The primary objective is to compare both ixekizumab regimens (80 mg Q2W or 80 mg Q4W) versus placebo in patients with active nonrad-axSpA at Week 16The major secondary objectives is to compare both ixekizumab regimens (80 mg Q2W or 80 mg Q4W versus…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of patients achieving an Assessment of Spondyloarthritis
International Society 40 (ASAS40) response
Secondary outcome
Secondary study parameters:
• Proportion of patients achieving an ASAS40 response at Week 52
• Change from baseline in ASDAS at Week 52
• Change from baseline in (BASFI) at Week 16
• Change from baseline in BASFI at Week 52
• Proportion of patients achieving ASDAS inactive disease at Week 16
• Proportion of patients achieving ASDAS inactive disease at Week 52
• Change from baseline in MRI of the (SIJ) [SPARCC] score) at Week 16
• Percent of patients without clinically meaningful changes in background
therapy at Week 52
• Proportion of patients who achieve ASAS20, ASAS40, ASAS5/6, and partial
remission by ASAS criteria
• Change from baseline in the individual components of the ASAS criteria
• Change from baseline in (BASDAI)
• Proportion of patients reaching BASDAI50
• Change from baseline in (ASDAS)
• Proportion of patients who experience clinically important improvement
(change of ASDAS from baseline >=1.1), major improvement (change
of ASDAS from baseline >=2.0), or inactive disease (ASDAS <1.3)
• Change from baseline in the measure of CRP
• Change from baseline in BASFI
• Change from baseline in mobility
• Bath Ankylosing Spondylitis Metrology Index (BASMI) (linear) and individual
components
• Chest expansion
• Change from baseline in occiput to wall distance
• Change from baseline to Week 52 in MRI of the SIJ (SPARCC score)
• Change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score
(MASES)
• Change from baseline in SPARCC Enthesitis Score
• The incidence and severity of peripheral arthritis by tender and swollen
joint count scores of 46/44 joints
• Incidence rate of anterior uveitis or uveitis flares
• Change from baseline in the following health outcome measures: Fatigue (NRS)
score, (ASAS-HI) score, Jenkins Sleep Evaluation
Questionnaire (JSEQ), Work Productivity Activity Impairment*
Spondyloarthritis (WPAI-SpA) scores, SF-36
• NSAID intake (ASAS-NSAID score and % of patients taking NSAIDs)
• Onset of action and treatment response (ASAS, ASDAS, CRP, BASFI)
• Efficacy response rates listed below at Weeks 16 and 52 by treatment-emergent
anti-drug antibody (TE-ADA) status and by neutralizing anti-
drug antibody (NAb) status
• Proportion of patients achieving ASAS40
• Proportion of patients achieving ASAS20
• Proportion of patients achieving ASDAS inactive disease
• Serum trough concentrations of ixekizumab
• Model parameters for the exposure-response relationship between ixekizumab
serum trough concentrations and efficacy endpoints (for
example, ASAS20, ASAS40) at Week 16 and/or Week 52
• Ixekizumab serum trough concentrations associated with anti-drug antibody
(ADA) titer
• Biomarkers contained in blood (including mRNA and DNA), serum, plasma, and
urine samples
Background summary
Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly
affecting the axial skeleton (sacroiliac joints and spine) with onset of
symptoms that typically appear in the second or third decade of life. AxSpA
affects up to 1.4% of the Caucasian adult population worldwide. Current
standard of care for nonrad-axSpA includes regular exercise, physical therapy,
and nonsteroidal anti-inflammatory drugs (NSAIDs). TNF inhibitors have also
demonstrated efficacy in nonrad-axSpA; however, they are not yet approved
globally for this indication, and approximately 40% of patients only obtain a
partial response on TNF inhibitors. Corticosteroid injections may also be of
some benefit. Though NSAIDs are the first line of drug treatment for axSpA,
they are not effective or well tolerated in all patients. In contrast to
patients with RA, patients with axSpA do not respond well to conventional
disease-modifying antirheumatic drugs (cDMARDs) or systemic corticosteroids.
Ixekizumab (LY2439821) is a humanized immunoglobulin G subclass 4 (IgG4)
monoclonal antibody (MAb) that neutralizes the cytokine interleukin-17A
(IL-17A, also known as IL-17). Compelling scientific evidence exists
indicating an important role of the IL-23/IL-17 pathway in axSpA pathogenesis.
Recently disclosed data from Phase 3 studies with secukinumab (Cosentyx®), a
drug with a similar mechanism of action (MoA) as ixekizumab, have demonstrated
the effectiveness of inhibiting IL-17A in patients with radiographic-axial
spondyloarthritis (rad-axSpA, also called Ankylosing Spondylitis) who were
biological disease modifying antirheumatic drug (bDMARD) naive or had
previously received tumor necrosis factor (TNF) inhibitors. The present study
evaluates the efficacy and safety of ixekizumab in nonradiographic-axSpA
(nonrad-axSpA) patients who are bDMARD naive.
Study objective
The primary objective is to compare both ixekizumab regimens (80 mg Q2W or 80
mg Q4W) versus placebo in patients with active nonrad-axSpA at Week 16
The major secondary objectives is to compare both ixekizumab regimens (80 mg
Q2W or 80 mg Q4W versus placebo in patients with active nonrad-axSpA at Week 16
and Week 52.
Other secondary objectives are:
• To compare both ixekizumab regimens (80mg Q2W or 80mg Q4W) to placebo during
the 52-week period
• To explore the effect of starting dose (160 mg compared to 80 mg)
• To evaluate the incidence of anti-ixekizumab antibodies and its relationship
to efficacy of ixekizumab
• To measure ixekizumab exposure and assess the relationship between exposure
and efficacy and exposure and immunogenicity
The main exploratory objective is to explore biomarkers related to the disease
or to the IL23/IL-17 pathway.
Study design
Study I1F-MC-RHBX (RHBX) is a Phase 3, multicenter, randomized, double-blind,
placebo controlled, parallel-group, outpatient study examining the efficacy and
safety of 2 ixekizumab treatment regimens (80 mg Q2W and 80 mg Q4W SC) as
compared to placebo SC in patients with active nonrad-axSpA who are bDMARD
naive, during a double blind, 52 week treatment period (Period 2). The study
has 3 treatment groups during the 52-week Blinded Treatment Dosing Period: 80
mg ixekizumab Q4W, 80 mg ixekizumab Q2W, and placebo at a 1:1:1 ratio. In each
ixekizumab treatment group, half of the patients will receive an 80 mg starting
dose and half a 160 mg starting dose (1:1 randomization). Randomization will
be stratified by country and baseline MRI/CRP status (positive MRI and elevated
C-reactive protein [CRP]; positive MRI and nonelevated CRP; negative MRI and
elevated CRP). All doses are administered via SC injection. This study will
include approximately 300 randomized patients.
Intervention
The Blinded Treatment Dosing Period (Period 2) involves a comparison of
ixekizumab at 2 treatment regimens (80 mg Q2W and 80 mg Q4W) with placebo
treatment. Each ixekizumab treatment regimen will include patients receiving
an 80 mg or a 160 mg starting dose; patients will be randomized to a starting
dose at a 1:1 ratio. All doses are administered via SC injection.
At baseline (Week 0), all patients will be randomized to a treatment group and
receive 2 injections. Patients assigned to an ixekizumab treatment regimen
with a 160 mg ixekizumab starting dose will receive 160 mg of ixekizumab as 2
SC injections (80 mg per SC injection). Patients assigned to an ixekizumab
treatment regimen with an 80 mg starting dose will receive 80 mg of ixekizumab
as 1 SC injection and 1 SC injection of placebo. Patients assigned to the
placebo treatment group will receive 2 SC injections of placebo. After Week 0
and through Week 50, all patients will receive 1 injection every 2 weeks.
Beginning at Week 16 and up to Week 44, any patient, regardless of their
original treatment group, may be identified by an investigator based on
clinical judgment as an inadequate responder. At such time, changes in
background therapy and/or addition of biologic rescue therapy (ixekizumab 80mg
Q2W) can be made at the discretion of the investigator, while remaining blinded
to the original randomization treatment assignment.
Study burden and risks
The Investigational Product and other medication required by Protocol and the
study procedures are associated with certain risks and discomforts, as
described in the patient information leaflet. The combination of experimental
medicine and study procedures may be associated with additional risks or
discomforts that at this point are not fully known. The most common side
effects associated with lxekizumab are: Runny nose and sore throat; cold
symptoms; Upper respiratory tract infection; injection site reaction; Headache;
Worsening of rheumatoid arthritis; Urinary tract Infection; Sinus irritation;
Injection site pain; Injection site redness; Diarrhea; Back pain; Bronchitis;
High blood pressure; Dizziness; Joint pain; Cough; Nausea; Vertigo.
The subjects undergo an number of study procedures such as SC injections, blood
collections, TB skin test, x-rays, MRI, and ECG tests. These procedures may
also be accompanied by certain risks. The procedures may also have other
unknown risks. These risks are described in the Informed consent form.
Selectively targeting IL-17A with ixekizumab is hypothesized to provide
therapeutic benefit without unduly impacting host defenses. As such,
ixekizumab may offer a therapeutic option for patients who have failed NSAIDs
and for patients who have lost response, failed to respond, or are intolerant
to current marketed drugs. Ixekizumab may offer a more favorable safety
profile compared to currently marketed therapies.
Papendorpseweg 83
Utrecht 3528 BJ
NL
Papendorpseweg 83
Utrecht 3528 BJ
NL
Listed location countries
Age
Inclusion criteria
Presence of sacroiliitis on MRI (according to ASAS/OMERACT criteria and based on central reading) (Rudwaleit et al. 2009d) and have at least 1 SpA feature ;OR;Are positive for HLA-B27 and have at least 2 additional SpA features, according to the ASAS criteria (Sieper et al. 2009; Rudwaleit et al. 2009a) SpA features listed in Appendix 5 ;Patients have a history of back pain >=3 months with age at onset <45 years. ;Have active nonrad-axSpA defined as BASDAI >=4 and total back pain >=4 on a NRS at screening and baseline (Sieper et al. 2009) ;Patients have objective signs of inflammation by presence of sacroiliitis on MRI (as defined by ASAS/OMERACT) or presence of elevated CRP (defined as CRP >5.00 mg/L). ;Must have had an inadequate response, as determined by the investigator, to 2 or more NSAIDs at the therapeutic dose range for a total duration of at least 4 weeks OR have a history of intolerance to NSAIDs ;Patients must have a history of prior therapy for axSpA of at least 12 weeks prior to screening. Examples of prior therapy may include but are not limited to physical therapy and NSAID treatment.
Exclusion criteria
Fulfillment of the modified New York (mNY) criteria (van der Linden et al. 1984) with sacroiliitis defined radiographically, based on central reading: sacroiliitis grade >=2 bilaterally or grades 3 to 4 unilaterally ;Have a history of other systemic inflammatory diseases that might confound the evaluations of benefit from ixekizumab therapy (such as, but not limited to, lupus, vasculitis, or RA), or other chronic pain conditions (such as but not limited to fibromyalgia);Note: Patients with psoriasis who do not require systemic treatment, such as, but not limited to, oral agents or biologic therapies, can be included provided these patients fulfill the study entry criteria. ;Have active Crohn*s disease (CD) or active ulcerative colitis (UC) ;Note: Patients may be enrolled if they have had a history of inflammatory bowel disease (IBD), including CD and UC, but have had no exacerbation for >=6 months prior to baseline, and, if currently on treatment, must be on stable treatment for >=6 months prior to baseline. ;Have evidence of active anterior uveitis (an acute episode) within the last 42 days prior to baseline randomization
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003938-27-NL |
| CCMO | NL57002.018.16 |