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Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis (TOLERANT)

Primary Purpose

Rheumatoid Arthritis

Status
Recruiting
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70
Sponsored by
UMC Utrecht
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Tolerogenic Dendritic Cells

Eligibility Criteria

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

Inclusion Criteria:

  • Diagnosis of rheumatoid arthritis (RA) according to the criteria which were valid at time of diagnosis (i.e. 1987 Rheumatoid Arthritis Classification or 2010 American College of Rheumatology/EULAR RA Classification Criteria)
  • Stable dose, for at least 12 weeks, of any combination of disease-modifying antirheumatic drugs and glucocorticoids (maximum of 7.5 mg per day), with exception of those drugs that are part of the exclusion criteria.
  • Disease in remission or in low disease activity for at least 12 weeks (disease activity score of 28 joints < 3.2)
  • Able and willing to give informed consent and to comply with the study protocol

Exclusion Criteria:

  • Intramuscular or intra-articular glucocorticoid injection during 12 weeks prior to inclusion
  • Use of JAK inhibitors
  • Active or chronic infection (except fungal nail infection)
  • Infection requiring hospitalization or IV antibiotics within 6 weeks of baseline
  • Immunization with live vaccine within 6 weeks of baseline
  • History of malignancy (except treated basal cell carcinoma of skin)
  • Use of other investigational medicinal products within 30 days prior to study entry
  • Major surgery within 8 weeks of baseline or planned within 12 weeks from baseline
  • Pregnancy, or women planning to become pregnant within the study period, or women who are breast feeding
  • Hb<6 mmol/L; neutrophils< 2.00 x10^9/L; platelets <150x10^9/L; alanine aminotransferase or alkaline phosphatase>2x upper limit of normal; renal insufficiency (clearance < 60 ml/min) at screening visit
  • Poor venous access or medical condition precluding leukapheresis
  • Serious or unstable co-morbidity deemed unsuitable by PI, e.g. chronic obstructive pulmonary disease, cardiac failure
  • Individuals of child bearing potential unwilling to use adequate contraception for duration the of study

Sites / Locations

  • Radboud University Medical Centre
  • University Medical Centre UtrechtRecruiting
  • Utrecht University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Intranodal TolDCB29 (low dose)

Intranodal TolDCB29 (intermediate dose)

Intranodal TolDCB29 (high dose)

Intranodal TolDCB29 (recommended dose)

Arm Description

Two administrations of 5 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.

Two administrations of 10 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.

Two administrations of 15 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.

Two administrations of the recommended dose of autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). The recommended dose will be advised by the data safety monitoring board after data review of the first three arms. This cohort will consist of nine patients.

Outcomes

Primary Outcome Measures

Safety as assessed by the occurrence and severity of adverse events
The occurrence and severity of adverse events will be recorded, including the occurrence of disease flares.
Quantity of good manufacturing practices (GMP)-grade TolDCB29 released according to Quality Control.
Number of TolDCB29 cells (millions of cells) per patient that were released according to the quality control standards of the IMPD.
Occurrence of out of specification (OOS) products.
Number of occurrences that out of specification TolDCB29 products were generated during manufacturing and/or reconsitution.

Secondary Outcome Measures

Changes in leukocyte numbers
Changes in CD4+ T lymphocytes subset frequencies
Lymphocyte proliferation to HSP70/B29 peptide

Full Information

First Posted
December 21, 2021
Last Updated
February 22, 2022
Sponsor
UMC Utrecht
Collaborators
Radboud University Medical Center, Utrecht University, Trajectum Pharma B.V., Dutch Arthritis Association, ZonMw: The Netherlands Organisation for Health Research and Development, Health Holland
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1. Study Identification

Unique Protocol Identification Number
NCT05251870
Brief Title
Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis
Acronym
TOLERANT
Official Title
Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis: the TOLERANT Trial
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 17, 2021 (Actual)
Primary Completion Date
August 2024 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UMC Utrecht
Collaborators
Radboud University Medical Center, Utrecht University, Trajectum Pharma B.V., Dutch Arthritis Association, ZonMw: The Netherlands Organisation for Health Research and Development, Health Holland

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Rationale: In rheumatoid arthritis, immune cells cause joint inflammation and destruction in response to autoantigens. Immunosuppressive therapies offer relief but fail to induce tolerance to autoantigens. Injection of antigen-loaded tolerogenic dendritic cells induces immune tolerance and ameliorates disease in arthritis models. The investigators hypothesize that dendritic cell therapy with TolDCB29 is safe and induces immune tolerance in rheumatoid arthritis patients. Objective: The aim of the study is to demonstrate the safety and feasibility of intranodal TolDCB29 administration. Secondary objectives are the characterization of B29-peptide specific immune reactivity in response to TolDCB29 treatment and the evaluation of the effect of the treatment on disease activity. Study design: Phase I/II, open-label, dose-escalation clinical trial. Study population: Adult patients (>18 years) with rheumatoid arthritis in remission or low disease activity while on disease modifying anti-rheumatic drugs (DMARD) will be included. Any combination and dose of DMARD is allowed, with exception of Janus kinase inhibitors. Concomitant use of a low dose of prednisone (7.5 mg per day or below) is allowed. Medication should be stable for at least twelve weeks. 18 patients will undergo the experimental treatment. Intervention: Study participants will receive two intranodal injections with the TolDCB29 product with a four-week interval. During the first phase of the study dose escalation is performed, in which the first group (n=3) receives two "low dose" injections, the second group (n=3) receives two "intermediate dose" injections, and the third group (n=3) receives two "high dose" injections. During the second phase, a fourth group (n=9) will receive the highest dosage without attributable serious adverse events thus far.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
Keywords
Tolerogenic Dendritic Cells

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intranodal TolDCB29 (low dose)
Arm Type
Experimental
Arm Description
Two administrations of 5 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.
Arm Title
Intranodal TolDCB29 (intermediate dose)
Arm Type
Experimental
Arm Description
Two administrations of 10 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.
Arm Title
Intranodal TolDCB29 (high dose)
Arm Type
Experimental
Arm Description
Two administrations of 15 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.
Arm Title
Intranodal TolDCB29 (recommended dose)
Arm Type
Experimental
Arm Description
Two administrations of the recommended dose of autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). The recommended dose will be advised by the data safety monitoring board after data review of the first three arms. This cohort will consist of nine patients.
Intervention Type
Drug
Intervention Name(s)
autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70
Other Intervention Name(s)
TolDCB29
Intervention Description
Intranodal administration into an inguinal lymphnode. Two administrations at the same injection site with a four week interval.
Primary Outcome Measure Information:
Title
Safety as assessed by the occurrence and severity of adverse events
Description
The occurrence and severity of adverse events will be recorded, including the occurrence of disease flares.
Time Frame
34 weeks
Title
Quantity of good manufacturing practices (GMP)-grade TolDCB29 released according to Quality Control.
Description
Number of TolDCB29 cells (millions of cells) per patient that were released according to the quality control standards of the IMPD.
Time Frame
34 weeks
Title
Occurrence of out of specification (OOS) products.
Description
Number of occurrences that out of specification TolDCB29 products were generated during manufacturing and/or reconsitution.
Time Frame
34 weeks
Secondary Outcome Measure Information:
Title
Changes in leukocyte numbers
Time Frame
34 weeks
Title
Changes in CD4+ T lymphocytes subset frequencies
Time Frame
34 weeks
Title
Lymphocyte proliferation to HSP70/B29 peptide
Time Frame
34 weeks
Other Pre-specified Outcome Measures:
Title
Disease activity of 28 joints (DAS28)
Description
Score ranges 0 - 9.4. Higher score means higher disease activity
Time Frame
34 weeks
Title
Quality of life (EQ-5D-5L)
Description
Score ranges from less than 0 to 1. In this score, 0 represents a health state equivalent to death and 1 represents full health.
Time Frame
34 weeks
Title
Mean functional ability (HAQ)
Description
Score ranges 0 - 3.0 in 0.1 increments. Higher scores indicate worse function and greater disability.
Time Frame
34 weeks
Title
Autoantibody levels
Description
Blood autoantibody levels in Units/mL
Time Frame
34 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of rheumatoid arthritis (RA) according to the criteria which were valid at time of diagnosis (i.e. 1987 Rheumatoid Arthritis Classification or 2010 American College of Rheumatology/EULAR RA Classification Criteria) Stable dose, for at least 12 weeks, of any combination of disease-modifying antirheumatic drugs and glucocorticoids (maximum of 7.5 mg per day), with exception of those drugs that are part of the exclusion criteria. Disease in remission or in low disease activity for at least 12 weeks (disease activity score of 28 joints < 3.2) Able and willing to give informed consent and to comply with the study protocol Exclusion Criteria: Intramuscular or intra-articular glucocorticoid injection during 12 weeks prior to inclusion Use of JAK inhibitors Active or chronic infection (except fungal nail infection) Infection requiring hospitalization or IV antibiotics within 6 weeks of baseline Immunization with live vaccine within 6 weeks of baseline History of malignancy (except treated basal cell carcinoma of skin) Use of other investigational medicinal products within 30 days prior to study entry Major surgery within 8 weeks of baseline or planned within 12 weeks from baseline Pregnancy, or women planning to become pregnant within the study period, or women who are breast feeding Hb<6 mmol/L; neutrophils< 2.00 x10^9/L; platelets <150x10^9/L; alanine aminotransferase or alkaline phosphatase>2x upper limit of normal; renal insufficiency (clearance < 60 ml/min) at screening visit Poor venous access or medical condition precluding leukapheresis Serious or unstable co-morbidity deemed unsuitable by PI, e.g. chronic obstructive pulmonary disease, cardiac failure Individuals of child bearing potential unwilling to use adequate contraception for duration the of study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Arie J Stoppelenburg, PhD
Phone
+31302535589
Email
a.j.stoppelenburg@umcutrecht.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Research nurses
Email
tolerant@umcutrecht.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jacob M van Laar, MD, PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Arie J Stoppelenburg, PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Study Director
Facility Information:
Facility Name
Radboud University Medical Centre
City
Nijmegen
Country
Netherlands
Individual Site Status
Active, not recruiting
Facility Name
University Medical Centre Utrecht
City
Utrecht
Country
Netherlands
Individual Site Status
Recruiting
Facility Name
Utrecht University
City
Utrecht
Country
Netherlands
Individual Site Status
Active, not recruiting

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis

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