Study of an Anti-TLR4 mAb in Rheumatoid Arthritis

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

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

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Other: Placebo; Drug: NI-0101

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bosnia and Herzegovina
  • Mostar, Bosnia and Herzegovina, 88000
    • Clinic for internal medicine with centre for dialysis
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • Multi-profile Hospital for Active Treatment "Trimontsium"
  • Plovdiv, Bulgaria, 4001
    • University Multiprofile Hospital for Active Treatment "Kaspela"
  • Shumen, Bulgaria, 9705
    • Multiprofile Hospital for Active Treatment - Shumen AD
  • Sofia, Bulgaria, 1612
    • University Multiprofile Hospital for Active TreatmenT "St. Ivan Rilski"
• Georgia
  • Tbilisi, Georgia, 0112
    • ARENSIA Phase I Unit at the Research Institute of Clinical Medicine
  • Tbilisi, Georgia, 0144
    • High Technology Medical Center; University clinic
  • Tbilisi, Georgia, 0159
    • Emergency Cardiology Center by Acad. G.Chapidze
  • Tbilisi, Georgia, 0159
    • Insitute of Clinical Cardiology
  • Tbilisi, Georgia, 0159
    • Tbilisi Central Hospital
  • Tbilisi, Georgia, 0186
    • Multiprofile Clinic Consilium Medulla
• Hungary
  • Miskolc, Hungary, 3529
    • CRU Hungary Ltd
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD2025
    • Republican Clinical Hospital, ARENSIA Phase I unit
• Poland
  • Bialystok, Poland, 15-297
    • Centrum Miriada
  • Lublin, Poland, 20-582
    • Zespol Poradni Specjalistycznych REUMED
• Serbia
  • Belgrade, Serbia, 11000
    • Institute of Rheumatology
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
  • Novi Sad, Serbia, 21112
    • Special Hospital for Rheumatic Diseases "Novi Sad"
  • Zrenjanin, Serbia, 23000
    • General Hospital "Djordje Joanovic"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Light Chain Bioscience - Novimmune SA
• Investigators: Principal Investigator: Ernest Choy, MD, Institute of Infection and Immunity, Cardiff University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2017
• Primary Completion (Actual): June 20, 2018
• Study Completion (Actual): June 20, 2018

Study Registration Dates

• First Submitted: June 26, 2017
• First Submitted That Met QC Criteria: August 4, 2017
• First Posted (Actual): August 7, 2017

Study Record Updates

• Last Update Posted (Actual): August 14, 2018
• Last Update Submitted That Met QC Criteria: August 13, 2018
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: NI-0101-04; 2016-005017-45 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No