Trial Outcomes & Findings for Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function (NCT NCT01686932)

NCT ID: NCT01686932

Last Updated: 2016-03-02

Results Overview

The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC\<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 51 participants
• Primary outcome timeframe: baseline and 0-24 hours post-dose on Days 2 to 5
• Results posted on: 2016-03-02

Participant Flow

Period 1: 8 weeks treatment with vildagliptin 50mg BID or sitagliptin 100mg QD, 1-4 weeks wash-out, followed by Period 2, 8 weeks treatment with sitagliptin 100mg QD or vildagliptin 50mg BID

Participant milestones

Measure	Vildagliptin Followed by Sitagliptin Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks	Sitagliptin Followed by Vildagliptin Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks
Period 1 STARTED	25	26
Period 1 COMPLETED	24	25
Period 1 NOT COMPLETED	1	1
Period 2 STARTED	24	25
Period 2 COMPLETED	24	25
Period 2 NOT COMPLETED	0	0

Reasons for withdrawal

Measure	Vildagliptin Followed by Sitagliptin Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks	Sitagliptin Followed by Vildagliptin Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks
Period 1 Adverse Event	1	1

Baseline Characteristics

Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function

Baseline characteristics by cohort

Measure	Vildagliptin Followed by Sitagliptin n=25 Participants Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks	Sitagliptin Followed by Vildagliptin n=26 Participants Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks	Total n=51 Participants Total of all reporting groups
Age, Continuous	64.8 years STANDARD_DEVIATION 6.0 • n=5 Participants	65.2 years STANDARD_DEVIATION 8.6 • n=7 Participants	65 years STANDARD_DEVIATION 7.4 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	20 Participants n=7 Participants	41 Participants n=5 Participants

PRIMARY outcome

Timeframe: baseline and 0-24 hours post-dose on Days 2 to 5

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 & 2	11.2 mmol/L/4d Standard Deviation 25.65	5.3 mmol/L/4d Standard Deviation 11.70

SECONDARY outcome

Timeframe: after 8 weeks period 1 and Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

Hypoglycemic events are defined as blood glucose values <70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose.

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment. continuous glucose monitoring (CGM)	69 number of hypoglycemic events	37 number of hypoglycemic events
Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment. self-monitored blood glucose (SMBG)	29 number of hypoglycemic events	13 number of hypoglycemic events

SECONDARY outcome

Timeframe: after 8 weeks for Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement.

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2	29.1 minutes Standard Deviation 44.71	28.0 minutes Standard Deviation 51.45

SECONDARY outcome

Timeframe: after 8 weeks Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 & Period 2

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2	0.2 mmol/L Standard Deviation 0.32	0.2 mmol/L Standard Deviation 0.36

SECONDARY outcome

Timeframe: after 8 weeks Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of <40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2	1 severe hypoglycemic events	1 severe hypoglycemic events

SECONDARY outcome

Timeframe: Day 2 after 8 weeks of treatment Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 & Period 2

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 & Period 2	4.7 mmol/L Standard Deviation 1.69	4.6 mmol/L Standard Deviation 1.36

SECONDARY outcome

Timeframe: after 8 weeks of treatment Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

ECG abnormalities are defined as either: • Occurrence of >30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) >440 ms. after 8 weeks of treatment Period 1 & Period 2

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 & Period 2 Patients with hypoglycemia (n=21,17)	14 participants	10 participants
Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 & Period 2 Patients without hypoglycemia (n=28,32)	19 participants	24 participants

SECONDARY outcome

Timeframe: Baseline, after 8 weeks Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 & Period 2	0.79 mg/L Standard Deviation 4.96	0.60 mg/L Standard Deviation 2.48

SECONDARY outcome

Timeframe: Baseline, after 8 weeks Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 & Period 2	0.40 pg/L Standard Deviation 3.90	0.08 pg/L Standard Deviation 0.93

SECONDARY outcome

Timeframe: Baseline, after 8 weeks Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 & Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 & Period 2	-0.34 Percentage Change Standard Deviation 0.47	-0.31 Percentage Change Standard Deviation 0.57

SECONDARY outcome

Timeframe: after 8 weeks Period 1 & Period 2

Population: Full Analysis Set (FAS) included all patients that was treated with study medication.

Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of >3 consecutive VES [salves]

Outcome measures

Measure	Vitagliptin n=49 Participants For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2	Sitagliptin n=49 Participants For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 # any VES Per.1 n=23, 25	879.7 number of occurrence Standard Deviation 1405.2	2786.7 number of occurrence Standard Deviation 6507.7
Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 # any VES Per.2 n=25, 23	4389.9 number of occurrence Standard Deviation 16692	1060.2 number of occurrence Standard Deviation 1812.4
Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 # couplets VES Per.1 n=23, 25	12.8 number of occurrence Standard Deviation 32.5	115.0 number of occurrence Standard Deviation 405.9
Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 # couplets VES Per.2 n=25, 23	6.7 number of occurrence Standard Deviation 10.3	2.4 number of occurrence Standard Deviation 3.0
Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 # salves VES Per.1 n=23, 25	1.0 number of occurrence Standard Deviation 2.4	15.8 number of occurrence Standard Deviation 52.6
Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 # salves VES Per.2 n=25, 23	0.8 number of occurrence Standard Deviation 1.7	0.9 number of occurrence Standard Deviation 1.9

Adverse Events

Sitagliptin

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Vildagliptin

Serious events: 2 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Measure	Sitagliptin n=50 participants at risk For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2	Vildagliptin n=50 participants at risk For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2
Cardiac disorders CORONARY ARTERY DISEASE	0.00% 0/50	2.0% 1/50
Cardiac disorders MYOCARDIAL INFARCTION	0.00% 0/50	2.0% 1/50
Cardiac disorders PERICARDITIS	0.00% 0/50	2.0% 1/50
Metabolism and nutrition disorders HYPOGLYCAEMIA	2.0% 1/50	0.00% 0/50
Neoplasms benign, malignant and unspecified (incl cysts and polyps) LUNG NEOPLASM MALIGNANT	0.00% 0/50	2.0% 1/50
Nervous system disorders TRANSIENT ISCHAEMIC ATTACK	2.0% 1/50	0.00% 0/50

Other adverse events

Measure	Sitagliptin n=50 participants at risk For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2	Vildagliptin n=50 participants at risk For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2
Investigations BLOOD GLUCOSE DECREASED	6.0% 3/50	8.0% 4/50
Metabolism and nutrition disorders HYPOGLYCAEMIA	14.0% 7/50	26.0% 13/50

Additional Information

Study Director

Novartis

Phone: 862-778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
• Publication restrictions are in place

Restriction type: OTHER