Rituximab for the Otolaryngologic Manifestations of Granulomatosis With Polyangiitis
Rituximab for the Otolaryngologic Manifestations of Granulomatosis With Polyangiitis
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.
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.
Inclusion Criteria:

 GPA Specific Inclusion:

 1. 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

 2. 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:

 3. Age 18 and older

 4. Willing and able to comply with treatment and follow-up procedures

 5. 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.

 6. 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:

 1. Creatinine >4.0mg/dl

 2. Respiratory failure requiring mechanical ventilatory support

 3. Previous treatment with rituximab (Rituxan® ) within 6 months of screening

 4. History of severe allergic or anaphylactic reaction or serious infusion reaction while
 receiving rituximab

 5. 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.