Systemic Vasculitis
Conditions
Brief summary
This study will address the following hypothesis: Rituximab therapy leads to an acquired immune deficiency, as demonstrated by impaired vaccine responses, in AAV patients. Aims: 1. To investigate whether rituximab leads to immune deficiency in patients with AAV when compared to both disease and healthy controls. 2. To investigate whether the degree of immune deficiency is associated with the degree of B cell depletion. 3. To investigate whether T-independent vaccine responses are more severely affected than T-dependent vaccine responses after rituximab and whether a conjugated vaccine will overcome this postulated deficit in T independent vaccine responses.
Interventions
BIOLOGICALPneumococcal Polysaccharide Conjugate vaccination and Pneumococcal Polysaccharide Vaccination
Pneumococcal vaccines
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Arthritis Research UK
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
This is a phase IIb, open label study to evaluate the responses of patients with ANCA associated vasculitis (AAV) to pneumococcal vaccination. It has been designed primarily to assess the immunogenicity of pneumococcal vaccines in patients with AAV treated with rituximab compared to disease controls, but also to provide mechanistic information on vaccine response by comparing AAV patients and healthy controls.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
To be included in the trial all participants must: * Have given written informed consent to participate * Be aged 40 years and over For patients in Group 1 only (rituximab treated): * Have a diagnosis of AAV \[granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (eGPA)\] * Have current or historical PR3/MPO ANCA positivity by ELISA or histological confirmation of AAV * Have received ≥ 2g rituximab * Have received their last dose of rituximab at least 12 months prior to enrolment * Be in stable remission with a prednisolone dose of ≤ 5mg/day For patients in Group 2 only (disease controls who have never received rituximab): * Have a diagnosis of AAV (GPA, MPA or eGPA) * Have current or historical PR3/MPO ANCA positivity by ELISA or histological confirmation of AAV * Have received cyclophosphamide (oral or IV) as initial induction therapy * Be on stable immunosuppression for the 6 months preceding screening including prednisolone ≤ 5mg/day AND either azathioprine, methotrexate or mycophenolate mofetil (at stable or tapering dose) For healthy controls: • Healthy individuals aged 40 years and over
Exclusion criteria
The presence of any of the following will preclude participant inclusion: * Age \< 40 years * History of severe allergic or anaphylactic reactions to pneumococcal vaccinations * Pneumococcal vaccination within 5 years prior to screening * Females who are pregnant, plan to become pregnant, or breast feeding * Medical, psychiatric, cognitive or other conditions that, in the investigator's opinion, compromise the patient's ability to understand the patient information, give informed consent, comply with the trial protocol, or to complete the study. * History of malignancy within the past five years or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure. * Replacement immunoglobulin (IVIg) administered intravenously or subcutaneously in the 12 weeks prior to screening visit. For patients in Groups 1 and 2 only (AAV patients): * Presence of another multisystem autoimmune rheumatic disease * The prior receipt of more than 36g of cumulative cyclophosphamide ever (either IV or oral) For patients in group 1 only (rituximab group) • The receipt of any immune suppressing agent (azathioprine, methotrexate or mycophenolate mofetil) after rituximab For patients in Group 2 only (disease controls): * A relapse of AAV within the 6 months prior to screening which has necessitated an increase in prednisolone or azathioprine, methotrexate or MMF dose. * Previous rituximab therapy at any time For healthy controls: * Any history of any autoimmune condition * Any history of use of immune suppressing medication, including \> 4 weeks of oral glucocorticoids, within the 5 years prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Rituximab Treated Patients Compared to Disease Controls Who Respond to the Pneumococcal Polysaccharide Conjugate Vaccine. | Measured at 28 (+/- 7) days after administration of vaccine. | Response is defined as at least a twofold increase in immunoglobulins in at least 6/13 pneumococcal serotypes tested. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Have Responded by Individual Serotype in the Pneumococcal Vaccine | Measured at month 1 in all participants | Immunoglobulin (IgG) titres for each individual serotype in the pneumococcal vaccine. Response is at least a two-fold increase in immunoglobulins from month 0. |
| Number of Participants Experiencing a Serious Adverse Event, or a Serious Adverse Event Specifically Related to the Vaccines Administered | 7 months: end of trial | Number of participants experiencing a serious adverse event, or a serious adverse events specifically related to the vaccines administered |
| Number of Participants With Infections by Severity | 7 months: end of trial | Number of participants with infections by severity |
| Changes in Immunoglobulin Levels | 6 months: end of trial | Changes in immunoglobulin levels at month 6 from month 0 |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORRona Smith, MD MRCP
University of Cambridge
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 67.4 years STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 107 Participants |
| Region of Enrollment United Kingdom | 53 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 54 | 11 / 53 | 2 / 7 |
| other Total, other adverse events | 10 / 54 | 11 / 53 | 1 / 7 |
| serious Total, serious adverse events | 2 / 54 | 3 / 53 | 1 / 7 |
Outcome results
None listed