Clinical trial NCT03350815: Study Estimating the Clinical Difference Between 300 mg and 150 mg of Secukinumab Following Dose Escalation to 300 mg in Patients With Ankylosing Spondylitis
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ankylosing Spondylitis
Keywords: Ankylosing spondylitis
ASDAS inactive disease
secukinumab
ASDAS
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-11-22
Enrollment: 322
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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),
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Proportion of Participants Who Achieved Inactive Disease Based on the Ankylosing Spondylitis Disease Activity Score (ASDAS) Measure
timeFrame: Week 52
Secondary outcomes:
measure: The Proportion of Participants Who Achieved a Clinically Important Improvement on the Ankylosing Spondylitis Disease Activity Score (ASDAS) Scale
timeFrame: Baseline, Week 52
measure: Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
timeFrame: Baseline, Week 52
measure: Proportion of Patients Who Achieved Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI-50)
timeFrame: Baseline, Week 52
measure: The Proportion of Participants Who Achieved an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria)
timeFrame: Week 52
measure: The Proportion of Participants Who Achieved an ASAS 40 Response
timeFrame: Week 52
measure: The Proportion of Patients Who Achieved an ASAS Partial Remission
timeFrame: Week 52
measure: Change in ASAS - Health Index Over Time
timeFrame: Baseline, Week 52
measure: Change in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Over Time
timeFrame: Baseline, Week 52
Other outcomes:
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state: Wisconsin
Study officials:
References: