Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes

NCT02597101 | Completed Phase 2 Results DMC

• 2 other identifiers: RC-60591UH3TR001372-01
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The role of individual leukocyte populations in type 2 diabetes (T2D) and immunometabolism in general represent important gaps in knowledge to better understand the etiopathogenesis of T2D. Emerging evidence indicates that certain leukocyte populations serve as an important nexus of T2D-associated inflammation. This novel and innovative clinical trial will test the efficacy of a leukocyte-selective anti-inflammatory small drug as adjunctive therapy in improving insulin sensitivity in obese, insulin-resistant type 2 diabetic subjects. This trial also offers a first-in-kind opportunity to better understand the role of specific leukocyte populations in type 2 diabetes. The drug's clinical profile suggests that it will be well-tolerated with few, if any, side effects, and the existence of simple methods that can indirectly measure its activity in vivo

Conditions

Type 2 Diabetes Mellitus; Insulin Resistance

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity at 6 Months From Baseline

  The primary outcome measure is the insulin sensitivity at 6 months from baseline, assessed by the hyperinsulinemic-euglycemic clamp method. This is calculated as the M/LBM. M/LBM = whole-body insulin sensitivity adjusted for lean body mass. M/LBM is calculated as the steady-state glucose disposal (in mL) per kilogram lean body mass divided by steady-state insulin concentrations (micro IU/mL).

  6 months

Secondary Outcomes (8)

• Severity of All Adverse Events Including Hypoglycemia

  12 months

• Severity of Known AEs of AZD9668

  12 months

• Severity of Known AEs of Saxagliptin

  12 months

• Severity of Known AEs of Metformin

  12 months

• Change in Glycated HbA1c Levels Compared to Baseline

  12 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day) and 60 mg placebo tablet twice daily

Drug: Metformin; Drug: saxagliptin; Drug: placebo

AZD9668

EXPERIMENTAL

60 mg AZD9668 twice daily in addition to 5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day)

Drug: Metformin; Drug: saxagliptin; Drug: AZD9668

Interventions

Metformin DRUG

background drug

AZD9668; Placebo

saxagliptin DRUG

background drug

Also known as: onglyza

AZD9668; Placebo

AZD9668 DRUG

study drug

AZD9668

placebo DRUG

placebo for AZD9668 to be added to background drugs

Placebo

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients 21-75 years of age inclusive who meet the American Diabetes Association standard criteria for type 2 diabetes mellitus (T2D).
• Subjects are currently on metformin (at least 1000 mg per day) for a minimum period of 4 weeks prior to screening visit alone, or in combination with any of the following diabetes medications or combinations:
• DPPIV inhibitor (any dose level/frequency)
• Sulfonylurea (any dose level/frequency)
• GLP1 agonist (any dose level/frequency)
• Sulfonylurea (any dose level/frequency) + GLP1 agonist (any dose level/frequency)
• Meglitinide (any dose level/frequency)
• SGLT2 inhibitor (any dose level/frequency)
• Patients must have a body-to-mass index (BMI) of greater than or equal to 27 kg/m2.
• Patients exhibit glycated HbA1c between 7.3-11.0 during eligibility screening and then \<=8.5 at final run-in visit.
• Subjects present adequate immune competence as assessed by immunoreactivity to viral antigens (CEF Pool Assay) in vitro at the time of screening.
• Participants of childbearing potential must agree to practice an effective form of birth control which may include any one of the following: barrier method, oral contraception, or surgery. These measures must be maintained throughout the study.
• Subjects must have good peripheral venous access for the hyperinsulinemic-euglycemic clamp and the 3-hr. OGTT procedures.
• Patients understand the study procedures, alternative treatments available, risks involved in the study, and voluntarily agree to participate by giving informed and signed written consent for screening and enrollment.
• Participants can be on anti-inflammatory therapies that are not diabetes-focused (e.g. non-salicylate anti-inflammatory therapies, non-salicylate NSAIDs) and/or anti-hypertensive medicaments or statins.

You may not qualify if:

• Patients with type 1 diabetes mellitus as defined by the American Diabetes Association criteria or a history of ketoacidosis, or the patients are assessed by the study team as possibly having type 1 diabetes mellitus confirmed with the presence of at least one of the typical autoantibodies (insulin, GAD65, IA-2, ZnT8) AND a serum C-peptide level of \<0.7 ng/mL.
• Patients have been treated with insulin within 2 months of the screening visit.
• Patients are currently participating in or have participated in another study with an investigational compound or device within the prior 12 weeks of signing the informed consent or do not agree to refrain from participating in any other study while participating in this study.
• Patients have a history of hypersensitivity or any contraindication to DPPIV inhibitors, including saxagliptin (Onglyza), or metformin based upon the labels of the USA.
• Patients are on a weight loss medication (such as orlistat, phentermine, Qsymia, or Belviq) within the prior 6 weeks.
• Patients are required by treating physicians to remain on any one of these agents during the trial:
• macrolide antibiotics, cisapride, anti-arrhythmics, steroids, rifampicin, phenobarbital, phenytoin, secobarbital, carbamazepine, norethindrone, isoniazid. AZD9668 is metabolized by CYP3A4, 3A5, and 2B6. SAXA is metabolized by CYP3A4 and 3A5, potentially leading to drug-drug interactions with hypothetical adverse events in patients on the above agents. Also, AZD9668 causes weak inhibition of CYP2C9 and therefore patients on fluconazole, amiodarone, fenofibrate, fluvoxamine, phenylbutazone, probenecid, sertraline, will also be excluded to avoid the hypothetical adverse events due to this effect.
• Patients have undergone major surgery within the 6 weeks prior to signing consent or have any type or form of major surgery planned during the study (at the discretion of the physician).
• Patients are on or are likely to require treatment with 14 consecutive days or repeated courses of pharmacologic doses of corticosteroids or any other immunomodulatory agent. For example, patients requiring chronic systemic corticosteroids (does not include topical or inhaled corticosteroids). Exceptions are over the counter non-salicylate NSAIDs.
• Enrollment or history of enrollment in a drug, or biologic therapy clinical trial that affects the immune system within the past 12 months (e.g., systemic immunosuppressive pharmacologics, immunosuppressive cytokines, therapeutic immunomodulating antibodies, therapeutic immunomodulating fusion proteins and/or cytokine receptor decoys as well as any intervention and/or non-intervention induced immunodeficiencies).
• Prior history of coronary artery disease (defined as myocardial infarction, angina, bypass surgery, or angioplasty)
• Prior history of arrhythmia (excludes premature beats)
• Prior history of heart failure defined as i) symptomatic OR ii) pulmonary edema, leg edema or low ejection fraction (\<40%)
• Evidence of refractory chronic migraine (defined in ICHD-3 and Martelletti et al.).
• History of persistent bradycardia within the last year prior screening visit (more than three episodes in a calendar year of a heart rate \<60 beats per minute that required hospitalization on each of these occasions).

Sponsors & Collaborators

• Nick Giannoukakis, PhD: lead
• National Institutes of Health (NIH): collaborator
• University of Pittsburgh: collaborator
• University of South Florida: collaborator
• AstraZeneca: collaborator

Study Sites (1)

Allegheny Health Network

Pittsburgh, Pennsylvania, 15224, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Insulin Resistance

Interventions

Metformin; saxagliptin; N-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

The failure to enroll a critical mass of study subjects renders the outcome difficult to interpret given the inability to conduct statistical analyses that would be more meaningful.

Results Point of Contact

• Title: Dr. Nick Giannoukakis
• Organization: Allegheny Health Network

nick.giannoukakis@ahn.org

412-359-6394

Study Officials

• Nick Giannoukakis, Ph.D.

  Allegheny Health Network

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Immunology and Biological Sciences

Study Record Dates

• First Submitted: November 3, 2015
• First Posted: November 5, 2015
• Study Start: November 1, 2015
• Primary Completion: June 10, 2019
• Study Completion: June 15, 2019
• Last Updated: May 13, 2021
• Results First Posted: May 13, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Immediate (as of January 29, 2021); available until January 31, 2031.
• Access Criteria: Upon request to the Study PI.

Locations

US (1)