Discontinuation of Methotrexate in Rheumatoid Arthritis Patients Achieving Clinical Remission by Treatment With Upadacitinib Plus Methotrexate (DOPPLER)

Discontinuation of Methotrexate in Rheumatoid Arthritis Patients Achieving Clinical Remission by Treatment With Upadacitinib Plus Methotrexate: an Interventional, Multicenter, Prospective, Open-label, Single-arm Clinical Trial With Clinical, Ultrasound and Biomarker Assessments

The administration of Janus kinase (JAK) inhibitors as well as biological disease-modifying anti-rheumatic drugs has dramatically improved even the clinical outcomes in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX). Upadacitinib is a selective JAK1 inhibitor to be approved for use in RA. Nearly half of patients added JAK inhibitors including upadacitinib can achieve clinical remission in RA patients with inadequate response to MTX. As the next step, it is the great issue whether disease activity can be maintained in good condition even if MTX is discontinued after achieving clinical remission in patients treated with the combination of JAK inhibitors and MTX. Thus, it is desirable to investigate the maintenance of clinical non-relapse after discontinuation of MTX in RA patients with clinical remission during treatment with upadacitinib plus MTX. In this study, we will evaluate the proportion of patients who maintained nonclinical relapse after discontinuation of MTX in patients with RA who achieved clinical remission after treatment with upadacitinib plus MTX. We will also use musculoskeletal ultrasound (MSUS) assessments to determine whether discontinuation of MTX can be maintained nonclinical relapse in RA patients achieving clinical remission.

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis; Biomarker; JAK Inhibitor; Musculoskeletal Ultrasound
• Intervention / Treatment: Drug: upadacitinib 15mg/day

• Study Type: Interventional
• Enrollment (Anticipated): 155
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Nagasaki, Japan, 852-8501
    • Recruiting
    • Nagasaki University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must meet all of the following requirements to be considered for entry into the study:

  1. ≥20 years old
  2. with the diagnosis of RA based on the American College of Rheumatology (ACR) /EULAR 2010 RA Classification Criteria
  3. with at least moderate DAS28-CRP >3.2 at the eligibility evaluation
  4. with at least one PD score positive joint of 22 joints examined MSUS at the eligibility evaluation
  5. treated with MTX for ≥8 weeks prior to the providing consent, including 4 weeks or more at the same doses of 6 to 16 mg per week
  6. ability and willingness to provide written informed consent and comply with the requirements of the study protocol.

Exclusion Criteria:

• The exclusion criteria are as follows:

  (1) concurrent use of a corticosteroid equivalent to >7.5 mg/day of prednisolone (2) applicable an item for the contraindication of upadacitinib (3) a previous use of a JAK inhibitor (4) treatment with a corticosteroid and change of dose within 4 weeks prior to the providing consent (5) treatment with a csDMARD except MTX within 2 weeks prior to the providing consent; (6) treatment with a biologic DMARD or a biosimilar DMARD (ie, infliximab, biosimilar of infliximab, adalimumab, golimumab, certolizumab pegol, tocilizumab, sarilumab or abatacept) within 8 weeks prior to the providing consent (7) treatment with a TNF inhibitor (ie, etanercept or biosimilar of etanercept) within 4 weeks prior to the providing consent (8) use of a prohibited drug or therapy, other than the agents noted above, within 4 weeks prior to the providing consent (9) a complication causing musculoskeletal disorders other than RA (ie, ankylosing spondyloarthritis, reactive arthritis, psoriatic arthritis, crystal-induced arthritis, systemic lupus erythematosus, systemic scleroderma, inflammatory myopathy, or mixed connective tissue disease) (10) current pregnancy, breastfeeding, or noncompliant with a medically approved contraceptive regimen during and 12 months after the study period (11) inappropriateness for inclusion in this study as determined by the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Upadacitinib; The administration of upadacitinib 15mg/day	Drug: upadacitinib 15mg/day; Patients will receive upadacitinib 15mg/day and continue to receive same doses of MTX until 24 weeks. If patients achieve a European League Against Rheumatism (EULAR) moderate response or a Disease Activity Score 28 (DAS28-CRP) ≤3.2 at 12 weeks, and a DAS28-CRP of <2.6 at 24 weeks, they will discontinue MTX, and continue upadacitinib until 48 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
maintenance of DAS28-CRP <=3.2 from week 24 to 48 in patients who achieve the DAS28-CRP <2.6 at week 24.	at week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
achievement of DAS28-CRP <=3.2		at weeks 12, 24 and 36
achievement of DAS28-CRP <2.6		at weeks 12, 24, 36 and 48
clinical relapse (DAS28-CRP >3.2) at week 48 in patients who achieve the DAS28-CRP <2.6 at week 24		at week 48
achievement of EULAR moderate response		at week 12
changes in the DAS28-CRP value	Higher scores mean a more active RA.	from baseline to weeks 12, 24, 36, and 48
changes in the DAS28-ESR value	Higher scores mean a more active RA.	from baseline to weeks 12, 24, 36, and 48
changes in the DAS28-CRP value	Higher scores mean a more active RA.	from week 24 to weeks 36 and 48
changes in the DAS28-ESR value	Higher scores mean a more active RA.	from week 24 to weeks 36 and 48
changes in the clinical disease activity index (CDAI) value	Higher scores mean a more active of RA.	from baseline to weeks 12, 24, 36, and 48
changes in the simplified disease activity index (SDAI) value	Higher scores mean a more active of RA.	from baseline to weeks 12, 24, 36, and 48
changes in the clinical disease activity index (CDAI) value	Higher scores mean a more active of RA.	from week 24 to weeks 36 and 48
changes in the simplified disease activity index (SDAI) value	Higher scores mean a more active of RA.	from week 24 to weeks 36 and 48
achievement of CDAI <=2.8		at weeks 12, 24, 36 and 48
achievement of SDAI <=3.3		at weeks 12, 24, 36 and 48
changes in the serum levels of biomarkers	We analyze the serum levels of multiple biomarkers such as cytokines and chemokines.	from baseline to weeks 12, 24, 36, and 48
changes in the serum levels of biomarkers	We analyze the serum levels of multiple biomarkers such as cytokines and chemokines.	from week 24 to weeks 36 and 48
changes in the total power Doppler (PD) score	The minimum: 0, max: 66. Higher scores mean a more active RA.	from baseline to weeks 12, 24, 36, and 48
changes in the total grayscale (GS) score	The minimum: 0, max: 66. Higher scores mean a more active RA.	from baseline to weeks 12, 24, 36, and 48
changes in the combined PD score	The minimum: 0, max: 66. Higher scores mean a more active RA.	from baseline to weeks 12, 24, 36, and 48
changes in the total PD score	The minimum: 0, max: 66. Higher scores mean a more active RA.	from week 24 to weeks 36 and 48
changes in the total GS score	The minimum: 0, max: 66. Higher scores mean a more active RA.	from week 24 to weeks 36 and 48
changes in the combined PD score	The minimum: 0, max: 66. Higher scores mean a more active RA.	from week 24 to weeks 36 and 48
change in van der Heijde-modified total Sharp score (vdH-mTSS)	The minimum: 0, max: 3. Higher scores mean a more joint destruction and deformity.	from baseline to weeks 12, 24, 36 and 48
change in vdH-mTSS	Higher scores mean a more joint destruction and deformity.	from week 24 to weeks 36 and 48

Collaborators and Investigators

• Sponsor: Atsushi Kawakami
• Collaborators: AbbVie GK.

Publications and helpful links

General Publications

• Shimizu T, Kawashiri SY, Sato S, Kawazoe Y, Kuroda S, Kawasaki R, Ito Y, Morimoto S, Yamamoto H, Kawakami A. Discontinuation of methotrexate in rheumatoid arthritis patients achieving clinical remission by treatment with upadacitinib plus methotrexate (DOPPLER study): A study protocol for an interventional, multicenter, open-label and single-arm clinical trial with clinical, ultrasound and biomarker assessments. Medicine (Baltimore). 2022 Jan 14;101(2):e28463. doi: 10.1097/MD.0000000000028463.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 12, 2021
• Primary Completion (ANTICIPATED): November 30, 2023
• Study Completion (ANTICIPATED): September 30, 2024

Study Registration Dates

• First Submitted: November 4, 2021
• First Submitted That Met QC Criteria: November 4, 2021
• First Posted (ACTUAL): November 16, 2021

Study Record Updates

• Last Update Posted (ACTUAL): December 8, 2021
• Last Update Submitted That Met QC Criteria: November 24, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Protein Kinase Inhibitors; Janus Kinase Inhibitors; Upadacitinib
• Other Study ID Numbers: CRB20-024

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No