| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Active Systemic Lupus Erythematosus |
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| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus |
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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 | 18.0 |
| 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 |
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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 assess the efficacy and safety of different dose regimens of ALX-0061 administered subcutaneously (s.c.) to subjects with moderate to severe active, seropositive SLE compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
| To assess the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, flare rate, steroid reduction and health-related quality of life, with different dose regimens of ALX-0061. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female adults ≥ 18 years and < 65 years of age at the time of signing the informed consent form (ICF). The minimum age for adults will depend on local regulations.
2. Have a diagnosis of SLE and fulfill the 1997 ACR (see Appendix 9.1) or 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for at least 6 months prior to screening.
3. Have moderate to severe active SLE, for the purpose of this study defined by a SLEDAI 2K score ≥ 6 at screening.
4. Have at least one A or one B score on the revised BILAG 2004 criteria for the mucocutaneous and/or musculoskeletal system.
5. Have seropositive disease at screening for ANA (≥ 1:80) and/or anti-dsDNA (≥ 30 IU/mL) measured at the central laboratory.
6. Subject at least must be on one or more of the following treatments for SLE:
a. If subject is on oral corticosteroids, the dose should be equivalent to a maximum dose of 25 mg of prednisone/day and stable for at least 4 weeks prior to baseline.
b. If subject is on antimalarials, he or she must have received antimalarials for at least 12 weeks with a stable dose of max. 400 mg/day for at least 4 weeks prior to baseline.
c. If subject is on immunosuppressants: azathioprine (max. 150 mg/day), mycophenolate mofetil (max. 1.5 g/day), methotrexate (max. 25 mg/day), cyclosporine (max. 200 mg), leflunomide (max. 20 mg/day), treatment duration must be at least 12 weeks with a stable dose for at least 4 weeks prior to baseline; either alone or in combination with corticosteroids and/or hydroxychloroquine.
7. If immunosuppressants were previously given but have been stopped, the last dose should have been received more than 4 weeks prior to baseline; for leflunomide and hydroxychloroquine, a leflunomide or hydroxychloroquine treatment-free period of at least 12 weeks should be respected (unless an adequate cholestyramine wash-out was done for leflunomide).
8. If subject is on angiotensin-converting-enzyme (ACE) inhibitor or angiotensin receptor blocker, the dose should have been stable for 4 weeks prior to baseline.
9. Chest radiograph performed within 12 weeks prior to the screening visit (or performed during the screening period) documenting no evidence of malignancy, infection, or abnormalities suggestive of tuberculosis (TB; report must be obtained and available in the subject’s study file prior to baseline).
10. Are considered eligible according to the following TB screening criteria:
a. Have no history of latent or active TB prior to screening. An exception is made for subjects with a history of latent TB and documentation of having completed appropriate treatment for latent TB prior to screening. It is the responsibility of the Investigator to verify the adequacy of previous anti-TB treatment and provide appropriate documentation.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination during screening.
c. Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specialized in TB to undergo additional evaluation and, if warranted, receive appropriate treatment.
d. Have a negative interferon gamma release assay (IGRA) screening test result. A subject whose initial IGRA test result is indeterminate should have the test repeated while still fulfilling the other TB criteria for inclusion. The test should not be repeated in case other risk factors for TB are present. In case the test is again indeterminate, the subject will be excluded. In case of a positive IGRA test result due to previous latent TB, the subject is eligible if adequate documentation of completed anti-TB treatment prior to screening is available.
e. Have a chest radiograph, read by a qualified radiologist, whose diagnostic assessment is consistent with no evidence of current active TB or old inactive TB, and taken within 12 weeks prior to screening as part of standard of care or during the screening period. In case local regulations do not allow radiographs during the study, a radiograph as part of standard of care should be available prior to screening.
11. Female subjects of childbearing potential (excluding postmenopausal women, sterilized, ovariectomized and hysterectomized women) must have a negative pregnancy test and must agree to use two generally accepted adequate contraceptive methods (1 highly effective and 1 barrier method e.g., hormonal contraception in combination with condom by partner) from screening until at least 3 months after last dosing.
Male subjects must use condoms for the duration of the study and for at least 3 months after last dosing.
12. Capability to comprehend and willingness to sign an ICF, which must be obtained prior to any study-related procedures (vulnerable subjects will be excluded, except subjects from ethnic minority groups who may participate).
13. An understanding, ability and willingness to adhere to the study requirements.
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| E.4 | Principal exclusion criteria |
1. Have an A score on the revised BILAG-2004 other than in the mucocutaneous and/or musculoskeletal system at screening.
2. Have a systemic inflammatory disease other than SLE, including but not limited to psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis or Lyme disease.
3. Infection treated with i.v. antibiotics, i.v. antivirals, or i.v. antifungals within 4 weeks prior to baseline or oral antibiotics, oral antivirals, or oral antifungals within 2 weeks prior to baseline.
4. Any active or recurrent viral infection that based on the Investigator´s clinical assessment makes the subject unsuitable for the study, such as current Cytomegalovirus (CMV) or Epstein-Barr Virus (EBV) infection or recurrent / disseminated herpes zoster.
5. Have a history of, or current, class III or IV congestive heart failure (CHF), as defined by the New-York Heart Association; history of unstable angina pectoris, myocardial infarction, cerebrovascular accident, thromboembolic event within 12 months before screening.
6. Have active lupus nephritis requiring cyclophosphamide or mycophenolate mofetil more than 1,5 g/day or other therapy not permitted by the protocol.
7. Have lupus-related central neurological problems (including lupus headache) or severe central nervous system (CNS) disease.
8. Have drug-induced lupus.
9. Have a history of demyelinating diseases such as multiple sclerosis.
10. History of diverticulitis or symptoms of acute diverticulitis with confirmatory imaging (i.e., CT scan).
11. Any history of malignancy or lymphoproliferative disease, except for successfully-treated non-melanoma skin cancer or resected cervical carcinoma in situ.
12. Have a transplanted organ or received stem cell transplantation.
13. Major surgery (including joint surgery) within 8 weeks prior to screening or hospitalization for a clinically relevant event within the 4 weeks prior to screening or planned major surgery during study or within 3 months after study end.
14. Have been treated with i.v. immunoglobulins, cyclophosphamide or tacrolimus within 12 months prior to baseline.
15. Have received i.v., intra-articular (i.a.), intramuscular (i.m.) or high dose (> 25 mg/day) oral corticosteroids during the 4 weeks prior to baseline.
16. Have a known hypersensitivity to the active product or any excipient of the study drug.
17. Have received approved or investigational biological therapies within 6 months or 5 half-lives of the concerned therapy (whichever is longer) prior to baseline.
18. Have received non-biological investigational therapies within 4 weeks or 5 half lives of the concerned therapy (whichever is longer) prior to baseline.
19. Have received prior therapy blocking the IL-6 pathway, such as but not limited to ALX 0061, sirukumab, tocilizumab, sarilumab, clazakizumab, olokizumab, or JAK inhibitors at any time.
20. Abnormality in screening laboratory test results:
a. ALT and/or AST ≥ 1.5 times the upper limit of normal (ULN).
b. Hemoglobin ≤ 85 g/L (8.5 g/dL).
c. Platelet count ≤ 75 x 109/L (75,000 cells/mm³).
d. White blood cell count ≤ 2.2 x 109/L (2,200 cells/mm³).
e. Neutrophils: ≤ 1.5 X 109/L.
f. Estimated proteinuria > 1 g/day measured by spot urine protein to creatinine ratio of 1.
g. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m² (based on the ‘modification of diet in renal disease’ [MDRD] formula [Appendix 9.4]).
h. Any other clinically significant abnormal screening laboratory results as evaluated by the Investigator.
21. Positive screening for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
22. Known history or presence of alcohol or drug abuse.
23. Blood donation (> 500 mL) or a comparable blood loss within 3 months prior to baseline.
24. Planned donation of germ cells, blood, organs, bone marrow during the course of the study or within 6 months thereafter.
25. Female subjects who are planning to become pregnant during the study or within 3 months after last dosing or male subjects who are considering fathering a child during the study and within 3 months after last dosing.
26. Pregnant woman or female subjects who are breastfeeding.
27. History of anaphylactic reactions.
28. Administration of a live, attenuated vaccine within 3 months before dosing with ALX 0061, or anticipation that such a live attenuated vaccine will be required during the study or within 6 months after last dosing.
29. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The percentage of subjects who achieved a response at Week 24 according to the composite mBICLA (BILAG-based Combined Lupus Assessment) score. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints will include:
• Composite endpoint (m)BICLA over time.
• Composite endpoint mSRI as well as standard SRI over time.
• (m)SRI with more stringent (m)SLEDAI-cut-offs: SRI-5, SRI-6, SRI-7, SRI-8 over time.
• Change from baseline in mSLEDAI-2K total score as well as standard SLEDAI 2K measured over time.
• Number and percent of subjects with BILAG-2004 improvement.
• BILAG-2004 (total score) over time.
• Improvement in individual organ systems of the BILAG-2004 over time.
• Number of BILAG-2004 systems in which activity increased, decreased or remained the same compared to previous visit (BILAG-2004 systems tally) over time.
• Change from baseline in PGA over time.
• Change from baseline in patient’s global assessment over time.
• Change from baseline in proteinuria/urine sediment/serum creatinine/eGFR over time.
• Proportion of treatment failures (defined as non-protocol allowed increase in steroid dose, start i.v. or i.m. steroids, start or increase of immunosuppressant) at Week 24 and at Week 48.
• Reduction in flare rate at Week 24 and at Week 48.
-Severe flare defined as a new A score in any system of the BILAG-2004 index; moderate flare defined as a new B score following a C, D or E score.
-SLEDAI flare index (SFI).
• Percent change from baseline in daily dose of steroids at Week 24 and 48.
• Percent subjects whose prednisone equivalent dose was >7.5 mg/day at baseline and reduced to ≤7.5 mg/day during Weeks 40–48 without experiencing a flare.
• Percent subjects who are able to discontinue prednisone by Week 48 without experiencing a flare.
• Changes from baseline in the physical and mental component scores of SF-36 at Week 24 and at Week 48.
• 28 Joints count over time and change from baseline in 28 joint count over time.
• Cutaneous lupus erythematosus disease area and severity index (CLASI) over time and change from baseline evaluation at Week 12, 24 and Week 48.
• PK parameters.
• PD markers, including total sIL-6R, CRP, fibrinogen, anti-dsDNA, C3, C4, CH50.
|
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| E.5.2.1 | Timepoint(s) of evaluation of this end 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) | 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 | 5 |
| 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 | 31 |
| 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 |
| Chile |
| Czech Republic |
| Germany |
| Hungary |
| Korea, Republic of |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| Spain |
| Taiwan |
| Ukraine |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 28 |
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