A Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Adults With Rheumatoid Arthritis Who Are on a Stable Dose of Methotrexate and Who Have an Inadequate Response to Methotrexate (SELECT-COMPARE)

AbbVie

Status and phase: Active, not recruiting; Phase 3

Conditions: Rheumatoid Arthritis

Treatments: Drug: Placebo for Upadacitinib; Drug: Upadacitinib; Drug: Adalimumab; Drug: Placebo for Adalimumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02629159

M14-465

2022-501017-31-00 (Other Identifier)

Details and patient eligibility

About

The purpose of this study was to assess efficacy, including inhibition of radiographic progression, and safety with upadacitinib versus placebo and versus an active comparator, adalimumab, in adults with with moderately to severely active rheumatoid arthritis (RA) who are on a stable background of methotrexate (MTX and who have an inadequate response to MTX.

Full description

This study consists of a 48-week double-blind treatment period (Period 1) and a long-term extension period (Period 2).

Period 1 is a 48-week randomized, double-blind, parallel-group, placebo-controlled and active comparator-controlled period designed to compare the safety and efficacy of upadacitinib versus placebo, and versus adalimumab. Participants will be randomized in a 2:2:1 ratio to one of three treatment groups:

• Placebo (up to Week 26)
• Upadacitinib 15 mg once daily (QD)
• Adalimumab 40 mg every other week (eow)

Participants randomized to placebo who do not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded upadacitinib treatment. At Week 26, all participants still receiving placebo will be switched to blinded upadacitinib treatment regardless of clinical response.

Participants randomized to adalimumab who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded upadacitinib. Participants still receiving adalimumab at Week 26 who do not achieve low disease activity (LDA) according to Clinical Disease Activity Index (CDAI; LDA is defined as CDAI ≤ 10) will be switched to blinded upadacitinib treatment to Week 48.

Participants randomized to upadacitinib who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded adalimumab; participants still receiving upadacitinib at Week 26 who do not achieve LDA (CDAI ≤ 10) will be switched to blinded adalimumab treatment to Week 48.

Participants who complete the Week 48 visit (end of Period 1) will enter the long-term extension phase of the study (Period 2), for up to 5 years. Participants will continue study treatment as assigned at the end of Period 1. Starting at the Week 48 and thereafter, at least 20% improvement in both TJC and SJC compared to Baseline is required to remain on study drug. Anyone who does not fulfill this criterion at 2 consecutive visits (starting at Week 48) will be discontinued.

Enrollment: 1,629 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adult male or female, at least 18 years old.
• Diagnosis of RA for greater than or equal to 3 months.
• Subjects must have been on oral or parenteral methotrexate (MTX) therapy greater than or equal to 3 months and on a stable prescription of greater than or equal to 15 to 25 mg/week (or greater than or equal to 10 mg/week in subjects intolerant of MTX at doses greater than or equal to 12.5 mg/week) for at least 4 weeks prior to the first dose of study drug. In addition all subjects should take a dietary supplement of folic acid or folinic acid throughout the study participation.
• Meets the following minimum disease activity criteria: greater than or equal to 6 swollen joints (based on 66 joint counts) and greater than or equal to 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.
• At least one of the following at Screening: greater than or equal to 3 bone erosions on x-ray OR greater than or equal to 1 bone erosion and a positive rheumatoid factor OR greater than or equal to 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibodies.
• Subjects with prior exposure to only one biological disease-modifying anti-rheumatic drugs (bDMARD) (except adalimumab) may be enrolled (up to 20% of total study population) if they have documented evidence of intolerance to the bDMARD or limited exposure (less than 3 months), but required washout periods need to be satisfied.
• Except for MTX, subject must have discontinued all conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).

Exclusion criteria

• Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).
• Subjects who have been exposed to adalimumab or who are considered inadequate responders to bDMARD therapy as determined by the Investigator.
• History of inflammatory joint disease other than RA. History of secondary Sjogren's Syndrome is permitted.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,629 participants in 3 patient groups, including a placebo group

Placebo followed by ABT-494

Placebo Comparator group

Description:

Participants were to receive placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26, all remaining participants were to be switched to 15 mg upadacitinib QD until Week 48 (end of Period 1). Participants who complete Period 1 will continue to receive 15 mg upadacitinib orally QD for up to 5 years in Period 2.

Treatment:

Drug: Placebo for Adalimumab

Drug: Upadacitinib

Drug: Placebo for Upadacitinib

Adalimumab

Active Comparator group

Description:

Participants were to receive placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26 remaining participants who did not achieve low disease activity (defined as Clinical Disease Activity Index \[CDAI\] ≤ 10) were to be switched to 15 mg upadacitinib orally QD until Week 48. Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.

Treatment:

Drug: Adalimumab

Drug: Upadacitinib

Drug: Placebo for Upadacitinib

Upadacitinib

Experimental group

Description:

Participants were to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 40 mg adalimumab eow. At Week 26 remaining participants who did not achieve low disease activity (defined as CDAI ≤ 10) were to be switched to 40 mg adalimumab eow until Week 48. Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.

Treatment:

Drug: Placebo for Adalimumab

Drug: Adalimumab

Drug: Upadacitinib