GLOBE: Glycemic Excursions in Type 2 Diabetic Patients With Vildagliptin and Metformin Versus Vildagliptin and Glimepiride

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02007278
• Collaborator: (none)
• Enrollment: 40
• Locations: 8
• Arms: 2
• Actual Duration (Months): 25.6
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study was to compare the effect of a fixed dose combination of vildagliptin plus metformin versus combination therapy of glimepiride plus metformin in glycemic variability in patients with type 2 diabetes who have not achieved adequate control of their disease prior to treatment with metformin monotherapy in optimal doses.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Hypoglycemia	Drug: vildagliptin and metformin (combination); Drug: glimepiride; Drug: Metformin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Glycemic Excursions in Type 2 Diabetic Patients Treated With Vildagliptin and Metformin (GalvusMet) Versus Glimepiride and Metformin
• Actual Study Start Date: Jan 3, 2014
• Actual Primary Completion Date: Feb 22, 2016
• Actual Study Completion Date: Feb 22, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: vildagliptin and metformin Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Drug: vildagliptin and metformin (combination); vildagliptin and metformin combination therapy as 50mg/850mg bid or 50mg/1000mg bid
Active Comparator: glimepiride and metformin Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin	Drug: glimepiride; Drug: Metformin

Outcome Measures

Primary Outcome Measures

1. Glycemic Variability Measured by Mean Amplitude of Glucose Excursions (MAGE) [Week 12]

   Mean Amplitude of Glycemic Excursions (MAGE) , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement.

Secondary Outcome Measures

1. Glycemic Variability Measured by Continuous Overlapping Net Glycemic Action (CONGA) [Week 12]

   Continuous Overlapping Net Glycemic Action (CONGA) which assesses intra-day glycemic variability by calculating the difference between values at different intervals, adjusted according to requirements with the advantage of being highly reproducible. CONGA is calculated in the conventional way with the formula √tқΣt = t1 (Dt -Ď2) / қ - 1, Ď = tқ Σ Dt t = t1 / қ, Dt = Gt-Gt-m (where қ = Observations with an observation n x 60 minutes, G = glucose measure) from the data of continuous monitoring of tissue glucose obtained during the measurement period.

2. Glycemic Variability Measured by Total Standard Deviation (TSD) [Week 12]

   Total standard deviation (TSD) or standard deviation of all values of a given measurement period, which has the advantage of being able to include all measured values on a given time period (even several days) through a common and simple statistical concept. TSD is calculated conventionally with the formula σ = √Σ (Xi - ῦ) 2 / N (where Xi represents each of the values, ῦ represents the population mean and N is the number of observations) from the data of continuous monitoring of tissue glucose obtained during the measurement.

3. Percentage of Patients Who Achieved a Decrease Equal to or Greater Than 0.3% in Value of HbA1c at Week 12 [Screening visit , 12 weeks of treatment]

4. Change in HbA1c at Week 12 of Treatment in Comparison to HbA1c at Baseline [baseline, 12 weeks of treatment]

5. Number of Patients With Incidence of Hypoglycemia [12 weeks]

   Hypoglycemia defined as Glycemia < 70 mg/dl

6. Mean Amplitude of Glycemic Excursions (MAGE) for Patients With Hypoglycemia Incidence After 12 Weeks of Treatment [12 weeks]

   MAGE , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement. In this endpoint, mean MAGE value is reported for hypo glycemic patients.

7. Number of Patients With Any Adverse Events, Serious Adverse Events and Death [12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• HbA1c between 8%-10.5% in stable metformin dose (>1500 mg/day), four weeks prior visit 1

Key Exclusion Criteria:

• Use of other antidiabetic oral therapy during the last 3 months (sulphonylurea, glitazones, GLP-1 analogues, DPP-4 inhibitors), except metformin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Medellín	Antioquia	Colombia
2	Novartis Investigative Site	Manizales	Caldas	Colombia	1700
3	Novartis Investigative Site	Bogotá	Cundinamarca	Colombia
4	Novartis Investigative Site	Chía	Cundinamarca	Colombia	11001000
5	Novartis Investigative Site	Cali	Valle del Cauca	Colombia	760001
6	Novartis Investigative Site	Bogotá		Colombia	00000
7	Novartis Investigative Site	Cali		Colombia
8	Novartis Investigative Site	Monteria		Colombia

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02007278
• Other Study ID Numbers: CLAF237ACO01
• First Posted: Dec 10, 2013
• Last Update Posted: Jul 11, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: diabetes; hypoglycemia; glycemic variability; vildagliptin; glimepiride
• Additional relevant MeSH terms: Hypoglycemia; Metformin; Glimepiride; Vildagliptin

Study Results

Participant Flow

Pre-assignment Detail	A total of 9 research centers participated in the study, from which 76 patients were screened for inclusion and exclusion criteria, obtaining 40 patients eligible for randomization

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Period Title: Overall Study
STARTED	20	20
COMPLETED	18	17
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin	Total
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin	Total of all reporting groups
Overall Participants	20	20	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.74 (10.58)	55.70 (11.51)	56.25 (10.92)
Sex: Female, Male (Count of Participants)
Female	15 75%	8 40%	23 57.5%
Male	5 25%	12 60%	17 42.5%

Outcome Measures

1. Primary Outcome

Title	Glycemic Variability Measured by Mean Amplitude of Glucose Excursions (MAGE)
Description	Mean Amplitude of Glycemic Excursions (MAGE) , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	16	16
Mean (Standard Deviation) [mg/dL]	6.68 (1.48)	6.23 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vildagliptin and Metformin, Glimepiride and Metformin
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power=95%; significance level=5%, characteristic operation curves were used with a non-central F distribution for the calculation of the sample size
Statistical Test of Hypothesis	p-Value	0.4510
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Glycemic Variability Measured by Continuous Overlapping Net Glycemic Action (CONGA)
Description	Continuous Overlapping Net Glycemic Action (CONGA) which assesses intra-day glycemic variability by calculating the difference between values at different intervals, adjusted according to requirements with the advantage of being highly reproducible. CONGA is calculated in the conventional way with the formula √tқΣt = t1 (Dt -Ď2) / қ - 1, Ď = tқ Σ Dt t = t1 / қ, Dt = Gt-Gt-m (where қ = Observations with an observation n x 60 minutes, G = glucose measure) from the data of continuous monitoring of tissue glucose obtained during the measurement period.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	16	16
Mean (Standard Deviation) [mg/dL]	2.92 (0.93)	3.01 (1.10)

3. Secondary Outcome

Title	Glycemic Variability Measured by Total Standard Deviation (TSD)
Description	Total standard deviation (TSD) or standard deviation of all values of a given measurement period, which has the advantage of being able to include all measured values on a given time period (even several days) through a common and simple statistical concept. TSD is calculated conventionally with the formula σ = √Σ (Xi - ῦ) 2 / N (where Xi represents each of the values, ῦ represents the population mean and N is the number of observations) from the data of continuous monitoring of tissue glucose obtained during the measurement.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	16	16
Mean (Standard Deviation) [mg/dL]	1.36 (0.40)	1.40 (0.42)

4. Secondary Outcome

Title	Percentage of Patients Who Achieved a Decrease Equal to or Greater Than 0.3% in Value of HbA1c at Week 12
Time Frame	Screening visit , 12 weeks of treatment

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have confirmed non-concordant data

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	17	17
Number [percentage of patients]	100.0	100.0

5. Secondary Outcome

Title	Change in HbA1c at Week 12 of Treatment in Comparison to HbA1c at Baseline
Time Frame	baseline, 12 weeks of treatment

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have confirmed non-concordant data

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	17	17
Mean (Standard Deviation) [Percentage of glycosylated haemoglobin]	1.92 (1.1)	2.28 (0.79)

6. Secondary Outcome

Title	Number of Patients With Incidence of Hypoglycemia
Description	Hypoglycemia defined as Glycemia < 70 mg/dl
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison.

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	16	16
Number [Patients]	1	4

7. Secondary Outcome

Title	Mean Amplitude of Glycemic Excursions (MAGE) for Patients With Hypoglycemia Incidence After 12 Weeks of Treatment
Description	MAGE , which determines the average blood glucose excursions either above or below a value of one standard deviation of the average value of glucose in a given day. MAGE is calculated from the data of continuous tissue glucose monitoring obtained during the measurement period. MAGE is calculated with the formula Σ λ / χ if λ> ν (where λ = changes in blood glucose from peak to nadir, χ = number of valid observations, ν = 1 standard deviation of the mean glucose during a period of 24 hours) from the data of continuous monitoring of the tissue glucose, obtained during the period of measurement. In this endpoint, mean MAGE value is reported for hypo glycemic patients.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis set includes all randomized patients excluding the ones who were prematurely withdrawn and the ones who have no data from visit 7 which required for comparison and had at least one hypoglycemia event.

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	1	4
Mean (Standard Deviation) [mg/dL]	5.23 (NA)	5.53 (0.82)

8. Secondary Outcome

Title	Number of Patients With Any Adverse Events, Serious Adverse Events and Death
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All the randomized patients.

Arm/Group Title	Vildagliptin and Metformin	Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks	Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
Measure Participants	20	20
Any adverse events (serious and non-serious)	9	13
Serious Adverse Events	0	1
Death	0	0

Adverse Events

Arm/Group Title	Vildagliptin and Metformin		Glimepiride and Metformin
Arm/Group Description	Based on basal dose of metformin, administration of vildagliptin/metformin 50 mg/850 mg twice daily (bid) or 50 mg/1000 mg bid for 12 weeks		Protocol specified dosage and frequency of glimepiride + metformin for 12 weeks based on basal dose of metformin
All Cause Mortality
	Vildagliptin and Metformin		Glimepiride and Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Vildagliptin and Metformin		Glimepiride and Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		1/20 (5%)
Infections and infestations
Erysipelas	0/20 (0%)		1/20 (5%)
Other (Not Including Serious) Adverse Events
	Vildagliptin and Metformin		Glimepiride and Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/20 (45%)		13/20 (65%)
Cardiac disorders
Palpitations	0/20 (0%)		1/20 (5%)
Ear and labyrinth disorders
Ear pain	1/20 (5%)		0/20 (0%)
Vertigo	1/20 (5%)		0/20 (0%)
Eye disorders
Cataract	0/20 (0%)		1/20 (5%)
Eye irritation	1/20 (5%)		0/20 (0%)
Eyelid oedema	1/20 (5%)		1/20 (5%)
Presbyopia	0/20 (0%)		1/20 (5%)
Refraction disorder	0/20 (0%)		1/20 (5%)
Gastrointestinal disorders
Diarrhoea	0/20 (0%)		1/20 (5%)
Nausea	1/20 (5%)		0/20 (0%)
Vomiting	0/20 (0%)		1/20 (5%)
General disorders
Asthenia	1/20 (5%)		0/20 (0%)
Chest pain	0/20 (0%)		1/20 (5%)
Hypothermia	1/20 (5%)		0/20 (0%)
Influenza like illness	3/20 (15%)		1/20 (5%)
Oedema	1/20 (5%)		0/20 (0%)
Oedema peripheral	0/20 (0%)		1/20 (5%)
Hepatobiliary disorders
Jaundice	1/20 (5%)		0/20 (0%)
Immune system disorders
Hypersensitivity	0/20 (0%)		1/20 (5%)
Infections and infestations
Chikungunya virus infection	0/20 (0%)		1/20 (5%)
Onychomycosis	0/20 (0%)		1/20 (5%)
Rhinitis	0/20 (0%)		1/20 (5%)
Tinea pedis	0/20 (0%)		1/20 (5%)
Tooth abscess	0/20 (0%)		1/20 (5%)
Injury, poisoning and procedural complications
Bone fissure	0/20 (0%)		1/20 (5%)
Limb injury	0/20 (0%)		1/20 (5%)
Soft tissue injury	1/20 (5%)		0/20 (0%)
Wound	0/20 (0%)		1/20 (5%)
Investigations
Blood pressure increased	0/20 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Hypoglycaemia	1/20 (5%)		5/20 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/20 (5%)		0/20 (0%)
Back pain	1/20 (5%)		0/20 (0%)
Costochondritis	0/20 (0%)		1/20 (5%)
Joint crepitation	0/20 (0%)		1/20 (5%)
Musculoskeletal pain	0/20 (0%)		1/20 (5%)
Neck pain	0/20 (0%)		1/20 (5%)
Pain in extremity	1/20 (5%)		2/20 (10%)
Nervous system disorders
Dizziness	0/20 (0%)		1/20 (5%)
Headache	2/20 (10%)		1/20 (5%)
Hypoaesthesia	1/20 (5%)		0/20 (0%)
Tremor	0/20 (0%)		3/20 (15%)
Renal and urinary disorders
Urine abnormality	0/20 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Pleuritic pain	0/20 (0%)		1/20 (5%)
Respiratory distress	0/20 (0%)		1/20 (5%)
Respiratory tract congestion	0/20 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/20 (0%)		2/20 (10%)
Pruritus	0/20 (0%)		1/20 (5%)
Rash maculo-papular	0/20 (0%)		1/20 (5%)
Vascular disorders
Hypertension	1/20 (5%)		1/20 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.