Osteoarthritis, Knee
Conditions
Brief summary
The main purpose of this study is to test if LY2951742 relieves mild to moderate knee pain. The study drugs will be given as an injection under the skin and as an oral capsule. The study will last about 28 weeks for each participant.
Interventions
DRUGLY2951742
Administered subcutaneously (SC)
OTHERPlacebo- oral
Administered orally
OTHERPlacebo - SC
Administered SC
DRUGCelecoxib
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Have osteoarthritis (OA) of the knee joint based on American College of Rheumatology (ACR) criteria and confirmed with X-rays and ACR functional class of I to III * Have been on stable dose of prescription Nonsteroidal Anti-Inflammatory Drugs (NSAIDS), celecoxib, tramadol, or acetaminophen of at least 2000 mg per day for at least 20 days in the past month * Willing to stop all analgesics for OA pain during the study * Experienced pain while walking in the target knee of 50-90 mm inclusive on 0-100 Visual Analog Scale (VAS) with an increase in pain while walking of at least 10 mm following washout of current Osteoarthritis pain medications at screening
Exclusion criteria
* Allergic to LY2951742, celecoxib, other NSAIDS, including aspirin, and similar drugs * Arthritis of the knee from other causes * Uncontrolled hypertension * Have OA pain that requires treatment with potent opioids, systemic corticosteroids, intra-articular injections, duloxetine, or venlafaxine * Moderate to severe renal impairment * Pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | Baseline, 8 Weeks | The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis (OA) symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales. The WOMAC pain subscale was calculated for each participant at each time point for analysis as the mean score (range 0-100 millimeter \[mm\] VAS; 0=very good and 100=very poor) of all 5 questions related to pain. Bayesian posterior adjusted mean was calculated using a Bayesian Normal Dynamic Linear Model (NDLM) dose response model with baseline and pooled investigator site included as baseline covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | Baseline, 8 Weeks | The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales. The WOMAC Osteoarthritis Index version 3.1 was administered according to the study schedule. The WOMAC physical function subscale was calculated for each participant at each time point for analysis as the mean score (range 0-100 mm VAS; 0=very good and 100=very poor) of all 17 questions related to physical function. Least Square Mean (LSM) was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. |
| Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | Baseline, 8 Weeks | The PGA is a patient-rated instrument that measures their assessment of overall OA symptoms. It is based on the participant's response to the question Considering all the ways your osteoarthritis affects you, how are you doing today? using a 100 mm VAS (0=very good and 100=very poor). LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. |
| Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 8 Weeks | The responders according to OMERACT-OARSI criteria: participants with at least 50 % improvement in pain or in function scores, along with absolute improvement of 20 mm, were considered responders. Alternatively, participants were considered responders if they showed at least 20% improvement and absolute improvement of 10 mm in at least two of the following scores: pain, function and Patients Global Assessment (PGA) scores. |
| Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | Baseline, 8 Weeks | The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales. The WOMAC stiffness subscale will be calculated for each participant at each time point for analysis as the mean score (range 0-100 mm VAS; 0=very good and 100=very poor) of 2 questions related to stiffness. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. |
| Change From Baseline to 8 Weeks in the WOMAC Total Score | Baseline, 8 Weeks | The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales.The WOMAC total score was calculated for each participant at each time point for analysis as the mean score (range 0-100 mm VAS; 0=very good and 100=very poor) of 24 questions. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo capsule orally, once daily for 16 weeks. Placebo subcutaneous (SC) once every 4 weeks for 16 weeks. | 76 |
| Celecoxib Celecoxib 200 milligram (mg) capsule orally once daily for 16 weeks. Placebo SC once every 4 weeks for 16 weeks. | 39 |
| LY2951742 5 mg + Placebo Placebo capsule orally, once daily for 16 weeks. SC dose of 5 mg LY2951742 once every 4 weeks for 16 weeks. | 38 |
| LY2951742 50 mg + Placebo Placebo capsule orally, once daily for 16 weeks. SC injection of 50 mg LY2951742 once every 4 weeks for 16 weeks. | 38 |
| LY2951742 120 mg + Placebo Placebo capsule orally, once daily for 16 weeks. SC injections of 120 mg LY2951742 once every 4 weeks for 16 weeks. | 38 |
| LY2951742 300 mg + Placebo Placebo capsule orally, once daily for 16 weeks. SC injections of 300 mg LY2951742 once every 4 weeks for 16 weeks. | 37 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Could not Keep Visit Schedule | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Inadequate Pain Relief | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 3 | 2 | 1 | 4 | 3 |
| Overall Study | Physician Decision | 2 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Positive Drug Screen | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Terminated by Sponsor | 43 | 23 | 20 | 23 | 21 | 23 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 2 | 1 | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo | Celecoxib | LY2951742 5 mg + Placebo | LY2951742 50 mg + Placebo | LY2951742 120 mg + Placebo | LY2951742 300 mg + Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 7.94 | 60.8 years STANDARD_DEVIATION 9.86 | 58.0 years STANDARD_DEVIATION 9.6 | 56.7 years STANDARD_DEVIATION 7.95 | 58 years STANDARD_DEVIATION 9.29 | 56.4 years STANDARD_DEVIATION 9.38 | 58.2 years STANDARD_DEVIATION 8.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 21 Participants | 17 Participants | 19 Participants | 19 Participants | 17 Participants | 135 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 18 Participants | 21 Participants | 19 Participants | 18 Participants | 20 Participants | 130 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 7 Participants | 11 Participants | 13 Participants | 12 Participants | 13 Participants | 75 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 54 Participants | 31 Participants | 25 Participants | 25 Participants | 23 Participants | 23 Participants | 181 Participants |
| Sex: Female, Male Female | 53 Participants | 24 Participants | 23 Participants | 22 Participants | 23 Participants | 19 Participants | 164 Participants |
| Sex: Female, Male Male | 23 Participants | 15 Participants | 15 Participants | 16 Participants | 15 Participants | 18 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 76 | 13 / 39 | 8 / 38 | 8 / 38 | 13 / 38 | 9 / 37 |
| serious Total, serious adverse events | 1 / 76 | 0 / 39 | 0 / 38 | 0 / 38 | 0 / 38 | 1 / 37 |
Outcome results
Primary
Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale
The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis (OA) symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales. The WOMAC pain subscale was calculated for each participant at each time point for analysis as the mean score (range 0-100 millimeter \[mm\] VAS; 0=very good and 100=very poor) of all 5 questions related to pain. Bayesian posterior adjusted mean was calculated using a Bayesian Normal Dynamic Linear Model (NDLM) dose response model with baseline and pooled investigator site included as baseline covariates.
Time frame: Baseline, 8 Weeks
Population: Full Analysis Set (FAS) is the number of randomized participants who received at least 1 dose of study drug and had at least 1 post-dose baseline efficacy assessment. N = participants in the full analysis set with an evaluable WOMAC assessment at weeks 2, 4, 6 or 8. The 95% Crl (Credible Interval) is reported, not confidence interval (CI).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | -19.2 mm |
| Celecoxib | Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | -31.3 mm |
| LY2951742 5 mg + Placebo | Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | -16.4 mm |
| LY2951742 50 mg + Placebo | Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | -24.2 mm |
| LY2951742 120 mg + Placebo | Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | -21.8 mm |
| LY2951742 300 mg + Placebo | Change From Baseline to 8 Weeks in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale | -17.7 mm |
Secondary
Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale
The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales. The WOMAC Osteoarthritis Index version 3.1 was administered according to the study schedule. The WOMAC physical function subscale was calculated for each participant at each time point for analysis as the mean score (range 0-100 mm VAS; 0=very good and 100=very poor) of all 17 questions related to physical function. Least Square Mean (LSM) was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates.
Time frame: Baseline, 8 Weeks
Population: FAS: Randomized participants who received at least 1 dose of study drug and had at least 1 post-dose baseline efficacy assessment. N = participants in the full analysis set with an evaluable WOMAC assessment at weeks 2, 4, 6 or 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | -16.5 mm |
| Celecoxib | Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | -30.6 mm |
| LY2951742 5 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | -15.4 mm |
| LY2951742 50 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | -23.5 mm |
| LY2951742 120 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | -19.5 mm |
| LY2951742 300 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Physical Function Subscale | -18.4 mm |
Secondary
Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale
The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales. The WOMAC stiffness subscale will be calculated for each participant at each time point for analysis as the mean score (range 0-100 mm VAS; 0=very good and 100=very poor) of 2 questions related to stiffness. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates.
Time frame: Baseline, 8 Weeks
Population: FAS: Randomized participants who received at least 1 dose of study drug and had at least 1 post-dose baseline efficacy assessment. N = participants in the full analysis set with an evaluable WOMAC assessment at weeks 2, 4, 6 or 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | -18.5 mm |
| Celecoxib | Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | -31.4 mm |
| LY2951742 5 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | -15.1 mm |
| LY2951742 50 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | -23.7 mm |
| LY2951742 120 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | -21.3 mm |
| LY2951742 300 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Stiffness Subscale | -17.3 mm |
Secondary
Change From Baseline to 8 Weeks in the WOMAC Total Score
The 24-question WOMAC Osteoarthritis Index assesses osteoarthritis symptoms using pain (5 questions), stiffness (2 questions) and physical function (17 questions) subscales.The WOMAC total score was calculated for each participant at each time point for analysis as the mean score (range 0-100 mm VAS; 0=very good and 100=very poor) of 24 questions. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates. LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates.
Time frame: Baseline, 8 Weeks
Population: FAS: Randomized participants who received at least 1 dose of study drug and had at least 1 post-dose baseline efficacy assessment. N = participants in the full analysis set with an evaluable WOMAC assessment at weeks 2, 4, 6 or 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 8 Weeks in the WOMAC Total Score | -17.0 mm |
| Celecoxib | Change From Baseline to 8 Weeks in the WOMAC Total Score | -31.1 mm |
| LY2951742 5 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Total Score | -15.6 mm |
| LY2951742 50 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Total Score | -23.7 mm |
| LY2951742 120 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Total Score | -20.0 mm |
| LY2951742 300 mg + Placebo | Change From Baseline to 8 Weeks in the WOMAC Total Score | -18.4 mm |
Secondary
Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis
The PGA is a patient-rated instrument that measures their assessment of overall OA symptoms. It is based on the participant's response to the question Considering all the ways your osteoarthritis affects you, how are you doing today? using a 100 mm VAS (0=very good and 100=very poor). LSM mean was calculated using a mixed-effects model repeated measures (MMRM) approach with treatment, visit and the interaction of treatment and visit were fitted as fixed effects in the model and baseline and pooled investigator site as baseline covariates.
Time frame: Baseline, 8 Weeks
Population: FAS: Randomized participants who received at least 1 dose of study drug and had at least 1 post-dose baseline efficacy assessment. N = participants in the full analysis set with an evaluable PGA assessment at weeks 2, 4, 6 or 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | -22.5 mm |
| Celecoxib | Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | -36.7 mm |
| LY2951742 5 mg + Placebo | Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | -18.5 mm |
| LY2951742 50 mg + Placebo | Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | -19.4 mm |
| LY2951742 120 mg + Placebo | Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | -21.2 mm |
| LY2951742 300 mg + Placebo | Change in Baseline to 8 Weeks in Patient's Global Assessment of Osteoarthritis | -20.4 mm |
Secondary
Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI)
The responders according to OMERACT-OARSI criteria: participants with at least 50 % improvement in pain or in function scores, along with absolute improvement of 20 mm, were considered responders. Alternatively, participants were considered responders if they showed at least 20% improvement and absolute improvement of 10 mm in at least two of the following scores: pain, function and Patients Global Assessment (PGA) scores.
Time frame: 8 Weeks
Population: FAS: Randomized participants who received at least 1 dose of study drug and had at least one post-dose efficacy assessment. N= participants analyzed in the full analysis set with an evaluable response rate at week 8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 21 participants |
| Celecoxib | Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 14 participants |
| LY2951742 5 mg + Placebo | Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 7 participants |
| LY2951742 50 mg + Placebo | Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 15 participants |
| LY2951742 120 mg + Placebo | Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 10 participants |
| LY2951742 300 mg + Placebo | Number of Participants With a Response Rate Measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) | 10 participants |