Evaluating the Effect of Digoxin and Ursodeoxycholic Acid in Patients With Rheumatoid Arthritis

NCT04834557 | Completed Phase 2

• 1 other identifier: Treating Rheumatoid Arthritis
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to investigate the potential therapeutic effects of the cardiac glycoside digoxin and the secondary bile acid ursodeoxycholic acid (UDCA) on synovial inflammation and disease activity when administered as add-on treatments to the current DMARDs treatments for rheumatoid arthritis patients with variant disease activity.

Conditions

Rheumatoid Arthritis

Keywords

Rheumatoid arthritis; Digoxin; Ursodeoxycholic acid; Synovial inflammation; leukocyte infiltration; Autoimmune diseases; Th17 and Treg cells; Synovial hypoxia

Outcome Measures

Primary Outcomes (2)

• Changes from Baseline in Clinical Disease Activity Index (CDAI) Score

  To evaluate the effect of the use of digoxin and UDCA as an add-on therapy in patients with rheumatoid arthritis by evaluating the change from baseline in the clinical findings as measured by Clinical Disease Activity Index (CDAI) scores. A lower CDAI score from Baseline would mean improvement in disease activity and an increase in CDAI score from Baseline would mean an increase in disease activity or a worsening in disease activity. Scores: 0.0-2.8 = Range for Remission; 2.9-10.0 = Range for Low disease activity; 10.1-22.0 Range for Moderate disease activity; 22.1-76 Range for High disease activity. Total range is from 0-100, with the high scores representing high disease activity.

  Baseline, after 12 weeks, after 24 weeks

• Changes in C-Reactive Protein (CRP) Values and Erythrocyte Sedimentation Rates (ESR)

  C- reactive Protein (CRP) values and Erythrocyte Sedimentation Rate (ESR) will be made at baseline and after 12 as well as 24 weeks to determine the number of patients whose test result improved or worsened CRP value (normal range \<1.0 mg/dl). ESR (normal range 0-28 mm/hr) . If the value is increased, the disease activity worsened. If the value is reduced the disease activity is improved.

  Baseline, after 12 weeks, after 24 weeks

Secondary Outcomes (2)

• Changes from baseline Measurement of IL-17A and HIF-1α at 12 and 24 weeks

  Baseline, after 12 weeks, after 24 weeks

• Numbers of participants with treatment-related adverse events

  Baseline, after 12 weeks, after 24 weeks

Study Arms (3)

Control

PLACEBO COMPARATOR

Participants in this arm will receive Placebo with the current DMARDs treatments for rheumatoid arthritis for 24 weeks.

Drug: Placebo

Digoxin

EXPERIMENTAL

Participants in this arm will receive digoxin 0.25 mg every other day + DMARDs for 24 weeks.

Drug: Digoxin 0.25 mg

Ursodeoxycholic acid (UDCA)

EXPERIMENTAL

Participants in this arm will receive ursodeoxycholic acid (UDCA) 500 mg/day + DMARDs for 24 weeks.

Drug: Ursodeoxycholic acid (UDCA) 500 mg

Interventions

Placebo DRUG

Placebo will be administered to the control group for 24 weeks as an add-on treatment to the current DMARDs treatments for rheumatoid arthritis.

Control

Digoxin 0.25 mg DRUG

All subjects will receive digoxin administered at 0.25 mg every other day for 24 weeks as an add-on treatment to the current DMARDs treatments for rheumatoid arthritis.

Digoxin

Ursodeoxycholic acid (UDCA) 500 mg DRUG

All subjects will receive Ursodeoxycholic acid (UDCA) administered at 500 mg/day for 24 weeks as an add-on treatment to the current DMARDs treatments for rheumatoid arthritis.

Ursodeoxycholic acid (UDCA)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosed with rheumatoid arthritis according to the ACR/EULAR 2010 criteria.
• Having active rheumatoid arthritis disease activity (the 28-joint disease activity score \[DAS28\] according to the CRP formula \> 2.6).
• Aged between 18 and 80 years.
• With clear consciousness and able to cooperate with this study.
• Personal willingness and ability to comply with the study follow-up schedule and other requirements of the study protocol.
• Both male and female will be included
• All patients receiving non-biological drugs will be also included.
• Sign an informed consent for the clinical study.

You may not qualify if:

• Pregnant or planning to be pregnant and breast-feeding women
• Patients suffering from any chronic diseases
• Patients with other autoimmune diseases, such as systemic lupus erythematosus, Sjogren's syndrome and mixed connective tissue disease.
• Patients who have a diagnosis of any other inflammatory arthritis (e.g., psoriatic arthritis or ankylosing spondylitis).
• Patients with a history of, or suspected, demyelinating disease of the central nervous system (e.g. multiple sclerosis or optic neuritis).
• Patients with a current or recent history of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, or cerebral disease.
• Patients treated with biological therapy such as TNF-α or IL-1β antagonists.
• Patients with infectious or inflammatory diseases, endocrine disorders, any past or current psychiatric or neurological diseases.
• Patients with cardiovascular diseases such as arrhythmias and acute myocardial infarction.
• Patients with electrolyte disturbances (such as hypokalemia, hypomagnesemia, and hypercalcemia) could potentially elevate the risk of digoxin toxicity.
• Patients with clinically significant hepatic and renal dysfunction or impairment.
• Alcohol abuse
• Patients with evidence of viral (HBV or HCV), autoimmune hepatitis, and decompensated liver disease.
• Patients with cancer currently diagnosed or in medical history, if no recovery was achieved.
• Patients who are allergic to digoxin or Ursodeoxycholic acid (UDCA)

Sponsors & Collaborators

• Tanta University: lead

Study Sites (1)

Menoufia University Hospital

Shibīn al Kawm, Egypt

Location

Related Publications (7)

• Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81. doi: 10.1002/art.27584.

  PMID: 20872595 BACKGROUND

• Neogi T, Aletaha D, Silman AJ, Naden RL, Felson DT, Aggarwal R, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Khanna D, Kvien TK, Laing T, Liao K, Mease P, Menard HA, Moreland LW, Nair R, Pincus T, Ringold S, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G; American College of Rheumatology; European League Against Rheumatism. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report. Arthritis Rheum. 2010 Sep;62(9):2582-91. doi: 10.1002/art.27580.

  PMID: 20872596 BACKGROUND

• Hua S, Dias TH. Hypoxia-Inducible Factor (HIF) as a Target for Novel Therapies in Rheumatoid Arthritis. Front Pharmacol. 2016 Jun 27;7:184. doi: 10.3389/fphar.2016.00184. eCollection 2016.

  PMID: 27445820 BACKGROUND

• Lee EJ, Kwon JE, Park MJ, Jung KA, Kim DS, Kim EK, Lee SH, Choi JY, Park SH, Cho ML. Ursodeoxycholic acid attenuates experimental autoimmune arthritis by targeting Th17 and inducing pAMPK and transcriptional corepressor SMILE. Immunol Lett. 2017 Aug;188:1-8. doi: 10.1016/j.imlet.2017.05.011. Epub 2017 May 21.

  PMID: 28539269 BACKGROUND

• O'Dwyer AM, Lajczak NK, Keyes JA, Ward JB, Greene CM, Keely SJ. Ursodeoxycholic acid inhibits TNFalpha-induced IL-8 release from monocytes. Am J Physiol Gastrointest Liver Physiol. 2016 Aug 1;311(2):G334-41. doi: 10.1152/ajpgi.00406.2015. Epub 2016 Jun 23.

  PMID: 27340129 BACKGROUND

• Saeed H, Mateen S, Moin S, Khan AQ, Owais M. Cardiac glycoside digoxin ameliorates pro-inflammatory cytokines in PBMCs of rheumatoid arthritis patients in vitro. Int Immunopharmacol. 2020 May;82:106331. doi: 10.1016/j.intimp.2020.106331. Epub 2020 Feb 24.

  PMID: 32106058 BACKGROUND

• El-Mahdy NA, Tadros MG, El-Masry TA, Binsaleh AY, Alsubaie N, Alrossies A, Abd Elhamid MI, Osman EY, Shalaby HM, Saif DS. Efficacy of the cardiac glycoside digoxin as an adjunct to csDMARDs in rheumatoid arthritis patients: a randomized, double-blind, placebo-controlled trial. Front Pharmacol. 2024 Oct 21;15:1445708. doi: 10.3389/fphar.2024.1445708. eCollection 2024.

  PMID: 39498340 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid; Autoimmune Diseases

Interventions

Digoxin; Ursodeoxycholic Acid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates; Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Cholanes

Study Officials

• Nageh Ahmed El-Mahdy, Professor

  Professor of Pharmacology and Toxicology Faculty of Pharmacy, Tanta University

  STUDY CHAIR

• Medhat Ismail Abdel Hamid, Professor

  Professor of Pharmacology and Toxicology Faculty of Medicine, Al-Azhar University

  STUDY CHAIR

• Dalia Salah Seif, PHD

  Associate Professor of Physical Medicine, Rheumatology and Rehabilitation Faculty of Medicine, Menoufyia University

  STUDY DIRECTOR

• Enass Yousef Osman, PHD

  Lecturer of Pharmacology and toxicology, Faculty of Pharmacy, Tanta University

  STUDY DIRECTOR

• Mariam George Tadros Bolous, Master

  Assistant Lecturer of Clinical pharmacy, Faculty of Pharmacy, Sinai University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Lecturer of Clinical pharmacy, Faculty of Pharmacy, Sinai University

Model Details: This study is a randomized controlled prospective study

Study Record Dates

• First Submitted: April 2, 2021
• First Posted: April 8, 2021
• Study Start: November 1, 2021
• Primary Completion: May 18, 2022
• Study Completion: September 30, 2022
• Last Updated: March 22, 2023

Record last verified: 2023-03

Locations

EG (1)