Roflumilast Plus Alogliptin Proof-of-Mechanism Study in Type2 Diabetes
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Roflumilast + alogliptin Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. |
Drug: Roflumilast
Roflumilast tablets
Other Names:
Drug: Alogliptin
Alogliptin tablets
Other Names:
|
| Experimental: Alogliptin alone Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. |
Drug: Alogliptin
Alogliptin tablets
Other Names:
Drug: Placebo to roflumilast
Placebo-matching roflumilast tablets
|
| Experimental: Roflumilast alone Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. |
Drug: Roflumilast
Roflumilast tablets
Other Names:
Drug: Placebo to alogliptin
Placebo-matching alogliptin tablets
|
| Active Comparator: Exenatide Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
Drug: Exenatide
Exenatide solution
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female, aged 18 to 80 years, inclusive, at the time of dosing on Day 1.
-
Has an historical diagnosis of type 2 diabetes mellitus (T2DM) disease.
-
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.
-
Has inadequate glycemic control at Screening, as evidenced by HbA1c (glycosylated hemoglobin) level between 7.0% and 10.0%, inclusive.
-
Has a body mass index (BMI) of ≥23.0 kg/m2 and ≤45.0 kg/m2, at Screening.
-
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.
-
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
-
In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
-
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:
-
Has a history of type 1 diabetes.
-
Has a history of acute metabolic diabetic complications.
-
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).
-
Has a history of diabetic gastroparesis or history of gastric bypass surgery.
-
Has a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening.
-
Has New York Heart Association heart failure of Class (III-IV) regardless of therapy.
-
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).
-
Has presence or history of neuropsychiatric disorder (eg, psychosis, psychotic disorders, depression associated with suicidal thinking, suicidal ideation or behavior).
-
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.
-
Has a hemoglobin ≤120 g/L for men and ≤100 g/L for women.
-
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.
-
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.
-
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.
-
If male, intends to donate sperm during the course of the study or for 30 days after last dose of study medication.
-
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.
-
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.
-
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.
-
Has a history of any hemoglobinopathy that may affect determination of HbA1c.
-
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).
-
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.
-
Has any clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further clinical evaluation (as assessed by the investigator).
-
Does not have an adequate standard of literacy to allow him or her to complete the study diary during non-clinic days.
-
Has poor peripheral venous access.
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Chula Vista | California | United States | ||
| 2 | Orlando | Florida | United States |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Study Director: AstraZeneca AstraZeneca, AstraZeneca
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ROF-T2D_107
- U1111-1128-6945
Study Results
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 Detail | 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. |
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Period Title: Overall Study | ||||
| STARTED | 10 | 11 | 10 | 9 |
| COMPLETED | 10 | 10 | 10 | 9 |
| NOT COMPLETED | 0 | 1 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. | Total of all reporting groups |
| Overall Participants | 10 | 11 | 10 | 9 | 40 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
50.7
(10.15)
|
52.9
(7.52)
|
60.7
(4.24)
|
54.6
(6.88)
|
54.7
(8.15)
|
| Age, Customized (participants) [Number] | |||||
| < 65 years |
10
100%
|
11
100%
|
9
90%
|
9
100%
|
39
97.5%
|
| ≥ 65 years |
0
0%
|
0
0%
|
1
10%
|
0
0%
|
1
2.5%
|
| Gender (Count of Participants) | |||||
| Female |
4
40%
|
3
27.3%
|
4
40%
|
4
44.4%
|
15
37.5%
|
| Male |
6
60%
|
8
72.7%
|
6
60%
|
5
55.6%
|
25
62.5%
|
| Race/Ethnicity, Customized (participants) [Number] | |||||
| Hispanic or Latino |
7
70%
|
6
54.5%
|
7
70%
|
6
66.7%
|
26
65%
|
| Non-Hispanic or Latino |
3
30%
|
5
45.5%
|
3
30%
|
3
33.3%
|
14
35%
|
| Race/Ethnicity, Customized (participants) [Number] | |||||
| Black or African American |
3
30%
|
3
27.3%
|
2
20%
|
0
0%
|
8
20%
|
| White |
7
70%
|
8
72.7%
|
8
80%
|
9
100%
|
32
80%
|
| Region of Enrollment (participants) [Number] | |||||
| United States |
10
100%
|
11
100%
|
10
100%
|
9
100%
|
40
100%
|
| Height (cm) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [cm] |
171.1
(8.91)
|
171.2
(6.03)
|
166.6
(10.44)
|
166.4
(5.90)
|
169.0
(8.09)
|
| Weight (kg) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [kg] |
103.12
(21.688)
|
93.24
(11.670)
|
89.33
(17.961)
|
86.98
(14.713)
|
93.32
(17.329)
|
| Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [kg/m^2] |
34.93
(4.708)
|
31.75
(3.184)
|
32.03
(5.311)
|
31.37
(4.653)
|
32.53
(4.548)
|
| Smoking Classification (participants) [Number] | |||||
| Never smoked |
6
60%
|
6
54.5%
|
10
100%
|
7
77.8%
|
29
72.5%
|
| Current smoker |
1
10%
|
0
0%
|
0
0%
|
0
0%
|
1
2.5%
|
| Ex-smoker |
3
30%
|
5
45.5%
|
0
0%
|
2
22.2%
|
10
25%
|
| Duration of Diabetes (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
6.9
(4.63)
|
8.5
(6.39)
|
7.0
(3.86)
|
8.2
(6.63)
|
7.7
(5.33)
|
| Metformin Dose (mg) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [mg] |
875.0
(151.38)
|
745.0
(225.40)
|
805.0
(220.42)
|
855.6
(211.31)
|
819.2
(202.49)
|
Outcome Measures
| Title | Change From Baseline in Postprandial Area Under the Curve From Time 0 to 8 Hours (AUC[0-8]) for Active Glucagon-like Peptide-1 |
|---|---|
| Description | 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). |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Measure Participants | 10 | 10 | 10 | 9 |
| Least Squares Mean (Standard Error) [pmol/L*hr] |
26.5
(4.04)
|
31.6
(4.01)
|
3.8
(3.94)
|
-2.3
(4.14)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Roflumilast + Alogliptin, Alogliptin Alone |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.388 |
| Comments | The comparison was evaluated at the 5% level of significance. | |
| Method | ANCOVA | |
| Comments | ANCOVA model with treatment as fixed effect, and baseline Postprandial AUC (0-8) of active GLP-1 as a continuous covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -5.1 | |
| Confidence Interval |
(2-Sided) 95% -16.9 to 6.7 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.82 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Roflumilast + Alogliptin, Roflumilast Alone |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | The comparison was evaluated at the 5% level of significance. | |
| Method | ANCOVA | |
| Comments | ANCOVA model with treatment as fixed effect, and Baseline Postprandial AUC (0-8) of active GLP-1 as a continuous covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 22.7 | |
| Confidence Interval |
(2-Sided) 95% 11.1 to 34.3 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.70 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Roflumilast + Alogliptin, Exenatide |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | The comparison was evaluated at the 5% level of significance. | |
| Method | ANCOVA | |
| Comments | ANCOVA model with treatment as fixed effect, and Baseline Postprandial AUC (0-8) of active GLP-1 as a continuous covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 28.8 | |
| Confidence Interval |
(2-Sided) 95% 17.1 to 40.5 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.76 |
|
| Estimation Comments | ||
| Title | Change From Baseline in AUC(0-8) of Postprandial Plasma Glucose |
|---|---|
| Description | 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). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Only participants with data at both Baseline and post-baseline visits are included. |
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Measure Participants | 10 | 10 | 10 | 9 |
| Least Squares Mean (Standard Error) [mmol/L*hr] |
-13.4
(2.70)
|
-9.8
(2.71)
|
-9.0
(2.71)
|
-18.5
(2.85)
|
| Title | Change From Baseline in Postprandial AUC(0-8) of C-peptide |
|---|---|
| Description | 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. |
| 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). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Only participants with data at both Baseline and post-baseline visits are included. |
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Measure Participants | 10 | 10 | 10 | 9 |
| Least Squares Mean (Standard Error) [ng/mL*hr] |
1.0
(1.15)
|
1.4
(1.16)
|
-0.7
(1.17)
|
0.0
(1.22)
|
| Title | Change From Baseline in Postprandial AUC(0-8) of Insulin |
|---|---|
| Description | 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. |
| 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). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Only participants with data at both Baseline and post-baseline visits are included. |
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Measure Participants | 10 | 10 | 10 | 9 |
| Least Squares Mean (Standard Error) [pmol/L*hr] |
-49.5
(181.09)
|
107.8
(180.75)
|
26.9
(180.38)
|
-136.4
(190.12)
|
| Title | Change From Baseline to Day 11 in AUC(0-8) of Appetite Sensation |
|---|---|
| Description | 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. |
| Time Frame | At Baseline and Day 11, every 30 minutes, starting 1 hour before eating until 8 hour after the meal. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Only participants with data at both Baseline and post-baseline visits are included. |
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Measure Participants | 10 | 10 | 10 | 9 |
| Fullness |
70.5
(59.73)
|
62.0
(56.52)
|
136.0
(57.81)
|
116.8
(59.51)
|
| Hunger |
-103.6
(52.61)
|
3.1
(52.18)
|
-132.7
(52.44)
|
-122.5
(54.92)
|
| Prospective consumption |
-97.1
(54.24)
|
-14.9
(53.76)
|
-169.5
(53.98)
|
-124.3
(56.53)
|
| Satiety |
-82.7
(53.66)
|
-3.2
(52.96)
|
-139.2
(53.58)
|
-127.7
(55.80)
|
| Title | Change From Baseline to Day 11 in 24-hour Average Plasma Glucose |
|---|---|
| Description | 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. |
| Time Frame | Baseline (Day -1) and Day 11, from 12 AM through 24 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Only participants with data at both Baseline and post-baseline visits are included. |
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide |
|---|---|---|---|---|
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. |
| Measure Participants | 10 | 10 | 10 | 9 |
| Least Squares Mean (Standard Error) [mg/dL] |
-25.4
(6.67)
|
-17.5
(6.67)
|
-14.5
(6.66)
|
-34.9
(7.02)
|
Adverse Events
| Time Frame | From the first dose of study medication to no more than 30 days after the last dose of the study medication (a maximum of 41 days). | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. | |||||||
| Arm/Group Title | Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide | ||||
| Arm/Group Description | Roflumilast 500 μg, tablets, orally and alogliptin 25 mg, tablets, orally, once a day for 11 days. | Placebo to roflumilast, tablets, orally and alogliptin, 25 mg, tablets, orally, once a day for 11 days. | Roflumilast 500 μg, tablets, orally and placebo to alogliptin, tablets, orally, once a day, for 11 days. | Exenatide 5 μg subcutaneous injection twice a day for 11 days. | ||||
All Cause Mortality |
||||||||
| Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/10 (10%) | 0/11 (0%) | 0/10 (0%) | 0/9 (0%) | ||||
| Infections and infestations | ||||||||
| Influenza | 1/10 (10%) | 0/11 (0%) | 0/10 (0%) | 0/9 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Roflumilast + Alogliptin | Alogliptin Alone | Roflumilast Alone | Exenatide | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/10 (60%) | 5/11 (45.5%) | 8/10 (80%) | 7/9 (77.8%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 0/10 (0%) | 0/11 (0%) | 1/10 (10%) | 1/9 (11.1%) | ||||
| Gastrointestinal disorders | ||||||||
| Diarrhoea | 0/10 (0%) | 3/11 (27.3%) | 4/10 (40%) | 4/9 (44.4%) | ||||
| Nausea | 2/10 (20%) | 1/11 (9.1%) | 5/10 (50%) | 2/9 (22.2%) | ||||
| Vomiting | 1/10 (10%) | 1/11 (9.1%) | 3/10 (30%) | 0/9 (0%) | ||||
| Abdominal pain | 0/10 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/9 (0%) | ||||
| Constipation | 1/10 (10%) | 0/11 (0%) | 0/10 (0%) | 0/9 (0%) | ||||
| General disorders | ||||||||
| Infusion site pain | 0/10 (0%) | 0/11 (0%) | 1/10 (10%) | 0/9 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Arthropod bite | 0/10 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/9 (0%) | ||||
| Contusion | 0/10 (0%) | 0/11 (0%) | 0/10 (0%) | 1/9 (11.1%) | ||||
| Lip injury | 0/10 (0%) | 0/11 (0%) | 1/10 (10%) | 0/9 (0%) | ||||
| Investigations | ||||||||
| Lipase increased | 1/10 (10%) | 0/11 (0%) | 0/10 (0%) | 0/9 (0%) | ||||
| Weight decreased | 1/10 (10%) | 0/11 (0%) | 0/10 (0%) | 0/9 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 1/10 (10%) | 2/11 (18.2%) | 2/10 (20%) | 1/9 (11.1%) | ||||
| Increased appetite | 0/10 (0%) | 0/11 (0%) | 1/10 (10%) | 0/9 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Myalgia | 0/10 (0%) | 0/11 (0%) | 1/10 (10%) | 0/9 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 3/10 (30%) | 2/11 (18.2%) | 2/10 (20%) | 2/9 (22.2%) | ||||
| Dizziness | 0/10 (0%) | 0/11 (0%) | 2/10 (20%) | 0/9 (0%) | ||||
| Psychiatric disorders | ||||||||
| Insomnia | 1/10 (10%) | 0/11 (0%) | 1/10 (10%) | 0/9 (0%) | ||||
| Anxiety | 0/10 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/9 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Oropharyngeal pain | 1/10 (10%) | 0/11 (0%) | 0/10 (0%) | 0/9 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Ecchymosis | 0/10 (0%) | 0/11 (0%) | 0/10 (0%) | 2/9 (22.2%) | ||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights therefrom or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.
Results Point of Contact
| Name/Title | AstraZeneca Clinical Study Information Center |
|---|---|
| Organization | AstraZeneca |
| Phone | 1-877-240-9479 |
| information.center@astrazeneca.com |
- ROF-T2D_107
- U1111-1128-6945