- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03686657
Evaluation of Superiority of Valsartan+Celecoxib+Metformin Over Metformin Alone in Type 2 Diabetes Patients (RESILIENCE)
A 26-week Single Site, Randomized, Double-blind, Active-controlled, Parallel Group, Human PoC Study to Evaluate Superiority of RK-01, Valsartan Plus Celecoxib Addon to Metformin Versus Metformin Alone in Type 2 Diabetes Patients
Evaluation of safety, tolerability and superiority of RK-01, a valsartan plus celecoxib dual add-on to metformin-HCL XR over metformin in newly diagnosed and obese adult type 2 diabetes patients with high blood pressure, arthritis and inadequate glycemic control with metformin monotherapy, diet and exercise over 26 weeks of treatment.
Objective: To assess effect of RK-01 on HbA1c levels, beta cell function and insulin resistance with co-administration of valsartan, celecoxib and metformin-HCl XR relative to metformin monotherapy.
Hypothesis: After 26 weeks of treatment with valsartan, celecoxib and metformin-HCl XR provides greater improvements in glycemic, inflammatory and atherogenic parameters compared to metformin monotherapy.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
PRIMARY:
In patients with type 2 diabetes with inadequate glycemic control with metformin monotherapy:
Objective: To assess effect of RK-01 on HbA1c levels, beta cell function and insulin resistance with co-administration of valsartan, celecoxib and metformin-HCl XR relative to metformin monotherapy. Improvements in glycemic, inflammatory and atherogenic parameters including beta cell function relative to adult healthy volunteers with normal glucose tolerance (NGT) treated with placebo for 26 weeks will also be assessed. An interim study assessment will also be performed after 12 weeks of treatment.
Hypothesis: After 26 weeks of treatment with valsartan, celecoxib and metformin-HCl XR provides greater improvements in glycemic, inflammatory and atherogenic parameters compared to metformin monotherapy.
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Ravi Kumar, Ph.D.
- Phone Number: (609) 977-1857
- Email: ravi.kumar@arkaytherapeutics.com
Study Contact Backup
- Name: Robert Busch, MD
- Phone Number: (518) 461-9734
- Email: buschr@mail.amc.edu
Study Locations
-
-
New York
-
Albany, New York, United States, 12206
- Albany Medical College
-
Contact:
- Kevin Fiesthamel, MS
- Phone Number: 518-264-4472
- Email: feistht@amc.edu
-
Contact:
- Spencer Phelps, CCRC
- Phone Number: 518-264-4474
- Email: phelpss2@amc.edu
-
Principal Investigator:
- Robert Busch, MD
-
Sub-Investigator:
- Grimm Loretta, FNP-C
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Males and females, Age: >18 to 70 years at the time of screening visit.
- Women of childbearing potential (WOCBP) must have negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent of HCG) within 24 hours prior to the start of the study.
- Women must not be breastfeeding.
- HbA1c≥8.0
Patients with inadequate blood glucose control with Metformin defined as a central laboratory glycosylated hemoglobin (HbA1c) >8.0 and <10.5 obtained at the screening visit. Metformin-HCl monotherapy was inadequate 3 months prior to the study as indicated by the lack of decrease and/or an increase in the A1c level.
Newly diagnosed drug naïve patients as defined by HbA1c>7.0 at the screening visit. Drug naïve subjects diagnosed with type 2 diabetes within 6 months of diagnosis will be considered and selected.
About half the patients are expected to be newly diagnosed in the study.
- Drug naive as well as osteoarthritis patients with Type 2 diabetes receiving a non-aspirin pain reliever (e.g. acetaminophen) or an NSAID (e.g. Naproxen).
- Max/maintenance dose Metformin. Subjects should have been taking the same daily dose of metformin for at least 8 weeks prior to the enrollment visit and subjects not receive these other antihyperglycemic medications within the 12 weeks prior to screening (except for short-term use of insulin [≤7 days] during concomitant illness or other stress).
- Patients with >25% AIRg at 2 minutes and 10 minutes.
- RAS blocker naïve patients
- 2-Hour OGTT ≥200 mg/dL
- FPG ≥140 mg/dL
- BMI ≥30
- Impaired first phase and second phase of insulin secretion
- BP ≥140/90 mm Hg (These patients might be on an anti-hypertensive drug)
- Non-fasting laboratory glucose >200 mg/dL with symptoms of polydipsia, polyuria and/or Polyphagia
- eGFR ≥ 60 ml/min/1.73m2
Exclusion Criteria:
- Age >70
- Patients with Type 1 diabetes, Screen for GAD (Glutamic acid decarboxylase) antibodies at the time of screening visit. To rule out latent autoimmune diabetes in adults (LADA), screening for other diabetes-related antibodies, such as insulinoma-associated protein (IA-2 and IA-2 beta), zinc transporter-8 (ZnT8), islet cell antibodies (ICA) or insulin autoantibody (IAA) will also be considered.
- Pregnant women
- Patients with a history of Ketoacidosis.
- Subjects at serious risk of gastrointestinal (GI) adverse events (e.g. current or recent history of GI bleeding ulceration, or perforation).
- Subjects with a planned radiologic study with intravenous contrast, surgery, or other planned procedures that may predispose them to metformin-associated lactic acidosis.
- Insulin dependent: <25% Beta-cell function: AIRg (Acute insulin response to glucose after 2 min and 10 min after glucose injection) INSULIN DEPENDENT STATE.
- Patients with a history of uncontrolled hyperglycemia >15.0 mmol/L (280 mg/dL) after an overnight fast that required rescue therapy.
- Patients with uncontrolled hyperglycemia >15.0 mmol/L (280 mg/dL) after an overnight fast that required rescue therapy during week 1-3 Metformin-HCl monotherapy or RK-01 therapy.
- eGFR, impaired kidney function < 60 ml/min/1.73m2.
- Poor metabolizers of Cyp450 2C9 to avoid very high concentration (Since Cytochrome 450 2C9 is responsible for the metabolism of both Valsartan and Celecoxib, patients who are known or suspected to be poor Cyp450 2C9 metabolizers based on previous history will be excluded from the study).
Any of the following cardiovascular (CV)/Vascular diseases within 3 months of the enrollment visit:
- Myocardial infarction (MI)
- Cardiac surgery or revascularization (coronary artery bypass surgery, Coronary Artery Bypass Graft [(CABG]/Percutaneous transluminal coronary angioplasty (PTCA)].
- Unstable angina
- Unstable congestive heart failure (CHF)
- Transient ischemic attack (TIA) or significant cerebrovascular disease
- Unstable or previously diagnosed arrhythmia
- Congestive heart failure, defined as New York Heart Association (NYHA) Class III and IV, unstable or acute heart failure and/or known left ventricular ejection fraction of ≤40%.
- Acute coronary syndrome, stroke or transient ischemic attack within 3 months prior to the informed consent.
- Previous bariatric surgery
- Treatment with anti-obesity drugs within 3 months prior to consent
- Patients with COPD
- Patients with liver disease
- Patients with renal disease
- Patients with autoimmune diseases e.g. Lupus, Psoriasis
- Patients with HIV/AIDS
- Patients with diabetes-related complications
- Patients with Hematological and Oncological Diseases/Conditions
- Hemoglobin <11.0 g/dL (110 g/L) for men; hemoglobin <10.0 g/dL (100 g/L) for women
- Patients with chronic disease e.g. Cancer, Epilepsy, Alzheimer, Parkinson, Asthma
- Abnormal free T4
- Patients with serious infection
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
No Intervention: Healthy adults with NGT
Healthy adults with normal glucose tolerance (NGT) and beta cell function will be administered placebo.
|
|
Active Comparator: Metformin-Drug naive patients & Patients with inadequate glycemic control with Metformin
Patients receive metformin once daily
|
1000 mg metformin-HCL XR once-a-day or maintenance dose of metformin for 26 weeks
Other Names:
|
Experimental: RK-01 Low
Patients receive valsartan, celecoxib and metformin (low dose) once daily
|
500 mg metformin-HCL XR plus 100 mg celecoxib once-a-day in the morning and 160 mg valsartan 6 hours later once-a-day in the afternoon for 26 weeks.
Other Names:
|
Experimental: RK-01 High
Patients receive valsartan, celecoxib and metformin (high dose) once daily
|
1000 mg metformin-HCL XR plus 200 mg celecoxib once-a-day in the morning and 320 mg valsartan once-a-day 6 hours later in the afternoon for 26 weeks.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in glycosylated Hemoglobin (HbA1c) for metformin background patients
Time Frame: Baseline and 26 weeks
|
Glycosylated hemoglobin (HbA1c) is a measurement of the percentage of hemoglobin that is glycated.
The change from baseline is calculated as the week 26 HbA1c minus the baseline HbA1c.
Since HbA1c is measured as a percentage, the change from baseline is also a percentage.
|
Baseline and 26 weeks
|
Change in glycosylated Hemoglobin (HbA1c) for treatment naive patients
Time Frame: Baseline and 26 weeks
|
Glycosylated hemoglobin (HbA1c) is a measurement of the percentage of hemoglobin that is glycated.
The change from baseline is calculated as the week 26 HbA1c minus the baseline HbA1c.
Since HbA1c is measured as a percentage, the change from baseline is also a percentage.
|
Baseline and 26 weeks
|
Change from baseline in acute insulin response to glucose (AIRg) for metformin background patients
Time Frame: Baseline and 26 weeks
|
Change in baseline in acute insulin response to glucose at week 26
|
Baseline and 26 weeks
|
Change from baseline in acute insulin response to glucose (AIRg) for treatment naive patients
Time Frame: Baseline and 26 weeks
|
Change in baseline in acute insulin response to glucose at week 26
|
Baseline and 26 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in glycosylated Hemoglobin (HbA1c) to <7.0%
Time Frame: Baseline and 26 weeks
|
Glycosylated hemoglobin (HbA1c) is a measurement of the percentage of hemoglobin that is glycated.
The change from baseline is calculated as the week 26 HbA1c minus the baseline HbA1c.
Since HbA1c is measured as a percentage, the change from baseline is also a percentage.
Percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c <7.0%.
|
Baseline and 26 weeks
|
Change from baseline in Body weight
Time Frame: Baseline and 26 weeks
|
Change in body weight at week 26
|
Baseline and 26 weeks
|
Change from baseline in fasting plasma glucose
Time Frame: Baseline and 26 weeks
|
Change in baseline in fasting plasma glucose at week 26
|
Baseline and 26 weeks
|
Change from baseline in Beta-cell function Index
Time Frame: Baseline and 26 weeks
|
Change in baseline in beta cell function index at week 26.
Beta-cell function Index is a measure of their capacity to respond to elevated blood glucose levels
|
Baseline and 26 weeks
|
Change from baseline in insulin sensitivity index (ISI or Si)
Time Frame: Baseline and 26 weeks
|
Change in baseline in insulin sensitivity at week 26
|
Baseline and 26 weeks
|
Change from baseline in glycosylated albumin (GA): glycosylated Hemoglobin A1c (HbA1c) ratio
Time Frame: Baseline and 26 weeks
|
Change in baseline in glycosylated albumin (GA): glycosylated Hemoglobin A1c (HbA1c) at week 26.
GA:HbA1c ratio provides a measure of post-prandial excursion
|
Baseline and 26 weeks
|
Change from baseline in HOMA2-b%
Time Frame: Baseline and 26 weeks
|
Change in baseline in HOMA of Beta-cell function index at week 26
|
Baseline and 26 weeks
|
Change from baseline in HOMA-IR
Time Frame: Baseline and 26 weeks
|
Change in baseline in HOMA-IR at week 26.
HOMA-IR is a measure of insulin resistance.
|
Baseline and 26 weeks
|
Leptin/Adiponectin ratio
Time Frame: Baseline and 26 weeks
|
Change in baseline in Leptin/Adiponectin ratio.
Indicator of insulin resistance
|
Baseline and 26 weeks
|
Change from baseline in Atherogenic Index (AI)
Time Frame: Baseline and 26 weeks
|
Change in baseline in Atherogenic Index at week 26.
Atherogenic Index (AI) is a predictor of cardiovascular risk
|
Baseline and 26 weeks
|
Change from baseline in glycosylated albumin (GA)
Time Frame: Baseline and 26 weeks
|
Change in baseline in glycosylated albumin (GA) at week 26
|
Baseline and 26 weeks
|
Change from baseline in Leptin
Time Frame: Baseline and 26 weeks
|
Change in baseline in Leptin at week 26
|
Baseline and 26 weeks
|
Change from baseline in Adiponectin
Time Frame: Baseline and 26 weeks
|
Change in baseline in Adiponectin at week 26
|
Baseline and 26 weeks
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Ravi Kumar, Ph.D., ARKAY Therapeutics
- Principal Investigator: Robert Busch, MD, Albany Medical College
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Glucose Metabolism Disorders
- Metabolic Diseases
- Endocrine System Diseases
- Hypertension
- Diabetes Mellitus
- Diabetes Mellitus, Type 2
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Cyclooxygenase Inhibitors
- Cyclooxygenase 2 Inhibitors
- Angiotensin II Type 1 Receptor Blockers
- Angiotensin Receptor Antagonists
- Celecoxib
- Valsartan
- Metformin
Other Study ID Numbers
- TriGlytza (RK-01) Prototype
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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