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New Immunomodulatory Therapy Strategies in Chronic Reactive Arthritis

Primary Purpose

Reactive Arthritis

Status
Unknown status
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
interferon-gamma
infliximab
dmard
Sponsored by
Charite University, Berlin, Germany
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional educational/counseling/training trial for Reactive Arthritis focused on measuring reactive arthritis, trial, interferon-gamma, infliximab, chronic, tnf-blocker

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: definite classification of the arthritis as ReA enteric ReA is defined as an arthritis, which occurs within 4 weeks after a preceding symptomatic infection of the gut with enteric bacteria such as yersinia, salmonella, campylobacter jejuni, shigella. If no symptomatic preceding infection can be remembered the triggering enterobacterium has to be clearly identified by serology or stool culture. Other causes for a diarrhea like for example inflammatory bowel disease have to be eliminated. urogenital (chlamydia-triggered) ReA is defined as an arthritis, which occurs within 4 weeks after a symptomatic urogenital infection or an infection of the upper airways or if chlamydia can be clearly identified be serology or direct proof. disease duration > 12 months age 18 to 70 years active arthritis in at least one joint constant demand of NSAIDs intensity of pain > 4 on a visual analogue scale (VAS; 0 to 10) patients are allowed to have been treated with so-called conventional therapy (Sulphasalazine, Methotrexate etc.) or steroids i.a. before, but they have to be stopped 4 weeks before enrolled into the trial able to self-administer s.c. injections or have a caregiver who will do so women of child bearing potential must have a negative pregnancy test at study baseline and use an adequate, effective method of contraception (such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, vasectomised partner) for a duration of 6 months after stop of therapy. Sexual active men must use an accepted method of contraception for a duration of 6 months after stop of therapy. reading a normal chest/ lung x-ray, negative Mendel-Mantoux-skin test (10,0 TE) (both not older than 4 weeks). If Mendel-Mantoux-skin test is positive and / or there are hints for a healed up tuberculosis in the chest x-ray (latent tuberculosis) and the patient shall receive infliximab or etanercept an additional therapy with isoniazid 300 mg daily starting 4 weeks before first administration of infliximab or etanercept has to be given. signed informed consent Exclusion Criteria: female subjects who are pregnant or breast-feeding previous treatment with cytokines or anti-cytokines (biological agents) severe infections within the last 3 months history of opportunistic infections within the last 2 months (herpes zoster, cytomegaly virus-, pneumocystis carinii-infection) HIV-infection history of malignancy receipt of any live (attenuated) vaccines within last 30 days before screening visit previous diagnosis or signs of demyelinating diseases history of uncontrolled diabetes, unstable ischemic heart disease, active inflammatory bowel disease, active peptic ulcer disease, recent stroke, ongoing congestive heart failure, and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the protocol. history of cytopenia laboratory exclusions are: hemoglobin level < 8,5 g/dl, white blood cell count < 3.5 x109/l, platelet count < 125 x 109 /l, creatinine level > 175 µmol/ liver enzymes > 1,5, alkaline phosphatase >2 times the upper limit of normal, Quick > 50. clinical examination showing significant abnormalities of clinical relevance participation in trials of other investigational medications within 30 days of entering the study history or current evidence of abuse of "hard" drugs (e.g. cocaine/heroine) current medication with 7,5 mg or more Prednisolon daily

Sites / Locations

  • Charite Campus Benjamin Franklin, RheumatologyRecruiting

Outcomes

Primary Outcome Measures

change in intensity of pain (VAS pain, scale 0-10)
change in funcion (WOMAC)

Secondary Outcome Measures

decrease of CRP/ESR
change of cytokine response
change of DNA detection
number of swollen and tender joints
number of entheseal localisations
improvement of quality of life, "Short form 36" (SF-36)
BASDAI (disease activity index)
Reduction of NSAIDs
Patient's global (scale 0-10).
Physician's global (scale 0-10).

Full Information

First Posted
October 24, 2005
Last Updated
September 7, 2006
Sponsor
Charite University, Berlin, Germany
Collaborators
dfg
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1. Study Identification

Unique Protocol Identification Number
NCT00244179
Brief Title
New Immunomodulatory Therapy Strategies in Chronic Reactive Arthritis
Official Title
New Immunomodulatory Therapy Strategies in Chronic Reactive Arthritis: Immunostimulation Plus Antibiotic Versus Immunosuppression Plus Antibiotic Versus Conventional Standardtherapy
Study Type
Interventional

2. Study Status

Record Verification Date
September 2006
Overall Recruitment Status
Unknown status
Study Start Date
January 2003 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Charite University, Berlin, Germany
Collaborators
dfg

4. Oversight

5. Study Description

Brief Summary
to investigate, whether one of the two alternative therapy strategies (antibiotic plus immunostimulation versus antibiotic plus immunosuppression) in chronic reactive arthritis is therapeutical superior to conventionel standardtherapy (DMARD). to investigate, whether one or more of the different therapy strategies cause an altered detection of bacterial DNA in the joint or colon. to measure the antigen-specific and -unspecific immune response (predominantly t-cell response) during therapy and correlate it with the clinical course. to gain knowledge from these analyses and the clinical course concerning the pathogenesis and the point of attack for possible therapies in chronic reactive arthritis. to compare cytokine-profiles of CD4- and CD8-positive T-cells from patients treated with infliximab to those treated with etanercept.
Detailed Description
Studybackground Enteric reactive arthritis (ReA) is an extraintestinal manifestation of an infection of colon mucosa caused by enterobacteria. At least in the chronic courses of ReA a bacterial persistence can be assumed which is most likely to be located in colon mucosa or colon associated lymph nodes. The persistence of bacteria might be in consequence of an insufficient t-helper-immune-response. On the other hand the persistence of the pathogen itself could be harmless and the local immune-pathology could be caused by a hypersensitivity immune response The project in hand shall assess whether 1.) immune stimulation or immune suppression is the best therapy for chronic reactive arthritis and 2.) enteric reactive arthritis is based on bacterial persistence or a hypersensitivity immune response. By gaining these data we hope to be able to draw conclusions concerning the pathogenesis and therapies of other infections that affect the mucosa. ReA occurs after infection of the intestine (enteric ReA) or after urogenital infection caused by chlamydia (urogenital ReA). Both forms of ReA are pathogenetically und immunogenically closely related and are treated as one entity. Patients who are enrolled in the trial with enteric ReA (colon as possible location of bacterial persistence), not those with urogenital ReA (location of bacterial persistence not known) undergo colonoscopy before and after treatment-period to obtain colon biopsies for further work up. Patients with knee involvement (arthritis of knee) undergo arthroscopy before and after treatment-period to obtain synovial biopsies for further work up. Recently collected data form our group concerning patients with ankylosing spondylitis under therapy with infliximab or etanercept have shown that the potential of CD4- and CD8-positive t-cells to produce interferon gamma (IFN Gamma) or tumornecrosisfactor alpha (TNF-Alpha) after antigen-specific or -unspecific stimulation was distinct reduced under therapy with infliximab, whereas this potential under therapy with etanercept increased. In context with recently collected data concerning Crohn´s disease it can be assumed that by binding not only soluble TNF-Alpha but as well membrane-associated TNF-Alpha infliximab induces apoptosis of t-cells, whereas etanercept induces no apoptosis. These results could explain, why infliximab but not etanercept is effective in treating Crohn´s disease Furthermore the induction of apoptosis could explain why therapy with infliximab is associated with a higher incidence of tuberculosis compared to etanercept. By means of FACS (Fluorescence activated cell sorting) we want to examine, whether TNF-blocking agents in patients with chronic ReA induce a t-cell-suppression and compare the cytokine-pattern of CD4- and CD8-positive t-cells from patients treated with infliximab with the cytokine-pattern of CD4- and CD8-positive t-cells from patients treated with etanercept. The comparison of both therapies - infliximab and etanercept - is of special interest, because both TNF-blocking agents obviously have a different active profile as well as different side effects. Background for dosage Ciprofloxacin 2 x 500 mg p.o. daily is conventional therapy for treating infections with enterobacteria. Clinical trials with infliximab 5 mg/kg in patients suffering from ankylosing spondylitis have been successfully performed. Dosages of infliximab 1 - 10 mg/kg have been used in treating succesfully patients with rheumatoid arthritis. A dosage of 5 mg/kg was more effective than 1 mg/kg, but 10 mg/kg was only slightly better. Infliximab has been approved for the indication rheumatoid arthritis and ankylosing spondylitis. Clinical trials with etanercept 25 mg s.c. 2 x per week in patients suffering from ankylosing spondylitis and rheumatoid arthritis have been performed successfully and effectively. Etanercept has been approved for the indication ankylosing spondylitis, rheumatoid arthritis and psoriasic-arthritis. To treat patients suffering from tuberculosis who do not respond to conventional anti-tuberculosis-therapy IFN-g (interferon-gamma) 3 x 100 - 150 µg/week s.c. has been succesfully administered. In a clinical trial to assess the efficacy in rheumatoid arthritis IFN-g 50 µg was administered daily during the first three weeks and every other day in the last week. Patients who receive standard-therapy (Sulphasalazine, Methotrexate, Leflunomide) are treated with common dosages of these drugs that are deduced from the common treatment of rheumatoid arthritis. Background for selection of patients 80% of patients suffering from acute ReA heal up within 6 months. About 40% of patients have severe symptoms for more than 6 months and about 20% develop a chronic course of arthritis. These patients with chronic ReA are regrettably insufficiently treated with the available drugs (NSAID, Methotrexate, Sulphasalazine, Leflunomide). Patients who are enrolled in this trial have to have a definite chronic ReA (disease duration of at least 12 months), a joint pain of > 4 (visual analogue scale, 0-10), a constant demand of NSAID and an active arthritis affecting at least one joint.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Reactive Arthritis
Keywords
reactive arthritis, trial, interferon-gamma, infliximab, chronic, tnf-blocker

7. Study Design

Primary Purpose
Educational/Counseling/Training
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
interferon-gamma
Intervention Type
Drug
Intervention Name(s)
infliximab
Intervention Type
Drug
Intervention Name(s)
dmard
Primary Outcome Measure Information:
Title
change in intensity of pain (VAS pain, scale 0-10)
Title
change in funcion (WOMAC)
Secondary Outcome Measure Information:
Title
decrease of CRP/ESR
Title
change of cytokine response
Title
change of DNA detection
Title
number of swollen and tender joints
Title
number of entheseal localisations
Title
improvement of quality of life, "Short form 36" (SF-36)
Title
BASDAI (disease activity index)
Title
Reduction of NSAIDs
Title
Patient's global (scale 0-10).
Title
Physician's global (scale 0-10).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: definite classification of the arthritis as ReA enteric ReA is defined as an arthritis, which occurs within 4 weeks after a preceding symptomatic infection of the gut with enteric bacteria such as yersinia, salmonella, campylobacter jejuni, shigella. If no symptomatic preceding infection can be remembered the triggering enterobacterium has to be clearly identified by serology or stool culture. Other causes for a diarrhea like for example inflammatory bowel disease have to be eliminated. urogenital (chlamydia-triggered) ReA is defined as an arthritis, which occurs within 4 weeks after a symptomatic urogenital infection or an infection of the upper airways or if chlamydia can be clearly identified be serology or direct proof. disease duration > 12 months age 18 to 70 years active arthritis in at least one joint constant demand of NSAIDs intensity of pain > 4 on a visual analogue scale (VAS; 0 to 10) patients are allowed to have been treated with so-called conventional therapy (Sulphasalazine, Methotrexate etc.) or steroids i.a. before, but they have to be stopped 4 weeks before enrolled into the trial able to self-administer s.c. injections or have a caregiver who will do so women of child bearing potential must have a negative pregnancy test at study baseline and use an adequate, effective method of contraception (such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, vasectomised partner) for a duration of 6 months after stop of therapy. Sexual active men must use an accepted method of contraception for a duration of 6 months after stop of therapy. reading a normal chest/ lung x-ray, negative Mendel-Mantoux-skin test (10,0 TE) (both not older than 4 weeks). If Mendel-Mantoux-skin test is positive and / or there are hints for a healed up tuberculosis in the chest x-ray (latent tuberculosis) and the patient shall receive infliximab or etanercept an additional therapy with isoniazid 300 mg daily starting 4 weeks before first administration of infliximab or etanercept has to be given. signed informed consent Exclusion Criteria: female subjects who are pregnant or breast-feeding previous treatment with cytokines or anti-cytokines (biological agents) severe infections within the last 3 months history of opportunistic infections within the last 2 months (herpes zoster, cytomegaly virus-, pneumocystis carinii-infection) HIV-infection history of malignancy receipt of any live (attenuated) vaccines within last 30 days before screening visit previous diagnosis or signs of demyelinating diseases history of uncontrolled diabetes, unstable ischemic heart disease, active inflammatory bowel disease, active peptic ulcer disease, recent stroke, ongoing congestive heart failure, and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the protocol. history of cytopenia laboratory exclusions are: hemoglobin level < 8,5 g/dl, white blood cell count < 3.5 x109/l, platelet count < 125 x 109 /l, creatinine level > 175 µmol/ liver enzymes > 1,5, alkaline phosphatase >2 times the upper limit of normal, Quick > 50. clinical examination showing significant abnormalities of clinical relevance participation in trials of other investigational medications within 30 days of entering the study history or current evidence of abuse of "hard" drugs (e.g. cocaine/heroine) current medication with 7,5 mg or more Prednisolon daily
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
joachim sieper, prof.
Phone
0049 30 8445
Ext
4414
Email
joachim.sieper@charite.de
First Name & Middle Initial & Last Name or Official Title & Degree
henning c brandt, md
Phone
0049 30 8445
Ext
4414
Email
henning.brandt@charite.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
joachim sieper, prof.
Organizational Affiliation
charite, campus benjamin franklin, rheumatology, berlin
Official's Role
Principal Investigator
Facility Information:
Facility Name
Charite Campus Benjamin Franklin, Rheumatology
City
Berlin
ZIP/Postal Code
12200
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
joachim sieper, prof.
Phone
0049 30 8445
Ext
4414
Email
joachim.sieper@charite.de
First Name & Middle Initial & Last Name & Degree
henning c brandt, md
Phone
0049 30 8445
Ext
4414
Email
henning.brandt@charite.de
First Name & Middle Initial & Last Name & Degree
joachim sieper, prof
First Name & Middle Initial & Last Name & Degree
henning c brandt, md
First Name & Middle Initial & Last Name & Degree
hildrun haibel, md
First Name & Middle Initial & Last Name & Degree
in-ho song, md
First Name & Middle Initial & Last Name & Degree
Martin Rudwaleit, MD

12. IPD Sharing Statement

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New Immunomodulatory Therapy Strategies in Chronic Reactive Arthritis

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