Combination Antibiotic Treatment for Reactive Arthritis Caused by Chlamydia Bacteria

Phase 3 Trial to Assess the Efficacy of Long-term (6 Months) Combination Antibiotics as a Treatment for Chlamydia-induced Reactive Arthritis

Reactive arthritis, also known as Reiter's syndrome, is a form of arthritis that occurs as a reaction to an infection elsewhere in the body. It is characterized by inflammation of the joints, tendons, urogenital tract, and eyes. Pain and swelling in the knees, ankles, and feet are common. This study will determine the effectiveness of antibiotic therapy in treating people with chlamydia-induced reactive arthritis that has lasted for more than 6 months.

Study Overview

• Status: Completed
• Conditions: Arthritis, Reactive; Reiter Disease
• Intervention / Treatment: Drug: Azithromycin and Rifampin; Drug: Doxycycline and Rifampin; Drug: Placebo

Detailed Description

The initial infection that causes reactive arthritis is caused by one of two bacteria: Chlamydia trachomatis, which is usually acquired through sexual contact, or Chlamydia pneumoniae, which can cause respiratory infections. Most people recover fully from the initial flare of arthritis symptoms. However, about 20% of people with reactive arthritis experience long-lasting symptoms. In these individuals, the Chlamydia bacteria exist in a persistent metabolically active state within the joint tissue, even years after the initial exposure. The bacteria produce heat shock proteins (HSPs), which are thought to play a key role in the chronic persistent state of Chlamydia and which may stimulate the immune inflammatory response seen in reactive arthritis. This indicates the need for antimicrobial therapy that can reduce Chlamydia's HSP production and block its metabolism. The purpose of this study is to determine the effectiveness of long-term combination antibiotic therapy in treating people with chronic reactive arthritis. The study will use two different combinations of common antibiotics: doxycycline paired with rifampin and azithromycin paired with rifampin.

This study will entail 6 months of treatment followed by 3 months of follow-up. After screening, eligible participants will be randomly assigned to one of three treatment groups: rifampin once a day plus doxycycline twice a day; rifampin once a day plus azithromycin once a day for 5 days, then twice weekly; or placebo. Study visits will occur at baseline and Months 1, 3, 6, and 9. At all visits, participants will undergo an interview, a physical examination, and blood collection. They will also complete a questionnaire related to their symptoms and functional status. At screening and Month 6, a synovial biopsy may be performed. This will involve taking a sample of the tissue that lines the joints.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • University of Toronto
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meet the following European Spondyloarthropathy Study Group Criteria:

  1. inflammatory spinal pain OR
  2. synovitis AND

  3. one or more of the following:

     1. positive family history
     2. urethritis or cervicitis within 1 month prior to onset of arthritis
     3. buttock pain
     4. enthesopathy
     5. sacroiliitis
• Disease duration of at least 6 months
• Negative pregnancy test at study baseline and willing to use an effective method of contraception other than combined oral contraceptives for the duration of the study (for women of childbearing age)

Exclusion Criteria:

• Sensitivity or history of allergic reaction to rifampin, doxycycline, or azithromycin
• Currently taking any medications that may interact with the study medications, specifically rifampin
• Liver transaminases greater than or equal to two times the normal level
• Significant abnormalities in the complete blood count (CBC)
• Pregnant
• Current psoriasis
• Diagnosis of inflammatory bowel disease
• Diagnosis of ankylosing spondylitis
• Previous prolonged exposure to antibiotics (more than 2 weeks) as a potential treatment for reactive arthritis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithromycin and Rifampin; Participants received Azithromycin and Rifampin	Drug: Azithromycin and Rifampin; Azithromycin 500mg daily for 5 days and then twice weekly; Rifampin 300mg daily (both for 6 months); Other Names: Zithromax and Rifadin
Active Comparator: Doxycycline and Rifampin; Participants received Doxycycline and Rifampin	Drug: Doxycycline and Rifampin; doxycycline 100mg daily; rifampin 300mg daily (both for 6 months); Other Names: Atridox and Rifadin
Placebo Comparator: received placebo; Participants received placebo	Drug: Placebo; Methylcellulose; Other Names: Placebo effect

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigate Whether a 6 Month Course of Combined Antibiotics Was Effective Treatment.	The outcome measure was a composite endpoint. Participants had to meet 4/6 clinical criteria. 17/24 subjects randomized to combination antibiotics did respond to treatment when compared to 3/10 randomized to placebo.	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With a Complete Response (Resolution of All Symptoms)	Patients who completed full 6 months of treatment that reported feeling complete resolution of symptoms at month 6 visit and had no worsening of condition at the month 9 follow up visit.	Months 6 and 9
Erythrocyte Sedimentation Rate (ESR)	Comparison of mean ESR rates of combination antibiotic group vs placebo group at Baseline, Month 1, 3, 6 and 9	Baseline Month 1, 3, 6 and 9
hsCRP	Comparison of high sensitivity C-reactive protein measurement in combination antibiotic group vs placebo group at Baseline, Month 1, 3, and 6	Baseline, Month 1, 3, and 6
HAQ DI Score	Comparison of HAQ-DI score of combination antibiotic group vs placebo group at Baseline, Month 1,3,6 and 9 The Health assessment questionnaire disability index (HAQ-DI) is a questionnaire for the assessment of Rheumatoid Arthritis. The questionnaire is a patient reported outcome (PRO) which is usually self-administered by the patient There are 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are 2 or 3 questions for each section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section, i.e. if one question is scored 1 and another 2, then the score for the section is 2. In addition, if an aide or device is used or if help is required from another individual, then the minimum score for that section is 2. If the section score is already 2 or more then no modification is made. The 8 scores of the 8 sections are summed and divided	Baseline, Month 1,3,6 and 9
PhGA Assessment	Comparison of Physician's global assessment of disease activity (PhGA) using 0-100mm visual analog scale (VAS) , where 0 indicates the best possible outcome and 100 indicates the worst possible outcome, in combination antibiotic vs placebo groups at Baseline, month 1,3,6 and 9	Baseline, month 1,3,6 and 9
Swollen 76 Joint Count (SJC)	Comparison of modified Swollen Joint Counts between combination antibiotic and placebo groups at Baseline, Month 1, 3, 6 and 9. Determination of swelling in each of the 76 joints was determined by any swelling or absence of swelling. Each swollen joint receives a value of 1, ranging from 0-76 as a possible score.	Baseline, month 1,3,6 and 9
78 Tender Joint Count (TJC)	Comparison of modified 78 Tender Joint Count (TJC) between combination antibiotic and placebo groups at Baseline, Month 1, 3, 6 and 9. Determination of tender joing in each of the 78 joints was determined by examination. Each tender joint receives a value of 1, ranging from 0-78 as a possible score.	Baseline, Month 1, 3, 6 and 9

Collaborators and Investigators

• Sponsor: University of South Florida
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: John D. Carter, MD, University of South Florida

Publications and helpful links

General Publications

• Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol. 2004 Oct;31(10):1973-80.
• Carter JD, Espinoza LR, Inman RD, Sneed KB, Ricca LR, Vasey FB, Valeriano J, Stanich JA, Oszust C, Gerard HC, Hudson AP. Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum. 2010 May;62(5):1298-307. doi: 10.1002/art.27394.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: July 10, 2006
• First Submitted That Met QC Criteria: July 10, 2006
• First Posted (Estimate): July 12, 2006

Study Record Updates

• Last Update Posted (Actual): November 13, 2018
• Last Update Submitted That Met QC Criteria: November 8, 2018
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Chlamydia
• Additional Relevant MeSH Terms: Infections; Communicable Diseases; Sexually Transmitted Diseases; Joint Diseases; Musculoskeletal Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Spinal Diseases; Bone Diseases; Spondylarthropathies; Spondylarthritis; Spondylitis; Chlamydiaceae Infections; Sexually Transmitted Diseases, Bacterial; Arthritis, Infectious; Arthritis; Chlamydia Infections; Arthritis, Reactive; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Antiprotozoal Agents; Antiparasitic Agents; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antimalarials; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Doxycycline; Rifampin; Azithromycin
• Other Study ID Numbers: R21AR053646 (U.S. NIH Grant/Contract); 1R21AR053646-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No