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Innovative Anti-pneumococcal Vaccine Strategies in Patients With ANCA-associated Vasculitis Receiving Rituximab Therapy (PNEUMOVAS)

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ClinicalTrials.gov Identifier: NCT03069703
Recruitment Status : Recruiting
First Posted : March 3, 2017
Last Update Posted : March 19, 2018
Sponsor:
Collaborators:
EUCLID Clinical Trials Platform
URC/CIC Cochin-Necker
CIC Cochin-Pasteur
Groupe Français d'Etude des Vascularites (GFEV)
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

The study hypothesis is that a "reinforced" pneumococcal combined vaccine strategy in patients with ANCA-associated vasculitides treated with rituximab will induce a better immune response than the current standard regimen, with an acceptable safety profile.

This study therefore aims at evaluating the immunogenicity and safety of two "reinforced" innovative pneumococcal vaccine regimen [one double dose at day0 and one double dose at day7 or a quadruple dose of 13-valent anti-pneumococcal conjugate vaccine (PCV13) followed by one dose of 23-valent unconjugated vaccine (PPV23) at month 5], compared to the standard regimen (one dose of PCV13 followed by one dose of PPV23 at month 5), in patients with ANCA-associated vasculitides receiving rituximab therapy.


Condition or disease Intervention/treatment Phase
Invasive Pneumococcal Infection Biological: PCV13 Biological: PPV23 Drug: Rituximab Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: The central laboratory performing the immunogenicity assessment (ELISA and OPA) will be blinded for the trial arm in order to limit measurement bias.
Primary Purpose: Prevention
Official Title: Multicenter Randomized Controlled Trial Comparing Immunogenicity and Safety of Two Innovative Anti-pneumococcal Vaccine Strategies to Standard Vaccination Regimen in Patients With ANCA-associated Vasculitis Receiving Rituximab Therapy
Actual Study Start Date : February 5, 2018
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : February 2022


Arm Intervention/treatment
Active Comparator: Prime-boost strategy
a single dose of 13-valent pneumococcal conjugate vaccine (Prevenar, PCV13) at Day 0 (lying within a window of ± 2 days of the first infusion of rituximab), followed by a single dose of 23-valent unconjugated vaccine (Pneumovax, PPV23) at month 5 (M5)
Biological: PCV13
one dose of PCV13 at D0 (arm A) or two double doses at D0 and D7 (Arm B) or one quadruple dose at D0 (arm C)
Other Name: Prevenar

Biological: PPV23
one dose of PPV23 at M5
Other Name: Pneumovax

Drug: Rituximab
375 mg/m2/week for 4 consecutive weeks, at Days 0 ± 2 days, Day 7 ± 2 days, Day 14 ± 2 days and Day 21 ± 2 days, as induction therapy of vasculitis flare, followed by 500 mg-rituximab infusion every 6 months as maintenance therapy, i.e. at Month 6, Month 12 and Month 18

Experimental: Innovative vaccine strategy 1
2 doses of PCV13 at Day 0 and 2 doses of PCV13 at Day 7, followed by a single dose of PPV23 at M5
Biological: PCV13
one dose of PCV13 at D0 (arm A) or two double doses at D0 and D7 (Arm B) or one quadruple dose at D0 (arm C)
Other Name: Prevenar

Biological: PPV23
one dose of PPV23 at M5
Other Name: Pneumovax

Drug: Rituximab
375 mg/m2/week for 4 consecutive weeks, at Days 0 ± 2 days, Day 7 ± 2 days, Day 14 ± 2 days and Day 21 ± 2 days, as induction therapy of vasculitis flare, followed by 500 mg-rituximab infusion every 6 months as maintenance therapy, i.e. at Month 6, Month 12 and Month 18

Experimental: Innovative vaccine strategy 2
4 doses of PCV13 at Day 0, followed by a single dose of PPV23 at M5
Biological: PCV13
one dose of PCV13 at D0 (arm A) or two double doses at D0 and D7 (Arm B) or one quadruple dose at D0 (arm C)
Other Name: Prevenar

Biological: PPV23
one dose of PPV23 at M5
Other Name: Pneumovax

Drug: Rituximab
375 mg/m2/week for 4 consecutive weeks, at Days 0 ± 2 days, Day 7 ± 2 days, Day 14 ± 2 days and Day 21 ± 2 days, as induction therapy of vasculitis flare, followed by 500 mg-rituximab infusion every 6 months as maintenance therapy, i.e. at Month 6, Month 12 and Month 18




Primary Outcome Measures :
  1. Immunogenicity [ Time Frame: 6 months ]
    Immune response at M6 against 12 pneumococcal serotypes, according to four ordered categories of response: positive response to 0-3, 4-6, 7-9, or 10-12 serotypes common to the PCV13 and PPV23 vaccines. This endpoint will be analyzed as the number and proportion of participants in each of the four response categories using a proportional odds model


Secondary Outcome Measures :
  1. Local and/or systemic solicited reactions 7 days following each vaccination [ Time Frame: 18 months ]
    proportion of participants with an event; number, nature, grade and time of occurrence.

  2. Any adverse event during the trial related or possibly related to vaccine immunization [ Time Frame: 18 months ]
    proportion of participants with an event; number, nature, grade and time of occurrence.


Other Outcome Measures:
  1. Any adverse event during the trial related to vaccine immunization and leading to discontinuation of the immunization regimen [ Time Frame: 18 months ]
    proportion of participants with an event; number, nature, grade and time of occurrence;

  2. Any serious adverse event during the study, regardless of the relationship to vaccine immunisation [ Time Frame: 18 months ]
    proportion, number, nature, grade and time of occurrence

  3. Proportion of patients with vasculitis flare according to EULAR criteria during the study period, and time to disease relapse. [ Time Frame: 18 months ]
  4. Titer of specific IgG against the 12 serotypes common to both conjugate and unconjugated vaccines (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19 A, 19F and 23F) measured by OPA at Day 0 and M6 [ Time Frame: 6 months ]
  5. Titer of specific IgG against the 3 specific serotypes of PPV23 (10A, 12F et 15B) at Day 0 and M6 [ Time Frame: 6 months ]
  6. Titer of specific IgG against the 12 serotypes common to both conjugate and unconjugated vaccines (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19 A, 19F and 23F) measured by ELISA at M1 and M5 [ Time Frame: 5 months ]
  7. Titer of specific IgG against the 12 serotypes common to both conjugate and unconjugated vaccines (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19 A, 19F and 23F) measured by ELISA at M12 and M18 [ Time Frame: 18 months ]
  8. Titer of specific IgG against the 12 serotypes common to both conjugate and unconjugated vaccines (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19 A, 19F and 23F) measured by OPA at M12 and M18 [ Time Frame: 18 months ]
  9. Frequency of occurrence of invasive pneumococcal infections in the different vaccine strategies [ Time Frame: 18 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participants with a diagnosis of ANCA-associated vasculitis, either granulomatosis with polyangiitis (GPA, Wegener) or microscopic polyangiitis (MPA), according to ACR 1990 criteria and/or revised Chapel Hill Consensus Conference definitions and/or European Medical Agency algorithm
  2. Participants (males and females) aged of 18 years or older
  3. Participants with childbearing potential having reliable contraception for all the duration of the study, such as established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that subject); surgical sterilization (hysterectomy, bilateral oophorectomy, tubal ligation) or true abstinence (when this is in line with the preferred and usual lifestyle of the subject) prior to enrollment at D0
  4. Participants with newly-diagnosed disease at the time of inclusion or presenting with a relapse of the disease. For relapsing patients, maintenance therapy at stable dose during the last 3 months will be admitted : prednisone dose ≤10 mg/day, azathioprine dose ≤3 mg/kg/day, methotrexate dose ≤25 mg/week, or mycophenolate mofetil dose ≤3 g/j
  5. Participants with an active disease defined as a BVAS ≥ 3
  6. Participants planned to receive rituximab as induction therapy using the recommended regimen (i.e. 375 mg/m2/week for 4 consecutive weeks)
  7. Participants able to give written informed consent prior to participation in the study
  8. Participants covered by social security regimen or equivalent

Exclusion Criteria:

  1. Participants with eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) or other vasculitis
  2. Participants with acute infections or chronic active infections at inclusion visit.
  3. Documented positive serology result for HIV, HBV (Ag Hbs), HCV at inclusion.
  4. Participants with disease associated with decreased immune response (splenectomy, hematopoietic stem cell transplantation, primary immune deficiency such as common variable immunodeficiency, cancer within the previous 5 years, drepanocytosis),
  5. Participants treated with rituximab within the previous 12 months,
  6. Participants who have received blood, blood products, and/or plasma derivatives including parenteral immunoglobulin preparations in the past 12 weeks before enrolment,
  7. Participants treated with new other immunosuppressive or immunomodulatory agents within the previous 3 months (including cyclophosphamide, anti-TNF-alpha, intravenous immunoglobulins, abatacept),
  8. Participants treated with prednisone dose >10 mg/day for a duration greater than 21 days before inclusion,
  9. Participants with vaccination with a conjugate anti-pneumococcal vaccine at any time,
  10. Participants with vaccination with PPV23 within the previous 3 years,
  11. Participants who have received any another vaccines within 4 weeks prior to enrolment or who are planning to receive any vaccine within the first 6 months of the study (except annual influenza vaccination which is permitted 4 weeks before and after each vaccination visit of the study and then allowed at any time during the study follow up)
  12. Pregnant women and lactation,
  13. Participants with contraindication to use rituximab,
  14. Participants with contraindication to intramuscular injections (hemophilia, anticoagulant therapy, thrombocytopenia < 50 000/mm3)
  15. Participants with hypersensitivity to previous vaccination
  16. Participants with hypersensitivity to aluminium phosphate, phenol or protein CRM197 protein from Corynebacterium diphtheria.
  17. Participants included in another investigational therapeutic study in the month prior D0. Participation to an observational research is allowed.
  18. Participants under legal guardianship or incapacitation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03069703


Contacts
Contact: Benjamin TERRIER, MD, PhD +33 1 58 41 14 61 benjamin.terrier@aphp.fr
Contact: Séverine POIGNANT, Master +33 1 58 41 12 11 severine.poignant@aphp.fr

Locations
France
Pôle de Médecine Interne, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques " Hôpital Cochin, Assistance Publique-Hôpitaux de Paris Recruiting
Paris, France, 75014
Contact: Benjamin TERRIER, MD, PhD    33 1 58 41 14 61    benjamin.terrier@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
EUCLID Clinical Trials Platform
URC/CIC Cochin-Necker
CIC Cochin-Pasteur
Groupe Français d'Etude des Vascularites (GFEV)
Investigators
Principal Investigator: Benjamin TERRIER, MD, PhD Pôle de Médecine Interne, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques " Hôpital Cochin, Assistance Publique-Hôpitaux de Paris
Study Chair: Fréderic BATTEUX, PhD Laboratoire d'Immunologie Plateforme d'immunomonitoring vaccinal Hôpital Cochin, Assistance Publique-Hôpitaux de Paris
Principal Investigator: Odile LAUNAY, MD, PhD Centre d'Investigation Clinique Cochin Pasteur Hôpital Cochin, Assistance Publique-Hôpitaux de Paris
Principal Investigator: Matthieu GROH, MD Hôpital Foch

Additional Information:
Publications:
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03069703     History of Changes
Other Study ID Numbers: P150964
2016-002888-33 ( EudraCT Number )
First Posted: March 3, 2017    Key Record Dates
Last Update Posted: March 19, 2018
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Vaccine
ANCA- associated vasculitides
pneumovax
prevenar
pneumovas

Additional relevant MeSH terms:
Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Systemic Vasculitis
Pneumococcal Infections
Vascular Diseases
Cardiovascular Diseases
Streptococcal Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Autoimmune Diseases
Immune System Diseases
Vaccines
Rituximab
Heptavalent Pneumococcal Conjugate Vaccine
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antirheumatic Agents