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Study of an Anti-TLR4 mAb in Rheumatoid Arthritis

Primary Purpose

Rheumatoid Arthritis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
NI-0101
Placebo
Sponsored by
Light Chain Bioscience - Novimmune SA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Clinic for internal medicine with centre for dialysis
  • Multi-profile Hospital for Active Treatment "Trimontsium"
  • University Multiprofile Hospital for Active Treatment "Kaspela"
  • Multiprofile Hospital for Active Treatment - Shumen AD
  • University Multiprofile Hospital for Active TreatmenT "St. Ivan Rilski"
  • ARENSIA Phase I Unit at the Research Institute of Clinical Medicine
  • High Technology Medical Center; University clinic
  • Emergency Cardiology Center by Acad. G.Chapidze
  • Insitute of Clinical Cardiology
  • Tbilisi Central Hospital
  • Multiprofile Clinic Consilium Medulla
  • CRU Hungary Ltd
  • Republican Clinical Hospital, ARENSIA Phase I unit
  • Centrum Miriada
  • Zespól Poradni Specjalistycznych REUMED
  • Institute of Rheumatology
  • Clinical Center Kragujevac
  • Special Hospital for Rheumatic Diseases "Novi Sad"
  • General Hospital "Djordje Joanovic"

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

NI-0101

Placebo

Arm Description

A therapeutic humanized monoclonal antibody, administered by intravenous infusion every 2 weeks.

The placebo matches NI-0101 without active ingredient, administered by intravenous infusion every 2 weeks.

Outcomes

Primary Outcome Measures

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
Withdrawal for safety reasons
Evolution of laboratory parameters
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).
Levels of CRP
Levels of C-Reactive protein (CRP)
Levels of inflammatory cytokines/chemokines
IL-6, TNFa, IP-10, MCP-1, sICAM, CXCL13
DAS28 CRP
Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and C-Reactive protein (CRP) - DAS28-CRP
ACR criteria
Proportion of patients achieving American College of Rheumatology Criteria (ACR20, ACR50 and ACR70)
Proportion of patient achieving remission
Proportion of patient achieving remission (defined as DAS28 < 2.6)
EULAR response
Proportion of patients achieving European League Against Rheumatism (EULAR) response criteria - good, moderate and no response
Joint Count
Mean number of Tender Joint Count/Swollen Joint Count.
SDAI score
Mean improvement from baseline in Simplified Disease Activity Index (SDAI) score
HAQ-DI score
Mean improvement from baseline in the Health Assessment Questionnaire without Disability Index (HAQ-DI) score
SF-36 score
Mean improvement from baseline in 36-Item Short-Form Health Survey (SF-36) score
DAS28-ESR
Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and Erythrocyte Sedimentation Rate (ESR) levels - DAS28-ESR
CDAI score
Mean improvement from baseline in Clinical Disease Activity Index (CDAI) score scores
Exploratory PK analysis - Cmax
Peak drug plasma concentration (Cmax)
Exploratory PK analysis - Tmax
Time when plasma concentration is at peak (Tmax)
Exploratory PK analysis - Ctrough
Plasma drug concentration immediately prior next dosing (Ctrough)
Exploratory PK analysis - AUC
Area under the plasma concentration versus time curve (AUC)
Exploratory PK analysis - CL
Systemic drug clearance (CL)

Secondary Outcome Measures

Full Information

First Posted
June 26, 2017
Last Updated
August 13, 2018
Sponsor
Light Chain Bioscience - Novimmune SA
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1. Study Identification

Unique Protocol Identification Number
NCT03241108
Brief Title
Study of an Anti-TLR4 mAb in Rheumatoid Arthritis
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2017
Overall Recruitment Status
Completed
Study Start Date
May 10, 2017 (Actual)
Primary Completion Date
June 20, 2018 (Actual)
Study Completion Date
June 20, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Light Chain Bioscience - Novimmune SA

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
90 (Actual)

8. Arms, Groups, and Interventions

Arm Title
NI-0101
Arm Type
Experimental
Arm Description
A therapeutic humanized monoclonal antibody, administered by intravenous infusion every 2 weeks.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
The placebo matches NI-0101 without active ingredient, administered by intravenous infusion every 2 weeks.
Intervention Type
Drug
Intervention Name(s)
NI-0101
Intervention Description
Humanized immunoglobulin gamma 1 (IgG1) kappa monoclonal antibody targeting TLR4
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Incidence, severity, causality and outcomes of Adverse Events (AEs)
Description
Incidence, severity, causality and outcomes of Adverse Events (AEs) (serious and non-serious), with particular attention being paid to infusion-related reactions and infections
Time Frame
From screening up to 24 weeks after first treatment administration
Title
Withdrawal for safety reasons
Time Frame
From randomization up to 24 weeks after first treatment administration
Title
Evolution of laboratory parameters
Time Frame
From screening up to 24 weeks after first treatment administration
Title
Level of potential circulating antibodies against NI-0101
Description
Level of potential circulating antibodies against NI-0101 to determine immunogenicity; i.e. the development of anti-drug antibodies (ADA).
Time Frame
From screening up to 24 weeks after first treatment administration
Title
Levels of CRP
Description
Levels of C-Reactive protein (CRP)
Time Frame
From screening up to 24 weeks after first treatment administration
Title
Levels of inflammatory cytokines/chemokines
Description
IL-6, TNFa, IP-10, MCP-1, sICAM, CXCL13
Time Frame
From screening up to 24 weeks after first treatment administration
Title
DAS28 CRP
Description
Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and C-Reactive protein (CRP) - DAS28-CRP
Time Frame
From screening to 24 weeks after first treatment administration
Title
ACR criteria
Description
Proportion of patients achieving American College of Rheumatology Criteria (ACR20, ACR50 and ACR70)
Time Frame
From randomization to 24 weeks after first treatment administration
Title
Proportion of patient achieving remission
Description
Proportion of patient achieving remission (defined as DAS28 < 2.6)
Time Frame
From randomization to 24 weeks after first treatment administration
Title
EULAR response
Description
Proportion of patients achieving European League Against Rheumatism (EULAR) response criteria - good, moderate and no response
Time Frame
From randomization to 24 weeks after first treatment administration
Title
Joint Count
Description
Mean number of Tender Joint Count/Swollen Joint Count.
Time Frame
From screening to 24 weeks after first treatment administration
Title
SDAI score
Description
Mean improvement from baseline in Simplified Disease Activity Index (SDAI) score
Time Frame
From randomization to 24 weeks after first treatment administration
Title
HAQ-DI score
Description
Mean improvement from baseline in the Health Assessment Questionnaire without Disability Index (HAQ-DI) score
Time Frame
From randomization to 24 weeks after first treatment administration
Title
SF-36 score
Description
Mean improvement from baseline in 36-Item Short-Form Health Survey (SF-36) score
Time Frame
from randomization to 24 weeks after first treatment administration
Title
DAS28-ESR
Description
Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and Erythrocyte Sedimentation Rate (ESR) levels - DAS28-ESR
Time Frame
From screening to 24 weeks after first treatment administration
Title
CDAI score
Description
Mean improvement from baseline in Clinical Disease Activity Index (CDAI) score scores
Time Frame
From randomization to 24 weeks after first treatment administration
Title
Exploratory PK analysis - Cmax
Description
Peak drug plasma concentration (Cmax)
Time Frame
From randomization to 24 weeks after first treatment administration
Title
Exploratory PK analysis - Tmax
Description
Time when plasma concentration is at peak (Tmax)
Time Frame
From screening up to 24 weeks after first treatment administration
Title
Exploratory PK analysis - Ctrough
Description
Plasma drug concentration immediately prior next dosing (Ctrough)
Time Frame
From randomization to 24 weeks after first treatment administration
Title
Exploratory PK analysis - AUC
Description
Area under the plasma concentration versus time curve (AUC)
Time Frame
From randomization to 24 weeks after first treatment administration
Title
Exploratory PK analysis - CL
Description
Systemic drug clearance (CL)
Time Frame
From randomization to 24 weeks after first treatment administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ernest Choy, MD
Organizational Affiliation
Institute of Infection and Immunity, Cardiff University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Clinic for internal medicine with centre for dialysis
City
Mostar
ZIP/Postal Code
88000
Country
Bosnia and Herzegovina
Facility Name
Multi-profile Hospital for Active Treatment "Trimontsium"
City
Plovdiv
ZIP/Postal Code
4000
Country
Bulgaria
Facility Name
University Multiprofile Hospital for Active Treatment "Kaspela"
City
Plovdiv
ZIP/Postal Code
4001
Country
Bulgaria
Facility Name
Multiprofile Hospital for Active Treatment - Shumen AD
City
Shumen
ZIP/Postal Code
9705
Country
Bulgaria
Facility Name
University Multiprofile Hospital for Active TreatmenT "St. Ivan Rilski"
City
Sofia
ZIP/Postal Code
1612
Country
Bulgaria
Facility Name
ARENSIA Phase I Unit at the Research Institute of Clinical Medicine
City
Tbilisi
ZIP/Postal Code
0112
Country
Georgia
Facility Name
High Technology Medical Center; University clinic
City
Tbilisi
ZIP/Postal Code
0144
Country
Georgia
Facility Name
Emergency Cardiology Center by Acad. G.Chapidze
City
Tbilisi
ZIP/Postal Code
0159
Country
Georgia
Facility Name
Insitute of Clinical Cardiology
City
Tbilisi
ZIP/Postal Code
0159
Country
Georgia
Facility Name
Tbilisi Central Hospital
City
Tbilisi
ZIP/Postal Code
0159
Country
Georgia
Facility Name
Multiprofile Clinic Consilium Medulla
City
Tbilisi
ZIP/Postal Code
0186
Country
Georgia
Facility Name
CRU Hungary Ltd
City
Miskolc
ZIP/Postal Code
3529
Country
Hungary
Facility Name
Republican Clinical Hospital, ARENSIA Phase I unit
City
Chisinau
ZIP/Postal Code
MD2025
Country
Moldova, Republic of
Facility Name
Centrum Miriada
City
Bialystok
ZIP/Postal Code
15-297
Country
Poland
Facility Name
Zespól Poradni Specjalistycznych REUMED
City
Lublin
ZIP/Postal Code
20-582
Country
Poland
Facility Name
Institute of Rheumatology
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Clinical Center Kragujevac
City
Kragujevac
ZIP/Postal Code
34000
Country
Serbia
Facility Name
Special Hospital for Rheumatic Diseases "Novi Sad"
City
Novi Sad
ZIP/Postal Code
21112
Country
Serbia
Facility Name
General Hospital "Djordje Joanovic"
City
Zrenjanin
ZIP/Postal Code
23000
Country
Serbia

12. IPD Sharing Statement

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Study of an Anti-TLR4 mAb in Rheumatoid Arthritis

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