Comparison of Effectiveness and Safety of Tofacitinib Versus Upadacitinib as Add-on to Methotrexate in Rheumatoid Arthritis

Effectiveness and Safety of Tofacitinib Versus Upadacitinib as Add-on to Methotrexate in Rheumatoid Arthritis; Comparative Clinical Study

The goal of this interventional study is to learn, whether Tofacitinib or upadacitinib is more effective in treating the patients of Rheumatoid Arthritis. It will also learn about the safety of these two agents. The main questions it aims to answer are:

• Which JAK inhibitor (Tofacitinib or Upadacitinib) is more effective to improve the disease activity of Rheumatoid arthritis in Pakistani population?
• What is the Disease Activity scores, ESR, CRP, RA factor level of patients?
• What are the side effects of both drugs, during the study time?

Participants:

• Of Group A will be taking 5mg Tofacitinib oral daily for 6 months along with 25mg of once weekly dose of oral Methotrexate, whereas of Group B will be taking 15mg Upadacitinib oral daily for 6 months along with 25mg of once weekly dose of oral methotrexate.
• Will Visit the clinic once at 3 months and then 6 months for checkups and tests
• Will Keep a diary of any infection, treatment taken, duration of infection
• Will inform the researcher about any unusual side effect during the study

Study Overview

• Status: Not yet recruiting
• Conditions: Rheumatoid Arthritis (RA)
• Intervention / Treatment: Drug: JAK inhibitor(tofacitinib/upadacitinib) as advised by the rheumatologist as add on to 25 mg methotrexate

Detailed Description

This study will be conducted in the Department of Pharmacology in collaboration with Rheumatology Department of Shaikh Zayed Medical Complex, Lahore.

The study population will consist of adult patients with diagnosis of RA on the basis of EULAR 2010 Classification Criteria: Moderate to severe disease activity indicated by DAS28 >3.2 and those with Inadequate response to methotrexate (MTX) characterized by Persistent active disease on ≥12 weeks of MTX treatment.

Sample size was estimated considering the following clinically significant variables: infection rate, thrombotic events, and cessation of treatment as a result of remission according to scientific publications. The maximum sample size was estimated among these methods in order to have adequate power.

If infection rate was considered as a key safety parameter, and taking into account the event rates of 0.7 and 1.2 per 100 patient-years for Tofacitinib and Upadacitinib, respectively22, the sample size would be 116 patients (58 per group) at 95% confidence interval and 80% power. In the case of thrombotic events with an assumed event rate of 0.2 and 0.4 per 100 patient-years23, the required sample size would be 100 patients (50 per group) at 95% confidence interval and 90% power.

Adult patients aged ≥18 years, regardless of gender will be included in the study. Whereas the following patients will not be included:

• Other autoimmune rheumatic disorders (SLE, psoriatic arthritis, AS, etc.)
• Administration of any biologic DMARD in the previous three months
• History of a serious infection (e.g., active tuberculosis or sepsis)
• Previous or existing history of recurrent infections or immunosuppressive status
• History of any malignancy in the last five years.
• Current chemotherapy, radiotherapy or intake of any genotoxic drug
• Severe liver impairment (e.g., ALT/AST >3× ULN)
• Severe renal impairment (e.g., estimated GFR <30 mL/min)
• Severe Haematological Abnormalities: Hb <8 g/dL, TLC <3,000 /mm³, Platelets <100,000 /mm³
• Past or present deep vein thrombosis or pulmonary embolism
• Pregnant or lactating women
• Women of reproductive age who are not practicing adequate contraception measures

Data collection procedure:

After the Evaluation by rheumatologist and prescribing the tofacitinib or Upadacitinib, an informed consent will be taken from the patient. Baseline investigations and history will be taken and added to the data collection sheet (Attached at the end). Patients will be followed vigilantly and then the clinical evaluation & biochemical investigations will be recorded at 3 months and 6 months.

Statistical Analysis:

All analyses will be conducted according to the ITT principle. A per protocol analysis will also be performed as sensitivity analysis. Two-sided p ≤ 0.05 will be considered statistically significant.

Continuous variable will be presented as mean±SD/median (IQR) and categorical variables will be presented as frequency (%).

Comparison of proportion between groups will be performed using the Chi-square/Fisher's exact test and effect sizes will be calculated as Risk difference, relative risk (RR) with 95% confidence interval.

Change in DAS28 will be compared by using Independent sample t-test/Mann Whitney-U test. Repeated measures analysis (mixed model/ANOVA) will be used to see the groups and time effect simultaneously. ACR responses will be analyzed by using Chi-square test Comparison of incidence rate between groups will be performed using Chi-square/Fisher's exact test and rates will be presented as proportion and/or incidences per 100 patient years.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Dr Sadia Maqsood Awan Assistant Professor Pharmacology FPGMI Lahore, MBBS, M.phil,MHPE; Phone Number: 03335032495; Email: sadia_maqsood_awan@yahoo.com
• Study Contact Backup: Name: Dr Mudassra yaseen HOD pharmacology FPGMI, Lahore, MBBS, M.phil, CMT, PhD; Phone Number: 03334162630; Email: Drmudassarayaseen@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Adult patients aged ≥18 years, regardless of gender

Exclusion Criteria:

• • Other autoimmune rheumatic disorders (SLE, psoriatic arthritis, AS, etc.)

  • Administration of any biologic DMARD in the previous three months
  • History of a serious infection (e.g., active tuberculosis or sepsis)
  • Previous or existing history of recurrent infections or immunosuppressive status
  • History of any malignancy in the last five years.
  • Current chemotherapy, radiotherapy or intake of any genotoxic drug
  • Severe liver impairment (e.g., ALT/AST >3× ULN)
  • Severe renal impairment (e.g., estimated GFR <30 mL/min)
  • Severe Haematological Abnormalities: Hb <8 g/dL, TLC <3,000 /mm³, Platelets <100,000 /mm³
  • Past or present deep vein thrombosis or pulmonary embolism
  • Pregnant or lactating women
  • Women of reproductive age who are not practicing adequate contraception measures

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: Tofacitinib; 5mg tofacitinib BD(oral) daily + 25mg Methotrexate oral once in a week	Drug: JAK inhibitor(tofacitinib/upadacitinib) as advised by the rheumatologist as add on to 25 mg methotrexate; There is no comparative study of tofacitinib with upadacitinib in Pakistan, as upadacitinib is recently been available here. There is no study yet in pakistan to compare the effectiveness and safety of these two JAK inhibitors in Pakistani population.
Experimental: Upadacitinib; 15mg Upadacitinib OD(oral) daily + 25mg Methotrexate oral once in a week	Drug: JAK inhibitor(tofacitinib/upadacitinib) as advised by the rheumatologist as add on to 25 mg methotrexate; There is no comparative study of tofacitinib with upadacitinib in Pakistan, as upadacitinib is recently been available here. There is no study yet in pakistan to compare the effectiveness and safety of these two JAK inhibitors in Pakistani population.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Disease activity score(DAS 28)	Change in Disease Activity Score-28 ranges from 0 to 10, with ≤2.6 indicates remission, 2.6-3.2 low disease activity, ≥ 3.2-5.1 moderate activity, ≥ 5.1 high disease activity.	From enrollment in the study to 6 months of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency & severity of opportunistic infections	Severity of opportunistic infections according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which classifies adverse events from Grade 1 (mild) to Grade 5 (death)21.; Grade 1 (Mild): Asymptomatic or mild infection; no or minimal intervention required; Grade 2 (Moderate): Symptomatic infection requiring medical treatment (e.g., oral antibiotics/antivirals); no hospitalization; Grade 3 (Severe): Severe infection requiring hospitalization or intravenous therapy; Grade 4 (Life-threatening): Life-threatening infection requiring urgent intervention/ICU care; Grade 5: Death related to infection	From enrollment in the study to 6 months of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid profile	Change in Lipid Profile; Total cholesterol >200 mg/dL , LDL >130 mg/dL ,HDL <40 mg/dL, Triglycerides >150 mg/dL	From enrollment in the study to 6 months of treatment

Collaborators and Investigators

• Sponsor: Sheikh Zayed Federal Postgraduate Medical Institute

Study record dates

Study Major Dates

• Study Start (Estimated): July 5, 2026
• Primary Completion (Estimated): March 5, 2027
• Study Completion (Estimated): May 10, 2027

Study Registration Dates

• First Submitted: April 29, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Skin and Connective Tissue Diseases; Arthritis, Rheumatoid; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pterins; Pteridines; Aminopterin; Methotrexate; upadacitinib
• Other Study ID Numbers: TERC/SC/INT/2026/47

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No