Study of Efficacy and Safety of Secukinumab in Psoriatic Arthritis and Axial Spondyloarthritis Patients With Active Enthesitis Including One Achilles Tendon Site

A Randomized, Double-blind, Placebo-controlled Multicenter Study of Subcutaneous Secukinumab to Demonstrate Efficacy in the Treatment of Enthesitis at the Achilles Tendon up to 1 Year in Adult Patients With Active Psoriatic Arthritis (PsA) and Axial Spondyloarthritis (axSpA) (ACHILLES)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02771210

Acronym

ACHILLES

Enrollment

204

Registered

2016-05-13

Start date

2016-08-30

Completion date

2019-12-11

Last updated

2021-05-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Axial Spondyloarthritis, Enthesitis, Psoriatic Arthritis

Keywords

Active psoriatic arthritis, Axial spondyloarthritides, Subcutaneous, Secukinumab in prefilled syringe, Enthesitis, Achilles tendon, AxSpA, PsA

Brief summary

The purpose of this study was to demonstrate efficacy, including effects on inflammation by magnetic resonance imaging (MRI) assessments, of secukinumab on Achilles tendon enthesitis for up to 1 year with a primary focus at Week 24, in patients with active Psoriatic Arthritis and axial Spondyloarthritis despite current or previous non-steroidal anti-inflammatory drugs (NSAID) and/or disease modifying anti-rheumatic drug (DMARD) and/or anti-TNFα therapy.

Detailed description

Primary endpoint was at week 24 but there was no interim Clinical Study Report. While Protocol states at chapter 9.7 that a week 24 analysis may be provided (not mandatory as per protocol), all data has been analyzed at week 52. Some of the secondary endpoints include the whole study period up to week 52 (to address questions on switching placebo to active drug)

Interventions

BIOLOGICALSecukinumab

Induction: Week 0,1,2,3 150 mg or 300 mg Secukinumab s.c. Maintenance: 150 mg or 300 mg Secukinumab s.c. every 4 weeks starting at Week 4

DRUGSecukinumab Placebo

Induction: Week 0,1,2,3 Secukinumab Placebo s.c. Maintenance: Secukinumab Placebo s.c. every 4 weeks starting at Week 4 until Week 24 followed by 150 or 300 mg Secukinumab s.c. every 4 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Intervention model description

Randomized Double-blind

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: \- Patients with Psoriatic arthritis: Diagnosis of Psoriatic arthritis as per the Classification criteria for Psoriatic Arthritis (CASPAR criteria) with symptoms for at least 6 months and active Psoriatic arthritis as assessed by ≥ 1 tender joints out of 78 and ≥ 1 swollen joints out of 76 at Baseline (dactylitis of a digit counts as one joint each). \- Patients with Axial Spondyloarthritis: Diagnosis of Axial Spondyloarthritis as per the classification of the Assessment of Spondyloarthritis International Society axial Spondyloarthritis (ASAS) criteria and objective signs of inflammation at Screening (magnetic resonance imaging (MRI) or definite radiographic sacroilitis and/or abnormal C-Reactive Protein) and active disease assessed by total Bath ankylosing spondylitis disease activity index (BASDAI) ≥ 4 (0-10) at Baseline. * Diagnosis of Achilles tendon enthesitis according to swelling and tenderness at the insertional site of the Achilles tendon into the calcaneus. * Onset of heel pain ≥ 1 month at Baseline. * Heel enthesitis that is magnetic resonance imaging (MRI)-positive according to the investigator's judgement. * Patients who have been exposed to up to two TNFα inhibitors. Key

Exclusion criteria

* Chest X-ray or chest magnetic resonance imaging (MRI) with evidence of ongoing infectious or malignant process. * Previous exposure to secukinumab or other biologic drug directly targeting Interleukin (IL)-17 or Interleukin (IL)-17 receptor. * Ongoing use of psoriasis treatments / medications (e.g. topical corticosteroids, ultraviolet (UV) therapy) at randomization. * Patients who have previously been exposed to more than two Tumor necrosis factor (TNF) inhibitors (investigational or approved). * Patients who have ever received biologic immunomodulating agents (investigational or approved), except those targeting Tumor necrosis factor (TNF) inhibitors. * Pregnant or nursing (lactating) women. * History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection.

Design outcomes

Primary

Measure	Time frame	Description
Number (%) of Patients With Resolution of Achilles Tendon Enthesitis	Week 24	Number (%) of patients with resolution of Achilles tendon enthesitis (affected foot) as assessed by respective subcomponent of Leeds enthesitis index (LEI) at Week 24. The primary analysis was performed via a logistic regression model with the factors treatment, country, and stratification factor diagnosis (PsA or axSpA); patients with a missing assessment were considered as responders if they had already met the response criterion at the time of last assessment.

Secondary

Measure	Time frame	Description
Number (%) of Patients With Improvement of Bone Marrow Edema	Week 24	Number (%) of patients with an improvement of bone marrow edema from baseline to Week 24 as assessed by the respective subcomponent of the Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) in the affected foot.
Number (%) of Patients With Resolution of Enthesitis as Assessed by LEI	Week 24	Number (%) of patients with resolution of enthesitis as assessed by the Leeds enthesitis index (LEI) at Week 24.
Mean Change of Physician's Global Assessment of Disease Activity	Week 24	Mean change of physician's global assessment (PhGA) of disease activity from baseline to Week 24 measured by Visual Analog Scale (VAS) ranging from 0 to 100, with 0 representing not severe and 100 representing very severe.
Mean Change of Patient's Global Assessment of Disease Activity	Week 24	Mean change of patient's global assessment (PGA) of disease activity from baseline to Week 24 measured by Visual Analog Scale (VAS) ranging from 0 to 100, with 0 representing not severe and 100 representing very severe.
Mean Change of Heel Pain	Week 24	Mean change of heel pain from baseline to Week 24 measured by Numeric Rating Scale (NRS) ranging from 0 to 10, with 0 representing no pain and 10 representing worst pain (e.g. pain as bad as you can imagine or worst pain imaginable).
Mean Change of Patient's Assessment of Heel Enthesopathy Activity	Week 24	Mean change of patient's assessment of heel enthesopathy activity from baseline to Week 24 measured by Visual Analog Scale (VAS) ranging from 0 to 100, with 0 representing not severe and 100 representing very severe.
Mean Change in Short Form-36 (SF-36) v2	Week 24	Mean change in Short Form-36 (SF-36) v2 as an indicator of overall health status The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. Scores range from 0 - 100 Lower scores = more disability, higher scores = less disability
Percentage of Patients With Resolution of Achilles Tendon Enthesitis After Switching From Placebo to Secukinumab	Weeks 24 and 52	Percentage of patients with resolution of Achilles tendon enthesitis (affected foot) after switching from placebo to secukinumab at Week 24
Mean Change of Heel Pain After Switching From Placebo to Secukinumab	Change from week 24 to week 52	Mean change of heel pain after switching from placebo to secukinumab from Week 24 to week 52 measured by Numeric Rating Scale (NRS) ranging from 0 to 10, with 0 representing no pain and 10 representing worst pain (e.g. pain as bad as you can imagine or worst pain imaginable).
Mean Change of Physician's Assessment of Heel Enthesopathy Activity	Week 24	Mean change of physician's assessment of heel enthesopathy activity from baseline to Week 24 measured by Visual Analog Scale (VAS) ranging from 0 to 100, with 0 representing not severe and 100 representing very severe.

Countries

Bulgaria, Czechia, Germany, Greece, Italy, Slovakia, Spain, United Kingdom

Participant flow

Recruitment details

304 patients were screened. Of these, 94 patients discontinued during screening phase, 6 patients were re-screened and 204 patients completed the screening phase and were randomized in the trial.

Pre-assignment details

A total of 175 patients (85.8%) completed treatment period 1 (up to Week 24); 29 patients (14.2%) discontinued study treatment in treatment period 1. A total of 170 patients (83.3%) completed treatment period 2 (up to Week 52); 5 patients (2.5%) discontinued in treatment period 2.

Participants by arm

Arm	Count
Secukinumab Secukinumab 150 mg or 300 mg s.c., administered at baseline, weeks 1, 2, 3, 4 and every 4 weeks until week 24, followed by Secukinumab 150 or 300 mg s.c. every 4 weeks; respective dose was assigned according to underlying condition, in case of PsA according to severity of concomitant Psoriasis or preexposure to anti-TNFα	102
Placebo Placebo 150 mg or 300 mg s.c., administered at baseline, weeks 1, 2, 3, 4 and every 4 weeks until week 24, followed by Secukinumab 150 or 300 mg s.c. every 4 weeks; respective dose was assigned according to underlying condition, in case of PsA according to severity of concomitant Psoriasis or preexposure to anti-TNFα	102
Total	204

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1	Adverse Event	5	3
Period 1	Lack of Efficacy	3	6
Period 1	Lost to Follow-up	2	0
Period 1	Physician Decision	0	1
Period 1	Withdrawal by Subject	0	3
Period 1	Withdrawal of informed consent	1	5
Period 2	Adverse Event	1	0
Period 2	Lack of Efficacy	0	1
Period 2	Withdrawal by Subject	1	0
Period 2	Withdrawal of informed consent	0	2

Baseline characteristics

Characteristic	Secukinumab	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	5 Participants	7 Participants	12 Participants
Age, Categorical Between 18 and 65 years	97 Participants	95 Participants	192 Participants
Age, Continuous	47.8 Years STANDARD_DEVIATION 11.33	47.7 Years STANDARD_DEVIATION 11.02	47.7 Years STANDARD_DEVIATION 11.18
Race/Ethnicity, Customized Asian	2 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Black	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Caucasian	99 Participants	99 Participants	198 Participants
Race/Ethnicity, Customized Other	1 Participants	2 Participants	3 Participants
Sex/Gender, Customized Female	58 Participants	55 Participants	113 Participants
Sex/Gender, Customized Male	44 Participants	47 Participants	91 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 102	0 / 102
other Total, other adverse events	33 / 102	34 / 102
serious Total, serious adverse events	7 / 102	6 / 102

Outcome results

Primary

Number (%) of Patients With Resolution of Achilles Tendon Enthesitis

Number (%) of patients with resolution of Achilles tendon enthesitis (affected foot) as assessed by respective subcomponent of Leeds enthesitis index (LEI) at Week 24. The primary analysis was performed via a logistic regression model with the factors treatment, country, and stratification factor diagnosis (PsA or axSpA); patients with a missing assessment were considered as responders if they had already met the response criterion at the time of last assessment.

Time frame: Week 24

Population: Full analysis set (FAS) included all patients to whom study medication had been assigned.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Secukinumab	Number (%) of Patients With Resolution of Achilles Tendon Enthesitis	43 Participants
Placebo	Number (%) of Patients With Resolution of Achilles Tendon Enthesitis	32 Participants

p-value: 0.13695% CI: [0.87, 3.08]Regression, Logistic

Secondary

Mean Change in Short Form-36 (SF-36) v2

Mean change in Short Form-36 (SF-36) v2 as an indicator of overall health status The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. Scores range from 0 - 100 Lower scores = more disability, higher scores = less disability

Time frame: Week 24