Acquired Immunodeficiency in ANCA Associated Vasculitis (ACQUIVAS)

Acquired Immunodeficiency in ANCA (Antineutrophil Cytoplasmic Antibody) Associated Vasculitis

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.

Study Overview

• Status: Unknown
• Conditions: Systemic Vasculitis
• Intervention / Treatment: Biological: Pneumococcal Polysaccharide Conjugate vaccination and Pneumococcal Polysaccharide Vaccination

• Study Type: Interventional
• Enrollment (Anticipated): 124
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AAV patients treated with rituximab; Pneumococcal Polysaccharide Conjugate vaccination at Month 0 and then Pneumococcal Polysaccharide Vaccination at Month 6.	Biological: Pneumococcal Polysaccharide Conjugate vaccination and Pneumococcal Polysaccharide Vaccination; Pneumococcal vaccines; Other Names: Prevnar 13 and Pneumovax
Experimental: AAV patients - never received rituximab; Pneumococcal Polysaccharide Conjugate vaccination at Month 0 and then Pneumococcal Polysaccharide Vaccination at Month 6.	Biological: Pneumococcal Polysaccharide Conjugate vaccination and Pneumococcal Polysaccharide Vaccination; Pneumococcal vaccines; Other Names: Prevnar 13 and Pneumovax
Experimental: Healthy controls; Pneumococcal Polysaccharide Conjugate vaccination at Month 0 and then Pneumococcal Polysaccharide Vaccination at Month 6.	Biological: Pneumococcal Polysaccharide Conjugate vaccination and Pneumococcal Polysaccharide Vaccination; Pneumococcal vaccines; Other Names: Prevnar 13 and Pneumovax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the proportions of rituximab treated patients 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.	Measured at 28 (+/- 7) days after administration of vaccine.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunoglobulin (IgG) titres for each individual serotype in the pneumococcal vaccine	Immunoglobulin (IgG) titres for each individual serotype in the pneumococcal vaccine	Measured at month 0, 1, 6 and 7 in all participants
Number of serious adverse events, and serious adverse events specifically related to the vaccines administered	Number of serious adverse events, and serious adverse events specifically related to the vaccines administered	7 months: end of trial
Incidence, type, severity and treatment of infections experienced by participants after vaccinations	Incidence, type, severity and treatment of infections experienced by participants after vaccinations	7 months: end of trial
Changes in immunoglobulin levels	Changes in immunoglobulin levels	7 months: end of trial

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: Arthritis Research UK

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2018
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): January 1, 2021

Study Registration Dates

• First Submitted: April 13, 2018
• First Submitted That Met QC Criteria: May 2, 2018
• First Posted (Actual): May 3, 2018

Study Record Updates

• Last Update Posted (Actual): May 3, 2018
• Last Update Submitted That Met QC Criteria: May 2, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Vasculitis; Systemic Vasculitis; Physiological Effects of Drugs; Immunologic Factors; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: CCTU0155

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No