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: Completed
• First Posted: December 5, 2018
• Results First Posted: April 26, 2023
• Last Update Posted: April 26, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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
Giant Cell Arteritis	Drug: Secukinumab 300 mg, s.c.; Drug: Prednisolone; Drug: Placebo	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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: January 30, 2019
• Actual Primary Completion Date: June 8, 2021
• Actual Study Completion Date: June 8, 2021

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 Name: AIN457; 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 :

1. Percentage of Participants in Sustained Remission Until Week 28 [ Time Frame: 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.

Secondary Outcome Measures :

1. Percentage of Participants in Remission at Week 12 [ Time Frame: 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.

2. Time to First GCA Flare After Clinical Remission [ Time Frame: Up to Week 52 (included) ]

   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.

3. Total Cumulative Prednisolone Dose Over 28 Weeks and 52 Weeks [ Time Frame: from Baseline to week 28, from baseline to week 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.
4. Percentage of Participants With GCA Who Had Sustained Remission Until Week 52 [ Time Frame: 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.

5. Number of Participants on Prednisolone Dose ≤ 5mg/Day [ Time Frame: Week 19, Week 28, Week 52 ]

   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].

6. Physicians Global Assessment (PhGA) of Disease Activity: Change From Baseline Score Via Visual Analogue Scale (VAS) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 ]
   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.
7. Patients Global Assessment (PGA) of Disease Activity: Change From Baseline Via Visual Analogue Scale (VAS) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 ]
   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.
8. Change From Baseline in FACIT-Fatigue Scale [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 ]
   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).
9. Change From Baseline in Short-Form (SF)-36 Questionnaire [ Time Frame: 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 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.
10. Change From Baseline in EQ-5D-5L (EuroQol 5D) Questionnaire [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44 & 52 ]
    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.
11. Change From Baseline in Erythrocyte Sedimentation Rate (ESR) [ Time Frame: Baseline, Week 28, Week 52 ]
    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.
12. Change From Baseline in C-Reactive Protein (CRP) Level [ Time Frame: 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. 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.

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Germany

Novartis Investigative Site

Berlin, Germany, 13125

Novartis Investigative Site

Dresden, Germany, 01067

Novartis Investigative Site

Erlangen, Germany, 91054

Novartis Investigative Site

Freiburg, Germany, 79106

Novartis Investigative Site

Germering, Germany, 82110

Novartis Investigative Site

Herne, Germany, 44649

Novartis Investigative Site

Koeln, Germany, 50937

Novartis Investigative Site

Ludwigshafen, Germany, 67063

Novartis Investigative Site

Luebeck, Germany, 23538

Novartis Investigative Site

Trier, Germany, 54292

Novartis Investigative Site

Wuerzburg, Germany, 97080

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] November 29, 2019

Statistical Analysis Plan  [PDF] July 15, 2021

More Information

Additional Information:

Clinical_Trials_Results_Word_Form-CAIN457ADE11C.docx attachment has been refreshed from the Clinical Trials Results Word Form template. Data may be populated from the following (as available) : Study (70.0), Protocol (4.22), Results(0.22) 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03765788
• Other Study ID Numbers: CAIN457ADE11C; 2018-002610-12 ( EudraCT Number )
• First Posted: December 5, 2018
• Results First Posted: April 26, 2023
• Last Update Posted: April 26, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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

• URL: https://www.clinicalstudydatarequest.com

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

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

GCA; ain457; Secukinumab; Subcutaneous; Vessel Inflammation; corticosteroid tapering; newly diagnosed or relapsing giant cell arteritis; prednisolone taper regimen; "escape"

Additional relevant MeSH terms:

Polymyalgia Rheumatica; Giant Cell Arteritis; Arteritis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Skin Diseases, Vascular; Skin Diseases; Autoimmune Diseases; Immune System Diseases; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Prednisolone; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents