Long-term Study of Nateglinide+Valsartan to Prevent or Delay Type II Diabetes Mellitus and Cardiovascular Complications

Study Overview
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Brief Summary
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This study is a test of the safety and effectiveness of two drugs, one for diabetes and one for hypertension, in keeping patients with high lab values of glucose from progressing to frank diabetes and developing cardiovascular complications. People in this study cannot have frank diabetes but are considered borderline based on blood tests. People in the study take none, one or both of the drugs and do not know which one(s) they are taking.

Official Title
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A Multinational, Randomized, Double-blind, Placebo-controlled, Forced-titration, 2 x 2 Factorial Design Study of the Efficacy and Safety of Long-term Administration of Nateglinide and Valsartan in the Prevention of Diabetes and Cardiovascular Outcomes in Subjects With Impaired Glucose Tolerance (IGT)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Valsartan 160 mg + nateglinide 60 mg
* Drug: Valsartan 160 mg + nateglinide placebo
* Drug: Nateglinide 60 mg + valsartan placebo
* Drug: Valsartan placebo + nateglinide placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults Impaired glucose tolerance Age dependent risk factors Exclusion Criteria: Frank diabetes For detailed information, call contact person.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valsartan 160 mg + nateglinide 60 mg<br>For the first 2 weeks of treatment, patients took the combination of nateglinide 30 mg (3 times daily, ante cibum [ac] before meals) and valsartan 80 mg (once daily [od] in the morning). After 2 weeks, patients were up-titrated to nateglinide 60 mg ac and valsartan 160 mg od. | Drug: Valsartan 160 mg + nateglinide 60 mg<br>* The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.<br>|
| Experimental: Valsartan 160 mg + nateglinide placebo<br>For the first 2 weeks of treatment, patients took valsartan 80 mg capsules (once daily [od] in the morning). After 2 weeks, patients were up-titrated to 160 mg valsartan od. Patients also received nateglinide placebo tablets (3 times daily, ante cibum [ac] before meals). | Drug: Valsartan 160 mg + nateglinide placebo<br>* The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.<br>|
| Experimental: Nateglinide 60 mg + valsartan placebo<br>For the first 2 weeks of treatment, patients took nateglinide 30 mg tablets (3 times daily, ante cibum [ac] before meals). After 2 weeks, patients were uptitrated to 60 mg nateglinide ac. Patients also received valsartan placebo capsules (once daily [od] in the morning). | Drug: Nateglinide 60 mg + valsartan placebo<br>* The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.<br>|
| Placebo Comparator: Placebo<br>Patients took 3 nateglinide placebo tablets (3 times daily, ante cibum [ac] before meals) and 1 valsartan placebo capsule (once daily [od] in the morning). | Drug: Valsartan placebo + nateglinide placebo<br>* The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Reaching the Endpoint: Progression to Diabetes - Valsartan Versus Non-valsartan | Progression to diabetes was determined by (a) an algorithm based on central laboratory measurements of fasting plasma glucose and/or a 2 hour oral glucose tolerance test or (b) adjudication by the Diabetes Endpoint Adjudication Committee. | Mean patient duration of 4.2 years | 
| Percentage of Patients Reaching the Endpoint: Extended Morbidity and Mortality Event - Valsartan Versus Non-valsartan | The extended cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization procedure, hospitalization for congestive heart failure, and hospitalization for unstable angina. | Mean patient duration of 5.6 years | 
| Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Valsartan Versus Non-valsartan | The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. | Mean patient duration of 5.8 years | 
| Percentage of Patients Reaching the Endpoint: Progression to Diabetes - Nateglinide Versus Non-nateglinide | Progression to diabetes was determined by (a) an algorithm based on central laboratory measurements of fasting plasma glucose and/or a 2 hour oral glucose tolerance test or (b) adjudication by the Diabetes Endpoint Adjudication Committee. | Mean patient duration of 4.2 years | 
| Percentage of Patients Reaching the Endpoint: Extended Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide | The extended cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization procedure, hospitalization for congestive heart failure, and hospitalization for unstable angina. | Mean patient duration of 5.6 years | 
| Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide | The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. | Mean patient duration of 5.8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention, Diabetes type 2, valsartan, nateglinide