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Evaluation of Superiority of Valsartan+Celecoxib+Metformin Over Metformin Alone in Type 2 Diabetes Patients (RESILIENCE)

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ClinicalTrials.gov Identifier: NCT03686657
Recruitment Status : Not yet recruiting
First Posted : September 27, 2018
Last Update Posted : October 9, 2019
Sponsor:
Collaborator:
Albany Medical College
Information provided by (Responsible Party):
ARKAY Therapeutics

Tracking Information
First Submitted Date  ICMJE September 23, 2018
First Posted Date  ICMJE September 27, 2018
Last Update Posted Date October 9, 2019
Estimated Study Start Date  ICMJE August 5, 2020
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2019)
  • 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.
  • 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.
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: September 25, 2018)
  • 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.
  • 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.
Change History Complete list of historical versions of study NCT03686657 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2019)
  • 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%.
  • Change from baseline in Body weight [ Time Frame: Baseline and 26 weeks ]
    Change in body weight at week 26
  • Change from baseline in fasting plasma glucose [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in fasting plasma glucose at week 26
  • 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
  • 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
  • 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
  • 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
  • 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.
  • Leptin/Adiponectin ratio [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in Leptin/Adiponectin ratio. Indicator of insulin resistance
  • 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
  • Change from baseline in glycosylated albumin (GA) [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in glycosylated albumin (GA) at week 26
  • Change from baseline in Leptin [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in Leptin at week 26
  • Change from baseline in Adiponectin [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in Adiponectin at week 26
Original Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2018)
  • 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%.
  • Change from baseline in Body weight [ Time Frame: Baseline and 26 weeks ]
    Change in body weight at week 26
  • Change from baseline in fasting plasma glucose [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in fasting plasma glucose at week 26
  • 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
  • Change from baseline in acute insulin response to glucose (AIRg) [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in acute insulin response to glucose at week 26.
  • 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
  • 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
  • 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
  • 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.
  • Leptin/Adiponectin ratio [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in Leptin/Adiponectin ratio. Indicator of insulin resistance
  • 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
  • Change from baseline in glycosylated albumin (GA) [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in glycosylated albumin (GA) at week 26
  • Change from baseline in Leptin [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in Leptin at week 26
  • Change from baseline in Adiponectin [ Time Frame: Baseline and 26 weeks ]
    Change in baseline in Adiponectin at week 26
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of Superiority of Valsartan+Celecoxib+Metformin Over Metformin Alone in Type 2 Diabetes Patients
Official Title  ICMJE 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
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes
  • High Blood Pressure
  • Arthritis
  • Obesity
Intervention  ICMJE
  • Drug: Metformin
    1000 mg metformin-HCL XR once-a-day or maintenance dose of metformin for 26 weeks
    Other Names:
    • Glucophage
    • Glucophage XR
  • Drug: Val, Cel and Met XR Low
    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:
    • Diovan
    • Celebrex
    • Glucophage XR
    • RK-01
  • Drug: Val, Cel and Met XR High
    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:
    • Diovan
    • Celebrex
    • Glucophage XR
    • RK-01
Study Arms  ICMJE
  • No Intervention: Healthy adults with NGT
    Healthy adults with normal glucose tolerance (NGT) and beta cell function will be administered placebo.
  • Active Comparator: Metformin
    Patients receive metformin once daily
    Intervention: Drug: Metformin
  • Experimental: Val, Cel and Met XR Low
    Patients receive valsartan, celecoxib and metformin (low dose) once daily
    Intervention: Drug: Val, Cel and Met XR Low
  • Experimental: Val, Cel and Met XR High
    Patients receive valsartan, celecoxib and metformin (high dose) once daily
    Intervention: Drug: Val, Cel and Met XR High
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: September 25, 2018)
115
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2022
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Males and females, Age: >18 to 70 years at the time of screening visit.
  2. 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.
  3. Women must not be breastfeeding.
  4. HbA1c≥8.0
  5. 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.

  6. 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).
  7. 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).
  8. Patients with >25% AIRg at 2 minutes and 10 minutes.
  9. RAS blocker naïve patients
  10. 2-Hour OGTT ≥200 mg/dL
  11. FPG ≥140 mg/dL
  12. BMI ≥30
  13. Impaired first phase and second phase of insulin secretion
  14. BP ≥140/90 mm Hg (These patients might be on an anti-hypertensive drug)
  15. Non-fasting laboratory glucose >200 mg/dL with symptoms of polydipsia, polyuria and/or Polyphagia
  16. eGFR ≥ 60 ml/min/1.73m2

Exclusion Criteria:

  1. Age >70
  2. 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.
  3. Pregnant women
  4. Patients with a history of Ketoacidosis.
  5. Subjects at serious risk of gastrointestinal (GI) adverse events (e.g. current or recent history of GI bleeding ulceration, or perforation).
  6. Subjects with a planned radiologic study with intravenous contrast, surgery, or other planned procedures that may predispose them to metformin-associated lactic acidosis.
  7. Insulin dependent: <25% Beta-cell function: AIRg (Acute insulin response to glucose after 2 min and 10 min after glucose injection) INSULIN DEPENDENT STATE.
  8. Patients with a history of uncontrolled hyperglycemia >15.0 mmol/L (280 mg/dL) after an overnight fast that required rescue therapy.
  9. 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.
  10. eGFR, impaired kidney function < 60 ml/min/1.73m2.
  11. 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).
  12. Any of the following cardiovascular (CV)/Vascular diseases within 3 months of the enrollment visit:

    1. Myocardial infarction (MI)
    2. Cardiac surgery or revascularization (coronary artery bypass surgery, Coronary Artery Bypass Graft [(CABG]/Percutaneous transluminal coronary angioplasty (PTCA)].
    3. Unstable angina
    4. Unstable congestive heart failure (CHF)
    5. Transient ischemic attack (TIA) or significant cerebrovascular disease
    6. Unstable or previously diagnosed arrhythmia
    7. 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%.
    8. Acute coronary syndrome, stroke or transient ischemic attack within 3 months prior to the informed consent.
  13. Previous bariatric surgery
  14. Treatment with anti-obesity drugs within 3 months prior to consent
  15. Patients with COPD
  16. Patients with liver disease
  17. Patients with renal disease
  18. Patients with autoimmune diseases e.g. Lupus, Psoriasis
  19. Patients with HIV/AIDS
  20. Patients with diabetes-related complications
  21. Patients with Hematological and Oncological Diseases/Conditions
  22. Hemoglobin <11.0 g/dL (110 g/L) for men; hemoglobin <10.0 g/dL (100 g/L) for women
  23. Patients with chronic disease e.g. Cancer, Epilepsy, Alzheimer, Parkinson, Asthma
  24. Abnormal free T4
  25. Patients with serious infection
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ravi Kumar, Ph.D. (609) 977-1857 ravi.kumar@arkaytherapeutics.com
Contact: Robert Busch, MD (518) 461-9734 buschr@mail.amc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03686657
Other Study ID Numbers  ICMJE RK-01 Prototype
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: Study results will be published on clinicaltrials.gov as well as a medical journal. We also plan to present the results at a conference such as American Diabetes Association's Scientific Sessions.
Responsible Party ARKAY Therapeutics
Study Sponsor  ICMJE ARKAY Therapeutics
Collaborators  ICMJE Albany Medical College
Investigators  ICMJE
Study Director: Ravi Kumar, Ph.D. ARKAY Therapeutics
Principal Investigator: Robert Busch, MD Albany Medical College
PRS Account ARKAY Therapeutics
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP