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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

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

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

NCT ID

NCT05251870

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

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

Studies a U.S. FDA-regulated Device Product

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

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

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

a.j.stoppelenburg@umcutrecht.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Research nurses

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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