Arthritis, Reactive, Reiter Disease
Conditions
Keywords
Chlamydia
Brief summary
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.
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.
Interventions
DRUGDoxycycline and Rifampin
doxycycline 100mg daily; rifampin 300mg daily (both for 6 months)
DRUGAzithromycin and Rifampin
Azithromycin 500mg daily for 5 days and then twice weekly; Rifampin 300mg daily (both for 6 months)
DRUGPlacebo
Methylcellulose
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
University of South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigate Whether a 6 Month Course of Combined Antibiotics Was Effective Treatment. | Month 6 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Erythrocyte Sedimentation Rate (ESR) | Baseline Month 1, 3, 6 and 9 | Comparison of mean ESR rates of combination antibiotic group vs placebo group at Baseline, Month 1, 3, 6 and 9 |
| hsCRP | Baseline, Month 1, 3, and 6 | Comparison of high sensitivity C-reactive protein measurement in combination antibiotic group vs placebo group at Baseline, Month 1, 3, and 6 |
| HAQ DI Score | Baseline, Month 1,3,6 and 9 | 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 |
| Number of Patients With a Complete Response (Resolution of All Symptoms) | Months 6 and 9 | 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. |
| Swollen 76 Joint Count (SJC) | Baseline, month 1,3,6 and 9 | 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. |
| 78 Tender Joint Count (TJC) | Baseline, Month 1, 3, 6 and 9 | 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. |
| PhGA Assessment | Baseline, month 1,3,6 and 9 | 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 |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin & Rifampin Participants will receive Azithromycin and Rifampin | 15 |
| Doxycycline & Rifampin Participants will receive Doxycycline and Rifampin | 12 |
| Placebo Participants will receive placebo | 15 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 | 5 |
Baseline characteristics
| Characteristic | Azithromycin & Rifampin | Doxycycline & Rifampin | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 12 Participants | 13 Participants | 40 Participants |
| Age, Continuous | 44.5 years STANDARD_DEVIATION 12 | 43.8 years STANDARD_DEVIATION 12.3 | 49 years STANDARD_DEVIATION 16.3 | 45.8 years STANDARD_DEVIATION 11.5 |
| Region of Enrollment Canada | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 15 participants | 12 participants | 14 participants | 41 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 6 Participants | 18 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 9 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 12 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 12 | 0 / 15 |
Outcome results
Primary
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.
Time frame: Month 6
Population: Efficacy and safety analyses were performed on an intent to treat(ITT) basis. Subjects who prematurely withdrew or who were lose to follow up for any reason were included in the ITT population and were considered nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azithromycin & Rifampin | Investigate Whether a 6 Month Course of Combined Antibiotics Was Effective Treatment. | 10 participants |
| Doxycycline & Rifampin | Investigate Whether a 6 Month Course of Combined Antibiotics Was Effective Treatment. | 7 participants |
| Placebo | Investigate Whether a 6 Month Course of Combined Antibiotics Was Effective Treatment. | 3 participants |
Comparison: Difference in the percentages of participants with response between all those who received combination therapy vs. placebop-value: 0.01Fisher Exact
Secondary
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.
Time frame: Baseline, Month 1, 3, 6 and 9
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Azithromycin & Rifampin | 78 Tender Joint Count (TJC) | Month 3 | 3.3 Tender Joints |
| Azithromycin & Rifampin | 78 Tender Joint Count (TJC) | Month 6 | 2.0 Tender Joints |
| Azithromycin & Rifampin | 78 Tender Joint Count (TJC) | Month 1 | 5.0 Tender Joints |
| Azithromycin & Rifampin | 78 Tender Joint Count (TJC) | Month 9 | 1.9 Tender Joints |
| Azithromycin & Rifampin | 78 Tender Joint Count (TJC) | Baseline | 7.4 Tender Joints |
| Doxycycline & Rifampin | 78 Tender Joint Count (TJC) | Month 9 | 10.9 Tender Joints |
| Doxycycline & Rifampin | 78 Tender Joint Count (TJC) | Baseline | 9.6 Tender Joints |
| Doxycycline & Rifampin | 78 Tender Joint Count (TJC) | Month 1 | 10.6 Tender Joints |
| Doxycycline & Rifampin | 78 Tender Joint Count (TJC) | Month 6 | 11.8 Tender Joints |
| Doxycycline & Rifampin | 78 Tender Joint Count (TJC) | Month 3 | 10.8 Tender Joints |
Secondary
Erythrocyte Sedimentation Rate (ESR)
Comparison of mean ESR rates of combination antibiotic group vs placebo group at Baseline, Month 1, 3, 6 and 9
Time frame: Baseline Month 1, 3, 6 and 9
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Azithromycin & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 1 | 17.8 millimeters/hour |
| Azithromycin & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 6 | 12.7 millimeters/hour |
| Azithromycin & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 3 | 17.7 millimeters/hour |
| Azithromycin & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 9 | 14.0 millimeters/hour |
| Azithromycin & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Baseline | 25.1 millimeters/hour |
| Doxycycline & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 9 | 18.4 millimeters/hour |
| Doxycycline & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Baseline | 18.9 millimeters/hour |
| Doxycycline & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 1 | 25.2 millimeters/hour |
| Doxycycline & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 3 | 19.8 millimeters/hour |
| Doxycycline & Rifampin | Erythrocyte Sedimentation Rate (ESR) | Month 6 | 17.0 millimeters/hour |
Secondary
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
Time frame: Baseline, Month 1,3,6 and 9
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Azithromycin & Rifampin | HAQ DI Score | Month 1 | 0.79 score on a scale |
| Azithromycin & Rifampin | HAQ DI Score | Month 6 | 0.71 score on a scale |
| Azithromycin & Rifampin | HAQ DI Score | Month 3 | 0.68 score on a scale |
| Azithromycin & Rifampin | HAQ DI Score | Month 9 | 0.57 score on a scale |
| Azithromycin & Rifampin | HAQ DI Score | Baseline | 0.84 score on a scale |
| Doxycycline & Rifampin | HAQ DI Score | Month 9 | 0.92 score on a scale |
| Doxycycline & Rifampin | HAQ DI Score | Baseline | 1.1 score on a scale |
| Doxycycline & Rifampin | HAQ DI Score | Month 1 | 0.92 score on a scale |
| Doxycycline & Rifampin | HAQ DI Score | Month 3 | 0.87 score on a scale |
| Doxycycline & Rifampin | HAQ DI Score | Month 6 | 0.99 score on a scale |
Secondary
hsCRP
Comparison of high sensitivity C-reactive protein measurement in combination antibiotic group vs placebo group at Baseline, Month 1, 3, and 6
Time frame: Baseline, Month 1, 3, and 6
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Azithromycin & Rifampin | hsCRP | Baseline | 1.07 mg/litre |
| Azithromycin & Rifampin | hsCRP | Month 1 | 0.56 mg/litre |
| Azithromycin & Rifampin | hsCRP | Month 3 | 0.63 mg/litre |
| Azithromycin & Rifampin | hsCRP | Month 6 | 0.41 mg/litre |
| Doxycycline & Rifampin | hsCRP | Month 6 | 0.34 mg/litre |
| Doxycycline & Rifampin | hsCRP | Baseline | 0.42 mg/litre |
| Doxycycline & Rifampin | hsCRP | Month 3 | 0.55 mg/litre |
| Doxycycline & Rifampin | hsCRP | Month 1 | 0.27 mg/litre |
Secondary
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.
Time frame: Months 6 and 9
Population: Patients randomized to combination antibiotics who believed that their disease went into complete remission during the trial
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin & Rifampin | Number of Patients With a Complete Response (Resolution of All Symptoms) | 5 Participants |
| Doxycycline & Rifampin | Number of Patients With a Complete Response (Resolution of All Symptoms) | 1 Participants |
| Placebo | Number of Patients With a Complete Response (Resolution of All Symptoms) | 0 Participants |
Secondary
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
Time frame: Baseline, month 1,3,6 and 9
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Azithromycin & Rifampin | PhGA Assessment | Month 1 | 35.2 units on a scale |
| Azithromycin & Rifampin | PhGA Assessment | Month 6 | 16.3 units on a scale |
| Azithromycin & Rifampin | PhGA Assessment | Month 3 | 23.2 units on a scale |
| Azithromycin & Rifampin | PhGA Assessment | Month 9 | 17.7 units on a scale |
| Azithromycin & Rifampin | PhGA Assessment | Baseline | 63.9 units on a scale |
| Doxycycline & Rifampin | PhGA Assessment | Month 9 | 43.8 units on a scale |
| Doxycycline & Rifampin | PhGA Assessment | Baseline | 60.2 units on a scale |
| Doxycycline & Rifampin | PhGA Assessment | Month 1 | 52.9 units on a scale |
| Doxycycline & Rifampin | PhGA Assessment | Month 3 | 49.4 units on a scale |
| Doxycycline & Rifampin | PhGA Assessment | Month 6 | 45.7 units on a scale |
Secondary
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.
Time frame: Baseline, month 1,3,6 and 9
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Azithromycin & Rifampin | Swollen 76 Joint Count (SJC) | Month 1 | 1.7 Swollen Joints |
| Azithromycin & Rifampin | Swollen 76 Joint Count (SJC) | Month 3 | 0.9 Swollen Joints |
| Azithromycin & Rifampin | Swollen 76 Joint Count (SJC) | Month 6 | 0.9 Swollen Joints |
| Azithromycin & Rifampin | Swollen 76 Joint Count (SJC) | Month 9 | 0.5 Swollen Joints |
| Azithromycin & Rifampin | Swollen 76 Joint Count (SJC) | Baseline | 4.1 Swollen Joints |
| Doxycycline & Rifampin | Swollen 76 Joint Count (SJC) | Month 6 | 5.2 Swollen Joints |
| Doxycycline & Rifampin | Swollen 76 Joint Count (SJC) | Month 1 | 3.5 Swollen Joints |
| Doxycycline & Rifampin | Swollen 76 Joint Count (SJC) | Baseline | 4.5 Swollen Joints |
| Doxycycline & Rifampin | Swollen 76 Joint Count (SJC) | Month 3 | 4.3 Swollen Joints |
| Doxycycline & Rifampin | Swollen 76 Joint Count (SJC) | Month 9 | 5.1 Swollen Joints |