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

• ClinicalTrials.gov Identifier: NCT03765788
• Recruitment Status: Active, not recruiting
• First Posted: December 5, 2018
• Last Update Posted: July 31, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: December 3, 2018
• First Posted Date: December 5, 2018
• Last Update Posted Date: July 31, 2020
• Actual Study Start Date: January 30, 2019
• Estimated Primary Completion Date: April 7, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 29, 2020)

Percentage of participants in sustained remission until Week 28 [ Time Frame: Up to Week 28 ]

Remission was defined as the absence of flare (see below). 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.

Original Primary Outcome Measures (submitted: December 4, 2018)

1. Percentage of participants in sustained remission until Week 28 [ Time Frame: Up to Week 28 ]

Remission was defined as the absence of signs and symptoms attributable to GCA and normalization of the C-reactive protein (CRP) (less than [<] 10.0 milligram per liter [mg/L]). 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.

Current Secondary Outcome Measures (submitted: July 29, 2020)

• Remission rate at Week 12 [ Time Frame: Week 12 ]
  Remission was defined as the absence of flare (see below). 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 [ Time Frame: Up to Week 52 ]
  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 [ Time Frame: Up to Week 28, up to Week 52 ]
  Total cumulative prednisolone dose will be summarized over time by treatment arm.
• Percentage of participants in sustained remission until Week 52 [ Time Frame: Up to Week 52 ]
  Remission was defined as the absence of flare (see below). 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.
• Daily prednisolone dose ≤ 5mg [ Time Frame: 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) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 and 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) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 and 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 [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 and 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 [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 and 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 [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 and 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 [ Time Frame: Baseline until 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 [ Time Frame: Baseline until 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.

Original Secondary Outcome Measures (submitted: December 4, 2018)

• 1. Remission rate at Week 12 [ Time Frame: Week 12 ]
  Remission was defined as the absence of signs and symptoms attributable to GCA and normalization of the C-reactive protein (CRP) (less than [<] 10.0 milligram per liter [mg/L]). 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.
• 2. Time to first GCA flare after clinical remission [ Time Frame: Up to 28 weeks ]
  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.
• 3. Total cumulative prednisolone dose [ Time Frame: Week 28 ]
  Total cumulative prednisolone dose over 28 weeks will be summarized over time by treatment arm.
• 4. Change from Baseline in physicians global assessment (PhGA) of disease activity via visual analogue scale (VAS) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and 28 ]
  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.
• 5. Change from Baseline in Glucocorticoid Toxicity Index-17 (GTI-17) [ Time Frame: Baseline, Week 4, 8, 12, 16, 20, 24 and 28 ]
  Clinician Reported Outcome: The Glucocorticoid toxicity index-17 can be used to assess the clinical value of steroid-sparing therapies, as well as to measure the impact of glucocorticoid (GC) toxicity.
• 6. Change from Baseline in patient global assessment (PGA) of disease activity via visual analogue scale (VAS) [ Time Frame: Baseline, Week 4, 8, 12, 16, 20, 24 and 28 ]
  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.
• 7. Change from Baseline in FACIT-Fatigue scale [ Time Frame: Baseline, Week 4, 8, 12, 16, 20, 24 and 28 ]
  Patient Reported Outcome: FACIT-Fatigue measures an individual's level of fatigue and their impact upon daily activities and function
• 8. Change from Baseline in Short-Form (SF)-36 questionnaire [ Time Frame: Baseline, Week 4, 8, 12, 16, 20, 24 and 28 ]
  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).
• 9. Change from Baseline in EQ (EuroQol)-5D-5L questionnaire [ Time Frame: Baseline, Week 4, 8, 12, 16, 20, 24 and 28 ]
  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.
• 10. Change from Baseline to Week 28 in Erythrocyte Sedimentation Rate [ Time Frame: Baseline until Week 28 ]
  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.
• 11. Change from Baseline to Week 28 in C-Reactive Protein (CRP) Level [ Time Frame: Baseline until Week 28 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: December 4, 2018)

• 8.Minimum Serum Concentration at Steady State (Cmin,ss) of Secukinumab [ Time Frame: Baseline until Week 36 ]
  Cmin,ss is minimum model-predicted serum steady state concentration of secukinumab measured in mcg/mL.
• Optional MR substudy on changes from Baseline to Week 28 in large vessel inflammation [ Time Frame: Screening Visit 1, Week 28 ]
  Changes in large vessel inflammation assessed by MR at Week 28 as compared to Screening Visit 1.
• Optional ultrasound substudy on changes from Baseline to Week 28 in large vessel inflammation [ Time Frame: Screening Visit 1, Week 28 ]
  Changes in large vessel inflammation assessed by ultrasound at Week 28 as compared to Screening Visit 1.

Descriptive Information

• Brief Title: 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)

Brief Summary

This randomized, parallel-group, double-blind, placebo-controlled, multicenter, Phase II study is 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 are naïve to biological therapy.

The study will consist of 6-week (maximum duration) screening period, a 52-week treatment period and a 8-week safety follow-up period.

Patients who do not achieve remission by Week 12, experience a flare after remission or cannot adhere to the prednisolone taper regimen will enter "escape". Upon entering "escape", patients will receive prednisolone at a dose determined by the physician's clinical judgment and continue to receive secukinumab or placebo in a blinded manner.

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

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

Double-blind

Primary Purpose: Treatment

• Condition: Giant Cell Arteritis

Intervention

• Biological: Secukinumab 300 mg, s.c.
  Secukinumab will be administered at a dose of 300 mg as s.c. injection at Baseline, Week 1,2,3,4 and then every 4 weeks thereafter through to Week 48.
  Other Name: Cosentyx, AIN457
• Drug: Prednisolone
  Prednisolone will be administered at tapering oral doses as tablets daily for 26 weeks according to the protocol-defined schedule. Prednisolone will also be administered as escape therapy to treat disease flares in an open-label manner at a dose and duration selected by the investigator.
• Drug: Placebo to match Secukinumab, s.c.
  Placebo will be administered as s.c. injection at Baseline, Week 1,2,3,4 and then every 4 weeks thereafter through to Week 48.

Study Arms

• Experimental: Secukinumab
  Participants will receive 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.
  Interventions:

  • Biological: Secukinumab 300 mg, s.c.
  • Drug: Prednisolone
• Placebo Comparator: Placebo
  Participants will receive 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.
  Interventions:

  • Drug: Prednisolone
  • Drug: Placebo to match Secukinumab, s.c.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 15, 2020): 52
• Original Estimated Enrollment (submitted: December 4, 2018): 50
• Estimated Study Completion Date: June 2, 2021
• Estimated Primary Completion Date: April 7, 2021 (Final data collection date for primary outcome measure)

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.

Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT03765788
• Other Study ID Numbers: CAIN457ADE11C; 2018-002610-12 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: July 2020