Roflumilast Plus Alogliptin Proof-of-Mechanism Study in Type2 Diabetes

This is a study to evaluate the antiglycemic efficacy and safety of roflumilast + alogliptin
compared to alogliptin alone and roflumilast alone; it will also include an open-label
exenatide treatment arm as a control. The antiglycemic efficacy of the combination will be
evaluated through the measurement of postprandial active GLP-1 level, ß cell secretion
activity (via the measurement of C-peptide and insulin levels), appetite sensations (as
assessed by VAS) and glycemic control as assessed by CGMS.

Inclusion Criteria:

1. The participant is male or female, aged 18 to 80 years, inclusive, at the time of
dosing on Day 1.

2. Has an historical diagnosis of type 2 diabetes mellitus (T2DM) disease.

3. Has a documented history of a diet and exercise plan and is receiving metformin as
monotherapy at a stable dose for at least 8 weeks prior to Screening; the participant
has no chronic use (>7 days) of any other antidiabetic therapy within the 8 weeks
prior to Screening.

4. Has inadequate glycemic control at Screening, as evidenced by HbA1c level between
7.0% and 10.0%, inclusive.

5. Has a body mass index (BMI) of ≥23.0 kg/m^2 and ≤45.0 kg/m^2, at Screening.

6. A female of childbearing potential who is sexually active with a nonsterilized male
partner agrees to use routinely adequate contraception from signing of informed
consent throughout the duration of the study and for 30 days after the last dose of
study drug.

7. A male who is nonsterilized and sexually active with a female partner of childbearing
potential agrees to use adequate contraception from signing of informed consent
throughout the duration of the study and for 30 days after last dose of study drug

8. In the opinion of the investigator, the participant is capable of understanding and
complying with protocol requirements.

9. The participant or, when applicable, the participant's legally acceptable
representative signs and dates a written, informed consent form and any required
privacy authorization prior to the initiation of any study procedures.

Exclusion Criteria:

1. Has a history of type 1 diabetes.

2. Has a history of acute metabolic diabetic complications.

3. Has has abnormal Screening or Check-in (Day -2) laboratory values that suggest a
clinically significant underlying disease (eg, active liver disease or jaundice) or
participant with the following laboratory abnormalities: alanine aminotransferase
(ALT) and/or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN).

4. Has a history of diabetic gastroparesis or history of gastric bypass surgery.

5. Has a history of coronary angioplasty, coronary stent placement, coronary bypass
surgery, or myocardial infarction within 6 months prior to Screening.

6. Has New York Heart Association heart failure of Class (III-IV) regardless of therapy.

7. Has a supine blood pressure >150 mm Hg for systolic or >90 mm Hg for diastolic,
confirmed on repeat testing within a maximum of 5 minutes, at Screening and Check-in
(Day -2).

8. Has presence or history of neuropsychiatric disorder (eg, psychosis, psychotic
disorders, depression associated with suicidal thinking, suicidal ideation or
behavior).

9. Has a history of drug abuse (defined as illicit drug use) or a history of alcohol
abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per
day) within the past 2 years or is unwilling to agree to abstain from alcohol and
drugs throughout the study.

10. Has a hemoglobin ≤120 g/L for men and ≤100 g/L for women.

11. Has a history of clinically significant allergies or idiosyncrasies to roflumilast,
alogliptin and exenatide or any inactive ingredient(s) of these products, eg, rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency,
glucose-galactose malabsorption or phenylketonuria.

12. Has received alogliptin or roflumilast in a previous clinical study or as a
therapeutic agent within 2 months prior to Screening, or is taking prescription
roflumilast for COPD, or has received any other investigational compound within 30
days prior to the first dose of study medication, or is participating or plans to
participate in any other clinical trial during this study.

13. If female, is pregnant or lactating or intending to become pregnant before, during,
or within 30 days after last dose; or intending to donate ova during such time
period.

14. If male, intends to donate sperm during the course of the study or for 30 days after
last dose of study medication.

15. Is an immediate family member, study site employee, or in a dependent relationship
with a study site employee who is involved in the conduct of this study (eg, spouse,
parent, child, sibling) or may consent under duress.

16. Has a history of cancer, except basal cell or squamous cell carcinoma which has been
in remission for at least 5 years prior to Day 1.

17. Serum creatinine ≥1.5 mg/dL for males and ≥1.4 mg/dL for females or creatinine
clearance <60 mL/minutes, based on calculation by central lab using the
Cockcroft-Gault approximation at Screening Visit.

18. Has a history of any hemoglobinopathy that may affect determination of HbA1c.

19. Has positive test result for Hepatitis B surface antigen (HBsAg), Hepatitis C
antibody (HCV), any known history of infection with human immunodeficiency virus
(HIV), any acute infection, or severe immunological diseases (eg, multiple sclerosis,
systemic lupus erythematosus, and progressive multifocal leukoencephalopathy).

20. Has a risk of suicide according to the Investigator's clinical judgment per
Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or has made a suicide
attempt in the past 6 months.

21. Has any clinically relevant abnormal laboratory values suggesting an unknown disease
and requiring further clinical evaluation (as assessed by the investigator).

22. Does not have an adequate standard of literacy to allow him or her to complete the
study diary during non-clinic days.

23. Has poor peripheral venous access.

24. Has Screening or Check-in (Day -2) abnormal clinically significant electrocardiogram
(ECG). Entry of any participant with abnormal not clinically significant ECG must be
approved and documented by signature of Principal Investigator and Medical Monitor.