| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Disease whereby the inflammation and swelling affects the joints resulting in pain |
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| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10039075 |
| E.1.2 | Term | Rheumatoid arthritis and associated conditions |
| E.1.2 | System Organ Class | 100000004870 |
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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 main objective of this study is to evaluate the safety and efficacy of ABBV-105, upadacitinib, and of ABBV-599 (ABBV-105 plus upadacitinib) vs placebo on a background of conventional synthetic DMARDs (csDMARDs) for the treatment of signs and symptoms of RA at 12 weeks in biological DMARD-inadequate response (bDMARD-IR) or bDMARD-intolerant subjects with moderately to severely active RA and to define optimal dose(s) for further development. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Adult male or female, at least 18 years old.
- Diagnosis of RA for ≥ 3 months based on the 2010 ACR/EULAR classification criteria for RA.
- Subject meets the following minimum disease activity criteria:
•≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits (Appendix E); and
•hsCRP ≥ 3 mg/L (central lab) at Screening Visit.
- Subjects must have been treated for ≥ 3 months with ≥ 1 bDMARD therapy but continue to exhibit active RA or had to discontinue due to intolerability or toxicity, irrespective of treatment duration
- Subjects must have discontinued all bDMARDs prior to the first dose of study drug. The washout period for bDMARDs prior to the first dose of study drug is specified below or should be at least five times the mean terminal elimination half-life of a drug:
•≥ 4 weeks for etanercept, adalimumab, infliximab, certolizumab, golimumab, tocilizumab and abatacept;
•≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pretreatment level or normal reference range (central lab) if pretreatment levels are not available (TBNKM cell testing may be completed at Screening rather than Baseline if B cell testing is indicated).
- Females must not be pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 30 days after the last dose of study drug.
- For all females of child-bearing potential: a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
- Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control that is effective from Study Day 1 through at least 30 days. If required per local practices, male or female condom with or without spermicide OR cap, diaphragm or sponge with spermicide should be used in addition to one of the highly effective protocol-specified birth control methods (excluding true abstinence). A condom is required in the following countries: UK, Germany and Spain. Female subjects of non-childbearing potential do not need to use birth control.
- Dose of non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen/paracetamol must have been at a stable dose ≥ 1 week prior to the first dose of study drug; oral corticosteroids (equivalent to prednisone ≤ 10 mg/day) or inhaled corticosteroids for stable medical conditions are allowed but must have been at a stable dose ≥ 4 weeks prior to the first dose of study drug.
- Subjects must have discontinued all high-potency opiates at least 1 week and oral traditional Chinese medicine for at least 4 weeks prior to the first dose of study drug (refer to Section 5.3 for prohibited medications).
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| E.4 | Principal exclusion criteria |
- History of any of the following cardiovascular conditions:
•Moderate to severe congestive heart failure (New York Heart Association Class III or IV)
•Recent history (within past 6 months) cerebrovascular accident (CVA), myocardial infarction, coronary stenting
•Uncontrolled hypertension as defined by a persistent systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg. For subjects with known hypertension, the subject's BP must be stable for at least 4 weeks on current, stable anti-hypertensive medications
•Prior unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) (i.e., any spontaneous event not directly attributable to trauma or vascular instrumentation)
•Any other condition which, in the opinion of the Investigator, would put the subject at risk by participating in the protocol.
- Treated with intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa, or intra-tendon sheath corticosteroids in the preceding 8 weeks prior to the first dose of study drug.
- Treated with any investigational drug within 30 days or five half-lives of the drug (whichever is longer) prior to the first dose of study drug or is currently enrolled in another clinical study.
- Receipt of any live vaccine within 4 weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 4 weeks after the last dose of oral study drug
- Any active or recurrent viral infection that, based on the Investigator's clinical assessment, makes the subject an unsuitable candidate for the study, including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, disseminated (even a single episode) herpes simplex, or human immunodeficiency virus (HIV).
Active HBV, HCV and HIV are defined as:
•HBV: hepatitis B surface antigen (HBs Ag) positive (+) or, for hepatitis B core antibody (HBc Ab) positive subjects, detection of HBV deoxyribonucleic acid (DNA) by polymerase chain reaction;
•HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab);
- Have active TB or meets TB exclusionary parameters (defined as the presence of active TB or latent TB not adequately treated as per protocol requirements). Exclude patients with active TB or latent TB without history of appropriate prophylaxis [latent TB as assessed by Interferon Gamma Release Assay (IGRA QuantiFERON Tuberculosis (TB) Gold in Tube Test or equivalent, i.e., or T SPOT TB test; as available and if compliant with local TB guidelines), and/or a purified protein derivative (PPD) test (or both if required per local guidelines).
- Have used known strong cytochrome P450 (CYP)3A or CYP1A2 inhibitors or strong CYP3A inducers from Screening through the end of the study.
- History of any malignancy except for successfully treated non-melanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
- History of clinically significant (per Investigator's judgment) drug or alcohol abuse within the last 6 months.
- History of gastrointestinal perforation (other than appendicitis or penetrating injury), diverticulitis or significantly increased risk for gastrointestinal perforation per investigator judgment.
- Any conditions that could interfere with drug absorption including but not limited to short bowel syndrome.
- Recipient of an organ transplant.
- History of clinically significant medical conditions or any other reason that in the opinion of the Investigator would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
- Active infection(s) requiring treatment with parenteral anti-infectives within 30 days, or oral anti-infectives within 14 days prior to the first dose of study drug.
- History of an allergic reaction or significant sensitivity to constituents of the study drugs (and its excipients) and/or other products in the same class.
- Treated for ≥ 3 months with ≥ 1 bDMARD therapy but continue to exhibit active RA or had to discontinue due to intolerability or toxicity, irrespective of treatment duration.
- Subjects receiving csDMARD therapy ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of study drug.
•The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the first dose of study drug): oral or parenteral methotrexate (MTX) (7.5 to 25 mg/week), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
•A combination of up to two background csDMARDs is allowed EXCEPT the combination of MTX and leflunomide.
- Subject with prior exposure to any JAK inhibitor for greater than 2 weeks (including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib). A washout period of ≥ 30 days is required for any JAK inhibitor prior to the first dose of study drug.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in disease activity score (DAS)28 (C-reactive protein [CRP]) at Week 12 |
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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) |
Change from baseline in clinical disease activity index (CDAI) and simplified disease activity index (SDAI) at all visits;
3. Proportion of subjects achieving Clinical Remission (CR) at Week 12. CR is defined as DAS28 CRP < 2.6;
4. Proportion of subjects achieving low disease activity (LDA) at Week 12. LDA is defined as DAS28 CRP ≤ 3.2;
5. Proportion of subjects achieving LDA or CR based on CDAI criteria at all visits;
6. ACR20/50/70 response rates at all visits;
a. ACR20 response rate will be determined based on 20% or greater improvement in Tender Joint Count (TJC) and Swollen Joint Count (SJC) and ≥ 3 of the 5 measures of Patient's Assessment of Pain (Visual Analog Scale [VAS]), Patient's Global Assessment of Disease Activity (PGA), Physician's Global Assessment of Disease Activity (PhGA), Health Assessment Questionnaire Disability Index (HAQ-DI), or high-sensitivity C-reactive protein (hsCRP);
7. Change from baseline in individual components of ACR response at all visits;
8. Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]) at all visits;
9. Change from baseline in Short Form-36 (SF-36) at Weeks 4, 8 and 12;
10. Change from baseline in morning stiffness at all visits;
11. Change from baseline in Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) at Weeks 4, 8, and 12;
12. Change from baseline in HAQ-DI;
13. Proportion of subjects achieving minimal clinically important difference (MCID) in change from baseline in HAQ-DI (defined as change from baseline in HAQ-DI ≤ –0.3) at all visits;
14. Proportion of subjects achieving American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Boolean remission at all visits.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 40 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Poland |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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