Study of Efficacy and Safety of Secukinumab in Patients With Ankylosing Spondylitis

Randomized, Double-blind, Placebo-controlled, Phase III Multicenter Study of Subcutaneous Secukinumab to Compare Efficacy at 16 Weeks With Placebo and Assess Safety and Tolerability up to 52 Weeks in Subjects With Active Ankylosing Spondylitis

The purpose of this trial is to demonstrate the clinical efficacy at week 16; and to demonstrate safety and tolerability of secukinumab compared to placebo in patients with ankylosing spondylitis at week 16 and long term safety up to Week 52.

Study Overview

• Status: Completed
• Conditions: Ankylosing Spondyloarthritis
• Intervention / Treatment: Drug: Secukinumab; Drug: Placebo

Detailed Description

This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design. A screening period running up to 10 weeks before randomization was used to assess eligibility, followed by 52 weeks of treatment.

At baseline, subjects were randomized to one of the two treatment groups:

• Group 1: 300 subjects, secukinumab 150 mg (1 mL, 150 mg/mL) s.c. pre-filled syringes (PFS) at BSL, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4
• Group 2: 150 subjects, placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, 4, 8, and 12, followed by secukinumab 150 mg (1 mL, 150 mg/mL) administration every four weeks starting at Week 16

The subjects were stratified at randomization according to the region (China and non-China). Approximately 70% of randomized subjects were from China (327 Chinese subjects) in order to evaluate the efficacy and safety in this subject population. No more than 30% TNFα inhibitor inadequate responders (TNF-IR) subjects were to be enrolled in the study.

Starting at Week 16, all subjects switched to open-label secukinumab 150 mg, including all placebo subjects; however, all subjects and investigators/site staff remained blinded to the original randomized treatment group assignment (150 mg vs placebo). Study treatment continued up to Week 48.

An end of treatment visit was done 4 weeks after last study treatment administration and a post treatment follow-up visit was done 12 weeks after last study treatment administration for all subjects (regardless of whether they completed the entire study as planned or discontinued prematurely).

Subjects were instructed in detail how to self-administer the s.c. injection using PFS. Each injection was administered into an appropriate injection site of the body (thighs, arms, or abdomen). All injections were performed at the study site. Site personnel administered the injections to subjects who were not able to, or felt insecure to self-administer. Rescue medication was not allowed until Week 20. However, subjects who were deemed by the investigator not to be benefiting from the study treatment based on safety and efficacy assessments or for any reason of their own accord were free to discontinue participation in the study at any time.

• Study Type: Interventional
• Enrollment (Actual): 458
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100029
    • Novartis Investigative Site
  • Bengbu, China, 233004
    • Novartis Investigative Site
  • Shanghai, China, 200127
    • Novartis Investigative Site
  • Shanghai, China, 200433
    • Novartis Investigative Site
  • Shanghai, China, 200040
    • Novartis Investigative Site
  • Shanghai, China
    • Novartis Investigative Site
  • Shanxi Province, China
    • Novartis Investigative Site
  • Tianjin, China, 300052
    • Novartis Investigative Site
  • Zhejiang, China
    • Novartis Investigative Site
  • Zhenjiang, China
    • Novartis Investigative Site
  • Anhui
    • Hefei, Anhui, China, 230001
      • Novartis Investigative Site
    • Hefei, Anhui, China, 230022
      • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100730
      • Novartis Investigative Site
    • Beijing, Beijing, China, 100039
      • Novartis Investigative Site
  • Fujian
    • Xiamen, Fujian, China, 361001
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
    • Guangzhou, Guangdong, China, 51000
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410008
      • Novartis Investigative Site
    • Changsha, Hunan, China, 410011
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Novartis Investigative Site
  • Shanxi
    • Taiyuan, Shanxi, China, 030001
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Xinjiang
    • Urumqi, Xinjiang, China, 830001
      • Novartis Investigative Site
• Czechia
  • Uherske Hradiste, Czechia, 686 01
    • Novartis Investigative Site
  • Czech Republic
    • Bruntal, Czech Republic, Czechia, 792 01
      • Novartis Investigative Site
    • Ostrava, Czech Republic, Czechia, 772 00
      • Novartis Investigative Site
    • Praha 11, Czech Republic, Czechia, 148 00
      • Novartis Investigative Site
    • Praha 2, Czech Republic, Czechia, 128 50
      • Novartis Investigative Site
• Korea, Republic of
  • Busan, Korea, Republic of, 602739
    • Novartis Investigative Site
  • Gwangju, Korea, Republic of, 61469
    • Novartis Investigative Site
  • Incheon, Korea, Republic of, 405 760
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 04763
    • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• United Kingdom
  • Bath, United Kingdom, BA1 1RL
    • Novartis Investigative Site
  • Doncaster, United Kingdom, DN2 5LT
    • Novartis Investigative Site
  • Hull, United Kingdom, HU16 5JQ
    • Novartis Investigative Site
  • London, United Kingdom, NW1
    • Novartis Investigative Site
  • Norwich, United Kingdom, NR1 3SR
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Wigan, United Kingdom, WN6 9EP
    • Novartis Investigative Site
  • Berkshire
    • Reading, Berkshire, United Kingdom, RG1 5AN
      • Novartis Investigative Site
  • West Yorkshire
    • Bradford, West Yorkshire, United Kingdom, BD9 6RJ
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Male or non-pregnant, non-lactating female patients at least 18 years of age

Diagnosis of moderate to severe AS with prior documented radiologic evidence (x-ray or radiologist's report) fulfilling the Modified New York criteria for AS:

• Active AS assessed by BASDAI ≥4 (0-10) at Baseline
• Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline
• Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline Patients should have had inadequate response or failure to respond to at least 2 NSAIDs at an approved dose for a minimum of 4 weeks in total and a minimum of 2 weeks for each NSAID prior to randomization, or less than 4 weeks if therapy had to be withdrawn due to intolerance, toxicity or contraindications Patients who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part of their AS therapy are required to be on a stable dose for at least 2 weeks before randomisation Patients who have been on a TNFα inhibitor (not more than one) must have experienced an inadequate response to previous or current treatment given at an approved dose for at least 3 months prior to randomization or have been intolerant to at least one administration of an anti-TNFα agent

Exclusion Criteria:

• Chest X-ray or MRI with evidence of ongoing infectious or malignant process

  • Patients taking high potency opioid analgesics
  • Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or IL-17 receptor
  • Pregnant or nursing (lactating) women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo s.c.	Drug: Placebo; Induction: 4x placebo s.c. weekly Maintenance: placebo s.c. monthly
Experimental: Secukinumab; Secukinumab 150 mg s.c. Arm includes all patients who received at least 1 dose of study drug including placebo switchers at Week 16	Drug: Secukinumab; Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly All Subjects received blinded treatment weekly starting at baseline, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until Week 16. At Week 16, Group 1 patients continued using secukinumab 150 mg and Group 2 patients started receiving secukinumab 150 mg dosing every four weeks. Treatment was provided open-label from Week 16 onward, as all patients took 150 mg s.c. every 4 weeks; however, subjects, investigators, and site staff remained blinded to initial randomized group assignment.; Other Names: AIN457

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Participants Who Achieve an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria)	ASAS20 response is defined as an improvement of ≥20% and ≥1 units on a scale of 10 in at least three of the four ASAS main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain	Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Participants Who Achieve an ASAS40 Response	ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.	The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Change in hsCRP Over Time	hsCRP is measured as a marker of inflammation from blood samples during the study The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.	Change from baseline to Week 16. The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Percentage of Participants Who Achieve an ASAS 5/6 at Week 16	The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.	Week 16: The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Participants With BASDAI Response at 16 Weeks	The BASDAI or Bath Ankylosing Spondylitis Disease Activity Index consists of a 0 through 10 scale (0 being no problem and 10 being the worst problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 5 major symptoms of AS The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.	The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Change in Short Form (36) - PCS Responders (Improvement of >= 2.5 Points) at Week 16	The Physical Component Summary (PCS) SF-36 is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.	The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Change in ASQoL Score Over Time	The Ankylosing Spondylitis Quality of Life (ASQoL) is an instrument to assess health-related quality of life among adult patients with Ankylosing Spondylitis. Each statement on the ASQoL is given a score of "1" or "0". A score of "1" is given where the item is affirmed, indicating adverse QoL. All item scores are summed to give a total score or index. Scores can range from 0 (good QoL) to 18 (poor QoL).	change from baseline to Week 16
The Proportion of Patients Who Achieve an ASAS Partial Remission	The The Assessment in SpondyloArthritis International Society (ASAS) partial remission criteria are defined as a value not above 2 units in each of the four main domains on a scale of 10 The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.	Week 16

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Merola JF, McInnes IB, Deodhar AA, Dey AK, Adamstein NH, Quebe-Fehling E, Aassi M, Peine M, Mehta NN. Effect of Secukinumab on Traditional Cardiovascular Risk Factors and Inflammatory Biomarkers: Post Hoc Analyses of Pooled Data Across Three Indications. Rheumatol Ther. 2022 Jun;9(3):935-955. doi: 10.1007/s40744-022-00434-z. Epub 2022 Mar 19.
• van der Horst-Bruinsma I, Miceli-Richard C, Braun J, Marzo-Ortega H, Pavelka K, Kivitz AJ, Deodhar A, Bao W, Porter B, Pournara E. A Pooled Analysis Reporting the Efficacy and Safety of Secukinumab in Male and Female Patients with Ankylosing Spondylitis. Rheumatol Ther. 2021 Dec;8(4):1775-1787. doi: 10.1007/s40744-021-00380-2. Epub 2021 Oct 7.
• Huang F, Sun F, Wan WG, Wu LJ, Dong LL, Zhang X, Kim TH, Sengupta R, Senolt L, Wang Y, Qiu HM, Porter B, Haemmerle S. Secukinumab provided significant and sustained improvement in the signs and symptoms of ankylosing spondylitis: results from the 52-week, Phase III China-centric study, MEASURE 5. Chin Med J (Engl). 2020 Nov 5;133(21):2521-2531. doi: 10.1097/CM9.0000000000001099.

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2016
• Primary Completion (Actual): May 14, 2018
• Study Completion (Actual): March 19, 2019

Study Registration Dates

• First Submitted: May 4, 2016
• First Submitted That Met QC Criteria: September 6, 2016
• First Posted (Estimate): September 12, 2016

Study Record Updates

• Last Update Posted (Actual): December 30, 2020
• Last Update Submitted That Met QC Criteria: December 4, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Ankylosing Spondyloarthritis; Axial spondyloarthritis
• Additional Relevant MeSH Terms: Infections; Joint Diseases; Musculoskeletal Diseases; Arthritis; Spinal Diseases; Bone Diseases; Spondylarthropathies; Bone Diseases, Infectious; Ankylosis; Spondylitis; Spondylarthritis; Spondylitis, Ankylosing
• Other Study ID Numbers: CAIN457F2308; 2015-005021-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No