Tocilizumab Plus a Short Prednisone Taper for GCA

This is an open-label pilot study of tocilizumab (TCZ) 162 mg weekly administered subcutaneously for 52 weeks in combination with 8 weeks of oral prednisone.

This is a single center, open label study that will assess the efficacy and safety of 52 weeks of tocilizumab (TCZ) in combination with 8-weeks of prednisone in 30 patients with active giant cell arteritis (GCA). Active disease is defined as signs and/or symptoms of GCA plus increased inflammatory markers (e.g., erythrosedimentation rate \[ESR\] and/or C-reactive protein \[CRP\]).

The study will enroll subjects with new onset and with relapsing/refractory GCA, and consist of a screening phase (up to 6 weeks), a treatment phase (52 weeks) and a safety follow up phase (4 weeks).

The primary endpoint of the study, sustained remission, will be assessed at week 52.

The definition of sustained remission contains 3 elements:

1. Absence of clinical signs and symptoms of active GCA along with the normalization of the ESR (\< 40 mm/hour) and CRP (\< 10 mg/L).
2. Completion of the pre-specified prednisone taper protocol
3. Absence of disease flare (relapse) since the induction of remission by week 8.

Disease flare is defined as the re-appearance of unequivocal signs or symptoms of active GCA (with or without elevation of ESR and/or CRP) or the elevation of the ESR and/or CRP that is thought to be due to active GCA and that requires escape therapy.

Eligibility Criteria:
Inclusion Criteria:

1. Ability and willingness to provide written informed consent and to comply with the study protocol
2. Diagnosis of GCA classified per the following criteria:

   • Age 50 years or older

   AND at least one of the following:
   * Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp tenderness, temporal artery tenderness or decreased pulsation, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication)
   * Symptoms of polymyalgia rheumatica (PMR), defined as shoulder and / or hip girdle pain associated with inflammatory morning stiffness

   AND at least one of the following:
   * Cranial artery biopsy revealing features of GCA (e.g., mononuclear cell infiltration or granulomatous inflammation).
   * Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as Image result for magnetic resonance angiogram (MRA), Computed tomography angiography (CTA) , or Image result for positron emission tomography (PET) and computed tomography (CT) (PET-CT)
   * Ultrasound demonstration of features of GCA in a cranial artery.
3. New-onset or relapsing/refractory active disease defined as follows:

   * New onset: diagnosis of GCA within 6 weeks of baseline visit
   * Relapsing/refractory: diagnosis of GCA \> 6 weeks before baseline visit

AND

• Active GCA within 6 weeks of baseline visit defined as the presence of clinical signs and symptoms \[cranial or PMR\] and erythrocyte sedimentation rate (ESR) ≥ 30 mm/hour or C-reactive protein (CRP) ≥ 10 mg/L)

Exclusion Criteria:

1. General exclusion criteria

   * Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after randomization
   * Transplanted organs (except corneal transplant performed more than 3 months prior to screening)
   * Major ischemic event, unrelated to GCA, within 12 weeks of screening
2. Exclusions related to prior or concomitant therapy\*

   * Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
   * Previous treatment with cell-depleting therapies, including investigational agents, including but not limited to Campath (alemtuzumab), anti-CD4 (cluster of differentiation 4), anti-CD5, anti-CD3, anti-CD19, and anti-CD20
   * Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid irradiation
   * Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to baseline
   * Treatment with cyclosporine A, azathioprine, cyclophosphamide or Mycophenolate mofetil (MMF) within 4 weeks of baseline. Patients on methotrexate at screening will require discontinuation of this agent prior to baseline visit.
   * Treatment with etanercept within 2 weeks; infliximab, certolizumab, golimumab, abatacept, or adalimumab within 8 weeks; or anakinra within 1 week of baseline
   * Patients requiring systemic glucocorticoid therapy for conditions other than GCA, which, in the opinion of the investigator, would interfere with adherence to the fixed glucocorticoid taper regimen and/or to assessment of efficacy in response to TCZ
   * Inability, in the opinion of the investigator, to withdraw GC treatment through protocol-defined taper regimen due to suspected or established adrenal insufficiency

     * Patients treated with TCZ before will be permitted to participate in the trial if they demonstrated treatment efficacy and they did not discontinue TCZ because of an adverse effect.
3. Exclusions related to general safety

   * History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies or to prednisone
   * Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, or gastrointestinal (GI) disease
   * Current liver disease, as determined by the investigator
   * History of diverticulitis or active chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
   * Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis \[TB\] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
   * Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
   * Active TB requiring treatment within the previous 3 years. Patients treated for TB with no recurrence within 3 years are eligible
   * Untreated latent TB infection (LTBI). Patients should be screened for latent TB and, if positive, treated according to local practice guidelines prior to initiating TCZ treatment. Patients treated for LTBI within 3 years are eligible. Patients with current LTBI are eligible for enrollment one month after initiating treatment for LTBI.
   * Primary or secondary immunodeficiency (history of or currently active)
   * Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured)
   * Females of childbearing potential and females who are breastfeeding
   * Males of reproductive potential who are not willing to use an effective method of contraception, such as condom, sterilization, or true abstinence throughout study and for a minimum of 6 months after study drug therapy
   * History of alcohol, drug, or chemical abuse within 1 year prior to screening
4. Laboratory exclusions

   * ALT or AST \> 1.5 × upper limit of normal (ULN)
   * Total bilirubin \> ULN
   * Platelet count \< 100× 109/L (100,000/mm3)
   * Hemoglobin \< 85 g/L (8.5 g/dL; 5.3 mmol/L)
   * White blood cells \< 3.0 × 109/L (3000/mm3)
   * Absolute neutrophil count \< 1.0 × 109/L (1000/mm3)
   * Absolute lymphocyte count \< 0.5 × 109/L (500/mm3)