Rituximab for the Otolaryngologic Manifestations of Granulomatosis With Polyangiitis

Study Overview
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Brief Summary
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This is a phase IV, single-center, randomized, placebo-controlled pilot study that will evaluate the efficacy of rituximab at inducing otolaryngologic remission in GPA patients with active otolaryngologic disease.

Detailed Description
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Patients with GPA and active ENT disease in at least two ENT domains, as defined after endoscopic visualization of the upper airway and audiometric evaluation by a single otolaryngologist using a validated GPA ENT disease activity score, will be eligible for inclusion. ENT disease may be new, grumbling or relapsing. All patients entering the trial will receive standard induction therapy with rituximab (375mg/m2 per week x 4). At week 16, patients will be randomized to receive maintenance rituximab (1000mg) every 4 months or placebo infusions. The primary outcome will be assessed at week 52. Patients will be treated with a standardized prednisone taper according to whether they had severe or limited disease at study entry, prednisone taper will be completed at week 16. The investigators plan to enroll 28 patients who will be randomized in a 1:1 fashion to rituximab or placebo. The investigators estimate accrual of these subjects will take 18 months from study initiation. Once enrolled, subjects are followed for 52 weeks until the primary endpoint is assessed.

Official Title
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Rituximab for the Otolaryngologic Manifestations of Granulomatosis With Polyangiitis

Conditions
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Granulomatosis With Polyangiitis (Wegener's Granulomatosis)

Intervention / Treatment
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* Drug: Rituximab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: GPA Specific Inclusion: Patients must have met at least 2 of the 5 modified ACR classification criteria for GPA. These do not need to be present at the time of study entry. The modified ACR criteria are: Nasal or oral inflammation, defined as the development of painful or painless oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph, defined as the presence of nodules, fixed infiltrates, or cavities Active urinary sediment, defined as microscopic hematuria (>5 red blood cells per high power field) or red blood cell casts Granulomatous inflammation on biopsy, defined as histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole) Positive anti-neutrophil cytoplasmic antibody (ANCA) test specific for proteinase-3, measured by enzyme-linked immunoassay Active GPA in the ENT domain within 1 month prior to screening, where the active disease is defined as a score of ≥2 on a GPA ENT disease activity score (7 items scored as 1= present 0= absent) performed by direct endoscopic visualization of the upper airway and audiometric evaluation by a single expert otolaryngologist. Items included in the GPA ENT disease activity score are: Bloody rhinorrhea (Daily blood stained nasal discharge) Objective stridor (Stridor assessed by doctor) Inflammation on nasal examination (Ulcers, granulation, friable mucosa on rigid nasendoscopy. Excluding crusting) Inflammation on flexible laryngoscopy (Ulcers, granulation, friable mucosa in the larynx) Inflamed TM*/middle ear (Persistent inflammation or granulation tissue in tympanic membrane/middle ear) Sudden sensorineural hearing loss (30db drop in 3 frequencies within 72 hours) Other ENT/upper airway manifestations of active GPA observed during structured ENT exam including but not limited to lacrimal gland dacryocystitis and endobronchial disease General Medical Concerns: Age 18 and older Willing and able to comply with treatment and follow-up procedures Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment. Willing and able to provide written informed consent Rituximab-Specific Concerns: ANC: > 1000/mm3 Platelets: > 100,000/mm3 Hemoglobin: > 7 gm/dL Adequate renal function as indicated by Cr >4.0mg/dl Adequate liver function as defined by AST or ALT <2x Upper Limit of Normal unless related to primary disease. Exclusion Criteria: Disease-Specific Concerns: Creatinine >4.0mg/dl Respiratory failure requiring mechanical ventilatory support Previous treatment with rituximab (Rituxan® ) within 6 months of screening History of severe allergic or anaphylactic reaction or serious infusion reaction while receiving rituximab Failure to respond to previous course of rituximab (Rituxan®) administered for treatment of GPA, as determined by the discretion of the PI 5. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies 6. Use of the maintenance immunosuppressive agent (methotrexate, azathioprine, mycophenolate mofetil or leflunomide) within 5 drug half-lives prior to baseline 7. Treatment with any other biologic agent, including belimumab, within the past 3 months of screening 8. Treatment with cyclophosphamide (oral or intravenous) within the past 1 month of screening General Medical Concerns: Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment), or lactating. Inability to comply with study and/or follow-up procedures. Rituximab-Specific Concerns: History of HIV. Presence of active infection.. New York Heart Association Classification III or IV heart disease (See Appendix D). Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. History of psychiatric disorder. At the Investigator's discretion, receipt of a live vaccine within 4 weeks prior to randomization. Positive hepatitis B or C serology is considered a potential exclusion criterion. Hepatitis B screening should include hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc) in all patients. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during Rituxan treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab Arm<br>All subjects in this arm will receive standard of care induction therapy, and then will receive two additional rituximab infusions at week 16 and week 32. | Drug: Rituximab<br>* Standard of care induction with Rituximab: 375mg/m2 weekly x 4 weeks. Once randomized, the rituximab dose will be 1000mg IV every 4 months x 2.<br>* Other names: Rituxan;|
| Placebo Comparator: Placebo Arm<br>All subjects in this arm will receive standard of care induction therapy, and then will receive two additional placebo infusions at week 16 and week 32. | Other: Placebo<br>* Will be given at two time-points (week 16 and week 32) to subjects in the Placebo Arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients in ENT remission without relapse at week 52 in each treatment group. | ENT remission is defined as a GPA ENT disease activity score of 0. | Assessed at week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of mean ENT disease activity scores between treatment arms |  | Assessed at week 52 | 
| Cumulative steroid dose |  | Assessed at week 52 | 
| Duration of steroid free remission |  | Assessed at week 52 | 
| Proportion of subject in remission without relapse and completed steroid taper |  | Assessed at week 52 | 
| Quality of Life as measured by the SNOT-22 Questionnaire |  | Assessed at week 0, 16, and 52 | 
| Change in VDI in the ENT domain |  | Assessed at week 52 | 
| Number of surgical procedures in the ENT domain required during the study period |  | Assessed at week 52 | 
| Number of ENT flares as measured by the ENT GPA DAS |  | Assessed at week 52 | 
| Number of GPA flares as measured by BVAS-WG |  | Assessed at week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Granulomatosis with Polyangiitis, Wegener's Granulomatosis, GPA, Rituximab, Rituxan, ENT GPA