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

A Phase 1b, Randomized, Double-Blind, Active Comparator (Open-Label Exenatide) Controlled Study to Evaluate the Effect of Roflumilast Plus Alogliptin on Postprandial Active GLP-1 Level and 24-hour Glucose Level in Subjects With Type 2 Diabetes Who Are Inadequately Controlled on a Stable Dose of Metformin

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01664624

Enrollment

Registered

2012-08-14

Start date

2012-07-31

Completion date

2012-11-30

Last updated

2017-02-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 2 Diabetes

Keywords

Drug Therapy

Brief summary

The purpose of this study is to assess the effect of roflumilast plus alogliptin on glucagon-like peptide-1 (GLP-1) and glucose levels in patients with type 2 diabetes.

Detailed description

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 a continuous glucose monitoring system (CGMS).

Interventions

DRUGRoflumilast

Roflumilast tablets

DRUGAlogliptin

Alogliptin tablets

DRUGExenatide

Exenatide solution

DRUGPlacebo to roflumilast

Placebo-matching roflumilast tablets

DRUGPlacebo to alogliptin

Placebo-matching alogliptin tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

1. 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; 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 (glycosylated hemoglobin) 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 chronic obstructive pulmonary disease (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.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1	Baseline and Day 11; samples were taken at -15 min and -5 min (pre-meal), and 15 min, 30 min, and 1, 2, 3, 4, 6, and 8 hours (post-meal).	The concentration of glucagon-like peptide-1 (GLP-1) in blood before and up to 8 hours after eating (postprandial) was plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an analysis of covariance (ANCOVA) model with treatment as fixed effect, and Baseline postprandial AUC (0-8) of active GLP-1 as a continuous covariate.

Secondary

Measure	Time frame	Description
Change From Baseline in AUC(0-8) of Postprandial Plasma Glucose	Baseline and Day 11 at -15 min and -5 min (pre-meal), and 15 min, 30 min, and 1, 2, 3, 4, 6, and 8 hours (post-meal).	The concentration of glucose in blood before and up to 8 hours after eating (postprandial) was plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an ANCOVA model with treatment as fixed effect, and baseline postprandial AUC (0-8) of plasma glucose as a continuous covariate.
Change From Baseline in Postprandial AUC(0-8) of C-peptide	Baseline and Day 11; samples were taken at -15 min and -5 min (pre-meal), and 15 min, 30 min, and 1, 2, 3, 4, 6, and 8 hours (post-meal).	The concentration of C-peptide in blood before and up to 8 hours after eating (postprandial) was plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an ANCOVA model with treatment as fixed effect, and Baseline postprandial AUC (0-8) of C-peptide as a continuous covariate.
Change From Baseline in Postprandial AUC(0-8) of Insulin	Baseline and Day 11; samples were taken at -15 min and -5 min (pre-meal), and 15 min, 30 min, and 1, 2, 3, 4, 6, and 8 hours (post-meal).	The concentration of insulin in blood before and up to 8 hours after eating was plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an ANCOVA model with treatment as fixed effect, and Baseline postprandial AUC (0-8) of insulin as a continuous covariate.
Change From Baseline to Day 11 in AUC(0-8) of Appetite Sensation	At Baseline and Day 11, every 30 minutes, starting 1 hour before eating until 8 hour after the meal.	Appetite sensations were measured using a visual analog scale (VAS) questionnaire. Participants were asked to indicate their level of fullness, hunger, satiety, and prospective consumption (how much do you think you can eat?) on a 100 mm line ranging from Not at all (0 mm) to extremely (100 mm). Appetite sensation scores before and up to 8 hours after eating were plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an ANCOVA model with treatment as fixed effect, and Baseline postprandial AUC (0-8) of appetite sensation VAS score as a continuous covariate.
Change From Baseline to Day 11 in 24-hour Average Plasma Glucose	Baseline (Day -1) and Day 11, from 12 AM through 24 hours.	Plasma glucose was measured by Continuous Glucose Monitoring System (CGMS). CGMS measures glucose every 5 minutes, starting in the fasting state 8 hour prior to the standardized breakfast (12 AM) until 16 hours after the breakfast. The average 24-hour plasma glucose concentration was calculated. Least squares means were obtained using an ANCOVA model with treatment as fixed effect, and Baseline 24-hour Glucose Measured by CGMS as a continuous covariate.

Countries

United States

Participant flow

Recruitment details

Participants took part in the study at 2 investigative sites in the United States from 10 July 2012 to 29 November 2012.

Pre-assignment details

Participants with a diagnosis of type 2 diabetes mellitus and inadequate glycemic control were enrolled equally in 1 of 4 treatment groups, roflumilast + alogliptin, alogliptin alone, roflumilast alone, or exenatide.

Participants by arm

Arm	Count
Roflumilast + Alogliptin Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days.	10
Alogliptin Alone Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days.	11
Roflumilast Alone Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days.	10
Exenatide Exenatide 5 μg subcutaneous injection twice a day for 11 days.	9
Total	40

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	0	1	0	0

Baseline characteristics

Characteristic	Total	Exenatide	Roflumilast Alone	Alogliptin Alone	Roflumilast + Alogliptin
Age, Continuous	54.7 years STANDARD_DEVIATION 8.15	54.6 years STANDARD_DEVIATION 6.88	60.7 years STANDARD_DEVIATION 4.24	52.9 years STANDARD_DEVIATION 7.52	50.7 years STANDARD_DEVIATION 10.15
Age, Customized < 65 years	39 participants	9 participants	9 participants	11 participants	10 participants
Age, Customized ≥ 65 years	1 participants	0 participants	1 participants	0 participants	0 participants
Body Mass Index (BMI)	32.53 kg/m^2 STANDARD_DEVIATION 4.548	31.37 kg/m^2 STANDARD_DEVIATION 4.653	32.03 kg/m^2 STANDARD_DEVIATION 5.311	31.75 kg/m^2 STANDARD_DEVIATION 3.184	34.93 kg/m^2 STANDARD_DEVIATION 4.708
Duration of Diabetes	7.7 years STANDARD_DEVIATION 5.33	8.2 years STANDARD_DEVIATION 6.63	7.0 years STANDARD_DEVIATION 3.86	8.5 years STANDARD_DEVIATION 6.39	6.9 years STANDARD_DEVIATION 4.63
Gender Female	15 Participants	4 Participants	4 Participants	3 Participants	4 Participants
Gender Male	25 Participants	5 Participants	6 Participants	8 Participants	6 Participants
Height	169.0 cm STANDARD_DEVIATION 8.09	166.4 cm STANDARD_DEVIATION 5.9	166.6 cm STANDARD_DEVIATION 10.44	171.2 cm STANDARD_DEVIATION 6.03	171.1 cm STANDARD_DEVIATION 8.91
Metformin Dose	819.2 mg STANDARD_DEVIATION 202.49	855.6 mg STANDARD_DEVIATION 211.31	805.0 mg STANDARD_DEVIATION 220.42	745.0 mg STANDARD_DEVIATION 225.4	875.0 mg STANDARD_DEVIATION 151.38
Race/Ethnicity, Customized Black or African American	8 participants	0 participants	2 participants	3 participants	3 participants
Race/Ethnicity, Customized Hispanic or Latino	26 participants	6 participants	7 participants	6 participants	7 participants
Race/Ethnicity, Customized Non-Hispanic or Latino	14 participants	3 participants	3 participants	5 participants	3 participants
Race/Ethnicity, Customized White	32 participants	9 participants	8 participants	8 participants	7 participants
Region of Enrollment United States	40 participants	9 participants	10 participants	11 participants	10 participants
Smoking Classification Current smoker	1 participants	0 participants	0 participants	0 participants	1 participants
Smoking Classification Ex-smoker	10 participants	2 participants	0 participants	5 participants	3 participants
Smoking Classification Never smoked	29 participants	7 participants	10 participants	6 participants	6 participants
Weight	93.32 kg STANDARD_DEVIATION 17.329	86.98 kg STANDARD_DEVIATION 14.713	89.33 kg STANDARD_DEVIATION 17.961	93.24 kg STANDARD_DEVIATION 11.67	103.12 kg STANDARD_DEVIATION 21.688

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	6 / 10	5 / 11	8 / 10	7 / 9
serious Total, serious adverse events	1 / 10	0 / 11	0 / 10	0 / 9

Outcome results

Primary

Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1

The concentration of glucagon-like peptide-1 (GLP-1) in blood before and up to 8 hours after eating (postprandial) was plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an analysis of covariance (ANCOVA) model with treatment as fixed effect, and Baseline postprandial AUC (0-8) of active GLP-1 as a continuous covariate.

Time frame: Baseline and Day 11; samples were taken at -15 min and -5 min (pre-meal), and 15 min, 30 min, and 1, 2, 3, 4, 6, and 8 hours (post-meal).

Population: Full analysis set defined as all randomized participants included in the safety analysis. Only participants with data at both Baseline and post-baseline visits are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Roflumilast + Alogliptin	Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1	26.5 pmol/L*hr	Standard Error 4.04
Alogliptin Alone	Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1	31.6 pmol/L*hr	Standard Error 4.01
Roflumilast Alone	Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1	3.8 pmol/L*hr	Standard Error 3.94
Exenatide	Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1	-2.3 pmol/L*hr	Standard Error 4.14

Comparison: ANCOVA was used to test the null hypothesis that the change from Baseline in the postprandial AUC(0-8) of active GLP-1 is no difference between the roflumilast + alogliptin and alogliptin alone.p-value: 0.38895% CI: [-16.9, 6.7]ANCOVA

Comparison: ANCOVA was used to test the null hypothesis that the change from Baseline in the postprandial AUC(0-8) of active GLP-1 is no difference between the roflumilast + alogliptin and roflumilast alone.p-value: <0.00195% CI: [11.1, 34.3]ANCOVA

Comparison: ANCOVA was used to test the null hypothesis that the change from Baseline in the postprandial AUC(0-8) of active GLP-1 is no difference between the roflumilast + alogliptin and roflumilast alone.p-value: <0.00195% CI: [17.1, 40.5]ANCOVA

Secondary

Change From Baseline in AUC(0-8) of Postprandial Plasma Glucose

The concentration of glucose in blood before and up to 8 hours after eating (postprandial) was plotted and the area under the curve calculated using the linear trapezoidal rule at Baseline and on Day 11. Least squares means of the change from Baseline to Day 11 were obtained using an ANCOVA model with treatment as fixed effect, and baseline postprandial AUC (0-8) of plasma glucose as a continuous covariate.

Time frame: Baseline and Day 11 at -15 min and -5 min (pre-meal), and 15 min, 30 min, and 1, 2, 3, 4, 6, and 8 hours (post-meal).