Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

— TOLERANT  

Official title:

Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis: the TOLERANT Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05251870
• Other study ID #: NL71296.000.20
• Secondary ID: 2019-003620-20
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 17, 2021
• Est. completion date: August 2025

Study information

• Verified date: February 2022
• Source: UMC Utrecht
• Contact: Arie J Stoppelenburg, PhD
• Phone: +31302535589
• Email: a.j.stoppelenburg[@]umcutrecht.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: August 2025
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70
Intranodal administration into an inguinal lymphnode. Two administrations at the same injection site with a four week interval.

Locations

Country	Name	City	State
Netherlands	Radboud University Medical Centre	Nijmegen
Netherlands	University Medical Centre Utrecht	Utrecht
Netherlands	Utrecht University	Utrecht

Sponsors (7)

Lead Sponsor	Collaborator
UMC Utrecht	Dutch Arthritis Association, Health Holland, Radboud University Medical Center, Trajectum Pharma B.V., Utrecht University, ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Disease activity of 28 joints (DAS28)	Score ranges 0 - 9.4. Higher score means higher disease activity	34 weeks
Other	Quality of life (EQ-5D-5L)	Score ranges from less than 0 to 1. In this score, 0 represents a health state equivalent to death and 1 represents full health.	34 weeks
Other	Mean functional ability (HAQ)	Score ranges 0 - 3.0 in 0.1 increments. Higher scores indicate worse function and greater disability.	34 weeks
Other	Autoantibody levels	Blood autoantibody levels in Units/mL	34 weeks
Primary	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.	34 weeks
Primary	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.	34 weeks
Primary	Occurrence of out of specification (OOS) products.	Number of occurrences that out of specification TolDCB29 products were generated during manufacturing and/or reconsitution.	34 weeks
Secondary	Changes in leukocyte numbers		34 weeks
Secondary	Changes in CD4+ T lymphocytes subset frequencies		34 weeks
Secondary	Lymphocyte proliferation to HSP70/B29 peptide		34 weeks