ASLeap: Study Estimating the Clinical Difference Between 300 mg and 150 mg of Secukinumab Following Dose Escalation to 300 mg in Patients With Ankylosing Spondylitis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03350815
• Collaborator: (none)
• Enrollment: 322
• Locations: 65
• Arms: 3
• Actual Duration (Months): 38.5
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a study estimating the clinical difference between 300 mg and 150 mg of secukinumab following dose escalation to 300 mg in patients with ankylosing spondylitis

Condition or Disease	Intervention/Treatment	Phase
Ankylosing Spondylitis	Drug: 150 mg open-label secukinumab; Drug: 150 mg double-blinded secukinumab; Drug: 300 mg double-blinded secukinumab	Phase 4

Detailed Description

The study used a multicenter design which included an initial 16 week open-label period (Treatment Period 1) followed by a randomized, double-blind, parallel-group period (Treatment Period 2),

1. Screening: A Screening Period took place over 2 separate visits, with the first visit used to assess eligibility and to washout prohibited medications (up to 11 weeks). The second Screening Visit, which occurred at a minimum of 2 weeks prior to the Baseline Visit for all patients, was used to further assess eligibility and to initiate patients on the sensor actigraphy device and morning sleep questionnaires which collected data over the 2-week Screening Period to establish Baseline data. Note: Patients who did not require a washout, and who satisfied all inclusion and none of the exclusion criteria at the first Screening Visit, could initiate the second Screening Visit 1 (SV1) week after their first Screening Visit.

2. Treatment Period 1: Patients who met all of the inclusion criteria and none of the exclusion criteria had a Baseline Visit performed to start Treatment Period 1. During this 16-week period, all patients received open-label secukinumab 150 mg (1 x 1.0mL subcutaneously [s.c.]) at Baseline, Weeks 1, 2, 3, 4, 8, and 12.

At Week 16, patients were placed into 1 of the following groups:

1. Responders (Rs): Patients who achieved ASDAS inactive disease (total score < 1.3) at both Week 12 and Week 16 and who achieved a decrease (improvement) from Baseline in total ASDAS score at both Week 12 and Week 16.

2. Inadequate responders (IRs): Patients who had active disease, defined as an ASDAS total score of ≥ 1.3 at either Week 12 or Week 16, and who achieved a decrease (improvement) from Baseline in total ASDAS score at both Week 12 and Week 16.

3. Nonresponders: Patients who exhibited no change or an increase (worsening) from Baseline in total ASDAS score at either Week 12 or Week 16.

Note: To minimize patient burden, at the Week 16 Visit, the hs-CRP measurement that is part of the ASDAS calculation was imputed from the Week 12 hs-CRP results to allow for assignment into the groups above. Historically, hs-CRP levels have varied little between Week 12 and Week 16 or in previous studies of secukinumab in active AS.

1. Treatment Period 2: Upon completion of the Week 16 visit,

2. Responders entered Treatment Period 2 and continued to receive secukinumab 150 mg every 4 weeks through Week 48 as well as 1 matched placebo dose (s.c. injection) to maintain the integrity of the blind for the randomized IR group.

3. Inadequate responders entered Treatment Period 2 and were randomized (1:1, double blinded) to secukinumab 300 mg or secukinumab 150 mg every 4 weeks through Week 48. Patients knew that they were on secukinumab, but were blinded to dose, so they did not know whether they were receiving 150 mg or 300 mg.

4. Nonresponders were discontinued from the study at Week 16. The only condition that was placed on enrollment targets was that no less than 60% of patients (162 patients) were tumor necrosis factor alpha (TNFα) inhibitor naive (or, no more than 40% of patients were TNF-IR). In theory the percentage of TNFα inhibitor naive patients could have reached 100%, although that was not anticipated.

Patients could discontinue the study at any time. If rescue treatment with prohibited medications (as described in Section 9.4.7) occurred, patients were discontinued from the study and were to return for an End of Study Visit. The End of Study Visit was scheduled approximately 4 weeks after the last study treatment and was performed before any new treatment was initiated. After the End of Study Visit, any serious adverse events (SAEs) that occurred in the following 30 days were required to be reported.

Study Design

• Study Type: Interventional
• Actual Enrollment: 322 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This was a randomized, double-blind, parallel-group, multicenter design which included an initial 16 week open-label period (Treatment Period 1) followed by a randomized, double-blind, parallel-group period (Treatment Period 2),This was a randomized, double-blind, parallel-group, multicenter design which included an initial 16 week open-label period (Treatment Period 1) followed by a randomized, double-blind, parallel-group period (Treatment Period 2),
• Masking: Double (Participant, Investigator)
• Masking Description: Patients and Investigators will be blinded to the secukinumab dose during Treatment Period 2.
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Multicenter Study of Secukinumab to Compare 300 mg and 150 mg at Week 52 in Patients With Ankylosing Spondylitis Who Are Randomized to Dose Escalation After Not Achieving Inactive Disease During an Initial 16 Weeks of Open-label Treatment With Secukinumab 150 mg (ASLeap)
• Actual Study Start Date: Mar 13, 2018
• Actual Primary Completion Date: Mar 11, 2021
• Actual Study Completion Date: May 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Responders Patients who achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (total score <1.3) at both Week 12 and Week 16.	Drug: 150 mg open-label secukinumab; All patients in Treatment Period 1 received 150 mg s.c. injection open-label secukinumab.; Other Names: AIN457 ; Drug: 150 mg double-blinded secukinumab; Treatment Period 2 Patients who achieved responder status entered Treatment Period 2 and continued to receive 150 mg s.c. (1 s.c. injection of secukinumab 150 mg); Other Names: AIN457
Active Comparator: Inadequate responders Patients who have active disease, defined as an Ankylosing Spondylitis Disease Activity Score (ASDAS) total score of >1.3 at both Week 12 and Week 16, and who achieved a decrease (improvement) from baseline in total ASDAS score at both Week 12 and Week 16.	Drug: 150 mg open-label secukinumab; All patients in Treatment Period 1 received 150 mg s.c. injection open-label secukinumab.; Other Names: AIN457 ; Drug: 150 mg double-blinded secukinumab; Treatment Period 2 Patients who achieved responder status entered Treatment Period 2 and continued to receive 150 mg s.c. (1 s.c. injection of secukinumab 150 mg); Other Names: AIN457 ; Drug: 300 mg double-blinded secukinumab; Treatment Period 2 300 mg (2 s.c. injections of the 150 mg dose); Other Names: AIN457
Active Comparator: Non-responders Patients who exhibit no change or an increase (worsening) from baseline in total Ankylosing Spondylitis Disease Activity Score (ASDAS) score at either Week 12 or Week 16. Non-responders were not entered Treatment Period 2. Non-responders were discontinued from the study at Week 16.	Drug: 150 mg open-label secukinumab; All patients in Treatment Period 1 received 150 mg s.c. injection open-label secukinumab.; Other Names: AIN457

Outcome Measures

Primary Outcome Measures

1. The Proportion of Participants Who Achieved Inactive Disease Based on the Ankylosing Spondylitis Disease Activity Score (ASDAS) Measure [Week 52]

   Proportion of participants with inadequate response at week 16 who achieved inactive disease at Week 52 The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess disease activity in AS. The ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) were utilized to assess the disease activity status. < 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate disease activity and high disease activity, and 3.5 between high disease activity and very high disease activity.

Secondary Outcome Measures

1. The Proportion of Participants Who Achieved a Clinically Important Improvement on the Ankylosing Spondylitis Disease Activity Score (ASDAS) Scale [Baseline, Week 52]

   A reduction from baseline in ASDAS score of ≥1.1 was considered a clinically important improvement in disease activity in Ankylosing Spondylitis. In this study, ASDAS is used to estimate the difference in response between 150mg and 300mg of secukinumab. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess disease activity in AS. The ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) wias utilized to assess the disease activity status. < 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate disease activity and high disease activity, and 3.5 between high disease activity and very high disease activity.

2. Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [Baseline, Week 52]

   BASDAI is a validated assessment tool using 0 through 10 scales (0 indicating "no problem" and 10 indicating "worst problem"), to characterize six clinical domains pertaining to five major symptoms of AS perceived by the patients. Computed composite scores of 4 or greater indicate suboptimal disease control. In this study, BASDAI is used to estimate the difference in response between 150mg and 300mg of secukinumab.

3. Proportion of Patients Who Achieved Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI-50) [Baseline, Week 52]

   BASDAI-50 represents a change from baseline (improvement) of at least 50% in BASDAI score. In this study, BASDAI is used to estimate the difference in response between 150mg and 300mg of secukinumab.

4. The Proportion of Participants Who Achieved an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria) [Week 52]

   ASAS 20 response is a validated composite assessment, reflecting the proportion of treated patients who achieve within a defined time frame at least 20% improvement in score in at least 3 of a conventional set of 4 clinical domains relevant to AS and no worsening in the fourth domain. In this study, ASAS20 is used to estimate the difference in response between 150mg and 300mg of secukinumab. An ASAS20 response is defined as an improvement of ≥20% from baseline and absolute improvement from baseline of at least 1 on a 0-to-10 scale in at least 3 of the following 4 domains: patient global, total back pain, function (BASFI), and inflammation (average of the last 2 questions of the BASDAI concerning morning stiffness). An absence of deterioration from baseline (deterioration defines as ≥20% worsening and absolute worsening of at last 1 on a 0-to-10 scale) in the potential remaining domain.

5. The Proportion of Participants Who Achieved an ASAS 40 Response [Week 52]

   ASAS 40 response is a validated composite assessment, reflecting the proportion of treated patients who achieve within a defined time frame at least 40% improvement in score in at least 3 of a conventional set of 4 clinical domains relevant to AS and no worsening in the fourth domain. In this study, ASAS40 is used to estimate the difference in response between 150mg and 300mg of secukinumab. An ASAS40 response is defined as a ≥40% improvement in 3 of the 4 domains with an absolute improvement of at least 2 on a 0-to-10 scale, and no worsening in the remaining domain.

6. The Proportion of Patients Who Achieved an ASAS Partial Remission [Week 52]

   The ASAS partial remission criteria are defined as a value not above 2 units in each of the four main domains on a scale of 0-10. In this study, ASAS partial remission is used to estimate the difference in response between 150mg and 300mg of secukinumab.

7. Change in ASAS - Health Index Over Time [Baseline, Week 52]

   The ASAS-HI is a self-administered questionnaire and measures functioning and health over 17 aspects of health and 9 environmental factors in patients with spondyloarthritis. Patients score each item as "I agree" and "I do not agree". In this study, ASAS-HI is used to estimate the difference in response between 150mg and 300mg of secukinumab. Lower score indicating a better health status

8. Change in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Over Time [Baseline, Week 52]

   Fatigue was assessed using the 13-item FACIT-fatigue scale for the assessment of fatigue in cancer patients.24 The FACIT-Fatigue is a validated questionnaire that was originally developed for the precise evaluation of fatigue levels in cancer patients with anemia. It consists of 13 questions using a 5 point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added with equal weight to obtain a total score. The range of possible scores is 0-52, with 0 corresponding to the highest level of fatigue and 52 corresponding to the lowest level of fatigue.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Understand and communicate with the investigator, comply with the requirements of the study and give a written, signed and dated informed consent

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

3. Diagnosis of moderate to severe Ankylosing Spondylitis (AS) with prior documented radiologic evidence fulfilling the Modified New York criteria for AS

4. Active AS assessed by total Bath Ankylosing Spondylitis Disease Activity index (BASDAI) ≥ 4 (0-10) at baseline

5. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at baseline

6. Total back pain as measured by visual analog scale (VAS) ≥ 40 mm (0-100 mm) at baseline

7. Patients should have been on non-steroidal anti-inflammatory drugs (NSAIDs) at the maximum tolerated dose for at least 4 weeks prior to their Baseline Visit, with an inadequate response or for less than 4 weeks if withdrawn for intolerance, toxicity or contraindications

8. Stable dose of NSAIDs including Cyclooxygenase-1 (COX-1) or Cyclooxygenase-2 (COX-2) inhibitors for at least 2 weeks before their Baseline Visit

9. Patients who have been on a tumor necrosis factor alpha (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 baseline or had been intolerant upon administration of an anti-TNFα agent

Key Exclusion Criteria:

1. Total ankylosis of the spine

2. Use of other investigational drugs within 5 half-lives of enrollment, or within 4 weeks before the Baseline Visit, whichever is longer.

3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes.

4. Chest x-ray, computerized tomography (CT) scan, or chest magnetic resonance imaging (MRI) with evidence of ongoing infectious or malignant process, obtained within 3 months prior to screening and evaluated by a qualified physician.

5. Previous exposure to secukinumab or any other biologic drug directly targeting Interleukin-17 (IL-17), Interleukin-12/23 (IL-12/23), or the IL-17 receptor, or any other biologic immunomodulating agent, except those targeting TNFα

6. Patients who have taken more than one anti-TNFα agent

7. Any intramuscular or intravenous corticosteroid injection within 2 weeks before baseline

8. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before baseline

9. Previous treatment with any cell-depleting therapies

10. Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone, morphine)

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Jonesboro	Arkansas	United States	72401
2	Novartis Investigative Site	Fullerton	California	United States	92835
3	Novartis Investigative Site	Loma Linda	California	United States	92354
4	Novartis Investigative Site	Palm Desert	California	United States	92260
5	Novartis Investigative Site	Tustin	California	United States	92780
6	Novartis Investigative Site	Upland	California	United States	91786
7	Novartis Investigative Site	Aventura	Florida	United States	33180
8	Novartis Investigative Site	Boca Raton	Florida	United States	33486
9	Novartis Investigative Site	Brandon	Florida	United States	33511
10	Novartis Investigative Site	DeLand	Florida	United States	32720
11	Novartis Investigative Site	Gainesville	Florida	United States	32608
12	Novartis Investigative Site	Orlando	Florida	United States	32810
13	Novartis Investigative Site	Plantation	Florida	United States	33324
14	Novartis Investigative Site	Saint Petersburg	Florida	United States	33705
15	Novartis Investigative Site	Tamarac	Florida	United States	33321
16	Novartis Investigative Site	Tampa	Florida	United States	33609
17	Novartis Investigative Site	Zephyrhills	Florida	United States	33542
18	Novartis Investigative Site	Duluth	Georgia	United States	30096
19	Novartis Investigative Site	Springfield	Illinois	United States	62703
20	Novartis Investigative Site	Vernon Hills	Illinois	United States	60061
21	Novartis Investigative Site	Evansville	Indiana	United States	47715
22	Novartis Investigative Site	Monroe	Louisiana	United States	71203
23	Novartis Investigative Site	Cumberland	Maryland	United States	21740
24	Novartis Investigative Site	Hagerstown	Maryland	United States	21740
25	Novartis Investigative Site	Wheaton	Maryland	United States	20902
26	Novartis Investigative Site	Boston	Massachusetts	United States	02111
27	Novartis Investigative Site	Worcester	Massachusetts	United States	01655
28	Novartis Investigative Site	Ann Arbor	Michigan	United States	48109 5271
29	Novartis Investigative Site	Saint Clair Shores	Michigan	United States	48081
30	Novartis Investigative Site	Edina	Minnesota	United States	55435
31	Novartis Investigative Site	Springfield	Missouri	United States	65810
32	Novartis Investigative Site	Midland Park	New Jersey	United States	07432
33	Novartis Investigative Site	Voorhees	New Jersey	United States	08043
34	Novartis Investigative Site	Albuquerque	New Mexico	United States	87102
35	Novartis Investigative Site	Santa Fe	New Mexico	United States	87505
36	Novartis Investigative Site	Brooklyn	New York	United States	11201
37	Novartis Investigative Site	New York	New York	United States	10016
38	Novartis Investigative Site	Orchard Park	New York	United States	14127
39	Novartis Investigative Site	Potsdam	New York	United States	13676
40	Novartis Investigative Site	Minot	North Dakota	United States	58701
41	Novartis Investigative Site	Cincinnati	Ohio	United States	45219
42	Novartis Investigative Site	Dayton	Ohio	United States	45402
43	Novartis Investigative Site	Middleburg Heights	Ohio	United States	44130
44	Novartis Investigative Site	Oklahoma City	Oklahoma	United States	73103
45	Novartis Investigative Site	Corvallis	Oregon	United States	97330
46	Novartis Investigative Site	Portland	Oregon	United States	97239
47	Novartis Investigative Site	Duncansville	Pennsylvania	United States	16635
48	Novartis Investigative Site	Wexford	Pennsylvania	United States	15090
49	Novartis Investigative Site	Charleston	South Carolina	United States	29460
50	Novartis Investigative Site	Columbia	South Carolina	United States	29204
51	Novartis Investigative Site	Jackson	Tennessee	United States	38305
52	Novartis Investigative Site	Memphis	Tennessee	United States	38119
53	Novartis Investigative Site	Beaumont	Texas	United States	77701
54	Novartis Investigative Site	Colleyville	Texas	United States	76034
55	Novartis Investigative Site	Dallas	Texas	United States	75231
56	Novartis Investigative Site	Houston	Texas	United States	77025
57	Novartis Investigative Site	Houston	Texas	United States	77089
58	Novartis Investigative Site	Mesquite	Texas	United States	75150
59	Novartis Investigative Site	Salt Lake City	Utah	United States	84132
60	Novartis Investigative Site	Seattle	Washington	United States	98104
61	Novartis Investigative Site	Seattle	Washington	United States	98195
62	Novartis Investigative Site	Spokane	Washington	United States	99204
63	Novartis Investigative Site	Charleston	West Virginia	United States	25304
64	Novartis Investigative Site	Manitowoc	Wisconsin	United States	54220
65	Novartis Investigative Site	Onalaska	Wisconsin	United States	54650

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 20, 2020
• Statistical Analysis Plan - Jul 8, 2021

More Information

Additional Information:

• A Plain Language Trial Summary is available on novctrd.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03350815
• Other Study ID Numbers: CAIN457FUS06
• First Posted: Nov 22, 2017
• Last Update Posted: Apr 29, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Ankylosing spondylitis; ASDAS inactive disease; secukinumab; ASDAS
• Additional relevant MeSH terms: Spondylitis; Spondylarthritis; Spondylitis, Ankylosing; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	322 participants were enrolled at 65 sites in the United States
Pre-assignment Detail	Of 435 patients screened in the study, 322 (74.0%) completed the Screening phase.

Arm/Group Title	Period 1: Secukinumab 150 mg	Period 2: Secukinumab 300 mg (Period 1 Inadequate Responders)	Secukinumab 150 mg (Period 1 Inadequate Responders)	Secukinumab 150 mg (Period 1 Responders)
Arm/Group Description	Participants received Secukinumab 150 mg in Period 1	Participants received Secukinumab 150 mg in Period 1 were assessed as inadequate responders and randomized to receive Secukinumab 300 mg in Period 2	Participants received Secukinumab 150 mg in Period 1 were assessed as inadequate responders and continued with Secukinumab 150 mg in Period 2	Participants received Secukinumab 150 mg in Period 1 were assessed as responders and continued with Secukinumab 150 mg in Period 2
Period Title: Period 1
STARTED	322	0	0	0
Non-responders	50	0	0	0
Inadequate Responders	207	0	0	0
Responders	22	0	0	0
COMPLETED	279	0	0	0
NOT COMPLETED	43	0	0	0
Period Title: Period 1
STARTED	0	102	105	22
COMPLETED	0	86	88	22
NOT COMPLETED	0	16	17	0

Baseline Characteristics

Arm/Group Title	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 150 mg
Overall Participants	322
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	283 87.9%
>=65 years	39 12.1%
Age (Mean) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Mean]	48.02 (13.692)
Sex: Female, Male (Count of Participants)
Female	155 48.1%
Male	167 51.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	284 88.2%
Black	18 5.6%
Asian	11 3.4%
Native American	1 0.3%
Pacific Islander	0 0%
Other	3 0.9%
Unknown	5 1.6%

Outcome Measures

1. Primary Outcome

Title	The Proportion of Participants Who Achieved Inactive Disease Based on the Ankylosing Spondylitis Disease Activity Score (ASDAS) Measure
Description	Proportion of participants with inadequate response at week 16 who achieved inactive disease at Week 52 The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess disease activity in AS. The ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) were utilized to assess the disease activity status. < 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate disease activity and high disease activity, and 3.5 between high disease activity and very high disease activity.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised all patients to whom study treatment had been assigned by randomization. According to intent-to-treat principle, patients were analyzed according to the treatment they were assigned to during the randomization procedure.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg (IR)
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg (IR)
Measure Participants	102	105
Count of Participants [Participants]	9 2.8%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis (logistic regression) of ASDAS inactive disease response by visit - in Treatment Period 2 (nonresponder imputation)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.28 to 2.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	The Proportion of Participants Who Achieved a Clinically Important Improvement on the Ankylosing Spondylitis Disease Activity Score (ASDAS) Scale
Description	A reduction from baseline in ASDAS score of ≥1.1 was considered a clinically important improvement in disease activity in Ankylosing Spondylitis. In this study, ASDAS is used to estimate the difference in response between 150mg and 300mg of secukinumab. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess disease activity in AS. The ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) wias utilized to assess the disease activity status. < 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate disease activity and high disease activity, and 3.5 between high disease activity and very high disease activity.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS (defined as a patient with inadequte respinse at week 16) for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg (IR)
Arm/Group Description	AIN457 150 mg - 300 mg This Arm represents inadequate responders who received 150 mg of the intervention in Period 1 and 2	AIN457 150 mg - 150 mg
Measure Participants	102	105
Count of Participants [Participants]	6 1.9%	3 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis (logistic regression) of reduction in ASDAS >= 1.1 response by visit - in Treatment Period 2 (nonresponder imputation)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.08
	Confidence Interval	(2-Sided) 95%; 0.50 to 8.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
Description	BASDAI is a validated assessment tool using 0 through 10 scales (0 indicating "no problem" and 10 indicating "worst problem"), to characterize six clinical domains pertaining to five major symptoms of AS perceived by the patients. Computed composite scores of 4 or greater indicate suboptimal disease control. In this study, BASDAI is used to estimate the difference in response between 150mg and 300mg of secukinumab.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	83	85
Least Squares Mean (Standard Error) [Score on a scale]	0.18 (0.191)	-0.05 (0.188)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis of total BASDAI change from Week 16 using MMRM - in Treatment Period 2 (FAS)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean of Treatment Differenc
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.263
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Patients Who Achieved Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI-50)
Description	BASDAI-50 represents a change from baseline (improvement) of at least 50% in BASDAI score. In this study, BASDAI is used to estimate the difference in response between 150mg and 300mg of secukinumab.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	102	105
Count of Participants [Participants]	11 3.4%	9 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis (logistic regression) of BASDAI50 response by visit - in Treatment Period 2 (nonresponder imputation) (FAS)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.50 to 3.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	The Proportion of Participants Who Achieved an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria)
Description	ASAS 20 response is a validated composite assessment, reflecting the proportion of treated patients who achieve within a defined time frame at least 20% improvement in score in at least 3 of a conventional set of 4 clinical domains relevant to AS and no worsening in the fourth domain. In this study, ASAS20 is used to estimate the difference in response between 150mg and 300mg of secukinumab. An ASAS20 response is defined as an improvement of ≥20% from baseline and absolute improvement from baseline of at least 1 on a 0-to-10 scale in at least 3 of the following 4 domains: patient global, total back pain, function (BASFI), and inflammation (average of the last 2 questions of the BASDAI concerning morning stiffness). An absence of deterioration from baseline (deterioration defines as ≥20% worsening and absolute worsening of at last 1 on a 0-to-10 scale) in the potential remaining domain.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	102	105
Count of Participants [Participants]	19 5.9%	22 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis (logistic regression) of BASDAI20 response by visit - in Treatment Period 2 (nonresponder imputation) (FAS)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	The Proportion of Participants Who Achieved an ASAS 40 Response
Description	ASAS 40 response is a validated composite assessment, reflecting the proportion of treated patients who achieve within a defined time frame at least 40% improvement in score in at least 3 of a conventional set of 4 clinical domains relevant to AS and no worsening in the fourth domain. In this study, ASAS40 is used to estimate the difference in response between 150mg and 300mg of secukinumab. An ASAS40 response is defined as a ≥40% improvement in 3 of the 4 domains with an absolute improvement of at least 2 on a 0-to-10 scale, and no worsening in the remaining domain.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	102	105
Count of Participants [Participants]	10 3.1%	8 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis (logistic regression) of ASAS40 response by visit - in Treatment Period 2 (nonresponder imputation) (FAS)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.49 to 3.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	The Proportion of Patients Who Achieved an ASAS Partial Remission
Description	The ASAS partial remission criteria are defined as a value not above 2 units in each of the four main domains on a scale of 0-10. In this study, ASAS partial remission is used to estimate the difference in response between 150mg and 300mg of secukinumab.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	102	105
Count of Participants [Participants]	12 3.7%	12 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis (logistic regression) of ASAS partial remission response by visit - in Treatment Period 2 (nonresponder imputation) (FAS)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.44 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change in ASAS - Health Index Over Time
Description	The ASAS-HI is a self-administered questionnaire and measures functioning and health over 17 aspects of health and 9 environmental factors in patients with spondyloarthritis. Patients score each item as "I agree" and "I do not agree". In this study, ASAS-HI is used to estimate the difference in response between 150mg and 300mg of secukinumab. Lower score indicating a better health status
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	83	85
Least Squares Mean (Standard Error) [scores on a scale]	0.51 (0.320)	0.38 (0.315)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments	Statistical analysis of change from Week 16 in ASAS-Health Index using MMRM by visit - in Treatment Period 2 (FAS)
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.74 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Over Time
Description	Fatigue was assessed using the 13-item FACIT-fatigue scale for the assessment of fatigue in cancer patients.24 The FACIT-Fatigue is a validated questionnaire that was originally developed for the precise evaluation of fatigue levels in cancer patients with anemia. It consists of 13 questions using a 5 point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added with equal weight to obtain a total score. The range of possible scores is 0-52, with 0 corresponding to the highest level of fatigue and 52 corresponding to the lowest level of fatigue.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS for patients with valid assessment for this endpoint.

Arm/Group Title	Secukinumab 150 mg - 300 mg (IR)	Secukinumab 150 mg - 150 mg
Arm/Group Description	AIN457 150 mg - 300 mg	AIN457 150 mg - 150 mg
Measure Participants	83	85
Least Squares Mean (Standard Error) [Score]	-1.93 (0.954)	-0.92 (0.938)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab 150 mg - 300 mg (IR), Secukinumab 150 mg - 150 mg (IR)
	Comments
	Type of Statistical Test	Other
	Comments	Statistical hypothesis tests were not performed for this study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -3.62 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AEs were collected from first dose of study treatment until end of study treatment at week 52
Adverse Event Reporting Description	Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and up to 52 weeks
Arm/Group Title	Treatment Period 2 Secukinumab 150 mg - 150 mg (R)		Treatment Period 1 Secukinumab 150 mg		Treatment Period 2 Secukinumab 150 mg - 300 mg (IR)		Treatment Period 2 Secukinumab 150 mg - 150 mg (IR)
Arm/Group Description	Treatment Period 2 Secukinumab 150 mg - 150 mg (R)		Treatment Period 1 Secukinumab 150 mg		Treatment Period 2 Secukinumab 150 mg - 300 mg (IR)		Treatment Period 2 Secukinumab 150 mg - 150 mg (IR)
All Cause Mortality
	Treatment Period 2 Secukinumab 150 mg - 150 mg (R)		Treatment Period 1 Secukinumab 150 mg		Treatment Period 2 Secukinumab 150 mg - 300 mg (IR)		Treatment Period 2 Secukinumab 150 mg - 150 mg (IR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/322 (0%)		0/101 (0%)		0/105 (0%)
Serious Adverse Events
	Treatment Period 2 Secukinumab 150 mg - 150 mg (R)		Treatment Period 1 Secukinumab 150 mg		Treatment Period 2 Secukinumab 150 mg - 300 mg (IR)		Treatment Period 2 Secukinumab 150 mg - 150 mg (IR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		11/322 (3.4%)		7/101 (6.9%)		3/105 (2.9%)
Cardiac disorders
Atrial fibrillation	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Coronary artery disease	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Gastrointestinal disorders
Abdominal pain	0/22 (0%)		1/322 (0.3%)		1/101 (1%)		0/105 (0%)
Colitis	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Colitis ulcerative	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Constipation	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Gastrooesophageal reflux disease	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Ileus	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Vomiting	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
General disorders
Chest pain	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Infections and infestations
Cellulitis	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Tooth abscess	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Urinary tract infection	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Injury, poisoning and procedural complications
Acetabulum fracture	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Compression fracture	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Lumbar vertebral fracture	0/22 (0%)		1/322 (0.3%)		1/101 (1%)		0/105 (0%)
Pulmonary contusion	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Rib fracture	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Road traffic accident	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Traumatic haemothorax	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	0/22 (0%)		0/322 (0%)		0/101 (0%)		1/105 (1%)
Hypocalcaemia	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Hypomagnesaemia	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Type 1 diabetes mellitus	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Systemic lupus erythematosus	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/22 (0%)		0/322 (0%)		0/101 (0%)		1/105 (1%)
Bladder cancer	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Breast cancer	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Hepatic cancer	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Prostate cancer	0/22 (0%)		0/322 (0%)		0/101 (0%)		1/105 (1%)
Nervous system disorders
Migraine	0/22 (0%)		1/322 (0.3%)		1/101 (1%)		0/105 (0%)
Neuralgia	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Seizure	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Syncope	0/22 (0%)		1/322 (0.3%)		0/101 (0%)		0/105 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Pneumothorax	0/22 (0%)		0/322 (0%)		1/101 (1%)		0/105 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Period 2 Secukinumab 150 mg - 150 mg (R)		Treatment Period 1 Secukinumab 150 mg		Treatment Period 2 Secukinumab 150 mg - 300 mg (IR)		Treatment Period 2 Secukinumab 150 mg - 150 mg (IR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/22 (31.8%)		50/322 (15.5%)		30/101 (29.7%)		32/105 (30.5%)
Gastrointestinal disorders
Diarrhoea	0/22 (0%)		18/322 (5.6%)		7/101 (6.9%)		3/105 (2.9%)
Infections and infestations
Upper respiratory tract infection	0/22 (0%)		15/322 (4.7%)		6/101 (5.9%)		8/105 (7.6%)
Investigations
SARS-CoV-2 test negative	2/22 (9.1%)		2/322 (0.6%)		7/101 (6.9%)		8/105 (7.6%)
Musculoskeletal and connective tissue disorders
Ankylosing spondylitis	2/22 (9.1%)		1/322 (0.3%)		5/101 (5%)		1/105 (1%)
Arthralgia	2/22 (9.1%)		15/322 (4.7%)		6/101 (5.9%)		10/105 (9.5%)
Back pain	2/22 (9.1%)		6/322 (1.9%)		4/101 (4%)		4/105 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.