Primary objective - To assess the efficacy of q4w x3 i.a. injections of LRX712 in restoring the morphometrics of articular cartilage in the medial femoral condyleSecondary objectives- To evaluate LRX712 and metabolite MAE344 pharmacokinetics in…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in the medial femoral condyle cartilage volume in the index region
measured by 7T MRI from baseline to week 28 in LRX712- vs. placebo-treated
patients
Secondary outcome
- PK parameters in plasma : Tmax, Cmax, Cmin in plasma
- PK parameter in synovial fluid : Concentration at Day 1, Week 4, Week 8 post
dosing
- Vital signs (blood pressure, heart rate, temperature) as per assessment
schedule
- Hematology, blood chemistry and urinalysis as per assessment schedule
- Local and Systemic Adverse Events
- ECG parameters (PR, QRS, heart rate, RR, QT, QTc) as per assessment schedule
- Change in articular cartilage [23Na] content from baseline compared to
placebo measured with 7T MRI at Week 16, 28 and 52 in LRX712- vs.
placebo-treated patients
- Change in the medial femoral condyle cartilage (volume) measured by 7T MRI
from baseline to Weeks16 and 52.
Background summary
There are currently no approved therapeutics or surgical procedures which
restore damaged articular cartilage damage to its native, hyaline state.
Previous compounds that failed to show efficacy have targeted catabolic
mechanisms in cartilage degeneration (e.g., with inhibitors of matrix
metalloproteinases and aggrecanases), where no preservation or improvement of
the cartilage was demonstrated and multiple adverse events were reported.
Surgical options exist, but healing often leads to fibrous and/or calcified
cartilage, which is not capable to withstand the biomechanical forces acting in
the joint. In fact, the vast majority of patients, do not benefit on a long
term follow-up from these surgical techniques. Clinical evidence has also shown
that focal defects may lead to osteoarthritis (OA), with the need for joint
replacement later in life. There is, therefore, a high unmet medical need for
earlier interventions capable to regenerate hyaline cartilage, in order to
restore the articular surface and prevent the onset of OA. LRX712 is a
synthetic, small molecular entity identified via phenotypic screening and
intended for intra-articular (i.a.) administration. The direct molecular target
of LRX712 has not yet been identified. However LRX712 drives cartilage
stem/progenitor cells (CSPCs) to undergo differentiation into chondrocytes and
facilitate hyaline articular cartilage repair, while not inducing molecules
involved in fibrosis and hypertrophy/ossification. LRX712 induces restoration
of hyaline articular cartilage in the efficacy models evaluated. While most of
the current approaches aim to improve surgical outcomes after cartilage injury,
treatment with LRX712 allows avoiding surgical intervention by promoting
hyaline cartilage regeneration upon i.a. administration.
Study objective
Primary objective
- To assess the efficacy of q4w x3 i.a. injections of LRX712 in restoring the
morphometrics of articular cartilage in the medial femoral condyle
Secondary objectives
- To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma and
synovial fluid
- To assess safety and local tolerability of multiple i.a. injections of LRX712
- To assess the efficacy of q4w x3 i.a. injections of LRX712 in regenerating
the articular hyaline cartilage composition in the medial femoral condyle
Study design
This is a 52 week, randomized, double-blind, placebo-controlled,
parallel-group, clinical study
Intervention
Three treatment arms are planned to test repeated dosing with three consecutive
i.a. injections of either LRX712 15 mg, LRX712 25 mg or placebo.
Study burden and risks
Given that study participants will have mild/moderate osteoarthritis and LRX712
have shown promising chondrogenic effects in preclinical studies, it is
possible that the 3 consecutive doses of the drug may elicit beneficial effects
on structural lesions in the articular cartilage with potential implications
for joint pain and function. Occasional and transient local tolerability
findings upon intra-articular injection are expected.
Haaksbergweg 16
Amsterdam 1101BX
NL
Haaksbergweg 16
Amsterdam 1101BX
NL
Listed location countries
Age
Inclusion criteria
- Patient must be between 35 and 75 years old at screening
- Patient must weigh at least 50 kg to participate in the study, and must have
a body mass index (BMI) within the range of 18 - 35 kg/m2 at screening. BMI =
Body weight (kg) / [Height (m)]2 at screening
- Patient must have knee osteoarthritis (OA) at screening. Structural signs of
Radiographic OA need to be confirmed by radiography taken in standing
weight-bearing fixed flexion position and PA view, indicating Kellgren-Lawrence
grade 2 or 3 in the index knee
- Patient must have symptomatic disease predominantly in one (the index) knee,
with minimal or no symptoms in the contralateral knee. Symptomatic disease is
defined as having pain in the knee >= 4 days of the week for at least 3 months
at screening.
- Patient must have radiographic confirmation of a medial joint space width of
1.5 to 3.5 mm for females, or 2 to 4 mm for males, measured at the X=0.225
fixed point location within the medial tibio-femoral compartment of the index
knee, at screening.
- Patients must be ambulatory at screening (walk without aid)
Exclusion criteria
- Patient has a known autoimmune disease, inflammatory or chronic arthropathy
other than OA (including but not limited to rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, SLE, (systemic lupus erythematosus), CPPD
(calcium pyrophosphate dihydrate crystal deposition disease),, gout and
fibromyalgia), active acute or chronic infection of the joint, Lyme disease
involving the knee, systemic cartilage disorder, or a known systemic connective
tissue disease
- Subject has had surgical treatment of the target knee using mosaicplasty,
microfracture, or resecting more than 50% of meniscal tissue
- Subject has symptomatic, isolated patello-femoral pain in the index knee as
per the Investigator's examination
- Subject has malalignment (valgus- or varus-deformity) in the index knee >=
7.5° as per anatomic PA axis measured by weight-bearing short knee radiography.
- Effusion in the index knee that clinically requireding aspiration in the past
12 weeks prior to screening, or that is clinically relevant in the index knee
as per physical examination (bulge sign, patellar tap) at screening or Day 1
- Any local i.a. treatment to the knee, including but not restricted to
viscosupplementation and corticosteroids, within 12 weeks prior to screening
- Signs or symptoms, in the judgment of the investigator, of a clinically
significant systemic
viral, bacterial or fungal infection within 30 days prior to screening;
COVID-19 specific: It is highly recommended that PCR or antigen testing for
COVID-19 be completed within 1 week prior to first dosing. If testing is
performed, negative test results are required prior to enrollment into the
study. Additional testing may occur at the discretion of the investigating
physician. This requirement may be ignored if the pandemic is declared ended by
the country where the site is located, and resumed if the pandemic recurs.
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 | EUCTR2019-002963-92-NL |
| ClinicalTrials.gov | NCT04097379 |
| CCMO | NL71327.056.19 |