Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02597101
• Date of registration: 03/11/2015
• Prospective Registration: No
• Primary sponsor: Nick Giannoukakis, PhD
• Public title: Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes
• Scientific title: Neutrophil Elastase Inhibition as Adjunctive Therapy to Improve Glucometabolic Variables in Overweight and Obese, Insulin-Resistant Type 2 Diabetic Patients
• Date of first enrolment: November 2015
• Target sample size: 14
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02597101
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Crossover Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

United States

Contacts

• Name: Nick Giannoukakis, Ph.D.
• Affiliation: Allegheny Health Network

Key inclusion & exclusion criteria

INCLUSION CRITERIA

1. Patients 21-75 years of age inclusive who meet the American Diabetes Association
standard criteria for type 2 diabetes mellitus (T2D).

2. 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:

1. DPPIV inhibitor (any dose level/frequency)

2. Sulfonylurea (any dose level/frequency)

3. GLP1 agonist (any dose level/frequency)

4. Sulfonylurea (any dose level/frequency) + GLP1 agonist (any dose level/frequency)

5. Meglitinide (any dose level/frequency)

6. SGLT2 inhibitor (any dose level/frequency)

3. Patients must have a body-to-mass index (BMI) of greater than or equal to 27 kg/m2.

4. Patients exhibit glycated HbA1c between 7.3-11.0 during eligibility screening and then
<=8.5 at final run-in visit.

5. Willingness to replace current diabetes therapies (listed in inclusion 2) with
metformin and saxagliptin and to adjust metformin dose during run-in period.

6. Subjects present adequate immune competence as assessed by immunoreactivity to viral
antigens (CEF Pool Assay) in vitro at the time of screening.

7. 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.

8. Subjects must have good peripheral venous access for the hyperinsulinemic-euglycemic
clamp and the 3-hr. OGTT procedures.

9. 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.

10. 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.

EXCLUSION CRITERIA

1. 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.

2. Patients have been treated with any therapies specific for their diabetes (other than
those listed in the inclusion criteria) within 4 weeks of the screening visit.

3. Patients have been treated with insulin within 2 months of the screening visit.

4. 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.

5. Patients have a history of hypersensitivity or any contraindication to DPPIV
inhibitors, including saxagliptin (Onglyza), or metformin based upon the labels of the
USA.

6. Patients are on a weight loss medication (such as orlistat, phentermine, Qsymia, or
Belviq) within the prior 6 weeks.

7. 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.

8. 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).

9. 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.

10. 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).

11. Prior history of coronary artery disease (defined as myocardial infarction, angina,
bypass surgery, or angioplasty)

12. Prior history of arrhythmia (excludes premature beats)

13. Prior history of heart failure defined as i) symptomatic OR ii) pulmonary edema, leg
edema or low ejection fraction (<40%)

14. Evidence of refractory chronic migraine (defined in ICHD-3 and Martelletti et al.).

15. 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).

16. Leukopenia (<3000 leukocytes/microliter), neutropenia (1500 neutrophils/microliter),
lymphopenia (<800 lymphocytes/microliter), or thrombocytopenia (<125000
platelets/microliter),. any other clinically relevant abnormal hematology value.

17. Positivity for HIV, active CMV, chlamydia, any evidence of serious fungal infection,
active HSV1and/or HSV2 (determined as IgM positivity of 2 standard deviations higher
than the highest value of the test reference range), hepatitis B or C, at screening.
Minor skin fungus, or minor candidiasis is not an enrollment or treatment exclusion
criterion. Also, with the exception of HIV history, hepatitis B and C,
successfully-treated, disease-free individuals (> 6 months between time of successful
treatment confirmation and time at screening) would be eligible for enrollment in this
trial.

18. Patients are required b


Age minimum: 21 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Type 2 Diabetes Mellitus

Insulin Resistance

Intervention(s)

Drug: saxagliptin

Drug: AZD9668

Drug: Metformin

Drug: placebo

Primary Outcome(s)

Improved insulin sensitivity [Time Frame: 6 months]

Secondary Outcome(s)

Improvement in the serum levels of inflammatory markers [Time Frame: 12 months]

Rate and severity of all adverse events including hypoglycemia [Time Frame: 12 months]

Improvement in glycated HbA1c levels compared to baseline [Time Frame: 12 months]

Improvement in OGTT-derived measurement of the product of the Matsuda Index times the Insulinogenic Index [Time Frame: 12 months]

Rate and severity of known AEs of Metformin [Time Frame: 12 months]

Improvement in OGTT-derived measurement of insulinogenic index using C-peptide [Time Frame: 12 months]

Rate and severity of known AEs of AZD9668 [Time Frame: 12 months]

Improvement in OGTT-derived measurement of glucose tolerance [Time Frame: 12 months]

Improvement in OGTT-derived measurement of Matsuda Index of insulin resistance [Time Frame: 12 months]

Rate and severity of known AEs of Saxagliptin [Time Frame: 12 months]

Secondary ID(s)

RC-6059

1UH3TR001372-01

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

University of South Florida

University of Pittsburgh

AstraZeneca

National Institutes of Health (NIH)