Arthritis, RheumatoidTocihelperNCT02569736
Characterization of the Effect of Tocilizumab in Vivo and in Vitro on T Follicular Helper Cells in Rheumatoid Arthritis Patients and Consequence on B Cells Maturation
An observational study of Arthritis, Rheumatoid and Tocilizumab, run by Association Aquitaine de Recherche Clinique en Rhumatologie at 1 site in France.
Trial summary
Naïve CD4+ helper T (Th) cells, upon encountering their cognate antigens presented on professional antigen-presenting cells, differentiate into different effector cells: Th1 cells produce Interferon-γ and regulate antigen presentation and immunity against intracellular pathogens; Th2 cells produce IL-4… Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Arthritis, Rheumatoid, Tocilizumab, T-Lymphocytes, Helper-Inducer
- How many people
- 60 participants
- Where
- 1 siteFrance
- Study dates
- Sep 2014to Dec 2016
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: This study will be performed as a prospective observational open-labeled study (non-interventional) to evaluate the impact of TCZ treatment on the evolution of circulating Tfh cells levels. The administration of treatments (TCZ and MTX) will be done according to current practice, and will not be motivated by the inclusion in this study. TCZ will be administered in association with a conventional DMARD, or in monotherapy, according to clinical recommendations. The objective of this study is to analyze the impact of new therapy set-up, and patients included in the TCZ group would be under MTX treatment for at least 3 months. The immunological analysis will be performed with drop-off of blood samples used in the recommended follow-up of patients treated by MTX or TCZ. For the healthy controls, the immunological analysis will be performed with drop-off of blood samples used in the recommended follow-up of patients treated for osteoporosis or osteoarthritis.
Who may be able to join
- Patients with active moderate to severe RA fulfilling ACR criteria and requiring TCZ or MTX treatment, according to the EU label and French authority recommendations, who accept to enter the study and to sign the informed consent.
- Patients > 18 years
- When treated with corticosteroids: Dose ≤10mg/jour within 4 weeks before inclusion and dose stable during the study.
- When treated with MTX (0.3 mg/kg/w): Dose stable within 4 weeks before inclusion and during the study to avoid confusion on Tfh levels evaluation.
- When treated by prior anti-TNF: according to the recommendations of the French "Club Rhumatismes Inflammatoires", a wash-out period of 5 half-lives will be defined to avoid confusion in the evaluation of Tfh cells initial levels.
- These patients will be consecutively included in the study until the number of needed patients will be reached.
- Healthy controls will be defined as people non-affected by an inflammatory disease (such as RA, ankylosing spondylitis, lupus…). This group will be constituted with patients affected by sciatica, osteoarthritis, osteoporosis…
- These patients will be included in a second phase in order to guarantee the quality of matching with cases.
Who cannot join
- Patients previously treated with TCZ
- Patients with a history of allergic reactions or Hypersensitivity to TCZor to any of the excipients
- Patients with severe and uncontrolled infections such as sepsis and opportunistic infections
- Patients with hepatitis B (with virus replication) or C, HIV-infection and tuberculosis
- Patients with history of cancer or lymphoma
- Patients with history of diabetes
Show all 18Show fewer
- Patients who presented one of the following laboratory abnormalities:
- Serum creatinine > 1.6 mg/dL (141 μmol/L) in female patients and > 1.9 mg/dL (168 μmol/L) in male patients, only for MTX treated patients.
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN).
- Platelet count < 100,000/mm3, (100 x 109/L).
- Hemoglobin < 8.0 g/dL, (5.0 mmol/L).
- White Blood Cells < 3000/mm3, (3.0 x 109/L).
- Absolute neutrophil count < 2000/mm3, (2.0 x 109/L).
- Absolute lymphocyte Count < 500/mm3, (0.5 x 109/L).
- Positive hepatitis BsAg or hepatitis C antibody
- Total bilirubin > ULN
- Pregnant or breast-feeding patients
- Patients who refuse to sign the informed consent
Trial locations and contacts
1 site in 1 country.
France1 site
Rheumatology department - Bordeaux University Hospital
Bordeaux, Aquitaine, 33076
About this study
Naïve CD4+ helper T (Th) cells, upon encountering their cognate antigens presented on professional antigen-presenting cells, differentiate into different effector cells:
- Th1 cells produce Interferon-γ and regulate antigen presentation and immunity against intracellular pathogens;
- Th2 cells produce IL-4 (Interleukin-4), IL-5 and IL-13, and mediate humoral responses and immunity against parasites;
- Th17 cells produce IL-17, IL-17F and IL-22 and regulate inflammatory responses by tissue cells.
Read more
An additional TH subset called follicular helper T (Tfh) cells has recently been identified in germinal centers and also in whole blood (circulating Tfh cells). These cells regulate B-cell maturation and immunoglobulin production during normal immune responses. They produce factors essential for B cell selection and maturation into memory B-cells or long-lived antibody-secreting plasma cells. Furthermore, they also seem to favor pathogenic autoantibody production in systemic autoimmunity, and therefore could potentially represent a novel therapeutic target in autoimmune diseases. Indeed, rheumatoid arthritis synovium is characterized by the presence of ectopic lymphoid structures, resembling germinal centers. Potentially, Tfh cells from these nonlymphoid tissues could promote B-cell maturation and synthesis of pathogenic autoantibody production, thus potentiating tissue injury. Interestingly, production of IL-21 by Tfh cells is implicated in B cell activation, and the same cytokine have been associated with rheumatoid arthritis (RA) pathogenesis.
IL-6 blocking therapy significantly reduces signs and symptoms as well as radiological progression in RA. However, so far, it has not been determined which of the pleiotropic IL-6 effects impact the observed clinical response. Recently, Samson et al have demonstrated that Tocilizumab (TCZ) corrects the imbalance between Th17 cells and Treg cells in patients with RA. More interestingly, the group of Hans-Peter Tony has reported the impact of TCZ on B cell compartment. They showed a significant reduction in the frequency of peripheral pre-switch and post-switch memory B cells but also a reduction of serum immunoglobulin levels, that could be the reflect of TCZ on Tfh cells development, circulation and/or function.
Most of the work studying the role of IL-6 on Tfh cells development has been performed in mice. They showed that optimal Tfh cells formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh cells differentiation.
To better understand the impact of IL-6 on human Tfh cells, the investigators would like to conduct a prospective study in patients with active RA and investigated the effects of blocking IL-6 with TCZ on circulating Tfh cells levels and Tfh cells subsets over a 12-week study period. Furthermore, the impact of TCZ treatment on Tfh cells generation will be explored in vitro.
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Tocilizumab | Patients with active moderate to severe RA fulfilling ACR criteria and requiring TCZ treatment, according to the EU label and French authority recommendations, who accept to enter the study and to sign the informed consent. | |
| Methotrexate | Patients with active moderate to severe RA fulfilling ACR criteria and requiring MTX treatment, according to the EU label and French authority recommendations, who accept to enter the study and to sign the informed consent. | |
| Healthy Controls | Healthy controls will be defined as people non-affected by an inflammatory disease (such as RA, ankylosing spondylitis, lupus…). This group will be constituted with patients affected by sciatica, osteoarthritis, osteoporosis… |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from Baseline in levels of circulating Tfh cells at 12 weeks for TCZ treated patients
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2015 (estimated)
- Study startSep 2014
- Primary completionSep 2016
- Study completionDec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Arthritis, RheumatoidStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Association Aquitaine de Recherche Clinique en Rhumatologie
- Sponsor type
- University, hospital or other
- Collaborators
- Roche Pharma AG, Chugai Pharma France
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02569736
- Sponsor's protocol ID
- ML29237
- Acronym
- Tocihelper
- Status last verified
- Jan 2019
- First submitted
- 6 Oct 2015
- Last updated
- 9 Jan 2019
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Characterization of the Effect of Tocilizumab in Vivo and in Vitro on T Follicular Helper Cells in Rheumatoid Arthritis Patients and Consequence on B Cells Maturation
- ClinicalTrials.gov ID
- NCT02569736
- Acronym / sponsor ID
- Tocihelper / ML29237
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Association Aquitaine de Recherche Clinique en RhumatologieUniversity, hospital or other
- Collaborators
- Roche Pharma AG, Chugai Pharma France
- Study start
- Sep 2014
- Primary completion
- Sep 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 7 Oct 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Naïve CD4+ helper T (Th) cells, upon encountering their cognate antigens presented on professional antigen-presenting cells, differentiate into different effector cells:
- Th1 cells produce Interferon-γ and regulate antigen presentation and immunity against intracellular pathogens;
- Th2 cells produce IL-4 (Interleukin-4), IL-5 and IL-13, and mediate humoral responses and immunity against parasites;
- Th17 cells produce IL-17, IL-17F and IL-22 and regulate inflammatory responses by tissue cells.
An additional TH subset called follicular helper T (Tfh) cells has recently been identified in germinal centers and also in whole blood (circulating Tfh cells). These cells regulate B-cell maturation and immunoglobulin production during normal immune responses. They produce factors essential for B cell selection and maturation into memory B-cells or long-lived antibody-secreting plasma cells. Furthermore, they also seem to favor pathogenic autoantibody production in systemic autoimmunity, and therefore could potentially represent a novel therapeutic target in autoimmune diseases. Indeed, rheumatoid arthritis synovium is characterized by the presence of ectopic lymphoid structures, resembling germinal centers. Potentially, Tfh cells from these nonlymphoid tissues could promote B-cell maturation and synthesis of pathogenic autoantibody production, thus potentiating tissue injury. Interestingly, production of IL-21 by Tfh cells is implicated in B cell activation, and the same cytokine have been associated with rheumatoid arthritis (RA) pathogenesis.
IL-6 blocking therapy significantly reduces signs and symptoms as well as radiological progression in RA. However, so far, it has not been determined which of the pleiotropic IL-6 effects impact the observed clinical response. Recently, Samson et al have demonstrated that Tocilizumab (TCZ) corrects the imbalance between Th17 cells and Treg cells in patients with RA. More interestingly, the group of Hans-Peter Tony has reported the impact of TCZ on B cell compartment. They showed a significant reduction in the frequency of peripheral pre-switch and post-switch memory B cells but also a reduction of serum immunoglobulin levels, that could be the reflect of TCZ on Tfh cells development, circulation and/or function.
Most of the work studying the role of IL-6 on Tfh cells development has been performed in mice. They showed that optimal Tfh cells formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh cells differentiation.
To better understand the impact of IL-6 on human Tfh cells, the investigators would like to conduct a prospective study in patients with active RA and investigated the effects of blocking IL-6 with TCZ on circulating Tfh cells levels and Tfh cells subsets over a 12-week study period. Furthermore, the impact of TCZ treatment on Tfh cells generation will be explored in vitro.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Tocilizumab | – | –Patients with active moderate to severe RA fulfilling ACR criteria and requiring TCZ treatment, according to the EU label and French authority recommendations, who accept to enter the study and to sign the informed consent. |
| Methotrexate | – | –Patients with active moderate to severe RA fulfilling ACR criteria and requiring MTX treatment, according to the EU label and French authority recommendations, who accept to enter the study and to sign the informed consent. |
| Healthy Controls | – | –Healthy controls will be defined as people non-affected by an inflammatory disease (such as RA, ankylosing spondylitis, lupus…). This group will be constituted with patients affected by sciatica, osteoarthritis, osteoporosis… |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- This study will be performed as a prospective observational open-labeled study (non-interventional) to evaluate the impact of TCZ treatment on the evolution of circulating Tfh cells levels. The administration of treatments (TCZ and MTX) will be done according to current practice, and will not be motivated by the inclusion in this study. TCZ will be administered in association with a conventional DMARD, or in monotherapy, according to clinical recommendations. The objective of this study is to analyze the impact of new therapy set-up, and patients included in the TCZ group would be under MTX treatment for at least 3 months. The immunological analysis will be performed with drop-off of blood samples used in the recommended follow-up of patients treated by MTX or TCZ. For the healthy controls, the immunological analysis will be performed with drop-off of blood samples used in the recommended follow-up of patients treated for osteoporosis or osteoarthritis.
Key inclusion criteria (8 listed)
- Patients with active moderate to severe RA fulfilling ACR criteria and requiring TCZ or MTX treatment, according to the EU label and French authority recommendations, who accept to enter the study and to sign the informed consent.
- Patients > 18 years
- When treated with corticosteroids: Dose ≤10mg/jour within 4 weeks before inclusion and dose stable during the study.
- When treated with MTX (0.3 mg/kg/w): Dose stable within 4 weeks before inclusion and during the study to avoid confusion on Tfh levels evaluation.
- When treated by prior anti-TNF: according to the recommendations of the French "Club Rhumatismes Inflammatoires", a wash-out period of 5 half-lives will be defined to avoid confusion in the evaluation of Tfh cells initial levels.
Key exclusion criteria (18 listed)
- Patients previously treated with TCZ
- Patients with a history of allergic reactions or Hypersensitivity to TCZor to any of the excipients
- Patients with severe and uncontrolled infections such as sepsis and opportunistic infections
- Patients with hepatitis B (with virus replication) or C, HIV-infection and tuberculosis
- Patients with history of cancer or lymphoma
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Change from Baseline in levels of circulating Tfh cells at 12 weeks for TCZ treated patients
Time frame: 12 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2019.
Related trials for Arthritis, Rheumatoid
RecruitingPhase 2
Study of PTC844 in Participants With Active Rheumatoid Arthritis
Rheumatoid Arthritis
Not yet recruitingPhase 1
An Ascending Dose Study of DKB903 in Participants With Rheumatoid Arthritis (RA) and Participants With Systemic Lupus Erythematosus (SLE)
Rheumatoid Arthritis and Systemic Lupus Erythematosus
Not yet recruitingPhase 1
R-2487 in Patients With Sjogren's Syndrome (SjD)
Sjogren's Syndrome, Sjögren
RecruitingPhase 1
A Trial in Healthy Adult Participants and Adults With Autoimmune Diseases to Test How HBM7020 is Tolerated and How it Behaves in the Body
Rheumatoid Arthritis, Systemic Lupus Erythematosus
Active, not recruitingPhase 2
A Study Evaluating the Safety and Efficacy of Inhaled AP01 in Participants With Progressive Pulmonary Fibrosis
Pulmonary Fibrosis, Progressive Pulmonary Fibrosis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Arthritis, Rheumatoid and Tocilizumab, run by Association Aquitaine de Recherche Clinique en Rhumatologie at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from Baseline in levels of circulating Tfh cells at 12 weeks for TCZ treated patients (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2019.