Program to Assess Adverse Events and Change in Disease Activity of Oral Upadacitinib in Adult Participants With Moderate to Severe Systemic Lupus Erythematosus

Study Overview
=================
Brief Summary
-----------------
Systemic Lupus Erythematosus (SLE) is an immune-mediated disease associated with inflammation of multiple organ systems. This study will assess how safe and effective upadacitinib is in treating adult participants with moderately to severely active SLE. Adverse events and change in the disease activity will be assessed. Upadacitinib is an approved drug for rheumatoid arthritis, psoriatic arthritis, and axial spondylarthritis and is being developed for the treatment of SLE. This study is double-blinded, which means that neither the trial participants nor the study doctors will know who will be given upadacitinib and who will be given placebo (does not contain treatment drug) . This study comprised of 3 sub studies. In Study 1 and Study 2, study doctors put the participants in 1 of the 2 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 2 chance that participants will be assigned to placebo. Eligible participants from Study 1 and Study 2 will enter Study 3 at week 52 to receive specific doses of upadacitinib based on their disease activity and their original treatment assignment in Study 1 or 2. Approximately 500 participants diagnosed with SLE will be enrolled in each of the Study 1 and Study 2 in approximately 320 sites across the world. Participants will receive oral tablets of upadacitinib or matching placebo once daily for 52 weeks in Study 1 and Study 2. Eligible participants from Study 1 and Study 2 will receive oral tablets of upadacitinib once daily for 52 weeks in Study 3. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, checking for side effects and completing questionnaires.

Official Title
-----------------
SELECT-SLE: A Phase 3 Program to Evaluate the Safety and Efficacy of Upadacitinib in Subjects With Moderately to Severely Active SLE

Conditions
-----------------
Systemic Lupus Erythematosus

Intervention / Treatment
-----------------
* Drug: Upadacitinib
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of systemic lupus erythematosus (SLE) at least 24 weeks prior to screening as defined by the 2019 European Alliance of Associations for Rheumatology (EULAR)/ American College of Rheumatology (ACR) classification criteria for SLE. At Screening, must have at least one of the following: antinuclear antibody (ANA) positive (titer >= 1:80) anti-double stranded deoxyribonucleic acid (dsDNA) positive anti-Smith positive Hybrid systemic lupus erythematosus disease activity index (hSLEDAI) >= 6, of which >= 4 points are clinical (not based on laboratory criteria), independently adjudicated at Screening. Clinical hSLEDAI score (not based on laboratory criteria) must be re-confirmed as >= 4 at the Baseline visit. Lupus headache or organic brain syndrome do not count towards the hSLEDAI points required for eligibility but should be documented on the hSLEDAI if present. Physician's Global Assessment (PhGA) >= 1 during screening period. On stable background treatment for >= 30 days prior to Baseline (with the exception of oral corticosteroid [OCS], which must be at a stable dose for >=14 days prior to Baseline) with antimalarial(s) [hydroxychloroquine <= 400 mg daily, chloroquine <= 500 mg daily, quinacrine <= 100 mg daily]; and/or prednisone (or prednisone-equivalent) (<= 20 mg daily); and/or no more than 1 of the following: azathioprine (<= 150 mg daily), mycophenolate mofetil (<= 2 g daily), mycophenolate sodium <= 1,440 mg/day, leflunomide (<= 20 mg daily), cyclosporine, tacrolimus, voclosporin (<= 23.7 mg twice daily), methotrexate (<= 25 mg weekly), or mizoribine (<=150 mg daily) Exclusion Criteria: Clinically relevant or significant ECG abnormalities at Screening. Planned elective surgery that would impact study procedures or assessments through the completion of the Week 52 assessments.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 63 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study 1- Upadacitinib Dose A<br>Participants will receive upadacitinib dose A once daily for 52 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Placebo Comparator: Study 1- Placebo<br>Participants will receive upadacitinib matching placebo once daily for 52 weeks. | Drug: Placebo<br>* Oral Tablet<br>|
| Experimental: Study 2- Upadacitinib Dose A<br>Participants will receive upadacitinib dose A once daily for 52 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Placebo Comparator: Study 2- Placebo<br>Participants will receive upadacitinib matching placebo once daily for 52 weeks. | Drug: Placebo<br>* Oral Tablet<br>|
| Experimental: Study 3- Low Disease Activity Upadacitinib (LDA) Dose A<br>Participants in the upadacitinib arms from Study 1 or Study 2 with LDA will receive upadacitinib dose A once daily for 52 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Experimental: Study 3- Low Disease Activity Upadacitinib Dose B<br>Participants in the upadacitinib arms from Study 1 or Study 2 with LDA will receive upadacitinib dose B once daily for 52 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Experimental: Study 3- No LDA Upadacitinib Dose A<br>Participants in the upadacitinib arms from Study 1 or Study 2 with no LDA will receive upadacitinib dose A once daily for 52 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Experimental: Study 3- Upadacitininb Dose A<br>Participants in the placebo arms of Study 1 or Study 2 will receive upadacitinib Dose A once daily for 52 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Experimental: Study 3- Open Label Upadacitinib Dose A<br>Participants who experience a suspected systemic lupus erythematosus (SLE) flare may receive open label upadacitinib Dose A once daily for the remainder of the study. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|
| Experimental: Study 3- Open Label Upadacitinib Dose B<br>Participants who reach >= 65 years of age and are still on study drug may receive open-label upadacitinib Dose B once daily, and participants who experience a suspected SLE flare while on upadacitinib Dose B may receive upadacitinib Dose A for the remainder of the study. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving British Isles Lupus Assessment Group Based Combined Lupus Assessment (BICLA) Response | BICLA is a composite responder index based on improvement in organ systems without worsening of the overall condition and improvement in disease activity. | At Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Flares Participants Experiencing Over Time (Number of Flares Per Patient-Year) | Flare is defined by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) Systemic lupus erythematosus disease activity index (SLEDAI) Flare Index (SFI). An index defining Systemic lupus erythematosus (SLE) flares using changes in the Hybrid SLEDAI (hSLEDAI) score, definitions of worsening signs and symptoms, treatment changes, and Physician's Global Assessment of Disease Activity. Flare rate is number of flares per patient-year. | Week 52 | 
| Percentage of Participants Achieving Systemic Lupus Erythematosus Responder Index (SRI) -4 | SRI is a composite responder index based on improvement in disease activity (number following SRI indicates numerical improvement in hSLEDAI 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). | At Week 52 | 
| Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) | LLDAS is a state of low disease activity based on SLEDAI score (hSLEDAI score <= 4 excluding hSLEDAI activity in major organ systems), absence of SLE disease activity in major organ systems and new disease activity, Physician's Global Assessment (PhGA <= 1), and concomitant medication usage. | At Week 52 | 
| Time to First Flare per SELENA SLEDAI Flare Index (SFI) | SFI is an index defining SLE flares using changes in the hSLEDAI score, definitions of worsening signs and symptoms, treatment changes, and Physician's Global Assessment of Disease Activity. | Week 52 | 
| Percentage of Participants Achieving Glucocorticoid Dose <=7.5 mg/day Prednisone-Equivalent | Achievement of glucocorticoid dose <=7.5 mg/day prednisone-equivalent among participants taking >= 10 mg/day prednisone-equivalent at baseline. | From Week 44 to Week 52 | 
| Change from Baseline in Lupus Pain Numerical Rating Scale (NRS) | The Lupus Pain-NRS is a single-item questionnaire in which participants are asked to rate their overall pain level due to lupus over the last week. The Lupus Pain-NRS scores range from 0 to 10, with higher scores indicating a higher level of pain. | Baseline to Week 28 | 
| Percentage of Participants Achieving >= 50% Improvement in Tender or Swollen Joints | Achievement of >= 50% improvement in tender or swollen joints among participants with >= 3 swollen joints and >= 6 total affected joints at Baseline. | Week 52 | 
| Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Version 4 | The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants. Participants respond to the questions on a scale from 0 (not at all) to 4 (very much). The FACIT-Fatigue score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue score ranges from 0 to 52, where higher scores represent less fatigue. | Baseline to Week 28 | 
| Change from Baseline in 36-Item Short Form Health Survey (SF-36) Acute Physical Component Summary (PCS) | The SF-36v2® Health Survey Acute is a general HRQoL instrument with extensive use in multiple disease states. The instrument comprises 36 total items (questions) targeting a participants's functional health and well-being in 8 dimensions (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Scoring is totaled into a Physical Component Summary and a Mental Component Summary. Higher scores indicate a better state of health. | Baseline to Week 28 | 
| Percentage of Participants Achieving >= 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | CLASI index used to assess cutaneous manifestations of SLE summarizing the activity of the disease. Scores range from 0 to 70, with higher scores indicating more severity. Achievement of >= 50% reduction in CLASI activity score among participants with baseline score >=10. | Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Systemic Lupus Erythematosus, SLE, Upadacitinib, Lupus