Effect of Probenecid on Synovial Fluid ATP Levels in CPPD

ANK-dependent ATP Efflux Causes Calcium Pyrophosphate Deposition in Cartilage

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.

Study Overview

• Status: Completed
• Conditions: Calcium Pyrophosphate Deposition Disease
• Intervention / Treatment: Drug: Probenecid

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 Type: Interventional
• Enrollment (Actual): 8
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53295-1000
      • Clement J. Zablocki VA Medical Center, Milwaukee, WI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probenecid; These patients will receive 5 days of probenecid.	Drug: Probenecid; Treatment; Other Names: uricosuric
No Intervention: No intervention; These patients will receive no intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ATP Levels in Synovial Fluid	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.	5 days

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Ann K Rosenthal, MD, Clement J. Zablocki VA Medical Center, Milwaukee, WI

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2014
• Primary Completion (Actual): April 8, 2021
• Study Completion (Actual): April 8, 2021

Study Registration Dates

• First Submitted: September 16, 2014
• First Submitted That Met QC Criteria: September 16, 2014
• First Posted (Estimate): September 18, 2014

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 22, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Probenecid; ATP; Chondrocalcinosis
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Arthritis; Crystal Arthropathies; Chondrocalcinosis; Antirheumatic Agents; Gout Suppressants; Renal Agents; Uricosuric Agents; Probenecid
• Other Study ID Numbers: IMMA-022-13F

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No