A Study Comparing Biologics + Methotrexate With Biologics + Tacrolimus in Patients With Rheumatoid Arthritis (RA)

Compare Efficacy and Safety Between Biologics + Methotrexate (MTX) vs Biologics + Tacrolimus (TAC) (Switched From Biologics + Methotrexate (MTX)) in the Patients With Rheumatoid Arthritis (RA): Randomized, Interventional, Open, Active Controlled, Parallel Group, Multicenter-designed, Phase 4 Clinical Trial

The purpose of this study is to compare the efficacy of Biologics + Methotrexate with Biologics + Tacrolimus measured by the disease activity score 28 (DAS28) erythrocyte sedimentation rate (ESR) and the American College of Rheumatology (ACR) scores. The study will also assess the safety of the combinations.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis (RA)
• Intervention / Treatment: Drug: tacrolimus; Biological: adalimumab; Biological: tocilizumab; Biological: abatacept; Drug: methotrexate

Detailed Description

This study will include 4-weeks screening and a 12-week open-label treatment period.The participants in this study will visit the center five (5) times over the study period.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Daegu, Korea, Republic of
    • Site KR82003
  • Daegu, Korea, Republic of
    • Site KR82007
  • Daejeon, Korea, Republic of
    • Site KR82006
  • Incheon, Korea, Republic of
    • Site KR82002
  • Seongnam, Korea, Republic of
    • Site KR82009
  • Seoul, Korea, Republic of
    • Site KR82001
  • Seoul, Korea, Republic of
    • Site KR82005
  • Seoul, Korea, Republic of
    • Site KR82010
  • Seoul, Korea, Republic of
    • Site KR82012
  • Suwon, Korea, Republic of
    • Site KR82013

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with rheumatoid arthritis (RA) diagnosed by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR).
• Subjects who have been treated with combination therapy of one of biologic agent (adalimumab, tocilizumab, or abatacept) + methotrexate (MTX) over 2 months prior to Visit 1.
• Disease Activity Score (DAS28) erythrocyte sedimentation rate (ESR) ≥ 3.2 at screening and baseline.
• Subject agrees not to participate in another interventional study while participating in the present study.

Exclusion Criteria:

• Subjects with a past history of allergic reaction to Investigational Product or Comparative Drug used in this study.
• Subjects who were given tacrolimus (TAC) within three months before participation in this study.
• Subjects who have been treated with combination therapy of one of biologic agent (adalimumab, tocilizumab, or abatacept) + MTX exceeds 3 months at Baseline.
• Subjects who were already taking 20 mg of MTX at Screening Period.
• Subjects who were given the prohibited concomitant medications prior to randomization.
• Subjects with a medical history of clinically significant blood, gastrointestinal, endocrine, lung, nerve, or brain diseases at screening.

• Subjects with a medical history of clinically significant liver, kidney, or heart diseases:

  • Liver disease: Aspartate Aminotransferase (AST) and Alanine aminotransferase (ALT) > 3 × upper limit of normal (ULN) at screening, viral infection, nonviral infection, and liver cirrhosis;
  • Kidney disease: serum creatinine > 2.0 mg/dL at screening;
  • Heart disease: heart failure of ≥ The New York Heart Association class 3, arrhythmia or ischemic heart disease requiring treatment, and QTc interval > 450 ms on Electrocardiogram (ECG) at screening;
• Subjects with a history of uncontrolled diabetes (glycosylated hemoglobin > 8.5%).
• Subjects with hyperkalemia or serum potassium level > ULN of site reference ranges at screening.
• Subjects with severe respiratory disease or chronic generalized infectious disease.
• Subject who have a history of chronic infection or severe or life-threatening infection within 24 weeks before the baseline visit.
• Subject who are known to be infected by Human Immunodeficiency Virus, Hepatitis B, or Hepatitis C.
• Subject has a history of active tuberculosis or latent tuberculosis infection without treatment.
• Subject with mental disorder uncontrolled by drugs.
• Subject with chronic diarrhea, ulcerative stomatitis, gastric ulcer, or ulcerative colitis.
• Subject with genetic disorders including galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
• Subject with maculopathy, retinal disorders, or clinically significant eye diseases that may lead to visual disorder.
• Subject with bone marrow disorder, leukopenia, and blood cell disorder such as severe anemia and thrombocytopenia.
• Subject with a history of major surgery within 12-weeks before screening.
• Subject who were diagnosed with malignant tumors within 5 years before screening or who need treatment for malignant tumors diagnosed in the past.
• Patients with basal cell and squamous cell carcinomas of the skin or carcinoma in situ of the cervix uteri that has been excised and cured, may be included on the study at the discretion of the investigator.
• Female subject who is positive for the serum pregnancy test at Visit 1 among a woman of childbearing potential (WOCBP) (menopausal is defined as amenorrhea for at least one year) or not surgically sterile, or is not willing to use appropriate contraception during the study. Female subject trying to become pregnant or is currently pregnant or breast feeding.
• Male subject who donates sperm during the treatment period and for at least 30 days whichever is longer after the final study drug administration.
• Male subject with a pregnant or breastfeeding partner(s) who do not agree to remain abstinent or use a condom for the duration of the pregnancy, or for the time partner is breastfeeding, throughout the study period and for 30 days whichever is longer after the final study drug administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tacrolimus + biologics; Participants will receive tacrolimus daily for 12 weeks. In addition, each participant will be administered one of adalimumab, tocilizumab, or abatacept for 12 weeks.	Drug: tacrolimus; Administered orally; Other Names: Prograf; FK506; Biological: adalimumab; Administered as subcutaneous injection; Biological: tocilizumab; Administered by intravenous injection; Biological: abatacept; Administered by intravenous injection
Active Comparator: methotrexate + biologics; Participants will receive methotrexate weekly for 12 weeks. In addition, each participant will be administered one of adalimumab, tocilizumab, or abatacept for 12 weeks.	Biological: adalimumab; Administered as subcutaneous injection; Biological: tocilizumab; Administered by intravenous injection; Biological: abatacept; Administered by intravenous injection; Drug: methotrexate; Administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in disease activity score 28 (DAS28) erythrocyte sedimentation rate score (ESR) score at 12 weeks	DAS28-ESR will be calculated using data from tender joint count (TJC) (28 joints), swollen joint count (SJC) (28 joints), ESR and Subject's Global Assessment of Arthritis (SGA) with the formula; DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x SGA. High disease activity: DAS28 score exceeding 5.1 Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1 Low disease activity: DAS28 score of less than or equal to 3.2 If the DAS28 score is less than 2.6, the participant will be considered to be in DAS28 remission.	From baseline (week 1) to week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease activity score 28 (DAS28) erythrocyte sedimentation rate (ESR) rate score at 4 weeks	DAS28-ESR will be calculated using data from TJC (28 joints), SJC (28 joints), ESR and SGA with the formula; DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x SGA. High disease activity: DAS28 score exceeding 5.1 Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1 Low disease activity: DAS28 score of less than or equal to 3.2 If the DAS28 score is less than 2.6, the participant will be considered to be in DAS28 remission.	At 4 weeks
DAS28 (ESR) score at 8 weeks	DAS28-ESR will be calculated using data from TJC (28 joints), SJC (28 joints), ESR and SGA with the formula; DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x SGA. High disease activity: DAS28 score exceeding 5.1 Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1 Low disease activity: DAS28 score of less than or equal to 3.2 If the DAS28 score is less than 2.6, the participant will be considered to be in DAS28 remission.	At 8 weeks
DAS28 (ESR) score at 12 weeks	DAS28-ESR will be calculated using data from TJC (28 joints), SJC (28 joints), ESR and SGA with the formula; DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x SGA. High disease activity: DAS28 score exceeding 5.1 Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1 Low disease activity: DAS28 score of less than or equal to 3.2 If the DAS28 score is less than 2.6, the participant will be considered to be in DAS28 remission.	At 12 weeks
Change in DAS28 (ESR) score at 4 weeks	DAS28-ESR will be calculated using data from TJC (28 joints), SJC (28 joints), ESR and SGA with the formula; DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x SGA. High disease activity: DAS28 score exceeding 5.1 Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1 Low disease activity: DAS28 score of less than or equal to 3.2 If the DAS28 score is less than 2.6, the participant will be considered to be in DAS28 remission.	From baseline (week 1) to week 4
Change in DAS28 (ESR) score at 8 weeks	DAS28-ESR will be calculated using data from TJC (28 joints), SJC (28 joints), ESR and SGA with the formula; DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x SGA. High disease activity: DAS28 score exceeding 5.1 Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1 Low disease activity: DAS28 score of less than or equal to 3.2 If the DAS28 score is less than 2.6, the participant will be considered to be in DAS28 remission.	From baseline (week 1) to week 8
ACR 20 response rate	Percent of participants with American College of Rheumatology (ACR) 20 response rate The ACR20 response requires that all criteria from (1) to (3) be met compared with Week 0 (baseline); (1), Tender Joint Count (TJC) >= 20% reduction; (2), Swollen Joint Count (SJC) >= 20% reduction;(3) >= 20% improvement in three or more of the following five parameters - [1] subject's assessment of pain, [2] Subject's Global Assessment of Arthritis (SGA), [3] Physician's Global Assessment of Arthritis (PGA), [4] health assessment questionnaire-disability index (HAQ-DI), [5] acute phase reactant (erythrocyte sedimentation rate (ESR)).	At 12 weeks
ACR50 response rate	Percent of participants with ACR50 response rate The ACR50 response indicates a 50% improvement in all criteria used in the ACR20 assessment.	At 12 weeks
ACR70 response rate	Percent of participants with ACR70 response rate The ACR70 response indicates a 70% improvement in all criteria used in the ACR70 assessment.	At 12 weeks
Safety assessed by Adverse Events (AEs)	An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.	Up to 16 weeks
Safety assessed by incidence of serious adverse events (SAE)	Adverse Event (AE) is considered "serious" if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event.	Up to 16 weeks
Safety assessed by incidence of treatment emergent adverse events (TEAE)	Treatment Emergent Adverse Event (TEAE) is defined as any AE which starts, or worsens, after the first dose of study drug through 30 days after the last dose of study drug.	Up to 12 weeks
Number of participants with laboratory value abnormalities and/or adverse events (AEs)	Number of participants with potentially clinically significant laboratory values.	Up to 16 weeks
Number of participants with vital sign abnormalities and /or adverse events (AEs)	Number of participants with potentially clinically significant vital sign values.	Up to 16 weeks
Number of participants with physical exam abnormalities and/or adverse events (AEs)	Number of participants with potentially clinically significant physical exam values.	Up to 16 weeks

Collaborators and Investigators

• Sponsor: Astellas Pharma Korea, Inc.

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2019
• Primary Completion (Actual): June 16, 2020
• Study Completion (Actual): June 16, 2020

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: November 8, 2018
• First Posted (Actual): November 9, 2018

Study Record Updates

• Last Update Posted (Actual): August 30, 2021
• Last Update Submitted That Met QC Criteria: August 26, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Prograf; adalimumab; methotrexate; FK506; abatacept; tocilizumab; tacrolimus
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Immune Checkpoint Inhibitors; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Adalimumab; Methotrexate; Tacrolimus; Abatacept
• Other Study ID Numbers: 506-MA-3187

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

Drug and device information, study documents

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