TitAIN: A Placebo-controlled Phase 2 Trial to Investigate the Safety and Efficacy of Secukinumab in Giant Cell Arteritis
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Secukinumab 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.
Secukinumab 300 mg was administered by subcutaneous (s.c.) injections using 1 mL pre-filled syringes (PFSs) throughout the study.
Other Names:
Drug: Prednisolone
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)
|
| Placebo Comparator: Placebo 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
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)
Drug: Placebo
Placebo 300 mg was administered by subcutaneous (s.c.) injections using 1 mL pre-filled syringes (PFSs) throughout the study.
|
Outcome Measures
Primary Outcome Measures
- Percentage of GCA participants in sustained remission at Week 28 [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.
Secondary Outcome Measures
- Remission rate at Week 12 [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.
- Time to first GCA flare after clinical remission [Up to Week 28]
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.
- Total cumulative prednisolone dose over 28 weeks [Over 28 weeks]
Total cumulative prednisolone dose was summarized over time by treatment arm.
- Percentage of participants with GCA who had sustained remission until Week 52 [Up to 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 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.
- Percentage of patients on prednisolone dose ≤ 5mg/day [Week 19, Week 28, Week 52]
Proportion of patients on prednisolone dose ≤ 5mg/day
- Change from Baseline in physicians global assessment (PhGA) of disease activity via visual analogue scale (VAS) [Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52]
Clinician Reported Outcome: Physicians global assessment (PhGA) using a VAS scale. VAS is a range of scores from 0-100, higher scores indicate greater disease activity.
- Change from Baseline in patient global assessment (PGA) of disease activity via visual analogue scale (VAS) [Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52]
Patient Reported Outcome: Patient global assessment (PGA) score using a VAS scale. VAS is a range of scores from 0-100. Higher scores indicate greater disease activity.
- Change from Baseline in FACIT-Fatigue scale [Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52]
Patient Reported Outcome: Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue measures an individual's level of fatigue and their impact upon daily activities and function. The level of fatigue is measured on a four point Likert scale. (4 = not at all fatigued to 0 = very much fatigued)
- Change from Baseline in Short-Form (SF)-36 questionnaire [Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52]
Patient Reported Outcome: The SF-36 is a standardized questionnaire used to measure health-related quality of life and is made up of eight Domains, These are: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Score (PCS) and Mental Component Score (MCS).
- Change from Baseline in EQ (EuroQol)-5D-5L questionnaire [Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52]
Patient Reported Outcome: The EQ-5D is a standardized questionnaire used to measure the health status. It consists of two components: health state description and evaluation. Health Status is measured in five dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For the evaluation component participants evaluate their overall health status using a visual analogue scale.
- Change from Baseline in Erythrocyte Sedimentation Rate (ESR) [Baseline, Week 28, Week 52]
ESR is a laboratory test that provides a non-specific measure of inflammation. 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.
- Change from Baseline in C-Reactive Protein (CRP) Level [Baseline, Week 28, Week 52]
The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement.
Eligibility Criteria
Criteria
Inclusion Criteria:
Diagnosis of GCA classified according to the following criteria:
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Age at onset of disease ≥ 50 years.
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History of ESR ≥ 30 mm/hr or CRP ≥ 10 mg/L.
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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
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Temporal artery biopsy revealing features of GCA AND/OR
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Berlin | Germany | 13125 | |
| 2 | Novartis Investigative Site | Dresden | Germany | 01067 | |
| 3 | Novartis Investigative Site | Erlangen | Germany | 91054 | |
| 4 | Novartis Investigative Site | Freiburg | Germany | 79106 | |
| 5 | Novartis Investigative Site | Germering | Germany | 82110 | |
| 6 | Novartis Investigative Site | Herne | Germany | 44649 | |
| 7 | Novartis Investigative Site | Koeln | Germany | 50937 | |
| 8 | Novartis Investigative Site | Ludwigshafen | Germany | D-67063 | |
| 9 | Novartis Investigative Site | Luebeck | Germany | 23538 | |
| 10 | Novartis Investigative Site | Trier | Germany | 54292 | |
| 11 | Novartis Investigative Site | Wuerzburg | Germany | 97080 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CAIN457ADE11C
- 2018-002610-12