Effect of Probenecid on Synovial Fluid ATP Levels in CPPD
Study Details
Study Description
Brief Summary
This study will investigate the hypothesis that probenecid, a medication currently used for gout, reduces levels of ATP in the joint fluid of patients with calcium pyrophosphate deposition disease (CPPD), another common type of crystal-related arthritis. There is good evidence that CPPD results from an excess of ATP in joints. The investigators will measure levels of ATP in joint fluid before and after 5 days of treatment with probenecid. This study will serve to rationalize larger studies of probenecid in CPPD.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Early Phase 1 |
Detailed Description
Objective: The objective of this study is to determine whether pharmacologic doses of the drug probenecid significantly decrease ATP and inorganic pyrophosphate (PPi) levels in the synovial fluid of patients with calcium pyrophosphate deposition disease (CPPD). The investigators have considerable evidence that synovial fluid ATP levels are high in patients with this disease and these high levels lead to calcium pyrophosphate (CPP) crystal formation which then produces acute and chronic arthritis. The investigators have identified the transmembrane protein known as ANK as the chief regulator of ATP levels in and around cartilage. Probenecid blocks function of ANK in vitro. The purpose of this study is to determine if probenecid used at normal doses are sufficient to block ANK function in vivo and whether this results in reduced ATP and PPi levels in synovial fluid.
Research design: This is a randomized un-controlled trial of probenecid vs. no drug in patients with a joint effusion and known CPPD.
Methodology: Power analysis based on an 80% chance to show a 20% difference in ATP levels in the treatment group resulted in a sample size of 20 patients in each group. Patients with known CPPD and a joint effusion will have an arthrocentesis to remove 2 ml of synovial fluid from their joint. Fluid will be sent to the investigators' research laboratory and ATP and PPi levels will be measured. Patients will be randomized to treatment with 2 grams/day of probenecid or no therapy. After 5 days, the remainder of the joint fluid will be removed and tested for ATP and PPi levels. The investigators will compare differences in ATP and PPi levels in the probenecid treated and the untreated group.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Probenecid These patients will receive 5 days of probenecid. |
Drug: Probenecid
Treatment
Other Names:
|
| No Intervention: No intervention These patients will receive no intervention. |
Outcome Measures
Primary Outcome Measures
- ATP Levels in Synovial Fluid [5 days]
The investigators will measure levels of ATP in synovial fluid from patients with CPPD before and after treatment with probenecid compared to patients receiving no therapy. ATP levels are measured with a standard bioluminescent assay.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age >21 years,
-
CPPD diagnosed by Ryan /McCarty criteria
-
Joint effusion in a shoulder or knee
Exclusion Criteria:
-
Inability to sign informed consent
-
Age <21 years
-
History of renal stones
-
Significant renal dysfunction (CKD >stage 2)
-
Blood dyscrasias
-
Current use of drugs which interact with probenecid
-
Concurrent gout
-
Active infection, including bacteremia and overlying cellulitis
-
Recent joint trauma
-
Intra-articular corticosteroids in the affected joint within three months
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Clement J. Zablocki VA Medical Center, Milwaukee, WI | Milwaukee | Wisconsin | United States | 53295-1000 |
Sponsors and Collaborators
- VA Office of Research and Development
Investigators
- Principal Investigator: Ann K Rosenthal, MD, Clement J. Zablocki VA Medical Center, Milwaukee, WI
Study Documents (Full-Text)
More Information
Publications
None provided.- IMMA-022-13F
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Probenecid | No Intervention |
|---|---|---|
| Arm/Group Description | These patients will receive 5 days of probenecid. Probenecid: Treatment | These patients will receive no intervention. |
| Period Title: Overall Study | ||
| STARTED | 3 | 5 |
| COMPLETED | 3 | 4 |
| NOT COMPLETED | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Probenecid | No Intervention | Total |
|---|---|---|---|
| Arm/Group Description | These patients will receive 5 days of probenecid. Probenecid: Treatment | These patients will receive no intervention. | Total of all reporting groups |
| Overall Participants | 3 | 5 | 8 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
77.6
(12.3)
|
68.4
(10.4)
|
71.8
(11.3)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
0
0%
|
0
0%
|
| Male |
3
100%
|
5
100%
|
8
100%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
3
100%
|
5
100%
|
8
100%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
3
100%
|
5
100%
|
8
100%
|
| ATP levels in synovial fluid at day 0 (nanomoles/ml) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [nanomoles/ml] |
1.2
(0.9)
|
4.5
(6.7)
|
2.85
(2.33)
|
Outcome Measures
| Title | ATP Levels in Synovial Fluid |
|---|---|
| Description | The investigators will measure levels of ATP in synovial fluid from patients with CPPD before and after treatment with probenecid compared to patients receiving no therapy. ATP levels are measured with a standard bioluminescent assay. |
| Time Frame | 5 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Two subjects ( one in probenecid and one in no intervention group) had no measurable ATP on the second aspirate, and one subject in the no intervention group did not have any synovial fluid on the second visit. |
| Arm/Group Title | Probenecid | no Intervention |
|---|---|---|
| Arm/Group Description | probenecid group after 5 days of drug | no intervention after 5 days |
| Measure Participants | 2 | 3 |
| Mean (Standard Deviation) [nanomoles/ml] |
4.4
(2.5)
|
31.4
(56.6)
|
Adverse Events
| Time Frame | 7 days | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Probenecid | No Intervention | ||
| Arm/Group Description | These patients will receive 5 days of probenecid. Probenecid: Treatment | These patients will receive no intervention. | ||
All Cause Mortality |
||||
| Probenecid | No Intervention | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/5 (0%) | ||
Serious Adverse Events |
||||
| Probenecid | No Intervention | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/5 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Probenecid | No Intervention | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/5 (0%) | ||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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.
Results Point of Contact
| Name/Title | Dr. Ann Rosenthal , MD ACOS/Research |
|---|---|
| Organization | Zablocki VA Medical Center |
| Phone | 414-384-2000 ext 41430 |
| ann.rosenthal@va.gov |
- IMMA-022-13F