Primary ObjectiveTo assess the effect of ABT-981 on OA knee pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at Week 16 and synovitis/effusion volume of the index knee using quantitative measures and semi-…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy:
The primary efficacy comparisons will be between each of the ABT-981 treatment
groups and the placebo treatment group for the primary efficacy measurement.
Safety:
Safety analyses will be carried out using the safety population, which includes
all patients who received at least one dose of study drug. Treatment-emergent
adverse events and serious adverse events, which include pre- and
post-treatment serious adverse events, will be summarized and reported.
Pharmacodynamic:
Assessment of pharmacodynamic effects of ABT-981 on knee osteoarthritis will be
explored by measuring several panels of biomarkers, such as MRI imaging
biomarkers, biochemistry biomarkers, and clinical biomarkers.
Secondary outcome
Pharmacokinetic:
Individual ABT-981 serum concentrations will be tabulated for each patient and
treatment group and summarized with appropriate statistical methods.
Immunogenicity data will be tabulated and summarized as appropriate. Synovial
fluid ABT-981 concentrations will be compared to measurements in serum to
determine the extent of synovial fluid distribution at steady-state.
Biomarkers:
Summary statistics for all biomarkers at baseline and post-treatment time
points, in addition to change from baseline at each time will be provided.
Background summary
Osteoarthritis (OA) is a joint disorder that involves degeneration of articular
cartilage, inflammation of the entire joint as manifested by synovitis, and
changes in the subchondral bone. OA is the most common form of arthritis and
the number one cause of workforce disability.
The importance of inflammatory elements in OA is increasingly recognized; the
role of cytokines and chemokines as the "inflammatory"
mediators that cause inflamed synovial tissue and cartilage in OA have been
extensively studied.
Among these inflammatory mediators, Interleukin-1 (IL-1) is identified as the
key factor in cartilage and synovium tissue signaling pathways. IL-1 has long
been known as the most potent catabolic cytokine and is thought to play a major
role in the development and progression of OA both in terms of disease
(structural progression) and symptoms (pain and functional deterioration).
IL-1α and IL-1β are 2 structurally distinct cytokines that bind to the IL-1
receptor complex. Both induce structural changes, such as cartilage
degradation, bone sclerosis and synovial proliferation, by inducing proteases
and proinflammatory cytokines in joints and have also been shown to play a role
in OA pain.
ABT-981 is a novel biologic drug candidate targeting IL-1α and IL-1β.
Study objective
Primary Objective
To assess the effect of ABT-981 on OA knee pain using the Western Ontario and
McMaster Universities Osteoarthritis Index (WOMAC) at Week 16 and
synovitis/effusion volume of the index knee using quantitative measures and
semi-quantitative MRI scoring at Week 26.
Secondary Objectives
* To evaluate the safety and tolerability of ABT-981 in patients with knee OA.
* To evaluate the effect of ABT-981 on physical function scores of the index
knee at Weeks 16, 26 and 52 using WOMAC.
* To evaluate the effect of ABT-981 on index knee pain scores at Weeks 26 and
52 using WOMAC.
* To evaluate the effect of ABT-981 in reduction of bone marrow lesions (BML)
of the index knee MRI at Weeks 26 and 52 using semi-quantitative measurements
(WORMS).
* To evaluate the effect of ABT-981 on index knee resting pain at Weeks 16, 26
and 52 using the Intermittent and Constant Osteoarthritis Pain (ICOAP) score.
* To evaluate the effect of ABT-981 on index knee resting pain at Weeks 16, 26
and 52 using the 11-point NRS scale (NRS-11).
* To evaluate the effect of ABT-981 on Patient Global Assessment of Arthritis
at Weeks 16, 26 and 52.
* To evaluate the effect of ABT-981 on the preservation of cartilage
volume/thickness of the index knee using MRI at Weeks 26 and 52.
Exploratory Objectives
* To evaluate the effect of ABT-981 on index knee joint structure using
semi-quantitative global assessment MRI scoring method (WORMS) at
Weeks 26 and 52.
* To evaluate the effect of ABT-981 on Outcome Measures in Rheumatology
Clinical Trials/Osteoarthritis Research Society International
(OMERACT/OARSI) responder criteria at Weeks 16, 26 and 52.
* To evaluate the effect of ABT-981 on synovitis and effusion volume of the
index knee MRI at Week 52.
* To evaluate the effect of ABT-981 on index knee joint stiffness using WOMAC
at Weeks 16, 26 and 52.
* To evaluate rescue medication use between treatment groups and control group.
* To evaluate the effect of ABT-981 on joint space width of the index knee
using X-ray at Week 52.
* To explore the pharmacokinetics (PK) and pharmacodynamics (PDyn) relationship
of ABT-981 using imaging and non-imaging biomarkers, as well as clinical
outcomes.
* To evaluate several panels of serum/plasma, urine and synovial fluid
biomarkers at various time points for use in further development of ABT-981.
Study design
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled,
parallel-group study designed to evaluate the safety, tolerability, efficacy
and pharmacodynamic effects of ABT-981 in patients diagnosed with
osteoarthritis of the knee. Approximately 320 (~80 per group)
patients meeting all of the inclusion criteria and none of the exclusion
criteria during Screening (within 45 days prior to the first dose of study
drug) will be enrolled. Patients taking analgesics must complete a Washout
Period and discontinue all analgesic medications for at least 5 half-lives of
the longest acting analgesic used, or 48 hours, whichever is longer, prior to
the first dose of study drug. Patients will be permitted to take acetaminophen
(paracetamol) as rescue mediation during the Washout Period through Week 26 MRI
exam. Between week 16 and week 26 ibuprofen can also be given additionally.
After the Week 26 MRI exam, patients will be allowed to resume approved oral
standard of care medications. Patients will be randomized to one of the four
treatment groups to receive either ABT-981 or placebo for 50 weeks (treatment
period).
Intervention
Approximately 320 (~80 per group) patients meeting all of the inclusion
criteria and none of the exclusion criteria during Screening (within
45 days prior to the first dose of study drug) will be enrolled. Patients
taking analgesics must complete a Washout Period and discontinue all analgesic
medications for at least 5 half-lives of the longest acting analgesic used, or
48 hours, whichever is longer, prior to the first dose of study drug. Patients
will be permitted to take acetaminophen (paracetamol) as rescue mediation
during the Washout Period through Week 26 MRI exam. After the Week 26 MRI exam,
patients will be allowed to resume approved oral standard of care medications.
Patients will be randomized to one of the four treatment groups to receive
either 25, 100, 200 mg ABT-981, or placebo for 50 weeks (treatment period).
Patients will undergo an ultrasound, 2 X-rays and 3 MRIs during the study.
Study burden and risks
The risks associated with this study are linked together with the possible side
effects of the investigational product. The burden of the subject will continue
to work with the study procedures, visits, and venapunctions. All subjects will
be closely monitored and supervised by experienced doctors and study staff for
possible side effects.
Wegalaan 9
Hoofddorp 2132 JD
NL
Wegalaan 9
Hoofddorp 2132 JD
NL
Listed location countries
Age
Inclusion criteria
1.Subject must have radiographic evidence of knee osteoarthritis in the medial compartment of the index knee with Kellgren-Lawrence Grade 2 or 3 (with minimum 2 mm joint space width) during Screening as evaluated by a qualified central imaging reader. Prior radiographs taken
no more than 3 months before Study Day 1 with Synaflexer* can be submitted for centralized eligibility reading.
2. Subject must have either constant or intermittent index knee pain at least 14 days (regardless of the intensity) over the past 30 days at the initial screening visit. The intensity of index knee pain is between 4 and 8, inclusive, at the initial Screening Visit and Study Day 1 (as recorded on Question 1 of the Index Knee Pain Intensity Questionnaire).
3.Subject has one or more clinical signs and symptoms of active inflammation in the index knee as defined by (but not limited to) localized pain, joint stiffness, swelling and effusion during Screening Period and Study Day 1.
4.Presence of synovitis in the index knee confirmed either by ultrasound or MRI during Screening.
5.Subject discontinued analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and nutraceuticals (e.g., glucosamine, chondroitin sulfate, shark cartilage, diacerein, soy extract). The washout period will be at least 5 half-lives of the longest acting analgesic used, or 48 hours, whichever is longer prior to first dose of study drug.
Exclusion criteria
1.History of major allergic reaction or significant sensitivity to any constituents of the study drug; or history of anaphylactic reaction to any agent (e.g., food products or bee stings) or history of a major reaction to any Immunoglobulin G (IgG) containing product.
2.Significant trauma or surgery to the index knee within the last year or arthroscopy of the index knee within 6 months of the initial Screening Visit.
3.Kellgren-Lawrence Grade 1 or 4 in the index knee.
4.Severe knee malalignment, either greater than 4.0° in varus; or greater than 8.0° in valgus angulation in the index knee.
5.Diagnosis of one or more of the following:
a.Inflammatory arthritis such as rheumatoid arthritis, autoimmune disorder, seronegative spondyloarthropathy, gout, or pseudogout (defined as acute episodic attacks of swollen , painful joints in a subject with X-Ray chondrocalcinosis or CPPD crystals);
b.Other chronic painful syndromes (such as Paget's disease and fibromyalgia) and clinically significant non-articular musculoskeletal pain that could interfere with assessment of pain at the index knee.
6. History or evidence of active tuberculosis (TB)
7. Any uncontrolled medical illness or unstable treatment.
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 | EUCTR2013-003467-60-NL |
| ClinicalTrials.gov | NCT01668511 |
| CCMO | NL48135.058.14 |