A Placebo-controlled Phase 2 Trial to Investigate the Safety and Efficacy of Secukinumab in Giant Cell Arteritis

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Giant Cell Arteritis

Intervention / Treatment
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* Drug: Secukinumab 300 mg, s.c.
* Drug: Prednisolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Secukinumab<br>Participants received secukinumab at a dose of 300 milligrams (mg) as subcutaneous (s.c.) injection at Baseline, Week 1,2,3,4 and then every 4 weeks thereafter through to week 48 along with a 26-week prednisolone tapering regimen. | Drug: Secukinumab 300 mg, s.c.<br>* Secukinumab 300 mg was administered by subcutaneous (s.c.) injections using 1 mL pre-filled syringes (PFSs) throughout the study.<br>* Other names: AIN457;Drug: Prednisolone<br>* Prednisolone was provided as tablets (1 mg, 5 mg, 10 mg, 20 mg tablets) for daily administration as tapered regimen from a dose of 25 mg to 60 mg at Baseline to 1 mg at Week 26 (last dose)<br>|
| Placebo Comparator: Placebo<br>Participants received placebo as subcutaneous (s.c.) injection at Baseline, Week 1,2,3,4 and then every 4 weeks thereafter through to week 48 along with a 26-week prednisolone tapering regimen. | Drug: Prednisolone<br>* Prednisolone was provided as tablets (1 mg, 5 mg, 10 mg, 20 mg tablets) for daily administration as tapered regimen from a dose of 25 mg to 60 mg at Baseline to 1 mg at Week 26 (last dose)<br>Drug: Placebo<br>* Placebo 300 mg was administered by subcutaneous (s.c.) injections using 1 mL pre-filled syringes (PFSs) throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Sustained Remission Until Week 28 | Remission was defined as the absence of flare. Sustained remission was defined as the absence of flare until Week 28 and in adherence to the protocol prednisolone taper regimen. Flare was determined by the investigator and was defined as the recurrence after remission of signs or symptoms of Giant Cell Arteritis (GCA) and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) and/or C-reactive Protein (CRP) (>/=10.0 mg/L) attributable to GCA. Patients were classified as non-responders if they did not achieve remission within 12 weeks of Baseline (remission referred to the absence of flare), were in the escape arm (this referred to patients entering escape between Baseline and Week 28), prematurely discontinued study treatment prior to Week 28 (absence of flare was checked prior to study treatment administration), did not have information to evaluate sustained remission response until Week 28. | Until week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Remission at Week 12 | Remission was defined as the absence of flare. Sustained remission was defined as the absence of flare until Week 28 and in adherence to the protocol prednisolone taper Regimen. Flare was determined by the investigator and was defined as the recurrence after remission of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) and/or CRP (>/=10.0 mg/L) attributable to GCA. Patients were classified as non-responders if they did not achieve remission within 12 weeks of Baseline (remission referred to the absence of flare), were in the escape arm (this referred to patients entering escape between Baseline and Week 28), prematurely discontinued study treatment prior to Week 28 (absence of flare was checked prior to study treatment administration), did not have information to evaluate sustained remission response until Week 28. | Week 12 | 
| Time to First GCA Flare After Clinical Remission | Flare was determined by the investigator and was defined as the recurrence after remission of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) and/or CRP (>/=10.0 mg/L) attributable to GCA. Time to first flare after remission referred to time from first day of study treatment until first post-Baseline flare. For time to first GCA flare after remission (up to and including Week 52), patients who prematurely discontinued study treatment prior to Week 52 were censored at the time of premature discontinuation and patients who completed treatment and did not have a flare were censored at their last visit in the treatment phase. Time to first GCA flare after remission was calculated using Kaplan-Meier plot of time. | Up to Week 52 (included) | 
| Total Cumulative Prednisolone Dose Over 28 Weeks and 52 Weeks | Total cumulative co-administered prednisolone treatment was summarized over time by treatment arm. Patients received a daily dose of prednisolone, which was decreased (i.e. tapered down) from Baseline to Week 26. No additional prednisolone or equivalent was permitted. | from Baseline to week 28, from baseline to week 52 weeks | 
| Percentage of Participants With GCA Who Had Sustained Remission Until Week 52 | Remission was defined as the absence of flare. Sustained remission was defined as patients without flare until Week 52 and in adherence to the protocol prednisolone taper regimen plus prednisolone-free phase from Week 27 onwards. Flare was determined by the investigator and was defined as the recurrence after remission of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) and/or CRP (>/=10.0 mg/L) attributable to GCA. Patients were classified as non-responders if they did not achieve remission within 12 weeks of Baseline (remission referred to the absence of flare), were in the escape arm (this referred to patients entering escape between Baseline and Week 28), prematurely discontinued study treatment prior to Week 28 (absence of flare was checked prior to study treatment administration), did not have information to evaluate sustained remission response until Week 28. | Until Week 52 | 
| Number of Participants on Prednisolone Dose ≤ 5mg/Day | Number of participants on co-administered prednisolone treatment ≤ 5mg/day who responded at Week 19, Week 26 and Week 52. Remission was defined as the absence of flare. Sustained remission was defined as the absence of flare until Week 28 and in adherence to the protocol prednisolone taper Regimen. There were 2 taper regimens: for patients on 40 to 60 mg/day prednisolone at Baseline and for patients on 25 to 40 mg/day prednisolone at Baseline depending on patients' prednisolone levels at Baseline. Prednisolone was tapered from a dose of 25 mg to 60 mg at Baseline to 1 mg at Week 26 [last dose]. | Week 19, Week 28, Week 52 | 
| Physicians Global Assessment (PhGA) of Disease Activity: Change From Baseline Score Via Visual Analogue Scale (VAS) | Clinician Reported Outcome: Physicians global assessment (PhGA) using a visual analogue scale (VAS) scale. VAS is a range of scores from 0-100, with lower change from baseline scores indicating a more favorable outcome and higher change from baseline scores indicating a greater disease activity. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 | 
| Patients Global Assessment (PGA) of Disease Activity: Change From Baseline Via Visual Analogue Scale (VAS) | Patient Reported Outcome: Patients global assessment (PGA) score using a VAS scale. VAS is a range of scores from 0-100, with lower change from baseline scores indicating a more favorable outcome and higher change from baseline scores indicating a greater disease activity. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 | 
| Change From Baseline in FACIT-Fatigue Scale | Patient Reported Outcome: Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue is a 13-item questionnaire with a full scale of 0 -52 that assesses self-reported fatigue and its impact upon daily activities and function. The higher the score the better functioning (less fatigue). | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 | 
| Change From Baseline in Short-Form (SF)-36 Questionnaire | Patient Reported Outcome: The SF-36 is a standardized questionnaire used to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of 8 subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. The higher the score (change from baseline) the more favorable the outcome. The values were reported by change from baseline in SF-36 domain scores. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 | 
| Change From Baseline in EQ-5D-5L (EuroQol 5D) Questionnaire | EQ-5D-5L, a self-administered questionnaire assessing health status in adults, is divided into 2 sections. The 1st section addresses 5 dimensions (mobility, self-care, usual activity, pain/discomfort, & anxiety/depression). Items are rated either no problem, slight problems, moderate problems, severe problems, or extreme problems/unable. A composite health index is defined by combining the levels for each dimension. The 2nd section measures self-rated (global) health status via vertically oriented VAS where 100 represents the best possible health state & 0 represents the worst possible health state. The EQ-5D-5L contains 6 items assessing health status via a single index value or health utility score and allows weighting by the patient of health states & generation of patient utilities. Published weights are available allowing for creation of a single summary health utility score. Scores range from 0 to 1, with lower scores representing a higher level of dysfunction. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) | ESR is a laboratory test that provides a non-specific measure of inflammation. This was assessed in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hr. A higher rate is consistent with inflammation. | Baseline, Week 28, Week 52 | 
| Change From Baseline in C-Reactive Protein (CRP) Level | The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. This was assessed in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Baseline, Week 28, Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GCA, ain457, Secukinumab, Subcutaneous, Vessel Inflammation, corticosteroid tapering, newly diagnosed or relapsing giant cell arteritis, prednisolone taper regimen, escape