Protocol Title: A Randomized, Double-blind, Active-controlled Study to Evaluate the
Effects of ZILRETTA (Triamcinolone Acetonide-Extended Release) and TA-IR (Triamcinolone
Acetonide-Immediate Release) on Blood Glucose Levels in Subjects with Osteoarthritis of
the Knee and Type 2 Diabetes Mellitus Brief Title: Zilretta Diabetic Knee OA Regulatory
Agency Identifier Number(s): IND 111325 Test Product, Dose, Mode of Administration, and
Lot Number Name: ZILRETTA (triamcinolone acetonide extended-release injectable
suspension; TA-ER) Active ingredient: Extended-release formulation of TA in 75:25 poly
(lactic-co-glycolic) acid (PLGA) microspheres Dosage: Nominal 32 mg TA, intra-articular
(IA) injection, administered as a 5 mL injection Mode of Administration: IA Knee
Injection Reference Product, Dose, Mode of Administration, and Lot Number Name:
Kenalog®-40 (triamcinolone acetonide injectable suspension) Active Ingredient:
Triamcinolone Acetonide- Immediate Release (TA-IR) Dosage: 40 mg/mL, IA, administered as
a 1 mL Injection: TA-IR Mode of Administration: IA Knee Injection Current Indication:
extended-release synthetic corticosteroid indicated as an IA injection for the management
of osteoarthritis pain of the knee.
Study Population and Number of Study Subjects: Subjects with Type 2 Diabetes Mellitus
(T2DM) with HbA1C ≤9 that is managed without insulin and have been diagnosed with
symptomatic unilateral or bilateral osteoarthritis (OA) of the knee, based on clinical
and radiological criteria (if bilateral, then a target knee will be selected)
Approximately 120 subjects (1:1 randomization, 60 ZILRETTA and 60 TA-IR) will be enrolled
for this study.
Note: Subject is considered enrolled, if subject meets initial eligibility criteria and
is randomized to a treatment arm.
Study Duration for Subjects:
Total study duration for individual subject will be about 4 months, which includes a
3-week Screening period, 10 days pretreatmentperiod, treatment day, and a 12-week
post-treatment period.
Overall Study Design:
This randomized clinical trial will include male and female subjects ≥40 years of age,
with known history of T2DM and symptomatic unilateral or bilateral OA of the knee.
Eligible subjects must be on stable doses of oral and/or injectable (non-insulin)
pharmacological agents (e.g. GLP-1 agonists) for at least 3 months prior to the study
screening and after the IA injection till EOS and have hemoglobin A1c (HbA1c) levels ≤9%
at Screening. Subjects on current insulin treatment will be excluded.
After signing informed consent, subjects will be screened and a total of 120 qualified
subjects with T2DM will be randomized to 1 of the 2 treatment groups (1:1). Randomized
subjects will be treated with either 32 mg ZILRETTA (60 subjects) or 40 mg TA-IR (60
subjects). Subjects who fail to meet eligibility criteria may be re-screened once at the
discretion of Principal Investigator (PI) after documenting the rationale for any
re-screening decision. Subjects who meet all eligibility criteria but are found to have
insufficient BG data at their Day 1 visit (ie, missing CGM data ≥ 30%) may repeat the
full 7-day pretreatment phase at the discretion of the PI.
BG Monitoring and Management of T2DM During the Trial After a Screening visit, BG levels
in each subject will be measured using a CGM device, for at least 10 days pre-injection
(pretreatment period) and for at least 10 days postinjection (post-treatment). The final
10 days of the pretreatment period will be also considered as Baseline for BG control.
Subjects and the assessor responsible for subject's clinical assessments and safety
monitoring will be blinded throughout the study to both treatment assignments. Subjects
will be blinded to the glucose readings, so as not to influence behaviors that could
alter blood glucose outcome measures. However, study endocrinologists will monitor
subjects' glucose readings. The study will involve between 6-12 outpatient visits
(depending on whether selected for salivary cortisol tesing) and up to 4 phone visits
that will include Screening, a Pretreatment visit (Day -14 where the CGM sensor will be
placed to initiate study BG data collection), Day 1 (Baseline and treatment), and 2
Posttreatment visits (Days 43, and 85). CGM data will be continuously collected from the
treatment visit through Day 15. On Day 15, subjects will remove the CGM sensor. Day 85
will be end-of-study (EOS) visit.
A subset of subjects will will return saliva for cortisol testing at baseline and on Days
1, 2, 3, 7, 14, 21, 42, 72, and 90 following treatment.
After IA treatment subjects are should not adjust their diabetes medications and Baseline
physical activity should remain unchanged.
Intermediate-acting glucocorticoids (GCs) represent the most commonly prescribed steroid
agents. In general, during the course of chronic GC treatment, GCs may require frequent
dose adaptations that result in more intensive altered requirements of glucose-lowering
therapies. However, since the selected diabetic population will receive a single IA
injection, large glucose fluctuations as experienced with chronic GC treatments are not
expected. Baseline glucose medication dosage will not change. Subjects' BG control will
be monitored in coordination with study endocrinologist.
The analyses of primary and secondary endpoints will be conducted mainly based on CGM
device.
Hypothalamic-Pituitary-Adrenal (HPA) Axis Evaluation Treatment with GCs represents one of
the most frequent causes of secondary adrenal insufficiency. When GCs are used at
supraphysiologic doses, HPA axis suppression causes adrenal glands' inability to produce
sufficient cortisol response to abrupt treatment cessation (Nicolaider et al, 2018). To
avoid HPA axis suppression, it is recommended not to exceed 3 GC IA injections per year
with a minimum of 30 days between (Johnston et al, 2015). Recovery of the HPA axis to
Baseline normally occurs within 1-4 weeks but can be longer in consideration of the dose
and frequency of injections (Habib, 2009). However, after single IA dose of GC injection
recovery after 1-2 weeks was observed in most of the patients (Mader et al, 2005). Thus,
an initial 90-day salivary cortisol assessment in a subset of this trial population
should suffice. An 8 AM salivary cortisol test will be completed at baseline and 1, 2, 3,
7, 14, 21, 42, 72, and 90 day following baseline to evaluate the effect of Zilretta and
TA-IR on the HPA axis and recovery time.
Intra-Articular Injection On Day 1 (Treatment Day), IA injections will be administered by
the assigned blinded, trained injector, who has experience in the administration of IA
injections and has been trained on study administration procedures. Injection into the
knee joint will be performed with/without ultrasound guidance.
Subjects will be advised to avoid strenuous or prolonged weight-bearing activities for
approximately 24 to 48 hours following the injection. If the subject has an immediate
reaction (eg, tenderness, increased pain, swelling, effusion, and/or decreased mobility
of the index knee), the subject should be treated according to clinical guidelines and
physician experience and judgment.
Pain will be assessed by NRS evaluating Worst Daily Knee Pain Intensity and Average Daily
Knee Pain, which will be recorded in the pain Diary per the Schedule of Assessments
(Table 1) and reviewed at each study visit. Physical performance will be assessed with
OARSI recommended10 physical performance measures (40m walk time and stair ascent time)
along with patient-reported physical function (KOOS-PS) and quality of life (KOOS-QoL) at
baseline and at intervals following IA injection.
Internal Safety Review Subject safety will be monitored by an endocrinologist. The
endocrinologist will review, at a minimum, safety, tolerability, and pharmacodynamic (PD)
data on ongoing basis. All members will be blinded to the treatment.
The study PI and study endocrinologist will review all SAEs on an ongoing basis (ie, as
the events are reported). The study PI is responsible for temporarily halting the study
if the type, frequency, or seriousness/severity of such events suggests a potential
threat to the safety of the study subjects. The safety review team will meet semiweekly
or monthly depending upon recruitment rate. Ad hoc meetings may be scheduled as
necessary.
The study PI may pause/stop the study if any of the following occurs:
Any deaths, regardless of causality. Non-fatal SAEs in 12 subjects (≥10% of total subject
population) where a clear unrelated causality is not readily apparent.
Grade 3 or higher AEs in 12 subjects (≥10% of total subject population) that are
clinically significant (Exception: PD parameters or related changes to labs and symptoms
will not be considered as AEs) In the event that any of the preceding criteria occurs,
enrollment will be paused during the review. If a pausing/stopping rule is met, a
decision will be made whether to resume the enrollment.
Case unblinding may be performed for above reviews if necessary and documented
accordingly.
Clinical Safety Assessments The index knee assessment will be performed by the designated
assessor at the visits indicated in the Schedule of Assessments (Table 1). The index knee
will be assessed for injection site reaction, joint effusion, range of motion and
presence of Baker's cyst.,. After Day 1 Baseline, new clinically significant findings or
findings that worsen from the subject's Baseline knee condition will be recorded as an
adverse event (AE).
PD parameters measured during this study such as BG levels (CGM or fingerstick), insulin
consumption, HPA axis evaluation parameters, and hyperglycemia symptoms will not be
reported as AEs.
Safety evaluations will be based on the assessment of AEs occurring after the initiation
of investigational product (IP) on Day 1 through the EOS Visit (Day 85). Results of
clinical safety assessments are to be recorded in the subject's medical records and
transcribed to the appropriate electronic case report form (eCRF), including the AE eCRF
for clinically significant findings.
AEs will be coded using CTCAE v.5. Incidences (number and percent) of TEAEs, those events
that started after dosing or worsened in severity after dosing, will be presented by
treatment group. Incidences of TEAEs will also be presented by maximum severity and
relationship to IP. Safety laboratory investigations and vital signs will be summarized
descriptively by time point collected along with changes from Baseline assessments.
Statistical Methods Descriptive statistics (n, mean, standard deviation [SD], median,
minimum, and maximum) will be calculated by treatment group and time point for continuous
variables. Frequencies and percentages will be presented by treatment group for
categorical and ordinal variables.
The primary endpoint of change in percent of time in TAR will be analyzed with linear
regression. Both models will have a fixed effect for treatment group along with
covariates (eg, the mean of the pretreatment BG values, BMI).
A step-down testing procedure will be employed for primary and key secondary endpoints,
with sequential testing proceeded as long as p < 0.05. Key secondary endpoints and order
of testing will be specified in the SAP (Holm, S., 1979. A simple sequentially rejective
multiple test procedure. Scandinavian journal of statistics, pp.65-70).
Study Sample Size A prior Phase II study found a difference of approximately 15
percentage points in TAR for TA-ER vs.#46;standard triamcinolone acetonide crystalline
suspension (TAcs) (~35% for TA-ER vs.#46; 50% for TAcs). 120 subjects will provide >80% power
to detect an effect size of 10 percentage points, assuming a standard deviation of 18.
The primary outcome will be measured 72 hours after treatment by a sensor automatically
uploading the data, thus we expect few dropouts are expected.
