Combination Antibiotic Treatment for Reactive Arthritis Caused by Chlamydia Bacteria

• Sponsor: University of South Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT00351273
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 42
• Locations: 3
• Arms: 3
• Duration (Months): 28.1
• Patients Per Site: 14
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Arthritis, Reactive; Reiter Disease	Drug: Doxycycline and Rifampin; Drug: Azithromycin and Rifampin; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3 Trial to Assess the Efficacy of Long-term (6 Months) Combination Antibiotics as a Treatment for Chlamydia-induced Reactive Arthritis
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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

4. 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

5. 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

6. 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.

7. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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:

4. positive family history

5. urethritis or cervicitis within 1 month prior to onset of arthritis

6. buttock pain

7. enthesopathy

8. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Florida	Tampa	Florida	United States	33612
2	Louisiana State University	New Orleans	Louisiana	United States	70112
3	University of Toronto	Toronto	Ontario	Canada	M5T 2S8

Sponsors and Collaborators

• University of South Florida
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: John D. Carter, MD, University of South Florida

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: University of South Florida
• ClinicalTrials.gov Identifier: NCT00351273
• Other Study ID Numbers: R21AR053646; R21AR053646; 1R21AR053646-01
• First Posted: Jul 12, 2006
• Last Update Posted: Nov 13, 2018
• Last Verified: Jun 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of South Florida: Chlamydia
• Additional relevant MeSH terms: Chlamydia Infections; Arthritis, Reactive; Arthritis; Azithromycin; Doxycycline; Rifampin

Study Results

Participant Flow

Arm/Group Title	Azithromycin & Rifampin	Doxycycline & Rifampin	Placebo
Arm/Group Description	Participants will receive Azithromycin and Rifampin	Participants will receive Doxycycline and Rifampin	Participants will receive placebo
Period Title: Overall Study
STARTED	15	12	15
COMPLETED	14	10	10
NOT COMPLETED	1	2	5

Baseline Characteristics

Arm/Group Title	Azithromycin & Rifampin	Doxycycline & Rifampin	Placebo	Total
Arm/Group Description	Participants will receive Azithromycin and Rifampin	Participants will receive Doxycycline and Rifampin	Participants will receive placebo	Total of all reporting groups
Overall Participants	15	12	15	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	15 100%	12 100%	13 86.7%	40 95.2%
>=65 years	0 0%	0 0%	2 13.3%	2 4.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.5 (12)	43.8 (12.3)	49 (16.3)	45.8 (11.5)
Sex: Female, Male (Count of Participants)
Female	7 46.7%	5 41.7%	6 40%	18 42.9%
Male	8 53.3%	7 58.3%	9 60%	24 57.1%
Region of Enrollment (participants) [Number]
United States	15 100%	12 100%	14 93.3%	41 97.6%
Canada	0 0%	0 0%	1 6.7%	1 2.4%

Outcome Measures

1. Primary Outcome

Title	Investigate Whether a 6 Month Course of Combined Antibiotics Was Effective Treatment.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Azithromycin & Rifampin	Doxycycline & Rifampin	Placebo
Arm/Group Description	Participants will receive Azithromycin and Rifampin	Participants will receive Doxycycline and Rifampin	Participants will receive placebo
Measure Participants	14	10	10
Number [participants]	10 66.7%	7 58.3%	3 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azithromycin & Rifampin, Doxycycline & Rifampin, Placebo
	Comments	Difference in the percentages of participants with response between all those who received combination therapy vs. placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	40.8
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients With a Complete Response (Resolution of All Symptoms)
Description	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

Outcome Measure Data

Analysis Population Description

Patients randomized to combination antibiotics who believed that their disease went into complete remission during the trial

Arm/Group Title	Azithromycin and Rifampin	Doxycycline and Rifampin	Received Placebo
Arm/Group Description	Participants received Azithromycin and Rifampin Azithromycin and Rifampin: Azithromycin 500mg daily for 5 days and then twice weekly; Rifampin 300mg daily (both for 6 months)	Participants received Doxycycline and Rifampin Doxycycline and Rifampin: doxycycline 100mg daily; rifampin 300mg daily (both for 6 months)	Participants received placebo Placebo: Methylcellulose
Measure Participants	10	7	3
Count of Participants [Participants]	5 33.3%	1 8.3%	0 0%

3. Secondary Outcome

Title	Erythrocyte Sedimentation Rate (ESR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Antibiotic	Placebo
Arm/Group Description	Group who recieved either combination of antibiotics	Group who recieved placebo
Measure Participants	27	15
Baseline	25.1	18.9
Month 1	17.8	25.2
Month 3	17.7	19.8
Month 6	12.7	17.0
Month 9	14.0	18.4

4. Secondary Outcome

Title	hsCRP
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Antibiotic	Placebo
Arm/Group Description	Group who recieved either combination of antibiotics	Group who recieved placebo
Measure Participants	27	15
Baseline	1.07	0.42
Month 1	0.56	0.27
Month 3	0.63	0.55
Month 6	0.41	0.34

5. Secondary Outcome

Title	HAQ DI Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Antibiotic	Placebo
Arm/Group Description	Group who recieved either combination of antibiotics	Group who recieved placebo
Measure Participants	27	15
Baseline	0.84	1.1
Month 1	0.79	0.92
Month 3	0.68	0.87
Month 6	0.71	0.99
Month 9	0.57	0.92

6. Secondary Outcome

Title	PhGA Assessment
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Antibiotic	Placebo
Arm/Group Description	Group who recieved either combination of antibiotics	Group who recieved placebo
Measure Participants	27	15
Baseline	63.9	60.2
Month 1	35.2	52.9
Month 3	23.2	49.4
Month 6	16.3	45.7
Month 9	17.7	43.8

7. Secondary Outcome

Title	Swollen 76 Joint Count (SJC)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Antibiotic	Placebo
Arm/Group Description	Group who recieved either combination of antibiotics	Group who recieved placebo
Measure Participants	27	15
Baseline	4.1	4.5
Month 1	1.7	3.5
Month 3	0.9	4.3
Month 6	0.9	5.2
Month 9	0.5	5.1

8. Secondary Outcome

Title	78 Tender Joint Count (TJC)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Antibiotic	Placebo
Arm/Group Description	Group who recieved either combination of antibiotics	Group who recieved placebo
Measure Participants	27	15
Baseline	7.4	9.6
Month 1	5.0	10.6
Month 3	3.3	10.8
Month 6	2.0	11.8
Month 9	1.9	10.9

Adverse Events

Arm/Group Title	Azithromycin & Rifampin		Doxycycline & Rifampin		Placebo
Arm/Group Description	Participants will receive Azithromycin and Rifampin		Participants will receive Doxycycline and Rifampin		Participants will receive placebo
All Cause Mortality
	Azithromycin & Rifampin		Doxycycline & Rifampin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Azithromycin & Rifampin		Doxycycline & Rifampin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/12 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Azithromycin & Rifampin		Doxycycline & Rifampin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/12 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.