Osteoarthritis, Knee
Conditions
Brief summary
This is a multicentre, randomised, placebo-controlled, double-blind, three-arm parallel, Phase IIa study to evaluate the efficacy, safety and tolerability of MIV-711 in patients with knee osteoarthritis (OA).
Interventions
DRUGMIV-711
MIV-711 administered orally once daily
DRUGPlacebo
Placebo manufactured to mimic MIV-711 capsule.
Sponsors
Medivir
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
* Current average knee pain, defined as pain in either knee, within 1 week before visit 1, for which the patient gives a severity score of ≥4, \<10 on a 0-10 NRS (Numeric Rating Scale). * Inclusive of 40-80 years old. * Diagnosis of primary knee osteoarthritis
Exclusion criteria
* The presence of any inflammatory arthritis * Any generalized pain condition that may interfere with the evaluation of the target knee pain (e.g., fibromyalgia) as judged by the investigator. * Any clinically severe or significant uncontrolled concurrent illness, which, in the opinion of the Investigator, would impair ability to give informed consent or take part in or complete this clinical study. * Known or suspected intolerance or hypersensitivity to the investigational product, closely related compounds, or any of the stated ingredients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Numeric Rating Scale (NRS) Average Target Knee Pain Score at Week 26 | baseline and 26 weeks | Change from Visit 2 (Baseline) to Visit 8 (Week 26) in NRS average target knee pain score. NRS (Numeric rating scale) ranges from 0 indicating -no pain, to 10 indicating - pain as bad as it could be. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Magnetic Resonance Imaging (MRI) of Cartilage Thickness (Femur) at Week 26 | baseline and 26 weeks | Change from Visit 2 (baseline) to Visit 8 (week 26) in MRI cartilage thickness in the Central Medial Femur Region of the target knee in mm. |
| Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Pain Score | baseline and 26 weeks | Change from Visit 2 (Baseline) to Visit 8 (Week 26) in normalised WOMAC pain score. The WOMAC responses are scored using an 11-point NRS where 0=none and 10=extreme. There are 5 questions in the WOMAC pain scale which is summed up for the total WOMAC score, leading to a range of 0 to 50. The total WOMAC pain score has been standardised to a scale with a range from 0 to 100 (where 100 is extreme pain): \- Normalised WOMAC pain score = Total WOMAC pain score multiplicated with 2. |
| Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Difficulty Score | baseline and 26 weeks | Change from Visit 2 (Baseline) to Visit 8 (Week 26) in normalised WOMAC difficulty score. The WOMAC responses are scored using an 11-point NRS where 0=none and 10=extreme. There are 17 questions in the WOMAC difficulty scale which is summed up for the total WOMAC difficulty score, leading to a range of 0 to 170. The total WOMAC difficulty score has been standardised to a scale with a range from 0 to 100 (where 100 is extreme pain): \- Normalised WOMAC difficulty score = Total WOMAC difficulty score divided with 1.7 |
| Magnetic Resonance Imaging (MRI) Bone Area of the Target Knee at Week 26 | baseline and 26 weeks | Change from Visit 2 (Baseline) to Visit 8 (Week 26) in MRI (Magnetic Resonance Imaging;) bone area of the target knee in mm\^2. |
| Serum C-terminal Telopeptide of Collagen Type I (CTX-I) at Week 26 | baseline and 26 weeks | Change from Visit 2 (baseline) to Visit 8 (week 26) in serum CTX-I, a biomarker for bone resorption. |
| Creatinine Corrected Urine C-terminal Telopeptide of Collagen Type II (CTX-II) at Week 26 | baseline and 26 weeks | Change from Visit 2 (baseline) to Visit 8 (week 26) in creatinine corrected urine CTX-II, a biomarker for cartilage degradation. |
| Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Score | baseline and 26 weeks | Change from Visit 2 (Baseline) to Visit 8 (Week 26) in normalised WOMAC stiffness score. The WOMAC responses are scored using an 11-point NRS where 0=none and 10=extreme. There are 2 questions in the WOMAC stiffness scale which is summed up for the total WOMAC stiffness score, leading to a range of 0 to 20. The total WOMAC stiffness score has been standardised to a scale with a range from 0 to 100 (where 100 is extreme pain): \- Normalised WOMAC stiffness score = Total WOMAC stiffness score multiplicated with 5 |
Countries
Bulgaria, Georgia, Germany, Moldova, Romania, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MIV-711:100 mg MIV-711 100 mg administered orally once daily for a total of 26 weeks | 82 |
| MIV-711:200 mg MIV-711 200 mg administered orally once daily for a total of 26 weeks | 81 |
| Placebo Placebo manufactured to mimic MIV-711 capsule administered orally once daily for a total of 26 weeks | 77 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 5 | 2 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Non-compliance | 0 | 1 | 1 |
| Overall Study | Overdosing | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 5 |
Baseline characteristics
| Characteristic | MIV-711:100 mg | MIV-711:200 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 61.2 years STANDARD_DEVIATION 6.58 | 62.0 years STANDARD_DEVIATION 7.33 | 62.3 years STANDARD_DEVIATION 6.59 | 61.8 years STANDARD_DEVIATION 6.83 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 82 Participants | 81 Participants | 75 Participants | 238 Participants |
| Region of Enrollment Bulgaria | 14 participants | 14 participants | 9 participants | 37 participants |
| Region of Enrollment Georgia | 13 participants | 13 participants | 7 participants | 33 participants |
| Region of Enrollment Germany | 26 participants | 22 participants | 21 participants | 69 participants |
| Region of Enrollment Moldova | 26 participants | 29 participants | 36 participants | 91 participants |
| Region of Enrollment Romania | 3 participants | 2 participants | 3 participants | 8 participants |
| Region of Enrollment United Kingdom | 0 participants | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 64 Participants | 58 Participants | 62 Participants | 184 Participants |
| Sex: Female, Male Male | 18 Participants | 23 Participants | 15 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 82 | 1 / 80 |
| other Total, other adverse events | 33 / 82 | 27 / 82 | 33 / 80 |
| serious Total, serious adverse events | 3 / 82 | 2 / 82 | 1 / 80 |
Outcome results
Primary
Numeric Rating Scale (NRS) Average Target Knee Pain Score at Week 26
Change from Visit 2 (Baseline) to Visit 8 (Week 26) in NRS average target knee pain score. NRS (Numeric rating scale) ranges from 0 indicating -no pain, to 10 indicating - pain as bad as it could be.
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an assessment at week 26. The analysis population is therefore equal to the number of patients completing the study for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Numeric Rating Scale (NRS) Average Target Knee Pain Score at Week 26 | -1.7 score | Standard Deviation 2.01 |
| MIV-711:200 mg | Numeric Rating Scale (NRS) Average Target Knee Pain Score at Week 26 | -1.5 score | Standard Deviation 1.95 |
| Placebo | Numeric Rating Scale (NRS) Average Target Knee Pain Score at Week 26 | -1.3 score | Standard Deviation 2.15 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment by time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline NRS was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.405595% CI: [-0.703, 0.55]Mixed Models Analysis
Secondary
Creatinine Corrected Urine C-terminal Telopeptide of Collagen Type II (CTX-II) at Week 26
Change from Visit 2 (baseline) to Visit 8 (week 26) in creatinine corrected urine CTX-II, a biomarker for cartilage degradation.
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an assessment at week 26. In addition, there was two missing samples for urine CTX-II. The analysis population is therefore smaller than in the Participant Flow.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Creatinine Corrected Urine C-terminal Telopeptide of Collagen Type II (CTX-II) at Week 26 | -138.0 ng/mmol | Standard Deviation 198.68 |
| MIV-711:200 mg | Creatinine Corrected Urine C-terminal Telopeptide of Collagen Type II (CTX-II) at Week 26 | -242.5 ng/mmol | Standard Deviation 266.56 |
| Placebo | Creatinine Corrected Urine C-terminal Telopeptide of Collagen Type II (CTX-II) at Week 26 | 28.4 ng/mmol | Standard Deviation 225.69 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-II score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: <0.000195% CI: [-339, -201]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by- time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-II score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: <0.000195% CI: [-262, -124]Mixed Models Analysis
Secondary
Magnetic Resonance Imaging (MRI) Bone Area of the Target Knee at Week 26
Change from Visit 2 (Baseline) to Visit 8 (Week 26) in MRI (Magnetic Resonance Imaging;) bone area of the target knee in mm\^2.
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an MRI assessment at week 26. In addition, there were patients with non valid MRIs. The analysis population is therefore smaller than the Participant Flow.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Magnetic Resonance Imaging (MRI) Bone Area of the Target Knee at Week 26 | 8.1290 mm^2 | Standard Deviation 31.10846 |
| MIV-711:200 mg | Magnetic Resonance Imaging (MRI) Bone Area of the Target Knee at Week 26 | 8.2142 mm^2 | Standard Deviation 29.39941 |
| Placebo | Magnetic Resonance Imaging (MRI) Bone Area of the Target Knee at Week 26 | 23.2234 mm^2 | Standard Deviation 32.68365 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline knee joint MRI bone area was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.003695% CI: [-25.3, -4.02]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline knee joint MRI bone area was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.002395% CI: [-26, -4.83]Mixed Models Analysis
Secondary
Magnetic Resonance Imaging (MRI) of Cartilage Thickness (Femur) at Week 26
Change from Visit 2 (baseline) to Visit 8 (week 26) in MRI cartilage thickness in the Central Medial Femur Region of the target knee in mm.
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an MRI assessment at week 26. In addition, there were patients with non valid MRIs. The analysis population is therefore smaller than the Participant Flow.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Magnetic Resonance Imaging (MRI) of Cartilage Thickness (Femur) at Week 26 | 0.0077 mm | Standard Deviation 0.19258 |
| MIV-711:200 mg | Magnetic Resonance Imaging (MRI) of Cartilage Thickness (Femur) at Week 26 | -0.0171 mm | Standard Deviation 0.24113 |
| Placebo | Magnetic Resonance Imaging (MRI) of Cartilage Thickness (Femur) at Week 26 | -0.0658 mm | Standard Deviation 0.21904 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline MRI of cartilage thickness was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.125395% CI: [-0.031, 0.118]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline MRI of cartilage thickness was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.022595% CI: [0.00173, 0.15]Mixed Models Analysis
Secondary
Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Difficulty Score
Change from Visit 2 (Baseline) to Visit 8 (Week 26) in normalised WOMAC difficulty score. The WOMAC responses are scored using an 11-point NRS where 0=none and 10=extreme. There are 17 questions in the WOMAC difficulty scale which is summed up for the total WOMAC difficulty score, leading to a range of 0 to 170. The total WOMAC difficulty score has been standardised to a scale with a range from 0 to 100 (where 100 is extreme pain): \- Normalised WOMAC difficulty score = Total WOMAC difficulty score divided with 1.7
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an assessment at week 26. The analysis population is therefore equal to the number of patients completing the study for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Difficulty Score | -16.39 score | Standard Deviation 20.937 |
| MIV-711:200 mg | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Difficulty Score | -13.95 score | Standard Deviation 20.668 |
| Placebo | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Difficulty Score | -9.9 score | Standard Deviation 21.862 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Difficulty score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.289895% CI: [-8.38, 4.7]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC difficulty score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.126295% CI: [-10.3, 2.72]Mixed Models Analysis
Secondary
Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Pain Score
Change from Visit 2 (Baseline) to Visit 8 (Week 26) in normalised WOMAC pain score. The WOMAC responses are scored using an 11-point NRS where 0=none and 10=extreme. There are 5 questions in the WOMAC pain scale which is summed up for the total WOMAC score, leading to a range of 0 to 50. The total WOMAC pain score has been standardised to a scale with a range from 0 to 100 (where 100 is extreme pain): \- Normalised WOMAC pain score = Total WOMAC pain score multiplicated with 2.
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an assessment at week 26. The analysis population is therefore equal to the number of patients completing the study for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Pain Score | -16.6 score | Standard Deviation 19.35 |
| MIV-711:200 mg | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Pain Score | -13.0 score | Standard Deviation 18.6 |
| Placebo | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Pain Score | -9.8 score | Standard Deviation 21.89 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time,baseline analgesic user (Yes/No), and random effect for clinical site. Baseline WOMAC Pain score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.288795% CI: [-8.02, 4.48]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Pain score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.075395% CI: [-10.8, 1.67]Mixed Models Analysis
Secondary
Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Score
Change from Visit 2 (Baseline) to Visit 8 (Week 26) in normalised WOMAC stiffness score. The WOMAC responses are scored using an 11-point NRS where 0=none and 10=extreme. There are 2 questions in the WOMAC stiffness scale which is summed up for the total WOMAC stiffness score, leading to a range of 0 to 20. The total WOMAC stiffness score has been standardised to a scale with a range from 0 to 100 (where 100 is extreme pain): \- Normalised WOMAC stiffness score = Total WOMAC stiffness score multiplicated with 5
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an assessment at week 26. The analysis population is therefore equal to the number of patients completing the study for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Score | -17 score | Standard Deviation 24.69 |
| MIV-711:200 mg | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Score | -14.5 score | Standard Deviation 22.71 |
| Placebo | Normalised Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Score | -9.8 score | Standard Deviation 24.71 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Stiffness score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.295% CI: [-10.2, 4.1]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline WOMAC stiffness score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: 0.086195% CI: [-12.1, 2.17]Mixed Models Analysis
Secondary
Serum C-terminal Telopeptide of Collagen Type I (CTX-I) at Week 26
Change from Visit 2 (baseline) to Visit 8 (week 26) in serum CTX-I, a biomarker for bone resorption.
Time frame: baseline and 26 weeks
Population: As there were discontinuations in the study, not all patients in the mITT population had an assessment at week 26. In addition, there was one missing sample for serum CTX-I. The analysis population is therefore smaller than in the Participant Flow.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIV-711:100 mg | Serum C-terminal Telopeptide of Collagen Type I (CTX-I) at Week 26 | -0.1209 ug/L | Standard Deviation 0.16733 |
| MIV-711:200 mg | Serum C-terminal Telopeptide of Collagen Type I (CTX-I) at Week 26 | -0.2575 ug/L | Standard Deviation 0.19931 |
| Placebo | Serum C-terminal Telopeptide of Collagen Type I (CTX-I) at Week 26 | 0.0000 ug/L | Standard Deviation 0.16165 |
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-I score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: <0.000195% CI: [-0.302, -0.206]Mixed Models Analysis
Comparison: A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-I score was included as a covariate for adjustment.~An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.p-value: <0.000195% CI: [-0.193, -0.0983]Mixed Models Analysis