Ignite Creation Date:
2024-07-17 @ 10:43 AM
Last Modification Date:
2024-10-26 @ 3:33 PM
Study NCT ID:
NCT06478186
Status:
RECRUITING
Last Update Posted:
2024-06-27
First Post:
2024-06-03
Brief Title:
Knee Osteoarthritis Treatment with Zilretta Vs Kenalog in the Context of Type II Diabetes
Sponsor:
University of Kansas Medical Center
Organization:
University of Kansas Medical Center
Study Overview
Official Title:
RCT to Evaluate the Effects of Zilretta Triamcinolone Acetonide- Extended Release and Kenalog Triamcinolone Acetonide- Immediate Release on Blood Glucose in Subjects with Osteoarthritis of the Knee and Type 2 Diabetes Mellitus
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
A Phase 2 Randomized Study to Evaluate the Effects of triamcinolone acetonide extended-release TA-ER Zilretta vs triamcinolone acetonide immediate-release TA-IR Kenalog on Blood Glucose Levels in Diabetic Subjects with Knee Osteoarthritis Subjects should have 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 selectedTotal study duration for individual subject will be about 4 months which includes 3 weeks of Screening period 10 days of pretreatment phase treatment day and 12 weeks of post-treatment period
Detailed Description:
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 Numbers 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 7525 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 mgmL 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 11 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 andor injectable non-insulin pharmacological agents eg 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 11 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 subjects 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 withwithout 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 andor 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 seriousnessseverity 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 pausestop 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 pausingstopping 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 Bakers cyst After Day 1 Baseline new clinically significant findings or findings that worsen from the subjects 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 subjects 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 v5 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 005 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 pp65-70
Study Sample Size A prior Phase II study found a difference of approximately 15 percentage points in TAR for TA-ER vs standard triamcinolone acetonide crystalline suspension TAcs 35 for TA-ER vs 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
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 11 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 andor injectable non-insulin pharmacological agents eg 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 11 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 subjects 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 withwithout 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 andor 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 seriousnessseverity 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 pausestop 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 pausingstopping 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 Bakers cyst After Day 1 Baseline new clinically significant findings or findings that worsen from the subjects 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 subjects 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 v5 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 005 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 pp65-70
Study Sample Size A prior Phase II study found a difference of approximately 15 percentage points in TAR for TA-ER vs standard triamcinolone acetonide crystalline suspension TAcs 35 for TA-ER vs 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 006-C-201 | OTHER_GRANT | None | None |