Clinical trial NCT03765788: A Placebo-controlled Phase 2 Trial to Investigate the Safety and Efficacy of Secukinumab in Giant Cell Arteritis
Official title: A Randomized, Parallel-group, Double-blind, Placebo-controlled, Multicenter Phase 2 Trial to Investigate the Safety and Efficacy of Secukinumab (AIN457) in Patients With Giant Cell Arteritis (TitAIN)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Giant Cell Arteritis
Keywords: GCA
ain457
Secukinumab
Subcutaneous
Vessel Inflammation
corticosteroid tapering
newly diagnosed or relapsing giant cell arteritis
prednisolone taper regimen
"escape"
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-12-05
Enrollment: 52
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study was designed to evaluate the efficacy and safety of secukinumab compared to placebo to maintain disease remission up to 28 weeks including corticosteroid tapering, as well as up to 1 year (52 weeks) in patients with newly diagnosed or relapsing giant cell arteritis (GCA) who were naïve to biological therapy.

Detailed description: This randomized, parallel-group, double-blind, placebo-controlled, multicenter, Phase II study was designed to evaluate the efficacy of secukinumab compared to placebo in combination with a 26-week prednisolone taper regimen in terms of sustained remission in patients with newly diagnosed or relapsing Giant Cell Arteritis (GCA) who were naïve to biological therapy. The study consisted of a Screening Period of up to 6 weeks (maximum duration), a 52-week Treatment Period and an 8-week Safety Follow-up Period

Patients who did not achieve remission by Week 12, experienced a flare after remission or could not adhere to the prednisolone taper regimen entered "escape". Upon entering "escape", patients received prednisolone at a dose determined by the physician's clinical judgment and continued to receive secukinumab or placebo in a blinded manner.

Safety evaluation was included in all visits including two safety follow-up visits performed 8 and 12 weeks after the last study drug administration.

Eligibility criteria: Inclusion Criteria:

Diagnosis of GCA classified according to the following criteria:

* Age at onset of disease ≥ 50 years.
* History of ESR ≥ 30 mm/hr or CRP ≥ 10 mg/L.
* Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication) AND/OR symptoms of polymyalgia rheumatica (PMR) defined as shoulder and/or hip girdle pain associated with inflammatory morning stiffness
* Temporal artery biopsy revealing features of GCA AND/OR
* evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), positron emission tomography-computed tomography (PET CT), or ultrasound

Patients with new onset GCA or relapsing GCA (Definition new onset: diagnosis of GCA within 6 weeks of Baseline Visit; Definition relapsing GCA: diagnosis of GCA (in accordance with inclusion criterion no. 4) \> 6 weeks before Baseline Visit and in the meantime achieved remission (absence of signs and symptoms attributable to GCA and normalization of ESR (\< 30 mm/hr) and CRP (\<10.0mg/L) included) including previous treatment with ≥ 25 mg/day prednisolone equivalent for ≥ 2 weeks.)

Active disease as defined by the presence of signs and symptoms of GCA (cranial or PMR) and elevated ESR ≥ 30 mm/hr, or CRP ≥ 10 mg/L, attributed to active GCA within 6 weeks of Baseline.

Prednisolone dose of 25-60 mg/day at Baseline.

Exclusion Criteria:

Previous exposure to secukinumab or other biologic drug directly targeting Interleukin(IL)-17 or IL-17 receptor.

Patients treated with any cell-depleting therapies including but not limited to anti-CD20 or investigational agents (e.g. anti-CD3, anti-CD4, anti-CD5 or anti-CD19).

Patients who have previously been treated with any biologic agent including but not limited to tocilizumab, sirukumab, abatacept, or tumor necrosis factor alpha (TNFα) inhibitors (infliximab, adalimumab, etanercept, certolizumab, golimumab).

Patients who have previously been treated with tofacitinib or baricitinib.

Patients treated with i.v. immunoglobulins or plasmapheresis within 8 weeks prior to Baseline.

Patients treated with cyclophosphamide, tacrolimus or everolimus within 6 months prior to Baseline.

Patients treated with hydroxychloroquine, cyclosporine A, azathioprine, sulfasalazine or mycophenolate mofetil within 4 weeks of Baseline.

Patients treated with leflunomide within 8 weeks of Baseline unless a cholestyramine washout has been performed in which case the patient must be treated within 4 weeks of Baseline.

Patients treated with an alkylating agent except for cyclophosphamide as mentioned above.

Patients requiring systemic chronic glucocorticoid therapy for any other reason than GCA.

Chronic systemic glucocorticoid therapy over the last 4 years or longer; or inability, in the opinion of the investigator, to withdraw glucocorticoid therapy through protocol-defined taper regimen due to suspected or established adrenal insufficiency.

Patients requiring chronic (i.e. not occasional "prn") high potency opioid analgesics for pain management.

Active ongoing inflammatory diseases or underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions, which in the opinion of the investigator immunosuppressed the patient and/or places the patient at unacceptable risk for participation in an immunomodulatory therapy.

History of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum creatinine level exceeding 1.8 mg/dL (159.12 μmol/L).

Screening total white blood cell (WBC) count \< 3000/μL, or platelets \< 100 000/μL or neutrophils \< 1500/μL or hemoglobin \< 8.3 g/dL (83 g/L).

Major ischemic event, unrelated to GCA, within 12 weeks of screening.

Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at screening or randomization.

Life vaccinations within 6 weeks prior to Baseline or planned vaccination during study participation until 12 weeks after last study treatment administration.

Primary outcomes:
measure: Percentage of Participants in Sustained Remission Until Week 28
timeFrame: Until week 28
Secondary outcomes:
measure: Percentage of Participants in Remission at Week 12
timeFrame: Week 12
measure: Time to First GCA Flare After Clinical Remission
timeFrame: Up to Week 52 (included)
measure: Total Cumulative Prednisolone Dose Over 28 Weeks and 52 Weeks
timeFrame: from Baseline to week 28, from baseline to week 52 weeks
measure: Percentage of Participants With GCA Who Had Sustained Remission Until Week 52
timeFrame: Until Week 52
measure: Number of Participants on Prednisolone Dose ≤ 5mg/Day
timeFrame: Week 19, Week 28, Week 52
measure: Physicians Global Assessment (PhGA) of Disease Activity: Change From Baseline Score Via Visual Analogue Scale (VAS)
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52
measure: Patients Global Assessment (PGA) of Disease Activity: Change From Baseline Via Visual Analogue Scale (VAS)
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52
measure: Change From Baseline in FACIT-Fatigue Scale
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52
measure: Change From Baseline in Short-Form (SF)-36 Questionnaire
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52
measure: Change From Baseline in EQ-5D-5L (EuroQol 5D) Questionnaire
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52
measure: Change From Baseline in Erythrocyte Sedimentation Rate (ESR)
timeFrame: Baseline, Week 28, Week 52
measure: Change From Baseline in C-Reactive Protein (CRP) Level
timeFrame: Baseline, Week 28, Week 52
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Germering
country: Germany
facility: Novartis Investigative Site
city: Herne
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Ludwigshafen
country: Germany
facility: Novartis Investigative Site
city: Luebeck
country: Germany
facility: Novartis Investigative Site
city: Trier
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Venhoff N, Schmidt WA, Lamprecht P, Tony HP, App C, Sieder C, Legeler C, Jentzsch C, Thiel J. Efficacy and safety of secukinumab in patients with giant cell arteritis: study protocol for a randomized, parallel group, double-blind, placebo-controlled phase II trial. Trials. 2021 Aug 17;22(1):543. doi: 10.1186/s13063-021-05520-1.