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

Phase 4

Completed

• Conditions: Ankylosing Spondylitis
• Interventions: Drug: 150 mg open-label secukinumab; Drug: 150 mg double-blinded secukinumab; Drug: 300 mg double-blinded secukinumab

• Registration Number: NCT03350815
• Lead Sponsor: Novartis Pharmaceuticals

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

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,

1. 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.

2. 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.

3. 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 Timeline

• Study First Submitted: 2017-10-31
• Study First Submitted QC: 2017-11-20
• Study First Posted: 2017-11-22
• Study Start: 2018-03-13
• Primary Completion: 2021-03-11
• Study Completion: 2021-05-29
• Results First Submitted: 2022-01-07
• Results First Submitted QC: 2022-03-15
• Status Verified: 2022-04
• Results First Posted: 2022-04-08
• Last Update Submitted: 2022-04-27
• Last Update Posted: 2022-04-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 322

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Responders	150 mg open-label secukinumab	Patients who achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (total score \<1.3) at both Week 12 and Week 16.
Responders	150 mg double-blinded secukinumab	Patients who achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (total score \<1.3) at both Week 12 and Week 16.
Inadequate responders	150 mg open-label secukinumab	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.
Inadequate responders	150 mg double-blinded secukinumab	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.
Inadequate responders	300 mg double-blinded secukinumab	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.
Non-responders	150 mg open-label secukinumab	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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
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.
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.
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.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇺🇸 Onalaska, Wisconsin, United States