Study to Assess the Effects of FX006 on Blood Glucose in Patients With OA of the Knee and Type 2 Diabetes

Study Overview
=================
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.

Official Title
-----------------
A Double-Blind, Randomized, Parallel Group Comparison of the Effects of FX006 and TCA IR (Triamcinolone Acetonide Suspension) on Blood Glucose in Patients With Osteoarthritis of the Knee and Type 2 Diabetes Mellitus

Conditions
-----------------
Osteoarthritis of the Knee, Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: FX006 32 mg
* Drug: TCA IR 40 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FX006 32 mg<br>Single 5 mL intra-articular (IA) injection Extended-release Formulation | Drug: FX006 32 mg<br>* Single 5 mL IA injection<br>* Other names: Zilretta;|
| Active Comparator: TCA IR 40 mg<br>Single 1 mL intra-articular (IA) injection Immediate-release Formulation | Drug: TCA IR 40 mg<br>* Single 1 mL IA injection<br>* Other names: Triamcinolone Acetonide Crystalline Suspension (TAcs);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline for Average Blood Glucose (mg/dL) | Average blood glucose was analyzed with a mixed model for repeated measures (MMRM) | Baseline and 72 Hours post intra-articular (IA) injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Days 1-3 | 
| 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. | Baseline to 72 hours post injection (hourly average blood glucose measurement over the time period) | 
| 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
osteoarthritis, knee, pain, diabetes, intra-articular, injection, corticosteroid