| 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 |
| SLE is a chronic disease where the body’s immune system may attack the body’s own skin, joints, kidneys, brain, and/or other organs. Women and people of African descent are more often affected. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 |
|
| 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 main objective of this study is to evaluate the safety and efficacy of elsubrutinib, upadacitinib and ABBV-599 (elsubrutinib/upadacitinib) combination vs placebo for the treatment of signs and symptoms of Systemic Lupus Erythematosus (SLE) at 24 and 48 weeks in subjects with moderately to severely active SLE and to define optimal dose(s) for further development. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Adult male or female, 18 to 65 years of age, inclusive, at Screening.
•Clinical diagnosis of SLE at least 24 weeks prior to Screening, meeting at least 4 of the 11 ACR criteria OR meeting at least 4 of the SLICC criteria including at least 1 clinical and 1 immunologic criterion.
• At Screening, must have at least one of the following:
∙ ANA+ (titer ≥ 1:80)
∙ anti-dsDNA+
∙ anti-Smith+
• SLEDAI-2K ≥ 6 despite background therapy as reported and independently adjudicated (clinical score ≥ 4, excluding lupus headache and/or organic brain syndrome) at Screening:
∙ If 4 points of the required entry points are for arthritis there must also be a minimum of 3 tender and 3 swollen joints
∙ If subject has rash and PI considers it to be attributable to SLE, subject must consent to skin photograph collection for adjudication.
∙ Score must be re-confirmed at the Baseline Visit
•The subject must be on background treatment throughout the study. The background treatment must be stable for 30 days prior to Baseline and throughout the study with:
∙ Antimalarial(s), prednisone (or prednisone-equivalent) (≤ 20 mg), azathioprine (≤ 150 mg), mycophenolate (≤ 2 g), leflunomide (≤ 20 mg), cyclosporine, tacrolimus, and/or MTX
(≤ 20 mg).
∙ The combination of background treatment with antimalarial(s) and/or prednisone (or equivalent) is permitted.
∙ And a single, but not multiple, additional immunosuppressant from the list above, is permitted. |
|
| E.4 | Principal exclusion criteria |
• Women of childbearing potential must not have a positive serum pregnancy test at the screening visit and must have a negative urine pregnancy test at baseline prior to the first dose of study drug. Note: Subjects with borderline serum pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of positive result.
• Must not be using IV or IM corticosteroids greater than or equal to a 40 mg prednisone-equivalent bolus within 30 days weeks of planned randomization
• Must not have active lupus nephritis (progressive Class IV or >1g/day equivalent [1 mg/mg] proteinuria) or have undergone induction therapy within the last 6 months.
• Must not have active neuropsychiatric SLE as defined by the CNS portion of SLEDAI-2K (excluding lupus headache).
Subjects must be naïve or have discontinued, if not currently benefiting from, the following prior to the first dose of study drug per the applicable washout period below or should be at least 5 times the mean terminal elimination half-life of a drug:
∙ ≥6 months for Plasmapheresis
∙ ≥3 months for Benlysta
∙ ≥1 year for rituximab OR ≥ 6 months if B cells have returned to ≥ 50 B cells per microliter
∙ ≥3 months for cyclophosphamide
∙ ≥4 weeks for abatacept, any anti-TNF therapy, and all other biologics
• Must not have positive titers for all 3 antiphospholipid antibodies known to be associated with venous thrombotic events at Screening: lupus anticoagulant, anti-beta 2 glycoprotein 1, and anticardiolipin antibody. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| SLE Responder Index (SRI)-4 and steroid dose ≤ 10 mg prednisone equivalent QD. SLE Responder Index (SRI)-4 is defined as ≥ 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score without worsening of the overall condition (no worsening in Physician's Global Assessment [PhGA], < 0.3 point increase) or the development of significant disease activity in new organ systems (no new British Isles Lupus Assessment Group ([BILAG]) A or > 1 new BILAG B). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. SRI-4 (without ≤ 10 mg prednisone equivalent QD requirement)
2. SRI-5, -6, -7, -8 (and steroid dose ≤ 10 mg prednisone equivalent QD at Weeks 24 and 48; without ≤ 10 mg prednisone equivalent QD requirement at all other visits)
3. BILAG-Based Combined Lupus Assessment (BICLA)
4. Lupus Low Disease Activity State (LLDAS)
5. 4-point decrease in SLEDAI-2K from Baseline
6. Steroid burden, assessed as change from Baseline
7. Number of mild, moderate or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare per patient compared across treatment arms
8. Time to first flare by SELENA SFI after first study drug administration up to Week 24 and Week 48
9. Achievement of 50% reduction of tender or swollen lupus joints (defined as ≥50% decrease in either tender or swollen joints (among those starting with ≥6 affected joints)
10. Achievement of 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score (of those starting with CLASI ≥10)
11. Change in SLEDAI-2K from Baseline
12. Change in BILAG from Baseline
13. Change in PhGA from Baseline
14. Change in Patient Global Assessment (PtGA) from Baseline
15. Change from Baseline Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) at Weeks 2, 12, 24, and 48
16. Change from Baseline in SF-36 at Weeks 2, 12, 24 and 48
17. Change from Baseline LupusQoL at Weeks 2, 12, 24 and 48
18. Change from Baseline Pain Numerical Rating Scale (NRS) at Weeks 2, 12, 24 and 48
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At all visits unless indicated otherwise. |
|
| 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 | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Canada |
| China |
| Colombia |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Poland |
| Puerto Rico |
| Romania |
| Spain |
| Taiwan |
| 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
|
| The end of study is defined as the date of the last subject's last contact, which will be a follow-up phone call 30 days after the last dose |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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