2-HOBA Phase 2 Clinical Trial in Rheumatoid Arthritis

Study Overview
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Brief Summary
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This is a phase 2 study to determine 2-HOBA's tolerability, safety, and effect on isoLG-adducts in patients with rheumatoid arthritis (RA) patients. Up to 32 subjects will be randomized to 750mg 2-HOBA or matching placebo three times a day for 4 weeks. As primary outcome measures investigators will compare tolerability and adverse events and changes in isoLG adducts in active and placebo arms. Among prespecified exploratory outcomes investigators will compare changes in markers of inflammation, DAS28 score, and 24-hour blood pressure in active and placebo arms. This pilot study will inform the feasibility and design of future studies to examine the efficacy of 2-HOBA in RA patients.

Detailed Description
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Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting 1% of the population. Aggressive treatment is a fundamental therapeutic strategy to improve disease-related outcomes and cardiovascular disease, which contributes to excess mortality in RA. Thus, therapeutics targeting novel pathways that treat RA and reduce cardiovascular risk are needed. A potential target is blocking the proinflammatory, immunogenic, and proatherogenic consequences of isolevuglandins (isoLGs). IsoLGs are highly reactive dicarbonyl products of oxidative stress that bind covalently to proteins causing conformational changes rendering them immunogenic and proinflammatory. Two decades of work at Vanderbilt led to the identification of 2-hydroxybenzylamine (2-HOBA) as a highly effective scavenger of reactive dicarbonyls such as isoLGs. Scavenging reactive dicarbonyls is preferable to using antioxidants because reactive oxygen species are necessary for normal cellular function. In animal models of autoimmunity, hypertension, and atherosclerosis 2-HOBA reduced inflammation, autoantibodies, blood pressure, and atherosclerosis, and in human phase 1 clinical studies in healthy volunteers 2-HOBA was well tolerated. In this phase 2 study investigators will randomize up to 32 subjects with RA meeting inclusion/exclusion criteria to 750mg 2-HOBA or matching placebo three times a day for 4 weeks. Randomized subjects will have study visits at week 0 and week 4. At each visit a history and physical exam with joint counts, questionnaire, blood draw and 24-hour blood pressure will be performed.

Official Title
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2-HOBA Phase 2 Clinical Trial in Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: 2-HOBA
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥18 years Meets 2010 American College of Rheumatology/European League Against Rheumatism Rheumatoid Arthritis classification criteria ≥ 4 tender or swollen joints No change in DMARDs, glucocorticoids in ≥ 4 weeks If of childbearing potential, willingness to use effective birth throughout study and 4 weeks after completion of the study (examples: condom, diaphragm, oral contraceptive pill, intrauterine device) If using non-steroidal anti-inflammatory drugs (NSAIDs), willingness to discontinue use of NSAIDs for 2 weeks prior to the study and throughout the study Exclusion Criteria: Pregnant or breastfeeding Active cancer except non-melanoma skin cancer Active infection Concomitant inflammatory autoimmune disease Major surgery in ≤ 3 months Aspirin allergy Use of MAO-I Estimated creatinine clearance <30 ml/min Prior diagnosis of liver cirrhosis or the following abnormal liver function studies: AST or ALT >1.5x the upper limit of normal or total bilirubin ≥1.5 mg/dl

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2-HOBA<br>2-HOBA acetate (2-Hydroxybenzlamine acetate) 750mg (provided as three 250mg capsules) three times per day for 4 weeks | Drug: 2-HOBA<br>* 2-HOBA acetate (2-Hydroxybenzlamine acetate) 750mg (provided as three 250mg capsules) three times per day for 4 weeks<br>* Other names: IUPAC name: 2-(aminomethyl)phenol;|
| Placebo Comparator: Placebo<br>Matching placebo (provided as three capsules) three times per day for 4 weeks | Other: Placebo<br>* Placebo (provided as three capsules) three times a day for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety/Tolerability (adverse events) | Rates of adverse events will be compared between active and placebo arms and presented as summary statistics. | Baseline to 4 weeks | 
| Cellular isolevuglandin (isoLG) adducts | Change in percentage of cellular isoLG adducts will be compared between active and placebo arms. | Baseline to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis