Study of an Anti-TLR4 mAb in Rheumatoid Arthritis

Study Overview
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Brief Summary
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This is a Phase 2, PoC, randomized, placebo-controlled, double blind, international multicentre study to explore the effect of a new antibody to treat patients with Rheumatoid Arthritis

Detailed Description
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The study foresees the randomization of at least 81 moderate to severe, ACPA positive, RA patients who are inadequate responders to MTX, in two double blind arms (NI-0101:placebo, with a ratio of 2:1). Patients will receive NI-0101 or placebo infusions up to a maximum of 6 administrations (every two weeks for 12 weeks). All patients will continue receiving a stable dose of MTX. After 12 weeks, patients will enter the follow up period with monthly visits for a minimum of 12 weeks.

Official Title
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Randomized, Placebo-Controlled, Double Blind, Multicenter Phase 2 Study to Explore Tolerability, Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Intravenous Multiple Infusions of NI-0101, an Anti-Toll Like Receptor 4 Monoclonal Antibody in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: NI-0101
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients Age >= 18 years old BMI: < 30 and > 18 Diagnosis of RA according to 2010 ACR/EULAR criteria and with a disease duration of at least 6 months since diagnosis Patient must present with active RA, characterized by at least 6 swollen joints out of 66 assessed and 6 tender joints out of 68 assessed and by the presence of synovitis (measured by ultrasound) in at least one of the 6 swollen joints C-reactive protein (CRP) level > 0.7 mg/dL or if the CRP level is between 0.3 mg/dL and 0.7 mg/dL (included) then patient must also present an ESR > 30mm/hr Patients must have received MTX treatment for at least 3 months and have been on a stable dose of MTX for at least 6 weeks prior to start of screening ACPA-positive RA patients Women must be postmenopausal (> 12 months without menses) or surgically sterile or using two effective contraception methods for at least 4 weeks prior to the randomization date and agree to continue contraception for the duration of their participation in the study (until the end of follow up period) Sexually active male patients must use a barrier method of contraception during the course of the study (and until the end of the follow up period) Patients must give written informed consent for study participation Exclusion Criteria: A documented history of an autoimmune disease other than RA by ACR classification, or Sjögren syndrome Administration of cytotoxic drugs and immune suppressants (other than MTX) within 3 months prior to screening Previous multiple administrations of any biological DMARD or targeted synthetic DMARD Known primary immunodeficiency Pregnant or breastfeeding women Suspicion of active or latent tuberculosis HIV, HCV, HBV infection Infection reported during screening not recovered 72h prior to first dose History of anaphylactic reactions to any protein therapeutics or excipients Any history of malignancy, excluding cured basal or squamous cell carcinoma of the skin, or cervical in situ carcinoma Clinically significant cardiac disease requiring medication, such as congestive heart failure, unstable angina, myocardial infarction within 6 months prior to randomization Moderate to severe renal insufficiency, clinically relevant liver function test abnormalities or pancytopenia Major psychiatric or neurological disorder

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NI-0101<br>A therapeutic humanized monoclonal antibody, administered by intravenous infusion every 2 weeks. | Drug: NI-0101<br>* Humanized immunoglobulin gamma 1 (IgG1) kappa monoclonal antibody targeting TLR4<br>|
| Placebo Comparator: Placebo<br>The placebo matches NI-0101 without active ingredient, administered by intravenous infusion every 2 weeks. | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, severity, causality and outcomes of Adverse Events (AEs) | Incidence, severity, causality and outcomes of Adverse Events (AEs) (serious and non-serious), with particular attention being paid to infusion-related reactions and infections | From screening up to 24 weeks after first treatment administration | 
| Withdrawal for safety reasons |  | From randomization up to 24 weeks after first treatment administration | 
| Evolution of laboratory parameters |  | From screening up to 24 weeks after first treatment administration | 
| Level of potential circulating antibodies against NI-0101 | Level of potential circulating antibodies against NI-0101 to determine immunogenicity; i.e. the development of anti-drug antibodies (ADA). | From screening up to 24 weeks after first treatment administration | 
| Levels of CRP | Levels of C-Reactive protein (CRP) | From screening up to 24 weeks after first treatment administration | 
| Levels of inflammatory cytokines/chemokines | IL-6, TNFa, IP-10, MCP-1, sICAM, CXCL13 | From screening up to 24 weeks after first treatment administration | 
| DAS28 CRP | Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and C-Reactive protein (CRP) - DAS28-CRP | From screening to 24 weeks after first treatment administration | 
| ACR criteria | Proportion of patients achieving American College of Rheumatology Criteria (ACR20, ACR50 and ACR70) | From randomization to 24 weeks after first treatment administration | 
| Proportion of patient achieving remission | Proportion of patient achieving remission (defined as DAS28 < 2.6) | From randomization to 24 weeks after first treatment administration | 
| EULAR response | Proportion of patients achieving European League Against Rheumatism (EULAR) response criteria - good, moderate and no response | From randomization to 24 weeks after first treatment administration | 
| Joint Count | Mean number of Tender Joint Count/Swollen Joint Count. | From screening to 24 weeks after first treatment administration | 
| SDAI score | Mean improvement from baseline in Simplified Disease Activity Index (SDAI) score | From randomization to 24 weeks after first treatment administration | 
| HAQ-DI score | Mean improvement from baseline in the Health Assessment Questionnaire without Disability Index (HAQ-DI) score | From randomization to 24 weeks after first treatment administration | 
| SF-36 score | Mean improvement from baseline in 36-Item Short-Form Health Survey (SF-36) score | from randomization to 24 weeks after first treatment administration | 
| DAS28-ESR | Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and Erythrocyte Sedimentation Rate (ESR) levels - DAS28-ESR | From screening to 24 weeks after first treatment administration | 
| CDAI score | Mean improvement from baseline in Clinical Disease Activity Index (CDAI) score scores | From randomization to 24 weeks after first treatment administration | 
| Exploratory PK analysis - Cmax | Peak drug plasma concentration (Cmax) | From randomization to 24 weeks after first treatment administration | 
| Exploratory PK analysis - Tmax | Time when plasma concentration is at peak (Tmax) | From screening up to 24 weeks after first treatment administration | 
| Exploratory PK analysis - Ctrough | Plasma drug concentration immediately prior next dosing (Ctrough) | From randomization to 24 weeks after first treatment administration | 
| Exploratory PK analysis - AUC | Area under the plasma concentration versus time curve (AUC) | From randomization to 24 weeks after first treatment administration | 
| Exploratory PK analysis - CL | Systemic drug clearance (CL) | From randomization to 24 weeks after first treatment administration |