Study of Efficacy, Safety and Tolerability of DFV890 in Patients With Knee Osteoarthritis

Novartis Pharmaceuticals115 enrolled

Overview

This was a double-blinded, two-arm, phase 2a study to assess efficacy, safety and tolerability of DFV890 in participants with symptomatic knee osteoarthritis.

The purpose of the Phase 2a proof of concept study was to evaluate the safety and tolerability of DFV890 in participants with symptomatic knee OA, and to determine the efficacy of DFV890 in reducing knee pain as evidenced by change in KOOS (knee injury and osteoarthritis outcome score). The study had a screening period up to 45 days, a treatment period of 12 weeks and a 4-week follow-up period. At most, the study duration was 21 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

115

Conditions

Symptomatic Knee Osteoarthritis

Interventions

DFV890DRUG

DFV890 was administered orally twice per day, 10 mg during 2 weeks and 25 mg during the next 10 weeks.

PlaceboDRUG

Matching Placebo was administered orally twice per day during 12 weeks.

Eligibility

Sex: ALLMin age: 50 YearsMax age: 80 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Male and female participants \>= 50 and \<= 80 years old on the day of Informed Consent signature. * Participants 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 * High sensitivity C-reactive protein (hsCRP) \>=1.8 mg/L at screening * Symptomatic OA with pain (corresponding to Numeric Rating Scale \[NRS\] 5-9, inclusive) in the target knee for the majority of days in the last 3 months prior to screening * KOOS pain sub-scale score \<= 60 in index knee at screening and baseline * Radiographic disease: K\&L grade 2 or 3 knee osteoarthritis in the target knee, confirmed by X-ray at screening. * Active synovial inflammation at screening (defined a summary score of ≥7 with at least one region scoring 2) on contrast enhanced MRI (CE-MRI) of the whole knee for synovitis detection from 11 sites. Key Exclusion Criteria: * Total WBC count \< 3,000/µL, absolute peripheral blood neutrophil count (ANC) \< 1,000/µL, hemoglobin \< 8.5 g/dL (85 g/L) or platelet count \< 100,000/µL at Screening * Known autoimmune disease with inflammatory arthritis (including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus), crystal-induced arthritis (gout, pseudogout associated arthritis), active acute or chronic infection or past infection of the knee joint, Lyme disease involving the knee, reactive arthritis, systemic cartilage disorders, moderate to severe fibromyalgia (widespread pain index, WPI, \>4 out of 19), or a known systemic connective tissue disease * Any known active infections, including skin or knee infections or infections that may compromise the immune system, such as HIV or chronic hepatitis B or C infection. COVID-19 specific: PCR or antigen test against COVID-19 is mandatory where required by the local Health Authority and/or by local regulation, e.g. in Germany. * Use of prohibited medications: any local i.a. treatment into the knee, including but not restricted to viscosupplementation and corticosteroids within 12 weeks prior to Day 1; long-term treatment (\>14 days) with oral corticosteroids \>5 mg/day within 4 weeks prior to Day 1; oral glucosamine, chondroitin sulfate, or any nutraceutical with potential activity on cartilage repairfrom screening 1; systemic Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), selective Cyclooxygenase-2 (COX- 2) inhibitors or other non-opioid analgesics not defined as basic pain medication within 5 half-lives from PRO assessments; any other immunomodulatory drugs or treatment which cannot be discontinued or switched to a different medication within 28 days or 5 half-lives of screening (whichever is longer if required by local regulations), or until the expected PD effect has returned to baseline. * Moderate to severe pain in the contralateral knee for the majority of days in the last 3 months prior to Screening, as per patient judgment. * Severe malalignment greater than 7.5 degrees in the target knee (either varus or valgus), measured using x-ray at Screening. Additional protocol-defined inclusion / exclusion criteria may apply.

Locations (31)

Outcomes

Primary Outcomes

Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain Subscale

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the pain frequency/severity during functional activities consisting of 9 questions with a recall of 7 days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no pain and 0 indicating extreme pain) is calculated for each subscale. Change from baseline in KOOS pain score was analyzed using a mixed effects model for repeated measures (MMRM) including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Week 12

Secondary Outcomes

Change From Baseline in Synovitis Activity Level Measured From Ktrans by Dynamic Contrast Enhanced MRI (DCE-MRI)

Magnetic resonance images (MRI) were obtained from the target knee with dynamic contrast enhancement (DCE) to visualize and quantify changes in k-trans as a marker of the activity of synovial inflammation. In dynamic contrast-enhanced MRI, ktrans is a parameter that reflects how quickly contrast agent moves from blood vessels into the surrounding tissue, capturing both blood flow and vascular permeability. In synovitis, inflamed synovial tissue shows increased perfusion and leaky microvasculature, so higher k-trans values are interpreted as indicating more active synovial inflammation. Change from baseline in synovitis activity level measured from ktrans was analyzed to compare treatment groups. The model included treatment as fixed effect and baseline as continuous covariate. Ktrans is a marker of synovial inflammation in relation to vascularity permeability.

Time frame: Baseline, Week 12

Change From Baseline in Serum High Sensitivity C-reactive Protein (hsCRP) Level

HsCRP is a protein produced by the liver in response to inflammation in the body, such as from an infection, injury, or chronic inflammatory conditions. HsCRP was used to assess the effect of DFV890 compared to placebo on systemic inflammatory status.

Data from ClinicalTrials.gov

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ARENSIA Explor Med Res Clinic

Phoenix, Arizona, United States

TriWest Reserach Associates

El Cajon, California, United States

Skylight Health Res Inc Color Spr

Colorado Springs, Colorado, United States

IRIS Research and Development

Plantation, Florida, United States

Conquest Research

Winter Park, Florida, United States

Ctr for Adv Research and Education

Gainesville, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

San Miguel, Tucumán Province, Argentina

Novartis Investigative Site

San Miguel de Tucumán, Argentina

...and 21 more locations

Time frame: Baseline, Weeks 2, 4, 8 and 12

Change From Baseline in Absolute Neutrophil Counts (ANC)

ANC measures the number of neutrophils, a type of white blood cell crucial for fighting infection, in a blood sample. ANC was used to judge target engagement of DFV890.

Time frame: Baseline, Weeks 2, 4, 8 and 12

Maximum Plasma Concentration (Cmax) of DFV890

Cmax is defined as the maximum (peak) observed concentration following a dose. DFV890 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8). DFV890 was determined by a validated LC-MS/MS method; the lower limit of quantification (LLOQ) is 1 ng/mL.

Time frame: Week 2 and Week 12: pre-dose, 1h, 3h, 5h, 8h

Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of DFV890

AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast). DFV890 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8). DFV890 was determined by a validated LC-MS/MS method; the lower limit of quantification (LLOQ) is 1 ng/mL.

Time frame: Week 2 and Week 12: pre-dose, 1h, 3h, 5h, 8h

Area Under Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of DFV890

AUC(0-12h) is the area under the plasma concentration-time curve from time zero to 12 hours. To calculate AUC0-12h (corresponding to AUCtau, or AUC within a dosing interval), the concentration at 0 hours was used also as a 12 hours time point or, if not feasible, AUC0-12h was extrapolated. DFV890 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8). DFV890 was determined by a validated LC-MS/MS method; the lower limit of quantification (LLOQ) is 1 ng/mL.

Time frame: Week 2 and Week 12: pre-dose, 1h, 3h, 5h, 8h

Pre-dose Trough Concentration (Ctrough) of DFV890

DFV890 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8). DFV890 was determined by a validated LC-MS/MS method; the anticipated lower limit of quantification (LLOQ) is 1 ng/mL.

Time frame: Week 2 and Week 12: pre-dose

Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Other Symptoms Subscale

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is other symptoms (eg., stiffness, swelling, clicking) consisting of 7 questions with a recall of 7 days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. Change from baseline in other symptoms score was analyzed using a MMRM including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Week 2, 4, 8 and 12

Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in Daily Living Subscale

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the Function in Daily Living consisting of 17 questions with a recall of 7 days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no impact on function in daily living and 0 indicating extreme impact on function in daily living) is calculated for each subscale. Change from baseline in KOOS daily living function score was analyzed using a MMRM including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Week 2, 4, 8 and 12

Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in Sport and Recreation Subscale

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the function in sport and recreation consisting of 5 questions with a recall of 7 days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no impact on sport and recreation and 0 indicating extreme impact on sport and recreation) is calculated for each subscale. Change from baseline in function in sport and recreation score was analyzed using a MMRM including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Week 2, 4, 8 and 12

Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Knee-related Quality of Life (QOL) Subscale

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the knee-related quality of life consisting of 4 questions with a recall of 7 days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no impact on knee-related quality of life and 0 indicating extreme impact on knee-related quality of life) is calculated for each subscale. Change from baseline in knee related quality of life score was analyzed using a MMRM including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Week 2, 4, 8 and 12

Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain Subscale

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is pain frequency/severity during functional activities consisting of 9 questions with a recall of 7 days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no pain and 0 indicating extreme pain) is calculated for each subscale. Change from baseline in KOOS pain score was analyzed using a MMRM including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Week 2, 4, 8

Change From Baseline in Numeric Rating Scale (NRS) for Pain

The Numerical Rating Scale (NRS) Pain is a subjective assessment in which individuals rate their pain on an eleven-point numerical scale. NRS pain score ranges from 0-10 and for analyses were transformed to a 0-100 scale to be consistent with KOOS pain scores. A negative change from baseline implied improvement in pain. The NRS Pain instrument had a recall period of 24 hours and the participants were asked to rate the pain intensity at its worst. Change from baseline in NRS pain score was analyzed using a MMRM including all time-points to compare treatment groups. The model includes baseline, treatment, timepoint, baseline-by-timepoints interaction and treatment-by-timepoints interaction as fixed effects. Missing data is assumed to be Missing at Random (MAR).

Time frame: Baseline, Weeks 2, 4, 8 and 12