An Artificial Intelligence-powered Approach to Precision Immunotherapy of Human Arthritis

An Artificial Intelligence-powered Approach to Precision Immunotherapy of Human Arthritis - A Double-blind, Randomized, Placebo-controlled Clinical Trial

This clinical study is a multi-center, randomized, double-blind, placebo-controlled, outpatient study comparing the efficacy of combination of dnaJP1 peptide and hydroxychloroquine versus combination of placebo and hydroxychloroquine in patients with moderately to severely active RA who are naive to cs-, b-, tsp.-DMARDs.

A sample size of 124 patients will be enrolled in the study. Each patient will receive either combination of dnaJP1 peptide and hydroxychloroquine or combination of placebo and hydroxychloroquine in 1:1 allocation ratio.

Despite the availability of a plethora of new drugs to treat Rheumatoid Arthritis (RA), a holistic and accurate understanding of how therapy with biologics works is still missing. The knowledge gap is particularly poignant if one considers that the second-generation drugs developed for immune therapy is still entirely suppressive. Thus, the dramatic advances in molecular immunology has yet to be translated into the needed evolution from immune suppression to true immune tolerization, an important step on the evolutionary pathway from therapy to cure.

This study is designed to be a multi-center, randomized, double-blind, placebo-controlled trial which has two fundamental objectives:

To identify and dissect mechanisms of induction of immune tolerance in RA patients in response to immune therapy with dnaJP1, a microbiome-derived peptide. Tangibly in the context of clinical development, the investigators aim to capitalize on this knowledge to identify and validate biomarkers predictor of efficacy and clinical response;

The investigators will also determine the effect size needed to demonstrate whether the combination of dnaJP1 peptide and hydroxychloroquine (HCQ) is superior to the combination of placebo and hydroxychloroquine in the treatment of patients with moderately to severely active RA naïve to disease modifying anti-rheumatic drugs (i.e. DMARDs and biologics-naïve).

Inclusion Criteria:

1. Diagnosis of rheumatoid arthritis (RA) based on 2010 ACR/EULAR classification criteria
2. DAS28-ESR score more than 3.2 (at least moderately active)
3. Male or female with age 21 or above
4. Ability to understand and sign informed consent
5. Agree to use acceptable methods of contraception for e.g. oral contraceptive pills, implanted contraception, barrier methods, and intra-uterine devices
6. Allowed used of oral Prednisone up to 10 mg/day and NSAIDs, as prescribed by the treating physician
7. Able and willing to comply with the protocol, including availability for all scheduled study visits and assessments.

Using the 2010 ACR/EULAR classification criteria for RA, classification as definite RA is based upon the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and the achievement of a total score of at least 6 (of a possible 10) from the individual scores in four domains. The highest score achieved in a given domain is used for this calculation. These domains and their values are:

1. Number and site of involved joints:

   • 2 to 10 large joints (from among shoulders, elbows, hips, knees, and ankles) = 1 point
   • 1 to 3 small joints (from among the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists) = 2 points
   • 4 to 10 small joints = 3 points
   • Greater than 10 joints (including at least 1 small joint) = 5 points

2. Serological abnormality (rheumatoid factor or anti-citrullinated peptide/protein antibody)

   • Low positive (above the upper limit of normal [ULN]) = 2 points
   • High positive (greater than three times the ULN) = 3 points

3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) above the ULN = 1 point

4. Symptom duration at least six weeks = 1 point

Exclusion Criteria:

1. On prednisolone >10 mg daily

2. History of receiving:

   • conventional synthetic (cs-) disease modifying anti-rheumatic drugs (DMARDs) such as sulfasalazine, methotrexate, and leflunomide administered 6 months prior to screening

     •. biological (b-) DMARDs such as rituximab, infliximab, tocilizumab, adalimumab, etc.

   • tissue-specific (tsp.-) DMARDs such as JAK inhibitors

3. History of lymphoma

4. Active malignancy requiring treatment the last 5 years except for non-melanoma skin cancers and carcinoma of the cervix in situ

5. Pregnancy

6. Breast-feeding

7. Active Infection, e.g., Hepatitis B, tuberculosis

8. A known hypersensitivity to dnaJP1 or to any of the excipients

9. Significant cardiac history, e.g., have experienced any of the following within 12 weeks of study entry: myocardial infarction, unstable ischemic heart disease, stroke, or New York Heart Association Stage IV heart failure

10. A history or presence of dermatological, cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, haematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute a risk when taking HCQ and/or the investigational product or could interfere with the interpretation of data

11. An eGFR based on the most recent available serum creatinine using the Modification of Diet in Renal Disease (MDRD) method of <40 ml/min/1.73 m2

12. A history of chronic liver disease with the most recent available aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the ULN or the most recent available total bilirubin 1.5 times the ULN