Osteoarthritis of the Knee, Type 2 Diabetes Mellitus
Conditions
Keywords
osteoarthritis, knee, pain, diabetes, intra-articular, injection, corticosteroid
Brief summary
The purpose of this study was to compare the effects of FX006 and Triamcinolone Acetonide Injectable Suspension, United States Pharmacopeia (USP) (referred to as TCA IR in the protocol) on blood glucose (BG) in patients with osteoarthritis (OA) of the knee and Type 2 diabetes mellitus (DM).
Detailed description
This study employed a double-blind, randomized, parallel group, single dose design to explore the pharmacodynamic effects on BG levels in type 2 diabetics following IA administration of 32 mg FX006 compared to 40 mg TCA IR. The study was conducted in male and female patients ≥40 years of age with OA of the knee and type 2 DM not managed by injectable agents. In order to be eligible for study participation, patients were to be treated with 1 or 2 oral agents and have hemoglobin A1c (HbA1c) levels between 6.5%-9.0%. Approximately 36 patients were planned to be randomized and treated to ensure there were at least 30 evaluable patients (15 patients on FX006 and 15 patients on TCA IR). Patients were randomized to 1 of 2 treatment groups (1:1) and treated with a single IA injection of either: * 32 mg FX006 (18 patients) or * 40 mg TCA IR (18 patients) BG levels in each patient were evaluated for a total of 3 weeks (1 week prior to IA injection and 2 weeks post IA injection). After a screening visit, patients' BG levels were measured using a Dexcom Z4 Platinum Professional™ continuous glucose monitor (CGM) device, set to blinded mode, for up to 1 week pre-injection and for 2 weeks post injection using the same blinded CGM device. Patients also were provided with a Bayer Contour™ standard glucose measuring meter in order to perform the necessary calibrations per the manufacturer's recommendations. A final safety visit was planned at 6 weeks post-injection.
Interventions
DRUGFX006 32 mg
Single 5 mL IA injection
DRUGTCA IR 40 mg
Single 1 mL IA injection
Sponsors
Pacira Pharmaceuticals, Inc
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Willingness and ability to comply with the study procedures and visit schedules and ability to follow verbal and written instructions * Male or female ≥40 years of age * Type 2 diabetes mellitus for at least 1 year prior to Screening and not managed with injectable agents (e.g. insulin or insulin analogs, exenatide, pramlintide, liraglutide) * Currently treated with 1 or 2 oral agents for diabetes, with stable doses for at least 2 months * HbA1c ≥6.5% and ≤ 9.0% * Currently meets American College of Rheumatology (ACR) Criteria (clinical or radiological) for OA. * Symptoms associated with OA of the knee for ≥ 6 months prior to Screening * Index knee pain on most days (\>15) over the last month (as reported by the patient) * Body mass index (BMI) ≤ 40 kg/m2 * Willingness to abstain from use of protocol-specified restricted medications during the study * Willingness to wear a CGM device uninterrupted for 24 hours per day throughout the study, remain with receiving range and comply with calibration requirements * Accustomed to using a Standard Blood Glucose Measuring device by finger stick
Exclusion criteria
* Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or arthritis associated with inflammatory bowel disease * History of infection in the index knee joint * Clinical signs and symptoms of active knee infection or crystal disease of the index knee within 1 month of Screening * Presence of surgical hardware or other foreign body in the index knee * Unstable joint (such as a torn anterior cruciate ligament) within 12 months of screening * IA corticosteroid (investigational or marketed) in any joint within 3 months of Screening * IA hyaluronic acid (investigational or marketed) in the index knee within 6 months of Screening * IV or intramuscular (IM) corticosteroids (investigational or marketed) within 3 months of Screening * Oral corticosteroids (investigational or marketed) within 1 month of Screening * Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of Screening * Any other IA investigational drug/biologic within 6 months of Screening * Prior use of FX006 * Use of acetaminophen, or acetaminophen containing products * Current use of a continuous glucose monitoring device * Women of child-bearing potential not using effective contraception or who are pregnant or nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline for Average Blood Glucose (mg/dL) | Baseline and 72 Hours post intra-articular (IA) injection | Average blood glucose was analyzed with a mixed model for repeated measures (MMRM) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Baseline to Days 1-3 | The glycemic variability was calculated as the coefficient of variation (CV) of the hourly averages in each of these time periods: Hour 1-24, Hour 1-48, Hour 1-72, Hour 1-168, and Hour 1-360. The % CV for each patient was derived using the formula: (SD/mean)\*100, using the values for each hourly average glucose measurement over the time period. Average % CV in the FX006 40 mg group was compared to the TCA IR 40 mg group using a linear model (ANCOVA) with fixed effects for treatment group. Model covariates were study center and baseline (72-hour) blood glucose average. |
| Glycemic Variability Coeffecient of Variation (CV) | Baseline to 72 hours post injection (hourly average blood glucose measurement over the time period) | The glycemic variability was calculated as the coefficient of variation (CV) of the hourly averages in each of these time periods: Hour 1-24, Hour 1-48, Hour 1-72, Hour 1-168, and Hour 1-360. The % CV for each patient was derived using the formula: (SD/mean)\*100, using the values for each hourly average glucose measurement over the time period. Average % CV in the FX006 40 mg group was compared to the TCA IR 40 mg group using a linear model (ANCOVA) with fixed effects for treatment group. Model covariates were study center and baseline (72-hour) blood glucose average. |
| Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Baseline to 72 hours post injection (-72 hr, 0 hr, and 1, 2, 3, 7, and 15 days post-dose) | — |
Other
| Measure | Time frame |
|---|---|
| Change From Baseline for Maximum Blood Glucose: Baseline Average Blood Glucose (Hour -72 to Hour -1) to Maximum Blood Glucose (Hour 1 to Hour 72) for FX006 32 mg Relative to TCA IR 40 mg | Baseline (Hour -72 to Hour -1) to Hour 1 to Hour 72 |
| Change in Average Blood Glucose From Baseline (Hour -48 to Hour -1) to Hour 1 to Hour 48 for FX006 32 mg Relative to TCA IR 40 mg. | Baseline (Hour -48 to Hour -1) to Hour 1 to Hour 48 |
| Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Baseline to Days 1-2 |
Countries
United States
Participant flow
Recruitment details
Patients were screened for study eligibility at 9 study centers in the United States (US).
Pre-assignment details
Patients were Randomized within 21 days of Screening.
Participants by arm
| Arm | Count |
|---|---|
| FX006 32 mg FX006: Single 5 mL IA injection | 18 |
| TCA IR 40 mg TCA IR: Single 1 mL IA injection | 15 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | FX006 32 mg | TCA IR 40 mg | Total |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 5.76 | 60.3 years STANDARD_DEVIATION 10.38 | 61.2 years STANDARD_DEVIATION 8.08 |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 12 Participants | 7 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 15 |
| other Total, other adverse events | 2 / 18 | 2 / 15 |
| serious Total, serious adverse events | 0 / 18 | 0 / 15 |
Outcome results
Primary
Change From Baseline for Average Blood Glucose (mg/dL)
Average blood glucose was analyzed with a mixed model for repeated measures (MMRM)
Time frame: Baseline and 72 Hours post intra-articular (IA) injection
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FX006 32 mg | Change From Baseline for Average Blood Glucose (mg/dL) | 14.66 mg/dL | Standard Error 7.032 |
| TCA IR 40 mg | Change From Baseline for Average Blood Glucose (mg/dL) | 33.88 mg/dL | Standard Error 6.612 |
p-value: 0.0452t-test, 2 sided
Secondary
Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR
Time frame: Baseline to 72 hours post injection (-72 hr, 0 hr, and 1, 2, 3, 7, and 15 days post-dose)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| FX006 32 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Baseline (Hour -72 to Hour -1) | 22089.0 hr*mg/dL | Standard Error 775.19 |
| FX006 32 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Day 1 | 3703.3 hr*mg/dL | Standard Error 239.62 |
| FX006 32 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-2 | 7902.6 hr*mg/dL | Standard Error 442.21 |
| FX006 32 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-3 | 11772.3 hr*mg/dL | Standard Error 652.17 |
| FX006 32 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-7 | 27245.7 hr*mg/dL | Standard Error 1615.93 |
| FX006 32 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-15 | 52112.8 hr*mg/dL | Standard Error 2966.97 |
| TCA IR 40 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-7 | 25987.0 hr*mg/dL | Standard Error 1519.37 |
| TCA IR 40 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Baseline (Hour -72 to Hour -1) | 23669.1 hr*mg/dL | Standard Error 728.86 |
| TCA IR 40 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-3 | 12950.9 hr*mg/dL | Standard Error 613.2 |
| TCA IR 40 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Day 1 | 4483.2 hr*mg/dL | Standard Error 225.3 |
| TCA IR 40 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-15 | 49532.2 hr*mg/dL | Standard Error 2789.67 |
| TCA IR 40 mg | Area Under the Effect (AUE) Curves for Average Blood Glucose - FX006 Versus TCA IR | Days 1-2 | 9251.7 hr*mg/dL | Standard Error 415.78 |
Secondary
Glycemic Variability Coeffecient of Variation (CV)
The glycemic variability was calculated as the coefficient of variation (CV) of the hourly averages in each of these time periods: Hour 1-24, Hour 1-48, Hour 1-72, Hour 1-168, and Hour 1-360. The % CV for each patient was derived using the formula: (SD/mean)\*100, using the values for each hourly average glucose measurement over the time period. Average % CV in the FX006 40 mg group was compared to the TCA IR 40 mg group using a linear model (ANCOVA) with fixed effects for treatment group. Model covariates were study center and baseline (72-hour) blood glucose average.
Time frame: Baseline to 72 hours post injection (hourly average blood glucose measurement over the time period)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FX006 32 mg | Glycemic Variability Coeffecient of Variation (CV) | 22.43 mg/dL | Standard Error 1.434 |
| TCA IR 40 mg | Glycemic Variability Coeffecient of Variation (CV) | 27.05 mg/dL | Standard Error 1.349 |
Secondary
Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl
The glycemic variability was calculated as the coefficient of variation (CV) of the hourly averages in each of these time periods: Hour 1-24, Hour 1-48, Hour 1-72, Hour 1-168, and Hour 1-360. The % CV for each patient was derived using the formula: (SD/mean)\*100, using the values for each hourly average glucose measurement over the time period. Average % CV in the FX006 40 mg group was compared to the TCA IR 40 mg group using a linear model (ANCOVA) with fixed effects for treatment group. Model covariates were study center and baseline (72-hour) blood glucose average.
Time frame: Baseline to Days 1-3
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 70 - 180 | 63.3 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 250.1 - 350.0 | 9.5 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 180.1 - 250.0 | 23.7 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Greater than 350.0 | 1.3 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Less than 70 | 2.2 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Greater than 350.0 | 4.3 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Less than 70 | 0.4 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 70 - 180 | 49.7 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 180.1 - 250.0 | 24.5 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 250.1 - 350.0 | 21.1 Percentage of time |
Other Pre-specified
Change From Baseline for Maximum Blood Glucose: Baseline Average Blood Glucose (Hour -72 to Hour -1) to Maximum Blood Glucose (Hour 1 to Hour 72) for FX006 32 mg Relative to TCA IR 40 mg
Time frame: Baseline (Hour -72 to Hour -1) to Hour 1 to Hour 72
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FX006 32 mg | Change From Baseline for Maximum Blood Glucose: Baseline Average Blood Glucose (Hour -72 to Hour -1) to Maximum Blood Glucose (Hour 1 to Hour 72) for FX006 32 mg Relative to TCA IR 40 mg | 110.04 mg/dL | Standard Error 10.084 |
| TCA IR 40 mg | Change From Baseline for Maximum Blood Glucose: Baseline Average Blood Glucose (Hour -72 to Hour -1) to Maximum Blood Glucose (Hour 1 to Hour 72) for FX006 32 mg Relative to TCA IR 40 mg | 158.46 mg/dL | Standard Error 9.481 |
Other Pre-specified
Change in Average Blood Glucose From Baseline (Hour -48 to Hour -1) to Hour 1 to Hour 48 for FX006 32 mg Relative to TCA IR 40 mg.
Time frame: Baseline (Hour -48 to Hour -1) to Hour 1 to Hour 48
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FX006 32 mg | Change in Average Blood Glucose From Baseline (Hour -48 to Hour -1) to Hour 1 to Hour 48 for FX006 32 mg Relative to TCA IR 40 mg. | 16.33 mg/dL | Standard Error 8.791 |
| TCA IR 40 mg | Change in Average Blood Glucose From Baseline (Hour -48 to Hour -1) to Hour 1 to Hour 48 for FX006 32 mg Relative to TCA IR 40 mg. | 43.62 mg/dL | Standard Error 8.255 |
Other Pre-specified
Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl
Time frame: Baseline to Days 1-2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 70.0 - 180.0 | 64.1 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 250.1 - 350.0 | 9.9 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 180.1 - 250.0 | 23.0 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Greater than 350.0 | 1.7 Percentage of time |
| FX006 32 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Less than 70.0 | 1.2 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Greater than 350.0 | 4.4 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | Less than 70.0 | 0.3 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 70.0 - 180.0 | 42.7 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 180.1 - 250.0 | 27.4 Percentage of time |
| TCA IR 40 mg | Percent Time Blood Glucose Less Than 70 mg/dl, 70 - 180 mg/dl, 180.1 - 250.0 mg/dl, 250.1 - 350.0 mg/dl, and Greater Than 350.0 mg/dl | 250.1 - 350.0 | 25.2 Percentage of time |