VERIFY:A Study to Compare Combination Regimen With Vildagliptin & Metformin Versus Metformin in Treatment-naïve Patients With Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A 5-year Study to Compare the Durability of Glycemic Control of a Combination Regimen With Vildagliptin & Metformin Versus Standard-of-care Monotherapy With Metformin, Initiated in Treatment-naïve Patients With Type 2 Diabetes Mellitus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01528254
• Other study ID #: CLAF237A23156
• Secondary ID: 2011-003712-23
• Status: Completed
• Phase: Phase 4
• Start date: March 30, 2012
• Est. completion date: April 4, 2019

Study information

• Verified date: September 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to determine whether the initiation of a vildagliptin plus metformin combination regimen would result in more durable glycemic control than metformin monotherapy in treatment-naïve patients with type-2 diabetes mellitus (T2DM).

Description:

This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period. Following a screening visit (Visit 1) and a screening period of up to 2 weeks, treatment-naïve patients, meeting all eligibility criteria entered the run-in period at Visit 2.

• Run-in period: At Visit 2, in all eligible patients, metformin treatment was initiated and/or up-titrated. At the end of the 3-week run-in period, patients who were able to tolerate a total dose of at least 1000 mg and up to 2000 mg daily proceeded to randomization and started in Period 1.

• Period 1 (vildagliptin/metformin combination versus metformin): At Visit 3, patients were randomized 1:1 to one of the following study regimens:

• Metformin up to 1000 mg bid plus vildagliptin 50mg bid or

• Metformin up to 1000 mg bid plus matching placebo bid

The duration of Period 1 could differ between patients depending on the time when the second of two HbA1c measurements taken at two consecutive visits after randomisation confirmed HbA1c ≥ 7.0%.

• Period 2 (vildagliptin/metformin combination versus vildagliptin add-on to metformin): In the case of two consecutive HbA1c measurements ≥7.0% from two consecutive study visits during Period 1, patients who were randomised to the placebo arm in Period 1 received vildagliptin 50 mg bid. Patients who were randomised to the active vildagliptin 50 mg bid arm in Period 1 continued to receive vildagliptin 50 mg bid. All patients continued to take their metformin dose unchanged. Period 2 remained masked to the patient and both patients and investigators remained masked to the treatment allocation in Period 1.

If, during Period 2, therapy intensification was required in accordance with the local guidelines, the patient entered Period 3. The duration of Period 2 could differ between patients. End of Period 2 was considered when insulin treatment was initiated, or alternatively when the patient was discontinued because insulin treatment was not initiated in Period 3.

• Period 3 (insulin initiation): In Period 3, patients were to be initiated on open-label insulin. The study drug regimen continued unchanged and remained masked to the patient in Period 3 and both patients and investigators remained masked to the treatment allocation in Period 1.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2004
• Est. completion date: April 4, 2019
• Est. primary completion date: April 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Key Inclusion Criteria:

• Type 2 Diabetes Mellitus (T2DM) diagnosed = 24 months ago

• glycosylated hemoglobin (HbA1c) =6.5% and =7.5% at Visit 1

• Treatment-naïve.

• Body mass index (BMI) =22 and =40 kg/m2 at Visit 1

Key Exclusion Criteria:

• Pregnant or nursing (lactating) women

• Fasting plasma glucose (FPG) = 270 mg/dL (= 15.0 mmol/L)

• Previous or current participation in any vildagliptin clinical study.

• History of hypersensitivity to dipeptidyl peptidase-4 (DPP-4) inhibitors.

• Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.

• Donation of blood or significant blood loss equaling to at least one unit of blood within the past 2 weeks of start of study or a blood transfusion within the past 12 weeks or planned regular transfusions during the study period.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Placebo of vildagliptin

• vildagliptin
One tablet (50 mg oral) of vildagliptin in the morning and one tablet in the evening with or without food.
• Metformin
Twice daily (bid) regimen during or after meals at the same time as vildagliptin.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Capital Federal
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	San Isidro	Buenos Aires
Australia	Novartis Investigative Site	Brookvale	New South Wales
Australia	Novartis Investigative Site	Morayfield	Queensland
Australia	Novartis Investigative Site	Woy Woy	New South Wales
Austria	Novartis Investigative Site	Wien
Brazil	Novartis Investigative Site	Belem	PA
Brazil	Novartis Investigative Site	Brasilia	DF
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Fortaleza	CE
Brazil	Novartis Investigative Site	Fortaleza	CE
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Mogi das Cruzes	SP
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Bulgaria	Novartis Investigative Site	Gabrovo
Bulgaria	Novartis Investigative Site	Kazanlak
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Razgrad
Bulgaria	Novartis Investigative Site	Ruse
Bulgaria	Novartis Investigative Site	Smolian
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Colombia	Novartis Investigative Site	Baranquilla
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Bogotá
Colombia	Novartis Investigative Site	Cartagena	Bolivar
Czechia	Novartis Investigative Site	Brandys Nad Labem
Czechia	Novartis Investigative Site	Pisek	Czech Republic
Czechia	Novartis Investigative Site	Prague 5	Czech Republic
Czechia	Novartis Investigative Site	Praha
Dominican Republic	Novartis Investigative Site	Santo Domingo	Republica Dominicana
Dominican Republic	Novartis Investigative Site	Santo Domingo
Estonia	Novartis Investigative Site	Saku
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
Finland	Novartis Investigative Site	Kerava
Finland	Novartis Investigative Site	Kouvola
Finland	Novartis Investigative Site	Lahti	Suomi
Finland	Novartis Investigative Site	Tampere
Germany	Novartis Investigative Site	Aschaffenburg
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Esslingen am Neckar
Germany	Novartis Investigative Site	Fulda
Germany	Novartis Investigative Site	Gelnhausen
Germany	Novartis Investigative Site	Hainstadt	Hainburg
Germany	Novartis Investigative Site	Kamp-Lintfort
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Ludwigshafen
Germany	Novartis Investigative Site	Neuwied
Germany	Novartis Investigative Site	Saint Ingbert - Oberwuerzbach
Germany	Novartis Investigative Site	Wangen
Guatemala	Novartis Investigative Site	Clinica
Guatemala	Novartis Investigative Site	Guatemala City
Guatemala	Novartis Investigative Site	Guatemala City
Hong Kong	Novartis Investigative Site	Hong Kong
Hong Kong	Novartis Investigative Site	HongKong
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Csongrad
Hungary	Novartis Investigative Site	Eger
Hungary	Novartis Investigative Site	Kalocsa
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Veszprem
Hungary	Novartis Investigative Site	Zalaegerszeg	Zala
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Chandigarh
India	Novartis Investigative Site	Chennai	Tamil Nadu
India	Novartis Investigative Site	Chennai	Tamilnadu
India	Novartis Investigative Site	Indore	Madhya Pradesh
India	Novartis Investigative Site	Jaipur	Rajasthan
India	Novartis Investigative Site	Jaipur	Rajasthan
India	Novartis Investigative Site	Kochi	Kerala
India	Novartis Investigative Site	New Delhi	Delhi
India	Novartis Investigative Site	Pune	Maharashtra
India	Novartis Investigative Site	Pune	Maharashtra
Israel	Novartis Investigative Site	Heifa
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Kfar Saba
Israel	Novartis Investigative Site	Rehovot
Israel	Novartis Investigative Site	Sefad
Israel	Novartis Investigative Site	Tel Aviv
Israel	Novartis Investigative Site	Tel Giborim, Holon
Italy	Novartis Investigative Site	Arenzano	GE
Italy	Novartis Investigative Site	Campobasso	CB
Italy	Novartis Investigative Site	Casorate Primo	PV
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Montichiari	BS
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Korea, Republic of	Novartis Investigative Site	Daejeon
Korea, Republic of	Novartis Investigative Site	Incheon
Korea, Republic of	Novartis Investigative Site	Incheon	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Suwon	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Uijeongbu-Si	Gyeonggi-do
Latvia	Novartis Investigative Site	Daugavpils
Latvia	Novartis Investigative Site	Jelgava	LV
Latvia	Novartis Investigative Site	Liepaja	LV
Latvia	Novartis Investigative Site	Ogre	LV
Latvia	Novartis Investigative Site	Riga	LV
Latvia	Novartis Investigative Site	Riga	LV
Latvia	Novartis Investigative Site	Riga
Latvia	Novartis Investigative Site	Riga
Latvia	Novartis Investigative Site	Talsi	LV
Lithuania	Novartis Investigative Site	Jonava
Lithuania	Novartis Investigative Site	Kaunas
Lithuania	Novartis Investigative Site	Kaunas
Lithuania	Novartis Investigative Site	Kaunas	LTU
Lithuania	Novartis Investigative Site	Vilnius	LT
Lithuania	Novartis Investigative Site	Vilnius
Malaysia	Novartis Investigative Site	Kota Bahru	Kelantan
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuala Lumpur
Mexico	Novartis Investigative Site	Aguascalientes
Mexico	Novartis Investigative Site	Ciudad De Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Cuautla	Morelos
Mexico	Novartis Investigative Site	Cuernavaca	Morelos
Mexico	Novartis Investigative Site	Distrito Federal
Mexico	Novartis Investigative Site	Durango
Mexico	Novartis Investigative Site	México	Distrito Federal
Mexico	Novartis Investigative Site	Mexico D.F	Distrito Federal
Mexico	Novartis Investigative Site	Querétaro
Norway	Novartis Investigative Site	Enebakk
Norway	Novartis Investigative Site	Fetsund
Norway	Novartis Investigative Site	Honefoss
Norway	Novartis Investigative Site	Oslo
Norway	Novartis Investigative Site	Spikkestad
Panama	Novartis Investigative Site	Panama City
Panama	Novartis Investigative Site	Panama City
Peru	Novartis Investigative Site	Arequipa
Peru	Novartis Investigative Site	Cercado De Lima	Lima
Peru	Novartis Investigative Site	Chorrillos	Lima
Peru	Novartis Investigative Site	Magdalena	Lima
Peru	Novartis Investigative Site	San Isidro	Lima
Peru	Novartis Investigative Site	San Martin de Porres	Lima
Peru	Novartis Investigative Site	Trujillo	La Libertad
Philippines	Novartis Investigative Site	Marikina	Metro Manila
Philippines	Novartis Investigative Site	Marikina City
Philippines	Novartis Investigative Site	Pasay City
Philippines	Novartis Investigative Site	Pasig City
Philippines	Novartis Investigative Site	Quezon City	Metro Manila
Philippines	Novartis Investigative Site	San Juan City
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Wroclaw
Poland	Novartis Investigative Site	Zabrze
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Oradea	Bihor
Romania	Novartis Investigative Site	Oradea	Jud. Bihor
Romania	Novartis Investigative Site	Ploiesti	Jud. Prahova
Romania	Novartis Investigative Site	Timisoara
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	N.Novgorod
Russian Federation	Novartis Investigative Site	Penza
Russian Federation	Novartis Investigative Site	Petrozavodsk
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saratov
Russian Federation	Novartis Investigative Site	Smolensk
Russian Federation	Novartis Investigative Site	St-Petersburg
Russian Federation	Novartis Investigative Site	St.- Petersburg
Slovakia	Novartis Investigative Site	Banska Bystrica
Slovakia	Novartis Investigative Site	Bratislava	Slovak Republic
Slovakia	Novartis Investigative Site	Kosice	Slovak Republic
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Levice
Slovakia	Novartis Investigative Site	Lucenec	Slovak Republic
Slovakia	Novartis Investigative Site	Namestovo	Slovak Republic
Slovakia	Novartis Investigative Site	Nové Zámky
Slovakia	Novartis Investigative Site	Presov
Slovakia	Novartis Investigative Site	Roznava	Slovak Republic
Slovakia	Novartis Investigative Site	Sabinov
Slovakia	Novartis Investigative Site	Sala	Slovak Republic
Slovakia	Novartis Investigative Site	Sered
Slovakia	Novartis Investigative Site	Sturovo
Slovakia	Novartis Investigative Site	Trebisov	Slovak Republic
Slovakia	Novartis Investigative Site	Zilina	Slovak Republic
Slovakia	Novartis Investigative Site	Zilina
South Africa	Novartis Investigative Site	Alberton
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Gauteng
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Pretoria
Spain	Novartis Investigative Site	Barcelona	Cataluña
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Sant Adria Del Besos	Barcelona
Spain	Novartis Investigative Site	Santa Coloma De Gramanet	Barcelona
Taiwan	Novartis Investigative Site	Hsintien
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Denizli
Turkey	Novartis Investigative Site	Diskapi / Ankara
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Kahramanmaras

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Argentina,  Australia,  Austria,  Brazil,  Bulgaria,  Colombia,  Czechia,  Dominican Republic,  Estonia,  Finland,  Germany,  Guatemala,  Hong Kong,  Hungary,  India,  Israel,  Italy,  Korea, Republic of,  Latvia,  Lithuania,  Malaysia,  Mexico,  Norway,  Panama,  Peru,  Philippines,  Poland,  Romania,  Russian Federation,  Slovakia,  South Africa,  Spain,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Initial Treatment Failure	Treatment failure was defined as two consecutive scheduled visits with HbA1c >= 7.0% (starting from 13 weeks after randomization) and the time to treatment failure was the number of days from randomization to the second of the consecutive scheduled visits.; Participants who discontinued the study for any reason during Period 1 were censored at the date of discontinuation. Participants who remained under the threshold (or whose measurement above the threshold was not confirmed at next scheduled visit) were censored at the date of last study visit.	Visit 4 (Week 13) up to End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
Secondary	Rate of Loss in Glycemic Control During Period 1	The rate of loss in glycemic control was estimated using the slope of HbA1c over time (years).; HbA1c data collected from Week 26 up to and including the end of Period 1 visit was included in the analysis. Baseline HbA1c was the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement was missing. End of Period 1 was defined as the final post-baseline assessment obtained at any visit within Period 1 (scheduled or unscheduled), up to the last scheduled visit.	Visit 5 (Week 26) to End of Period 1
Secondary	Rate of Loss in Glycemic Control in HbA1c Over Time During Period 2	The rate of loss in glycemic control was estimated using the slope of HbA1c over time (years).; HbA1c data collected from 26 weeks after the start of Period 2 to the end of Period 2 were included in the analysis, for participants who started insulin therapy in Period 3 or discontinued during Period 2 due to being unable or unwilling to initiate insulin therapy in period 3. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis.	From 26 weeks after start of Period 2 to end of Period 2
Secondary	Rate of Loss in Glycemic Control in Fasting Plasma Glucose (FPG) During Period 1	Rate of loss in glycemic control was estimated using the slope of FPG over time (years).; FPG (fasting plasma glucose) data from Week 26 to the end of Period 1 was included in the analysis. Baseline FPG was the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement is missing. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis.	Visit 5 (Week 26) to End of Period 1
Secondary	Rate of Loss in Glycemic Control in Fasting Plasma Glucose (FPG) Over Time During Period 2	Rate of loss in glycemic control was estimated using the slope of FPG over time (years).; FPG (fasting plasma glucose) data from 26 weeks after the start of Period 2 to then end of Period 2 was included in the analysis. Only participants who started insulin therapy in Period 3 or discontinued during Period 2 due to being unable or unwilling to initiate insulin therapy in period 3 were included. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis.	From 26 weeks after start of Period 2 to end of Period 2
Secondary	Rate of Loss of Beta Cell Function From Baseline to End of Study	The rate of change of beta cell function was assessed using the slope of AUC of ISR/G over time (years) where AUC of ISR/G is defined as (Area under curve of Insulin secretion rate (derived using c-peptide))/(Area under curve of Glucose), using meal-test data from 0 to 120 minutes. Baseline AUC of ISR/G was derived based on samples obtained on day 1, or samples obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurements were missing. Three analyses were included, using data from Week 13 to the end of Period 1, end of Period 2 and end of study, respectively.	Visit 4 (Week 13), End of Period 1, End of Period 2, End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
Secondary	Rate of Change in Insulin Sensitivity From Baseline to End of Study	The rate of change of insulin sensitivity is assessed using the slope of OGIS over time (years) where Oral glucose insulin sensitivity (OGIS) was calculated as a function of glucose and insulin, using meal-test data from 0 to 120 minutes. Baseline OGIS is derived based on samples obtained on day 1, or samples obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurements are missing. Three analyses were included, using data from Week 13 to the end of Period 1, end of Period 2 and end of study, respectively.	Visit 4 (Week 13), End of Period 1, End of Period 2, End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
Secondary	Percentage of Participants With Adverse Events, Serious Adverse Events and Death	Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) in each treatment arm to demonstrate that LAF237 is safe for the treatment of naïve patients with type 2 diabetes mellitus through the monitoring of relevant clinical and laboratory safety parameters.	From first dose of study treatment until End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)