Synergy104: Safety and Efficacy of Once-Daily KRP-104 in Type 2 Diabetics With Inadequate Glycemic Control on Metformin Alone

• Sponsor: ActivX Biosciences, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00995345
• Collaborator: Kyorin Pharmaceutical Co.,Ltd (Industry)
• Enrollment: 403
• Locations: 46
• Arms: 5
• Duration (Months): 15
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: KRP-104; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 403 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Asses the Safety and Efficacy of Once-Daily KRP-104 in Patients With Type 2 Diabetes With Inadequate Glycemic Control on Metformin Alone.
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose 1: KRP-104 40 mg Tablet, once-daily for 24 weeks	Drug: KRP-104; Tablet
Experimental: Dose 2: KRP-104 80 mg Tablet, once-daily for 24 weeks	Drug: KRP-104; Tablet
Experimental: Dose 3: KRP-104 100 mg Tablet, once-daily for 24 weeks	Drug: KRP-104; Tablet
Experimental: Dose 4: KRP-104 20/120mg Tablet, once-daily for 24 weeks (dose switch from 20 to 120 mg at week 12)	Drug: KRP-104; Tablet
Placebo Comparator: Placebo Tablet, once-daily for 24 weeks	Drug: Placebo; Tablet

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Change in Body Weight [24 weeks]

   Mean Change in Body Weight (kg) from Baseline to Week 24 with LOCF- ITT

2. 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

3. Percentage of Patients Requiring Rescue Therapy for Elevated Glucose [24 weeks of treatment.]

   Percentage of Subjects Requiring Rescue Therapy - Intent-to-Treat Population

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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;

1. Fasting plasma glucose/blood glucose greater than 240 mg/dL (13.3 mmol/L) at Visit 3 (Week -2) (1 laboratory retest permitted);

2. Body mass index less than or equal to 20 kg/m2 and greater than or equal to 48 kg/m2;

3. 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);

4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 X the upper limit of normal (ULN) (1 laboratory retest permitted);

5. Creatine phosphokinase (CPK) greater than 2 X the ULN (if not explained by muscular trauma or exercise) (1 laboratory retest permitted);

6. Serum creatinine >1.5 mg/dL for males (132.6 μmol/L) and 1.4 mg/dL for females (123.8 μmol/L);

7. 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);

8. 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);

9. Treatment with any type of insulin (ie, injected or inhaled) within the previous 3 months;

10. Must meet other laboratory and Medical History clinical criteria. Please contact recruitment center for referrals

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Phoenix	Arizona	United States
3		Los Angeles	California	United States
4		Valley Village	California	United States
5		Honolulu	Hawaii	United States
6		Winston-Salem	North Carolina	United States
7		Cincinnati	Ohio	United States
8		Delaware	Ohio	United States
9		Marion	Ohio	United States
10		Beaver	Pennsylvania	United States
11		Jenkintown	Pennsylvania	United States
12		Greer	South Carolina	United States
13		Austin	Texas	United States
14		Houston	Texas	United States
15		San Antonio	Texas	United States
16		Sandy	Utah	United States
17		West Jordan	Utah	United States
18		Ciudad Autonoma de Buenos Aires		Argentina
19		Cordoba		Argentina
20		Loma Hermos Buenos Aires		Argentina
21		Chrudim III		Czech Republic
22		Holesov		Czech Republic
23		Melnik		Czech Republic
24		Ostrava		Czech Republic
25		Praha 10		Czech Republic
26		Praha 8		Czech Republic
27		Guatemala City		Guatemala
28		Bialystok		Poland
29		Gdansk		Poland
30		Krakow		Poland
31		Lodz		Poland
32		Warszawa		Poland
33		Wroclaw		Poland
34		Arkhangel'sk		Russian Federation
35		Kemerovo		Russian Federation
36		Moscow		Russian Federation
37		Novosibirsk		Russian Federation
38		St. Petersburg		Russian Federation
39		Port Elizabeth	Eastern Cape	South Africa
40		Bloemfontein	Free State	South Africa
41		Johannesburg	Gauteng	South Africa
42		Soweto	Gauteng	South Africa
43		Durban	Kwazula-Natal	South Africa
44		Cape Town	Western Cape	South Africa
45		Paarl	Western Cape	South Africa
46		Somerset West	Western Cape	South Africa

Sponsors and Collaborators

• ActivX Biosciences, Inc.
• Kyorin Pharmaceutical Co.,Ltd

Investigators

• Study Director: Diane J Plotkin, PhD, ActivX Biosciences, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ActivX Biosciences, Inc.
• ClinicalTrials.gov Identifier: NCT00995345
• Other Study ID Numbers: 0104-005
• First Posted: Oct 15, 2009
• Last Update Posted: Jun 26, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by ActivX Biosciences, Inc.: Type 2 Diabetes; Metformin
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2

Study Results

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 Detail	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.

Arm/Group Title	Placebo	Dose 1: KRP-104	Dose 2: KRP-104	Dose 3: KRP-104	Dose 4: KRP-104
Arm/Group Description	Tablet	40 mg QD	80 mg QD	100 mg QD	20 mg /120 mg QD (dose switch at week12)
Period Title: Overall Study
STARTED	81	81	80	81	80
COMPLETED	70	74	73	76	75
NOT COMPLETED	11	7	7	5	5

Baseline Characteristics

Arm/Group Title	Placebo	Dose 1: KRP-104	Dose 2: KRP-104	Dose 3: KRP-104	Dose 4: KRP-104	Total
Arm/Group Description	Tablet	40 mg QD	80 mg QD	100 mg QD	20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24)	Total of all reporting groups
Overall Participants	81	81	80	81	80	403
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	60 74.1%	69 85.2%	66 82.5%	64 79%	73 91.3%	332 82.4%
>=65 years	21 25.9%	12 14.8%	14 17.5%	17 21%	7 8.8%	71 17.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.3 (9.43)	54.2 (10.59)	55.7 (9.10)	56.3 (9.40)	55.5 (8.27)	55.8 (9.40)
Sex: Female, Male (Count of Participants)
Female	44 54.3%	59 72.8%	52 65%	49 60.5%	55 68.8%	259 64.3%
Male	37 45.7%	22 27.2%	28 35%	32 39.5%	25 31.3%	144 35.7%
Region of Enrollment (participants) [Number]
United States	21 25.9%	20 24.7%	21 26.3%	21 25.9%	20 25%	103 25.6%
Czech Republic	6 7.4%	6 7.4%	5 6.3%	6 7.4%	5 6.3%	28 6.9%
Poland	4 4.9%	3 3.7%	2 2.5%	4 4.9%	3 3.8%	16 4%
Guatemala	16 19.8%	15 18.5%	15 18.8%	14 17.3%	16 20%	76 18.9%
South Africa	21 25.9%	23 28.4%	23 28.8%	22 27.2%	22 27.5%	111 27.5%
Russian Federation	13 16%	14 17.3%	14 17.5%	14 17.3%	14 17.5%	69 17.1%

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline (Week 0) to Week 24
Description	Mean Change in HbA1c (%) from Baseline to Week 24 with LOCF, ITT population LS mean (SE)
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Dose 1: KRP-104	Dose 2: KRP-104	Dose 3: KRP-104	Dose 4: KRP-104
Arm/Group Description	Tablet	40 mg QD	80 mg QD	100 mg QD	20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24)
Measure Participants	78	79	79	80	79
Least Squares Mean (95% Confidence Interval) [% HbA1c]	-0.09 (0.097)	-0.41 (0)	-0.70	-0.71	-0.73

2. Secondary Outcome

Title	Change in Body Weight
Description	Mean Change in Body Weight (kg) from Baseline to Week 24 with LOCF- ITT
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Dose 1: KRP-104	Dose 2: KRP-104	Dose 3: KRP-104	Dose 4: KRP-104
Arm/Group Description	Tablet	40 mg QD	80 mg QD	100 mg QD	20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24)
Measure Participants	78	79	79	80	79
Least Squares Mean (Standard Error) [kg body weight on scale]	-0.73 (0.303)	-1.13 (0.303)	-1.31 (0.302)	-0.70 (0.300)	-0.18 (0.302)

3. Secondary Outcome

Title	Percentage of Patients Achieving HbA1c Less Than 7%
Description	Subjects Achieving Target of Hemoglobin A1c <7.0% at Week 24 with LOCF - Intent-to-Treat Population
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Dose 1: KRP-104	Dose 2: KRP-104	Dose 3: KRP-104	Dose 4: KRP-104
Arm/Group Description	Tablet	40 mg QD	80 mg QD	100 mg QD	20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24)
Measure Participants	78	79	79	80	79
Number [% of subjects in group]	23.08	31.65	49.37	43.75	41.77

4. Secondary Outcome

Title	Percentage of Patients Requiring Rescue Therapy for Elevated Glucose
Description	Percentage of Subjects Requiring Rescue Therapy - Intent-to-Treat Population
Time Frame	24 weeks of treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Dose 1: KRP-104	Dose 2: KRP-104	Dose 3: KRP-104	Dose 4: KRP-104
Arm/Group Description	Tablet	40 mg QD	80 mg QD	100 mg QD	20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24)
Measure Participants	79	79	79	80	79
Number [% of subjects in group]	6.33	10.1	5.06	3.75	3.8

Adverse Events

Time Frame	From first site open on 19 October 2009 through 30 days after last subject out on 20 January 2011, approximately 1 year 5 months.
Adverse Event Reporting Description	Only treatment related adverse events were reported in the clinical study report. There were no occurrences of serious adverse events that were considered related to drug, thus none met criterion of reportable event.
Arm/Group Title	Placebo		Dose 1: KRP-104		Dose 2: KRP-104		Dose 3: KRP-104		Dose 4: KRP-104
Arm/Group Description	Tablet		40 mg QD		80 mg QD		100 mg QD		20 mg QD (weeks 1-12)/120 mg QD (weeks 12-24)
All Cause Mortality
	Placebo		Dose 1: KRP-104		Dose 2: KRP-104		Dose 3: KRP-104		Dose 4: KRP-104
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Dose 1: KRP-104		Dose 2: KRP-104		Dose 3: KRP-104		Dose 4: KRP-104
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/81 (3.7%)		2/81 (2.5%)		4/80 (5%)		1/81 (1.2%)		1/80 (1.3%)
Cardiac disorders
Atrial Fibrillation	0/81 (0%)	0	0/81 (0%)	0	0/80 (0%)	0	0/81 (0%)	0	1/80 (1.3%)	1
Hepatobiliary disorders
Cholecystolithiasis	0/81 (0%)	0	0/81 (0%)	0	1/80 (1.3%)	1	0/81 (0%)	0	0/80 (0%)	0
Infections and infestations
tuberculosis meningitis	1/81 (1.2%)	1	0/81 (0%)	0	0/80 (0%)	0	0/81 (0%)	0	0/80 (0%)	0
Lyme Disease	0/81 (0%)	0	1/81 (1.2%)	1	0/80 (0%)	0	0/81 (0%)	0	0/80 (0%)	0
Bronchitis	0/81 (0%)	0	0/81 (0%)	0	1/80 (1.3%)	1	0/81 (0%)	0	0/80 (0%)	0
Injury, poisoning and procedural complications
Fracture Of The Left Anterior Lamina Papyracea (Ethmoid Bone)	0/81 (0%)	0	1/81 (1.2%)	1	0/80 (0%)	0	0/81 (0%)	0	0/80 (0%)	0
Musculoskeletal and connective tissue disorders
Costochondritis	0/81 (0%)	0	0/81 (0%)	0	1/80 (1.3%)	1	0/81 (0%)	0	0/80 (0%)	0
Intractable Low Back Pain	0/81 (0%)	0	0/81 (0%)	0	0/80 (0%)	0	1/81 (1.2%)	1	0/80 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer (left breast)	1/81 (1.2%)	1	0/81 (0%)	0	0/80 (0%)	0	0/81 (0%)	0	0/80 (0%)	0
lung cancer	0/81 (0%)	0	0/81 (0%)	0	1/80 (1.3%)	1	0/81 (0%)	0	0/80 (0%)	0
Respiratory, thoracic and mediastinal disorders
COPD exacerbation	1/81 (1.2%)	1	0/81 (0%)	0	0/80 (0%)	0	0/81 (0%)	0	0/80 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Dose 1: KRP-104		Dose 2: KRP-104		Dose 3: KRP-104		Dose 4: KRP-104
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/81 (29.6%)		16/81 (19.8%)		16/80 (20%)		17/81 (21%)		19/80 (23.8%)
Gastrointestinal disorders
Diarrhea	4/81 (4.9%)		1/81 (1.2%)		2/80 (2.5%)		5/81 (6.2%)		2/80 (2.5%)
Infections and infestations
Urinary tract infection	5/81 (6.2%)		6/81 (7.4%)		9/80 (11.3%)		5/81 (6.2%)		6/80 (7.5%)
Influenza	5/81 (6.2%)		4/81 (4.9%)		2/80 (2.5%)		4/81 (4.9%)		5/80 (6.3%)
Upper respiratory tract infection	4/81 (4.9%)		3/81 (3.7%)		1/80 (1.3%)		2/81 (2.5%)		4/80 (5%)
Vascular disorders
Hypertension	6/81 (7.4%)		2/81 (2.5%)		2/80 (2.5%)		1/81 (1.2%)		2/80 (2.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No explicit limitations on discussion by PI. PI may not publish results before a coordinated multicenter publication has been submitted for publication, marketing approval obtained, or until 7 years after the study has ended, whichever occurs first. Thereafter, the study site will have the opportunity to publish the results of the study, provided that the Sponsor has had the opportunity to review and comment on the study site's proposed publication prior to it being submitted for publication.