Clinical trial NCT05251870: Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis
Official title: Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis: the TOLERANT Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Rheumatoid Arthritis
Keywords: Tolerogenic Dendritic Cells
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
name: Utrecht University
name: Trajectum Pharma B.V.
name: Dutch Arthritis Association
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Health Holland
First posted: 2022-02-23
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Safety as assessed by the occurrence and severity of adverse events
timeFrame: 34 weeks
measure: Quantity of good manufacturing practices (GMP)-grade TolDCB29 released according to Quality Control.
timeFrame: 34 weeks
measure: Occurrence of out of specification (OOS) products.
timeFrame: 34 weeks
Secondary outcomes:
measure: Changes in leukocyte numbers
timeFrame: 34 weeks
measure: Changes in CD4+ T lymphocytes subset frequencies
timeFrame: 34 weeks
measure: Lymphocyte proliferation to HSP70/B29 peptide
timeFrame: 34 weeks
Other outcomes:
measure: Disease activity of 28 joints (DAS28)
timeFrame: 34 weeks
measure: Quality of life (EQ-5D-5L)
timeFrame: 34 weeks
measure: Mean functional ability (HAQ)
timeFrame: 34 weeks
measure: Autoantibody levels
timeFrame: 34 weeks
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
city: Utrecht
country: Netherlands
facility: Utrecht University
Study officials:
affiliation: UMC Utrecht
name: Jacob M van Laar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Arie J Stoppelenburg, PhD
role: STUDY_DIRECTOR
References: