Rheumatoid ArthritisPhase 4NCT01980836
Effect of Tocilizumab to the Cellular Immune Response to Influenza Vaccine
A Phase 4 study testing Seasonal influenza vaccine in people with Rheumatoid Arthritis and Cellular Immune Response, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.
Trial summary
Patients with rheumatoid arthritis (RA) are prone to respiratory infections and therefore recommmended to receive vaccination against seasonal influenza. We and others have shown a relatively preserved humoral response to vaccination in RA patients. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Rheumatoid Arthritis, Cellular Immune Response
- What is being tested?
- Seasonal influenza vaccine
- Type of treatment
- Vaccines
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteIsrael
- Study dates
- Nov 2013to Feb 2014
- Phase
- Phase 4
- 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
Who may be able to join
- Rheumatoid Arthritis patients treated with Tocilizumab for at least 3 months
- Above the age of 18
Who cannot join
- Allergy to eggs
Trial locations and contacts
1 site in 1 country.
Israel1 site
Tel Aviv Medical Center
Tel Aviv, 64239
Ori Elkayam, M.D, 97236973668, ORIE@TLVMC.GOV.IL
Uri Arad, M.D
About this study
Official title: The Effect of Tocilizumab on the Cellular Immune Response to Seasonal Influnza Vaccine in Patients With Rheumatoid Arthritis
Patients with rheumatoid arthritis (RA) are prone to respiratory infections and therefore recommmended to receive vaccination against seasonal influenza. We and others have shown a relatively preserved humoral response to vaccination in RA patients. However, the cellular response as well as the effect of biologics such as tocilizumab on the cellular response has not been weel studied. The purpose of this study is the evaluate the effect of tocilizumab on the cellular immune response to influenza vaccine in patients with RA in comparison with healthy controls
Read the detailed description
Inclusion criteria :
- RA patients
- Above the age of 18
- Treated with tocilizumab at least 3 months
Exclusion criteria:
-egg allergy
Design of the study :
- Patients and controls will be vaccinated against sesaonal influenza. Blood will be taken the day of vaccination and 4 weeks after.
PBMC isolation The PBMCs will bere isolated from heparinized venous blood by density gradient centrifugation on Lymphoprep (Axis-Shield, Oslo, Norway) immediately after blood was drawn. The cells will be counted and suspended in RPMI 1640 supplemented with heat-inactivated 10% fetal calf serum, penicillin 100U/ml, streptomycin 0.1 mg/ml, and 2 mM L-glutamine (Biological Industries, Israel).
IFN-gamma secretion from PBMCs IFN-gamma secretion levels will be measured by ELISA in the supernatants of PBMCs that will be stimulated with either an influenza antigen mixture or with SEB, or left untreated.
Granzyme B activity assay The PBMCs will be cultured at 0.5 ml/well in 48-well plates (1.8X106 cells/well) and stimulated with an influenza antigen mix and SEB as described above. The cells will be lysed in lysis buffer (150mM NaCl, 15mM Tris, 1% Triton x100), then stored at
-760C. Granzyme B activity will be measured according to the protocol described by Gijzen et al. [13]. Briefly, frozen cell lysates will be subjected to three freeze/thaw cycles to enable the release of Granzyme B. Recombinant Granzyme B standards (Enzo Life Sciences International, Inc., PA) and cell lysates will be added in duplicate to a 96-well plate (20 µl/well). The reaction will start upon the addition of 80 μl of substrate solution containing 400 μM of Ac-IEPD-pNA substrate (Calbiochem, Darmstadt, Germany) in assay buffer (100mM HEPES pH 7.5, 10% (w/v), sucrose, 0.1% (w/v) CHAPS, and 10 mM DTT (Sigma Aldrich, Rehovot, Israel). The plate will be sealed, covered and incubated in a dark humidified chamber at 370C for 20 h. After incubation, the plate will be read at 405 nm. Granzyme B units will be calculated using a 4th order polynominal curve with a log (concentration)-log (absorbance) plot, and corrected for protein concentrations by the BCA protein assay (Thermo Scientific, IL).
The humoral response The antibody response will be measured by the HI test according to a standard WHO procedure as previously described [14]. The titer of an antiserum not showing any inhibition will be recorded as 1/10. Humoral response is defined as either a fourfold or greater rise in the titer of HI antibodies, or a rise from a non-protective baseline level (<1/40) to 1/40). Geometric mean titers of antibodies wull be calculated to assess the immunity of the whole group.
- Conditions
- Rheumatoid Arthritis, Cellular Immune Response
- Being tested
- Seasonal influenza vaccine
- Keywords
- Rheumatoid arthritis, Tocilizumab, Seasonal influenza vaccine
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Seasonal influenza vaccineBiological
| Study group | Role | What they receive |
|---|---|---|
| Seasonal influenza vaccine in tocilizumab treated RA patients | Active comparator | RA patients treated with tocilizumab Receives: Biological: Seasonal influenza vaccine |
| Seasonal influenza vaccine to Healthy controls | Active comparator | Healthy controls will be vaccinated against seasonal influenza Receives: Biological: Seasonal influenza vaccine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cellular response
As described in the study design using the Interferin gamma and granzyme B levels
Measured: 4 weeks
Secondary outcomes (1)
Humoral response
Using an hemaglutination inhibition test as described in the study design
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2013 (estimated)
- Study startNov 2013
- Primary completionFeb 2014 (estimated)
- Study completionFeb 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by Tel-Aviv Sourasky Medical CenterThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Tel-Aviv Sourasky Medical Center
- Sponsor type
- Other government
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01980836
- Sponsor's protocol ID
- TASMC-13-OE-245-CTIL
- Status last verified
- Nov 2013
- First submitted
- 4 Nov 2013
- Last updated
- 11 Nov 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Elkayam O, Amir S, Mendelson E, Schwaber M, Grotto I, Wollman J, Arad U, Brill A, Paran D, Levartovsky D, Wigler I, Caspi D, Mandelboim M. Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus among patients with rheumatic diseases. Arthritis Care Res (Hoboken). 2011 Jul;63(7):1062-7. doi: 10.1002/acr.20465.
PubMed 21425247Arad U, Tzadok S, Amir S, Mandelboim M, Mendelson E, Wigler I, Sarbagil-Maman H, Paran D, Caspi D, Elkayam O. The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab. Vaccine. 2011 Feb 11;29(8):1643-8. doi: 10.1016/j.vaccine.2010.12.072. Epub 2011 Jan 4.
PubMed 21211590
Study at a glance
From the registry record, last updated by the sponsor on 11 Nov 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Tocilizumab on the Cellular Immune Response to Seasonal Influnza Vaccine in Patients With Rheumatoid Arthritis
- ClinicalTrials.gov ID
- NCT01980836
- Acronym / sponsor ID
- TASMC-13-OE-245-CTIL
- Conditions
- Rheumatoid Arthritis, Cellular Immune Response
- Keywords
- Rheumatoid arthritis, Tocilizumab, Seasonal influenza vaccine
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Tel-Aviv Sourasky Medical CenterOther government
- Study start
- Nov 2013
- Primary completion
- Feb 2014 (estimated)
- Study completion
- Feb 2014 (estimated)
- First posted
- 11 Nov 2013 (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.
Patients with rheumatoid arthritis (RA) are prone to respiratory infections and therefore recommmended to receive vaccination against seasonal influenza. We and others have shown a relatively preserved humoral response to vaccination in RA patients. However, the cellular response as well as the effect of biologics such as tocilizumab on the cellular response has not been weel studied. The purpose of this study is the evaluate the effect of tocilizumab on the cellular immune response to influenza vaccine in patients with RA in comparison with healthy controls
Detailed description
Inclusion criteria :
- RA patients
- Above the age of 18
- Treated with tocilizumab at least 3 months
Exclusion criteria:
-egg allergy
Design of the study :
- Patients and controls will be vaccinated against sesaonal influenza. Blood will be taken the day of vaccination and 4 weeks after.
PBMC isolation The PBMCs will bere isolated from heparinized venous blood by density gradient centrifugation on Lymphoprep (Axis-Shield, Oslo, Norway) immediately after blood was drawn. The cells will be counted and suspended in RPMI 1640 supplemented with heat-inactivated 10% fetal calf serum, penicillin 100U/ml, streptomycin 0.1 mg/ml, and 2 mM L-glutamine (Biological Industries, Israel).
IFN-gamma secretion from PBMCs IFN-gamma secretion levels will be measured by ELISA in the supernatants of PBMCs that will be stimulated with either an influenza antigen mixture or with SEB, or left untreated.
Granzyme B activity assay The PBMCs will be cultured at 0.5 ml/well in 48-well plates (1.8X106 cells/well) and stimulated with an influenza antigen mix and SEB as described above. The cells will be lysed in lysis buffer (150mM NaCl, 15mM Tris, 1% Triton x100), then stored at
-760C. Granzyme B activity will be measured according to the protocol described by Gijzen et al. [13]. Briefly, frozen cell lysates will be subjected to three freeze/thaw cycles to enable the release of Granzyme B. Recombinant Granzyme B standards (Enzo Life Sciences International, Inc., PA) and cell lysates will be added in duplicate to a 96-well plate (20 µl/well). The reaction will start upon the addition of 80 μl of substrate solution containing 400 μM of Ac-IEPD-pNA substrate (Calbiochem, Darmstadt, Germany) in assay buffer (100mM HEPES pH 7.5, 10% (w/v), sucrose, 0.1% (w/v) CHAPS, and 10 mM DTT (Sigma Aldrich, Rehovot, Israel). The plate will be sealed, covered and incubated in a dark humidified chamber at 370C for 20 h. After incubation, the plate will be read at 405 nm. Granzyme B units will be calculated using a 4th order polynominal curve with a log (concentration)-log (absorbance) plot, and corrected for protein concentrations by the BCA protein assay (Thermo Scientific, IL).
The humoral response The antibody response will be measured by the HI test according to a standard WHO procedure as previously described [14]. The titer of an antiserum not showing any inhibition will be recorded as 1/10. Humoral response is defined as either a fourfold or greater rise in the titer of HI antibodies, or a rise from a non-protective baseline level (<1/40) to 1/40). Geometric mean titers of antibodies wull be calculated to assess the immunity of the whole group.
Study design
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Seasonal influenza vaccine in tocilizumab treated RA patients | Active comparator | Biological: Seasonal influenza vaccineRA patients treated with tocilizumab |
| Seasonal influenza vaccine to Healthy controls | Active comparator | Biological: Seasonal influenza vaccineHealthy controls will be vaccinated against seasonal influenza |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Rheumatoid Arthritis patients treated with Tocilizumab for at least 3 months
- Above the age of 18
Key exclusion criteria (1 listed)
- Allergy to eggs
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Seasonal influenza vaccine | Biological | Seasonal influenza vaccine in tocilizumab treated RA patients, Seasonal influenza vaccine to Healthy controls |
Primary outcome
Cellular response
Time frame: 4 weeks
As described in the study design using the Interferin gamma and granzyme B levels
1 secondary outcome
Humoral response
Time frame: 4 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Nov 2013.
- Background: PubMed 21425247Elkayam O, Amir S, Mendelson E, Schwaber M, Grotto I, Wollman J, Arad U, Brill A, Paran D, Levartovsky D, Wigler I, Caspi D, Mandelboim M. Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus among patients with rheumatic diseases. Arthritis Care Res (Hoboken). 2011 Jul;63(7):1062-7. doi: 10.1002/acr.20465.
- Background: PubMed 21211590Arad U, Tzadok S, Amir S, Mandelboim M, Mendelson E, Wigler I, Sarbagil-Maman H, Paran D, Caspi D, Elkayam O. The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab. Vaccine. 2011 Feb 11;29(8):1643-8. doi: 10.1016/j.vaccine.2010.12.072. Epub 2011 Jan 4.
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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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Seasonal influenza vaccine in people with Rheumatoid Arthritis and Cellular Immune Response, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.
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 2 inclusion and 1 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: status not confirmed, as of the sponsor's last update on 11 Nov 2013. 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 Israel. 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.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ori Elkayam Elkayam, M.D (97236973668, ORIE@TLVMC.GOV.IL), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cellular response (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01980836, which also lists 2 linked publications.
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 11 Nov 2013.