Chikungunya Arthritis in the Americas

• ClinicalTrials.gov Identifier: NCT02463968
• Recruitment Status: Completed
• First Posted: June 4, 2015
• Last Update Posted: June 27, 2017
• Sponsor: George Washington University
• Collaborators: Global Disease Research; United States Army Medical Research Institute of Infectious Diseases; Broad Institute; Allied Research Society
• Information provided by (Responsible Party): Aileen Chang, George Washington University

Tracking Information

• First Submitted Date: May 29, 2015
• First Posted Date: June 4, 2015
• Last Update Posted Date: June 27, 2017
• Actual Study Start Date: August 27, 2016
• Actual Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2015)

Presence of chikungunya virus in the synovial fluid of chronic arthritis patients [ Time Frame: Participants will be followed for the duration of a clinic visit which has an expected average time of 1-2 hours ]

Assess the joint for persistence of the chikungunya virus

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 4, 2015)

• Disease Severity Measured by Disease Activity Score-28 Validated Composite Measure [ Time Frame: Participants will be followed for the duration of a clinic visit which has an expected average time of 1-2 hours ]
  Disease Severity Measured by Disease Activity Score-28 Validated Survey that is a series of questions about disease severity that gives a composite score for arthritis severity and C-reactive protein level measured in mg/L.
• Inflammatory Cytokine Levels [ Time Frame: Participants will be followed for the duration of a clinic visit which has an expected average time of 1-2 hours ]
  Inflammatory cytokines such as IL-10, IL-6, GM-CSF, TNF, IL-2, IL-4, and IL-13 in units of pg/ml will be assessed and compared between acute and chronic patients.

Original Secondary Outcome Measures (submitted: June 3, 2015)

• Disease Severity Measured by Disease Activity Score-28 Validated Survey and C-reactive protein level. [ Time Frame: Participants will be followed for the duration of a clinic visit which has an expected average time of 1-2 hours ]
  Disease Severity Measured by Disease Activity Score-28 Validated Survey that is a series of questions about disease severity that gives a score for arthritis severity and C-reactive protein level measured in mg/L.
• Inflammatory Cytokine Levels [ Time Frame: Participants will be followed for the duration of a clinic visit which has an expected average time of 1-2 hours ]
  Inflammatory cytokines such as IL-10, IL-6, GM-CSF, TNF, IL-2, IL-4, and IL-13 in units of pg/ml will be assessed and compared between acute and chronic patients.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Chikungunya Arthritis in the Americas
• Official Title: A Pilot Study of the Pathogenesis of Chikungunya Arthritis in the Americas
• Brief Summary: Chikungunya is a mosquito-borne viral illness that leads to chronic joint pain in approximately one half of patients. The mechanisms leading to long term arthritis in humans has not been well established. There is some evidence from animal studies that activated macrophages with persistent viral infection may play a role in chronic arthritis however these mechanisms have not yet been identified in humans. It is hypothesized that activated macrophages harboring persistent active chikungunya virus are responsible for chronic arthritis and joint pain in patients. The focus of this proposal is to evaluate synovial fluid and blood for direct viral persistence and activated macrophages that may clarify the mechanism of inflammatory injury. The results of this study will be directly applicable to tailoring trials of therapeutics.
• Detailed Description: Chikungunya is rapidly spreading throughout the Americas and causes debilitating chronic arthritis in approximately one fourth of patients. There is currently no standard treatment for chikungunya arthritis, and the mechanisms leading to this chronic arthritis are unclear. Further characterization of the disease pathophysiology is needed in order to guide evaluation of potential therapeutics. It is hypothesized that chronic chikungunya arthritis is due to persistence of active virus in the synovial fluid where macrophages serve as a viral reservoir. The predominance of activated macrophages in persistently infected tissue and the presence of viral genome within these macrophages in non-human primates makes our hypothesis plausible. To test this hypothesis, this study has three Specific Aims. Aim 1, describe host characteristics affect susceptibility to severe or persistent arthritis. Aim 2, determine if chikungunya virus persists in synovial fluid and synovial fluid macrophages in humans as shown in non-human primates. Aim 3, investigate how these macrophages may be activated and modulated by cytokines. To date, these pathophysiologic factors have not been well characterized in humans. Information gained from this study can directly lead to recommendations for the further evaluation of antiviral versus immune modulating medications.
• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Cross-Sectional
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Cohort 1 CHRONIC CHIKUNGUNYA: Blood samples include one cell preparation tube with Sodium Citrate will be collected for cytokine analysis by mesoscale and mass spectrophotometer analyses, one blood RNA tube for PCR and one blood DNA tube for HLA typing. Synovial fluid samples will be drawn for chronic patients with a knee effusion with one CPT and a blood RNA tube.

Cohort 2 ACUTE CHIKUNGUNYA: Blood samples include one CPT for evaluation of biomarkers by mass spectrophotometry, two blood RNA tubes drawn for mass spectrophotometry of viral signaling and genomic analysis and one blood DNA tube for genomic analysis.

Cohort 3 HEALTHY CONTROLS: Participants will have one blood RNA tube, one blood DNA tube, and one CPT tube drawn as controls for the other measurements.

• Sampling Method: Non-Probability Sample
• Study Population: Patients living in Baranquilla, Colombia during the study period.

Condition

• Chikungunya
• Arthritis

Intervention

• Procedure: Venipuncture for blood draw
  Samples will include blood. Blood samples will be collected via venipuncture.This is a part of standard of care of new new onset joint effusion and is not a novel intervention.
• Procedure: Arthrocentesis for synovial fluid draw
  Samples will include joint fluid analysis in participants with a knee effusion. Synovial fluid will be drawn via arthrocentesis under sterile conditions. This is a part of standard of care of new new onset joint effusion and is not a novel intervention.

Study Groups/Cohorts

• CHRONIC CHIKUNGUNYA
  Twenty participants with chronic chikungunya defined as continued knee joint effusion at least three months after diagnosis of chikungunya will be enrolled in the study.
  Interventions:

  • Procedure: Venipuncture for blood draw
  • Procedure: Arthrocentesis for synovial fluid draw
• ACUTE CHIKUNGUNYA
  Ten participants with acute chikungunya defined as clinical symptoms of chikungunya with acute fever and joint pain within 10 days the onset of symptoms.
  Intervention: Procedure: Venipuncture for blood draw
• HEALTHY CONTROLS
  Five healthy controls will have only blood drawn once.
  Intervention: Procedure: Venipuncture for blood draw

• Publications *: Chang AY, Martins KAO, Encinales L, Reid SP, Acuña M, Encinales C, Matranga CB, Pacheco N, Cure C, Shukla B, Ruiz Arteta T, Amdur R, Cazares LH, Gregory M, Ward MD, Porras A, Rico Mendoza A, Dong L, Kenny T, Brueggemann E, Downey LG, Kamalapathy P, Lichtenberger P, Falls O, Simon GL, Bethony JM, Firestein GS. Chikungunya Arthritis Mechanisms in the Americas: A Cross-Sectional Analysis of Chikungunya Arthritis Patients Twenty-Two Months After Infection Demonstrating No Detectable Viral Persistence in Synovial Fluid. Arthritis Rheumatol. 2018 Apr;70(4):585-593. doi: 10.1002/art.40383. Epub 2018 Mar 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 25, 2017): 50
• Original Estimated Enrollment (submitted: June 3, 2015): 35
• Actual Study Completion Date: June 2017
• Actual Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• There will be three cohorts of patients.

  • Cohort 1 Chronic chikungunya: Twenty participants with chronic chikungunya with knee effusion defined as continued knee joint effusion at least three months after diagnosis of chikungunya.
  • Cohort 2 Acute chikungunya: Ten participants with acute chikungunya defined as clinical symptoms of chikungunya with acute fever >38°C and joint pain within 10 days the onset of symptoms without other more likely diagnosis or laboratory confirmed chikungunya.
  • Cohort 3 Healthy controls: Five healthy participants will participate that will provide baseline measurements of the cytokine profile and mononuclear cell sample recovery.

All subjects will be adults ≥18 years old. Cohort 1 participants will only be enrolled in the study if they have a knee effusion at baseline presentation. Laboratory confirmation of chikungunya includes positive viral PCR or positive IgM antibody. All patients will be able to understand and give informed consent in Spanish.

Exclusion Criteria:

• Participants will be excluded if they have a known bleeding disorders or if they are on warfarin, clopidogrel, and ticagrelor therapy they will be excluded for increased bleeding risk.
• The study will also exclude children, adults unable to give consent, prisoners, and pregnant women.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT02463968
• Other Study ID Numbers: 20150352
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Aileen Chang, George Washington University
• Study Sponsor: George Washington University

Collaborators

• Global Disease Research
• United States Army Medical Research Institute of Infectious Diseases
• Broad Institute
• Allied Research Society

Investigators

• Principal Investigator: Aileen Y Chang, MD MSPH; George Washington University

• PRS Account: George Washington University
• Verification Date: June 2017