Osteoarthritis, Knee
Conditions
Keywords
Tibiofemoral OA, K&L grade 2 to 3 OA in the target knee, Oral RHH646 treatment
Brief summary
The purpose of this study was to evaluate the articular cartilage-regenerating capacity of RHH646 in the knee as well as to assess safety and tolerability in participants with knee osteoarthritis.
Detailed description
This was a non-confirmatory, randomized, Investigator and participant blinded, two-arm, placebo controlled, Phase IIa study to assess safety, tolerability, and efficacy of orally administered RHH646 in adult participants with symptomatic, mild to moderate radiographic knee osteoarthritis in the target knee and with pain requiring analgesic therapy. The study comprised of a Screening period (up to 6 weeks), a treatment period (52 weeks) and a follow up period (4 weeks after the last administration of study treatment) before the End of Study (EOS) visit. The total duration for each participant was up to 62 weeks.
Interventions
DRUGRHH646
RHH646 capsule for oral use
DRUGPlacebo
RHH646 placebo capsule for oral use
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participant is ≥35 and ≤75 years old, at time of screening * Participants must weigh at least 50 kg to participate in the study and must have a body mass index (BMI) ≤35 kg/m2. BMI = Body weight (kg) / \[Height (m)\]2 * Diagnosis of tibiofemoral OA in at least one knee by standard American College of Rheumatology clinical and radiographic criteria (Altman et al 1986) at screening * K\&L grade 2 to 3 OA in the target knee evaluated with X-Ray by the Central Reader at screening * Predominantly medial tibiofemoral compartment involvement defined as medial Joint Space Narrowing (medJSN) 1-2 (Altman et al 1995; Altman, Gold 2007) and medJSN \> lateral Joint Space Narrowing (latJSN) in the target knee evaluated with X-Ray by the Central Reader at screening * Symptomatic disease, defined as having pain in the target knee at least 3 days per week during the last 3 months from screening that is relieved by analgesic therapy (e.g. acetaminophen or non-steroidal anti-inflammatory drugs), according to the investigator's evaluation and judgment of the patient's history
Exclusion criteria
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception. In EEA countries, women of child-bearing potential will be excluded from participation in this trial, irrespective of the use of highly effective methods of contraception. * Arthroscopy of the target knee within the 6 months prior to screening or planned arthroscopy during the study * Previous surgical treatment of the target knee using mosaicplasty, microfracture, meniscectomy \>50% or osteotomy; planned surgery for either knee during the study * Unstable target knee joint (including, but not limited to, post-traumatic or congenital laxity) or insufficiently reconstructed ligaments based on medical history and/or physical examination by the investigator * Participant has severe malalignment (valgus or varus deformity) in the target knee \>7.5° based on X-ray evaluation by the Central Reader at screening. * K\&L grade 4 OA in either knee * Presence of severe hip OA that either (i) alters lower limb function to a degree that increases or abnormally changes the mechanical forces in the knee while walking, according to investigator's evaluation or (ii) currently requires or is likely to require specific medical or surgical management during the study period * Other pathologies affecting the knee, including subchondral insufficiency fractures, bone fracture (acute or subacute within the 6 months prior to screening) or bone bruise, osteonecrosis, malignant bone marrow infiltration, solid tumors, and/or patellofemoral dysplasia based on clinical assessment, or imaging * Known autoimmune disease with inflammatory arthritis (including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus), crystal-induced arthritides (gout or pseudogout arthritis), active acute or chronic infection of the knee joint, Lyme disease involving the knee, reactive arthritis, systemic cartilage disorders, moderate to severe fibromyalgia, a known systemic connective tissue disease or a widespread pain index \>4. * Inability to undergo MRI (e.g., claustrophobia, body size, leg not fitting in the coil) or contraindications to MRI (e.g., non MRI-compatible metallic implants, metallic foreign bodies, pacemaker, defibrillator)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cartilage Volume in the Index Region of the Target Knee by MRI | Baseline, Week 52 | Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in the volume of cartilage in the index region. The index region was defined as the combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 56 weeks. | Number of participants with treatment emergent adverse events (any AE regardless of seriousness), and SAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: RHH646 Plasma Concentrations | Baseline (4 hours post dose), Week 4 (pre dose) | RHH646 concentration was determined by a validated LC-MS/MS method; the anticipated Lower Limit of Quantification (LLOQ) was 2 ng/mL. RHH646 concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . |
Countries
Argentina, Denmark, Poland, Spain, United States
Participant flow
Recruitment details
Participants took part in 10 investigative sites in 5 countries.
Pre-assignment details
The study consisted of a screening period up to 6 weeks.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62.16 years STANDARD_DEVIATION 7.295 |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized White | 76 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 41 | 0 / 82 |
| other Total, other adverse events | 34 / 41 | 35 / 41 | 69 / 82 |
| serious Total, serious adverse events | 1 / 41 | 3 / 41 | 4 / 82 |
Outcome results
None listed