEDAI-2K score ≥4 points
9. OCS dose stable for at least 2 weeks prior to randomisation
10. Stable SLE SOC treatment at the time of randomisation
11. Women of child-bearing potential must have a negative serum β-hCG test at screening and a negative urine pregnancy test at randomisation (Day 1), prior to administration of investigational product
12. In the opinion of the Investigator, must be able to comprehend the ICF and all protocol related assessments, such that the patient can complete all study required documents, procedures, and outcome measures. |
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E.4 | Principal exclusion criteria |
1. Receipt of any of the following:
(a) Where prednisone is the single standard of care medication, any new oral prednisone therapy (or equivalent) any time in the 8 weeks prior to Day 1, OR any change in/discontinuation of current oral prednisone dose (or equivalent) anytime within the 2 weeks prior to randomisation
(b) Where prednisone is not the single standard of care medication:
(i) Any addition of a new oral prednisone therapy (or equivalent) any time from 2 weeks prior to signing of the informed consent form through Day 1, OR any change in/discontinuation of current oral prednisone dose (or equivalent) anytime within 2 weeks prior randomisation
(ii) Any addition of a new dose of any of the following anytime in the 12 weeks prior to signing of the informed consent through Day 1, or change in/discontinuation of current dose anytime in the 8 weeks prior to signing of the informed consent through Day 1: azathioprine; any antimalarial (eg, chloroquine, hydroxychloroquine, quinacrine); mycophenolate mofetil/mycophenolic acid; oral, SC, or intramuscular methotrexate; mizoribine
2. Receipt of any of the following:
(a) Azathioprine >200 mg/day
(b) Mycophenolate mofetil >2 g/day or mycophenolic acid >1.44 g/day
(c) Oral, SC, or intramuscular methotrexate >25 mg/week
(d) Mizoribine >150 mg/day
(e) Any change in route of administration of oral, SC, or intramuscular methotrexate anytime within the 8 weeks prior to signing of the informed consent through Day 1
3. Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater
4. Receipt of epratuzumab or tabalumab ≤26 weeks prior to signing the ICF, or belimumab <12 weeks prior to signing the ICF
5. Receipt of any of the following:
(a) Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks prior to Day 1
6. History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.
7. Active severe or unstable neuropsychiatric SLE
8. Active severe SLE-driven renal disease
9. Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE and SSc.
10. History of, or current, inflammatory joint or skin disease other than SLE
11. History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than 2 weeks within the 24 weeks prior to signing the ICF
12. Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the subject to infection, or a positive result for human immunodeficiency virus (HIV) infection confirmed by central laboratory at screening. Subjects refusing HIV testing during the screening period will not be eligible for study participation.
13. Confirmed positive test for hepatitis B or hepatitis C
14. Any severe herpes infection at any time prior to Week 0 (Day 1)
15. Opportunistic infection requiring hospitalisation or intravenous antimicrobial treatment within 3 years prior to randomization
16. History of cancer, apart from:
(a) Squamous or basal cell carcinoma of the skin treated with documented success
(b) Cervical cancer in situ that has been successfully treated
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the difference in proportions of subjects achieving Systemic Lupus Erythematosus Responder Index SRI(4) at Week 52 comparing anifrolumab 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) |
1a. The composite endpoint SRI4 will be the measure of this objective.
1b. Maintained OCS reduction defined by the following criteria:
- Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40 and
- Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to Week 52 and
- No discontinuation of investigational product or use of restricted medications beyond the protocol-allowed threshold before assessment
1c. 50% reduction in CLASI activity score compared to baseline defined by the following criteria:
- Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline and
- No discontinuation of investigational product or use of restricted medications beyond the protocol-allowed threshold before assessment
1d. The composite endpoint SRI4 will be the measure of this objective
1e. Annualised flare rate with flare defined as either 1 or more new BILAG-2004 A or 2 or more new BILAG-2004 B items compared to the previous visit
2. The composite endpoint SRI4 will be the measure of this objective
3. The following safety data will be collected: vital signs, physical examination, 12-lead ECG, haematology, clinical chemistry, urinalysis, C-SSRS, PHQ-8, SLEDAI 2K Flare Index, and reported AEs
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1a. - Week 52
1b. - Week 52
1c. - Week 12
1d. - Week 24
1e. - Weeks 0- 52
2. - Week 52
3. - Weeks 0-52 |
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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 | 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 | 66 |
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 |
Brazil |
Chile |
Colombia |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
New Zealand |
Peru |
Poland |
Romania |
Taiwan |
Ukraine |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |