Knee Osteoarthritis
Conditions
Keywords
Osteoarthritis, Knee, Arthritis, WOMAC, Injections, intra-articular, Fasitibant, MEN 16132
Brief summary
This study is designed as a double-blind, randomised, placebo-controlled, four parallel arm, dose-finding study, to be conducted in approximately 26 sites, to evaluate the efficacy, safety, tolerability, and pharmacokinetics of single intra-articular (IA) injections of fasitibant in patients with symptomatic osteoarthritis (OA) of the knee. Approximately 400 male and female patients 40-80 years old, with BMI \< 30 kg/m² and with a clinical diagnosis of symptomatic primary osteoarthritis of the knee will be randomised to a total of 4 treatment arms. Each arm includes a single intra-articular injection of one of three dosages of fasitibant (low, intermediate and high dose) OR placebo. The randomisation ratio will be 1:1:1:1. The primary efficacy variable will be the change of the Western Ontario and McMaster Universities Visual Analogue Scale 3.1 A (WOMAC VA 3.1 A) (total pain) subscore from baseline up to 2 weeks after randomisation. Safety will be assessed by monitoring adverse events and clinical laboratory tests; local tolerability at the injection site will also be assessed. In addition, the population pharmacokinetics and the exposure-response relationship will be evaluated. The individual experimental clinical phase will last up to maximal 15 weeks encompassing 7 planned visits at site, including screening, randomisation, 4 follow-up visits and the End of study visit.
Interventions
DRUGFasitibant- low dose
Single intra-articular injection of low dose of fasitibant
DRUGFasitibant- intermediate dose
Single intra-articular injection of intermediate dose of fasitibant
DRUGFasitibant- high dose
Single intra-articular injection of high dose of fasitibant
DRUGPlacebo comparator
Single intra-articular injection of placebo
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged 40 to 80 years with BMI \< 30 kg/m² * Patient with Kellgren-Lawrence Grade 2 to 3, symptomatic primary osteoarthritis at the index knee (ACR criteria), for which an IA treatment is indicated * Pain of moderate to severe intensity, even if treated with chronic doses of non steroidal antinflammatory drugs
Exclusion criteria
* History of hypersensitivity/allergy to drugs including paracetamol and to disinfectants * Any pharmacological treatment of concomitant disease(s) started or changed during 4 weeks prior to randomisation, or likely to be changed during the course of the study * Use of systemic or topical corticosteroids \> 10 mg prednisolone equivalent per day, or immunosuppressant drugs * Current use of any pain or OA medication (e.g. NSAIDs, COX-2 inhibitors, analgesics, antidepressive agents), including topical treatments * Viscosupplementation to the target knee administered \< 4 months prior to randomisation and/or scheduled during the course of the study * Evidence of clinically significant hepatic disease or of moderate or severe renal insufficiency * Current use of any medications that are substrate of CYP3A4 and/or moderate or strong CYP3A4 inhibitors * Patients with any clinically relevant or unstable disease, or malignant neoplasms that, in the opinion of the Investigator, may pose the patient at risk, or confound the efficacy and safety results of the study * Patients with any clinically relevant abnormal safety laboratory test results, and/or abnormalities in vital signs, and/or ECG parameters * Pregnant and breastfeeding women * Any sign of significant immunodeficiency, systemic infection, knee infection or knee bursitis * Patients with bleeding diathesis or on therapy with anticoagulants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in WOMAC A | from baseline up to 2 weeks after randomisation | The validated Western Ontario and McMaster University questionnaire (WOMAC) was used to measure total knee pain choosing its visual analogue scale version (VAS). The WOMAC VA 3.1 A subscore (WOMAC A) ranges from 0 to 500 mm (summing up five VAS 0-100 mm) with higher scores indicating more pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | from baseline up to 6 weeks after randomisation | Response based on change ≥ 20 % from baseline for EQ-5D-5L index value |
| Change in WOMAC INDEX | from baseline up to 6 weeks after randomisation | The WOMAC VA 3.1 Index score (WOMAC INDEX) is the sum of WOMAC A (total pain), WOMAC B (stiffness) and WOMAC C (functional impairment) subscores. The WOMAC INDEX score ranges from 0 to 2400 mm, with higher scores indicating higher disease burden. |
| Responder Rate According to OMERACT-OARSI Criteria | from baseline up to 6 weeks after randomisation | Percentage of responders according to Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria (OMERACT-OARSI criteria). Patients with at least 50 % improvement in pain or in function scores are considered responders. Alternatively, patients are considered responders if they show at least 20% improvement in at least two of the following scores: pain, function and Patients's Global Assessment (PGA) scores. |
Countries
Czechia, Germany, Italy, United States
Participant flow
Recruitment details
The first patient was screened on 28th April 2014. The first patient was randomised on 6th May 2014. The last patient completed the study on 6th January 2015. The study was conducted in 25 study sites in Czech Republic, Germany, Italy and US.
Pre-assignment details
A total of 645 patients entered a 2-week Screening period (including wash out); 209 of them were screen failed. One patient randomised to PLACEBO did not receive the study treatment (counted for ITT but not in safety population). Five patients received the study treatment without randomisation (not counted for ITT, but in safety population).
Participants by arm
| Arm | Count |
|---|---|
| Fasitibant Low Dose Drug: solution for intra-articular injection
Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant | 108 |
| Fasitibant Intermediate Dose Drug: solution for intra-articular injection
Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant | 108 |
| Fasitibant High Dose Drug: solution for intra-articular injection
Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant | 107 |
| PLACEBO Drug: solution for intra-articular injection
Placebo comparator: Single intra-articular injection of placebo | 108 |
| Total | 431 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | not compliant with study procedures | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Fasitibant Intermediate Dose | Fasitibant Low Dose | Fasitibant High Dose | PLACEBO | Total |
|---|---|---|---|---|---|
| Age, Continuous Age | 63.2 years STANDARD_DEVIATION 8.73 | 65.3 years STANDARD_DEVIATION 7.61 | 64.7 years STANDARD_DEVIATION 8.43 | 64.4 years STANDARD_DEVIATION 8.5 | 64.4 years STANDARD_DEVIATION 8.34 |
| BMI | 26.5 kg/m2 STANDARD_DEVIATION 2.83 | 27.1 kg/m2 STANDARD_DEVIATION 2.12 | 27.1 kg/m2 STANDARD_DEVIATION 2.35 | 27.0 kg/m2 STANDARD_DEVIATION 2.6 | 26.9 kg/m2 STANDARD_DEVIATION 2.5 |
| EQ VAS | 64.3 units on a scale STANDARD_DEVIATION 17.21 | 63.1 units on a scale STANDARD_DEVIATION 20.54 | 67.4 units on a scale STANDARD_DEVIATION 18.18 | 65.7 units on a scale STANDARD_DEVIATION 19.47 | 65.1 units on a scale STANDARD_DEVIATION 18.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 107 Participants | 106 Participants | 106 Participants | 427 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 71 Participants | 62 Participants | 64 Participants | 66 Participants | 263 Participants |
| Sex: Female, Male Male | 37 Participants | 46 Participants | 43 Participants | 42 Participants | 168 Participants |
| WOMAC A | 282.7 units on a scale STANDARD_DEVIATION 40.08 | 286.5 units on a scale STANDARD_DEVIATION 40.4 | 278.3 units on a scale STANDARD_DEVIATION 38.11 | 275.5 units on a scale STANDARD_DEVIATION 39.81 | 280.8 units on a scale STANDARD_DEVIATION 39.61 |
| WOMAC INDEX | 1275.4 units on a scale STANDARD_DEVIATION 283.6 | 1321.5 units on a scale STANDARD_DEVIATION 278.88 | 1282.6 units on a scale STANDARD_DEVIATION 274.5 | 1293.5 units on a scale STANDARD_DEVIATION 239.73 | 1293.3 units on a scale STANDARD_DEVIATION 269.35 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 110 | 46 / 110 | 36 / 108 | 44 / 107 |
| serious Total, serious adverse events | 2 / 110 | 2 / 110 | 2 / 108 | 4 / 107 |
Outcome results
Primary
Change in WOMAC A
The validated Western Ontario and McMaster University questionnaire (WOMAC) was used to measure total knee pain choosing its visual analogue scale version (VAS). The WOMAC VA 3.1 A subscore (WOMAC A) ranges from 0 to 500 mm (summing up five VAS 0-100 mm) with higher scores indicating more pain.
Time frame: from baseline up to 2 weeks after randomisation
Population: The primary efficacy analysis was performed on the ITT-population (n=431).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fasitibant Low Dose | Change in WOMAC A | Week 2 after randomisation | -106.1 units on a scale | Standard Deviation 101.88 |
| Fasitibant Low Dose | Change in WOMAC A | Week 1 after randomisation | -91.8 units on a scale | Standard Deviation 101.85 |
| Fasitibant Intermediate Dose | Change in WOMAC A | Week 1 after randomisation | -110.0 units on a scale | Standard Deviation 99.48 |
| Fasitibant Intermediate Dose | Change in WOMAC A | Week 2 after randomisation | -131.5 units on a scale | Standard Deviation 96.41 |
| Fasitibant High Dose | Change in WOMAC A | Week 1 after randomisation | -109.8 units on a scale | Standard Deviation 94.65 |
| Fasitibant High Dose | Change in WOMAC A | Week 2 after randomisation | -115.9 units on a scale | Standard Deviation 104.61 |
| PLACEBO | Change in WOMAC A | Week 2 after randomisation | -117.2 units on a scale | Standard Deviation 90.15 |
| PLACEBO | Change in WOMAC A | Week 1 after randomisation | -93.7 units on a scale | Standard Deviation 94.15 |
p-value: <0.05mixed linear model for repeated measures
Secondary
Change in WOMAC INDEX
The WOMAC VA 3.1 Index score (WOMAC INDEX) is the sum of WOMAC A (total pain), WOMAC B (stiffness) and WOMAC C (functional impairment) subscores. The WOMAC INDEX score ranges from 0 to 2400 mm, with higher scores indicating higher disease burden.
Time frame: from baseline up to 6 weeks after randomisation
Population: The secondary efficacy analysis was performed on the ITT population (n=431).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fasitibant Low Dose | Change in WOMAC INDEX | Week 1 after randomisation | -396.0 units on a scale | Standard Deviation 464.24 |
| Fasitibant Low Dose | Change in WOMAC INDEX | Week 2 after randomisation | -448.0 units on a scale | Standard Deviation 477.95 |
| Fasitibant Low Dose | Change in WOMAC INDEX | week 4 after randomisation | -516.4 units on a scale | Standard Deviation 513.7 |
| Fasitibant Low Dose | Change in WOMAC INDEX | Week 6 after randomisation | -566.3 units on a scale | Standard Deviation 525.63 |
| Fasitibant Intermediate Dose | Change in WOMAC INDEX | Week 2 after randomisation | -563.0 units on a scale | Standard Deviation 456.71 |
| Fasitibant Intermediate Dose | Change in WOMAC INDEX | week 4 after randomisation | -628.4 units on a scale | Standard Deviation 500.17 |
| Fasitibant Intermediate Dose | Change in WOMAC INDEX | Week 6 after randomisation | -653.8 units on a scale | Standard Deviation 516.31 |
| Fasitibant Intermediate Dose | Change in WOMAC INDEX | Week 1 after randomisation | -460.5 units on a scale | Standard Deviation 469.68 |
| Fasitibant High Dose | Change in WOMAC INDEX | week 4 after randomisation | -493.4 units on a scale | Standard Deviation 513.94 |
| Fasitibant High Dose | Change in WOMAC INDEX | Week 2 after randomisation | -488.7 units on a scale | Standard Deviation 480.39 |
| Fasitibant High Dose | Change in WOMAC INDEX | Week 6 after randomisation | -547.6 units on a scale | Standard Deviation 522.37 |
| Fasitibant High Dose | Change in WOMAC INDEX | Week 1 after randomisation | -445.2 units on a scale | Standard Deviation 424.07 |
| PLACEBO | Change in WOMAC INDEX | Week 6 after randomisation | -581.3 units on a scale | Standard Deviation 503.37 |
| PLACEBO | Change in WOMAC INDEX | Week 2 after randomisation | -517.7 units on a scale | Standard Deviation 440.75 |
| PLACEBO | Change in WOMAC INDEX | Week 1 after randomisation | -413.2 units on a scale | Standard Deviation 452.04 |
| PLACEBO | Change in WOMAC INDEX | week 4 after randomisation | -562.3 units on a scale | Standard Deviation 487.25 |
Comparison: All secondary efficacy variables were analysed on the ITT population only. Multiplicity was adjusted using the Hochberg procedure. The continuous secondary efficacy variables were analysed over time and were treated in the same way as the primary efficacy variable with respective output.p-value: <0.05mixed linear model for repeated measures
Secondary
Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate
Response based on change ≥ 20 % from baseline for EQ-5D-5L index value
Time frame: from baseline up to 6 weeks after randomisation
Population: The secondary efficacy analysis was performed on the ITT-population (n=431).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fasitibant Low Dose | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 2 after randomisation | 18.5 percentage of responders |
| Fasitibant Low Dose | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 6 after randomisation | 23.1 percentage of responders |
| Fasitibant Intermediate Dose | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 6 after randomisation | 27.8 percentage of responders |
| Fasitibant Intermediate Dose | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 2 after randomisation | 18.5 percentage of responders |
| Fasitibant High Dose | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 2 after randomisation | 20.6 percentage of responders |
| Fasitibant High Dose | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 6 after randomisation | 25.2 percentage of responders |
| PLACEBO | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 2 after randomisation | 24.1 percentage of responders |
| PLACEBO | Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate | Week 6 after randomisation | 21.3 percentage of responders |
Secondary
Responder Rate According to OMERACT-OARSI Criteria
Percentage of responders according to Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria (OMERACT-OARSI criteria). Patients with at least 50 % improvement in pain or in function scores are considered responders. Alternatively, patients are considered responders if they show at least 20% improvement in at least two of the following scores: pain, function and Patients's Global Assessment (PGA) scores.
Time frame: from baseline up to 6 weeks after randomisation
Population: The secondary efficacy variables were analysed in the ITT population (n=431).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fasitibant Low Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 1 after randomisation | 51.9 percentage of responders |
| Fasitibant Low Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 2 after randomisation | 59.3 percentage of responders |
| Fasitibant Low Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 4 after randomisation | 65.7 percentage of responders |
| Fasitibant Low Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 6 after randomisation | 71.3 percentage of responders |
| Fasitibant Intermediate Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 2 after randomisation | 72.2 percentage of responders |
| Fasitibant Intermediate Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 4 after randomisation | 72.2 percentage of responders |
| Fasitibant Intermediate Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 6 after randomisation | 74.1 percentage of responders |
| Fasitibant Intermediate Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 1 after randomisation | 56.5 percentage of responders |
| Fasitibant High Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 4 after randomisation | 65.4 percentage of responders |
| Fasitibant High Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 2 after randomisation | 62.6 percentage of responders |
| Fasitibant High Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 6 after randomisation | 67.3 percentage of responders |
| Fasitibant High Dose | Responder Rate According to OMERACT-OARSI Criteria | Week 1 after randomisation | 63.6 percentage of responders |
| PLACEBO | Responder Rate According to OMERACT-OARSI Criteria | Week 6 after randomisation | 67.6 percentage of responders |
| PLACEBO | Responder Rate According to OMERACT-OARSI Criteria | Week 2 after randomisation | 68.5 percentage of responders |
| PLACEBO | Responder Rate According to OMERACT-OARSI Criteria | Week 1 after randomisation | 55.6 percentage of responders |
| PLACEBO | Responder Rate According to OMERACT-OARSI Criteria | Week 4 after randomisation | 66.7 percentage of responders |