Type 2 Diabetes
Conditions
Keywords
Type 2 Diabetes, Metformin
Brief summary
The purpose of this study is to assess the safety and effectiveness of KRP-104 on glycemic control in patients with type 2 diabetes inadequately controlled on metformin alone.
Interventions
DRUGKRP-104
Tablet
DRUGPlacebo
Tablet
Sponsors
Kyorin Pharmaceutical Co.,Ltd
ActivX Biosciences, Inc.
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 75 Years
Healthy volunteers
No
Inclusion criteria
Patients meeting the following criteria at the screening visit (Visit 1) will be eligible to participate in the trial: 1. Signed written informed consent; 2. Males and females 18 to 75 years of age, inclusive; 3. Females of childbearing potential must agree to use 2 adequate forms of barrier method contraception (eg, latex condom AND intrauterine device or a diaphragm) to avoid pregnancy while in the study; 4. On a stable dose (Greater than or equal to 10 weeks at the same dose) of metformin monotherapy (Less than or equal to 1500 mg/day or maximum tolerated dose), have an HbA1c greater than or equal to 7.0% and less than or equal to 10.5%; or * On metformin (less than or equal to 1500 mg/day) and 1 other antidiabetic agent (excluding TZD, insulin, or incretin therapies \[DPP-4 inhibitors and GLP-1 analogues\]) and have an HbA1c greater than or equal to 6.8% and less than or equal to 10.0%; or * Not on antidiabetic therapy (for at least 3 months prior to Visit 1) or have not been on a stable dose of metformin monotherapy for 10 weeks and have an HbA1c greater than or equal to 8.0% and less than or equal to 11.0%.
Exclusion criteria
1. History of type 1 diabetes mellitus or history of diabetic ketoacidosis or persistent hypoglycemia; 2. History or presence of alcoholism or drug abuse within the 2 years prior to dosing; 3. Typical consumption of greater than or equal to 10 drinks of alcohol weekly; 4. Presence of any of the following conditions: * Significant renal impairment (glomerular filtration rate less than 60 mL/min); * Diabetic gastroparesis; * Active liver disease (other than asymptomatic nonalcoholic fatty liver disease), cirrhosis, or symptomatic gallbladder disease; 5. Fasting plasma glucose/blood glucose greater than 240 mg/dL (13.3 mmol/L) at Visit 3 (Week -2) (1 laboratory retest permitted); 6. Body mass index less than or equal to 20 kg/m2 and greater than or equal to 48 kg/m2; 7. Systolic blood pressure \<100 mmHg or \>160 mmHg and diastolic blood pressure \<50 mmHg or \>100 mmHg at Visit 3 (Note: medication to control blood pressure is allowed and should be optimized and stabilized prior to Visit 3); 8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2 X the upper limit of normal (ULN) (1 laboratory retest permitted); 9. Creatine phosphokinase (CPK) greater than 2 X the ULN (if not explained by muscular trauma or exercise) (1 laboratory retest permitted); 10. Serum creatinine \>1.5 mg/dL for males (132.6 μmol/L) and 1.4 mg/dL for females (123.8 μmol/L); 11. Fasting triglycerides (TG) \>600 mg/dL (6.78 mmol/L) at Visit 3 (Week -2) (Note: diet/exercise and lipid-lowering medication to control elevated TG is allowed; medications should be optimized and stabilized prior to Visit 3); 12. Treatment with pioglitazone or rosiglitazone within the previous 10 weeks (Visit 1); treatment with incretin therapy (DPP-4 inhibitors or GLP-1 analogues) within the previous 4 weeks (Visit 1); 13. Treatment with any type of insulin (ie, injected or inhaled) within the previous 3 months; 14. Must meet other laboratory and Medical History clinical criteria. Please contact recruitment center for referrals
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline (Week 0) to Week 24 | Week 24 | Mean Change in HbA1c (%) from Baseline to Week 24 with LOCF, ITT population LS mean (SE) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight | 24 weeks | Mean Change in Body Weight (kg) from Baseline to Week 24 with LOCF- ITT |
| Percentage of Patients Achieving HbA1c Less Than 7% | 24 weeks | Subjects Achieving Target of Hemoglobin A1c \<7.0% at Week 24 with LOCF - Intent-to-Treat Population |
| Percentage of Patients Requiring Rescue Therapy for Elevated Glucose | 24 weeks of treatment. | Percentage of Subjects Requiring Rescue Therapy - Intent-to-Treat Population |
Countries
Argentina, Czechia, Guatemala, Poland, Russia, South Africa, United States
Participant flow
Recruitment details
Conducted in 55 medical clinics in 6 countries: US, Guatemala, South Africa, Russia, Czech Republic, Poland. First site opened 19 October 2009.
Pre-assignment details
Variable screening duration to allow for wash-out of one oral therapy, optimization and stabilization of dose on metformin monotherapy (\>= 10 weeks);followed by 2 week placebo run-in. Fasting CBG \<240 mg/dL at start of run in and prior to randomization required.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Tablet | 81 |
| Dose 1: KRP-104 40 mg QD | 81 |
| Dose 2: KRP-104 80 mg QD | 80 |
| Dose 3: KRP-104 100 mg QD | 81 |
| Dose 4: KRP-104 20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24) | 80 |
| Total | 403 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 2 | 0 | 1 |
| Overall Study | all other reasons combined | 2 | 2 | 2 | 1 | 3 |
| Overall Study | Lost to Follow-up | 2 | 2 | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 2 | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Dose 1: KRP-104 | Dose 2: KRP-104 | Dose 3: KRP-104 | Placebo | Dose 4: KRP-104 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 14 Participants | 17 Participants | 21 Participants | 7 Participants | 71 Participants |
| Age, Categorical Between 18 and 65 years | 69 Participants | 66 Participants | 64 Participants | 60 Participants | 73 Participants | 332 Participants |
| Age, Continuous | 54.2 years STANDARD_DEVIATION 10.59 | 55.7 years STANDARD_DEVIATION 9.1 | 56.3 years STANDARD_DEVIATION 9.4 | 57.3 years STANDARD_DEVIATION 9.43 | 55.5 years STANDARD_DEVIATION 8.27 | 55.8 years STANDARD_DEVIATION 9.4 |
| Region of Enrollment Czech Republic | 6 participants | 5 participants | 6 participants | 6 participants | 5 participants | 28 participants |
| Region of Enrollment Guatemala | 15 participants | 15 participants | 14 participants | 16 participants | 16 participants | 76 participants |
| Region of Enrollment Poland | 3 participants | 2 participants | 4 participants | 4 participants | 3 participants | 16 participants |
| Region of Enrollment Russian Federation | 14 participants | 14 participants | 14 participants | 13 participants | 14 participants | 69 participants |
| Region of Enrollment South Africa | 23 participants | 23 participants | 22 participants | 21 participants | 22 participants | 111 participants |
| Region of Enrollment United States | 20 participants | 21 participants | 21 participants | 21 participants | 20 participants | 103 participants |
| Sex: Female, Male Female | 59 Participants | 52 Participants | 49 Participants | 44 Participants | 55 Participants | 259 Participants |
| Sex: Female, Male Male | 22 Participants | 28 Participants | 32 Participants | 37 Participants | 25 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 81 | 16 / 81 | 16 / 80 | 17 / 81 | 19 / 80 |
| serious Total, serious adverse events | 3 / 81 | 2 / 81 | 4 / 80 | 1 / 81 | 1 / 80 |
Outcome results
Primary
Change in HbA1c From Baseline (Week 0) to Week 24
Mean Change in HbA1c (%) from Baseline to Week 24 with LOCF, ITT population LS mean (SE)
Time frame: Week 24
Population: Conducted analyses of ITT population of change in HbA1c from baseline (Week 0) to Week 24. If the Wk 24 measurement was missing, the last valid post-baseline observation (LOCF) algorithm was used to impute Week 24 value (1 on-treatment value required). Efficacy data collected after the initiation of rescue therapy was excluded from the analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in HbA1c From Baseline (Week 0) to Week 24 | -0.09 % HbA1c | 95% Confidence Interval 0.097 |
| Dose 1: KRP-104 | Change in HbA1c From Baseline (Week 0) to Week 24 | -0.41 % HbA1c | 95% Confidence Interval 0 |
| Dose 2: KRP-104 | Change in HbA1c From Baseline (Week 0) to Week 24 | -0.70 % HbA1c | — |
| Dose 3: KRP-104 | Change in HbA1c From Baseline (Week 0) to Week 24 | -0.71 % HbA1c | — |
| Dose 4: KRP-104 | Change in HbA1c From Baseline (Week 0) to Week 24 | -0.73 % HbA1c | — |
Secondary
Change in Body Weight
Mean Change in Body Weight (kg) from Baseline to Week 24 with LOCF- ITT
Time frame: 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Body Weight | -0.73 kg body weight on scale | Standard Error 0.303 |
| Dose 1: KRP-104 | Change in Body Weight | -1.13 kg body weight on scale | Standard Error 0.303 |
| Dose 2: KRP-104 | Change in Body Weight | -1.31 kg body weight on scale | Standard Error 0.302 |
| Dose 3: KRP-104 | Change in Body Weight | -0.70 kg body weight on scale | Standard Error 0.3 |
| Dose 4: KRP-104 | Change in Body Weight | -0.18 kg body weight on scale | Standard Error 0.302 |
Secondary
Percentage of Patients Achieving HbA1c Less Than 7%
Subjects Achieving Target of Hemoglobin A1c \<7.0% at Week 24 with LOCF - Intent-to-Treat Population
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Achieving HbA1c Less Than 7% | 23.08 % of subjects in group |
| Dose 1: KRP-104 | Percentage of Patients Achieving HbA1c Less Than 7% | 31.65 % of subjects in group |
| Dose 2: KRP-104 | Percentage of Patients Achieving HbA1c Less Than 7% | 49.37 % of subjects in group |
| Dose 3: KRP-104 | Percentage of Patients Achieving HbA1c Less Than 7% | 43.75 % of subjects in group |
| Dose 4: KRP-104 | Percentage of Patients Achieving HbA1c Less Than 7% | 41.77 % of subjects in group |
Secondary
Percentage of Patients Requiring Rescue Therapy for Elevated Glucose
Percentage of Subjects Requiring Rescue Therapy - Intent-to-Treat Population
Time frame: 24 weeks of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Requiring Rescue Therapy for Elevated Glucose | 6.33 % of subjects in group |
| Dose 1: KRP-104 | Percentage of Patients Requiring Rescue Therapy for Elevated Glucose | 10.1 % of subjects in group |
| Dose 2: KRP-104 | Percentage of Patients Requiring Rescue Therapy for Elevated Glucose | 5.06 % of subjects in group |
| Dose 3: KRP-104 | Percentage of Patients Requiring Rescue Therapy for Elevated Glucose | 3.75 % of subjects in group |
| Dose 4: KRP-104 | Percentage of Patients Requiring Rescue Therapy for Elevated Glucose | 3.8 % of subjects in group |