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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Factorial Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Prevention
Condition:	Diabetes Mellitus, Type 2
Interventions:	Drug: Valsartan 160 mg + nateglinide 60 mg Drug: Valsartan 160 mg + nateglinide placebo Drug: Nateglinide 60 mg + valsartan placebo Drug: Valsartan placebo + nateglinide placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Initially enrolled 9518, 212 excluded.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Valsartan 160 mg od + Nateglinide 60 mg ac	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 uptitrated to nateglinide 60 mg ac and valsartan 160 mg od.
Valsartan 160 mg od + Placebo Nateglinide	For the first 2 weeks of treatment, patients took valsartan 80 mg once daily (od) once in the morning. After 2 weeks, patients were uptitrated to 160 mg valsartan od. Patient also received placebo matching nateglinide tablets identical to the active nateglinide tablets (ac, before meals).
Nateglinide 60 mg ac + Placebo Valsartan	For the first 2 weeks of treatment, patients took one 30 mg tablet of nateglinide with a glass of water 1-30 minutes before each main meal of the day, ie, 3 times daily ante cibum (ac, before meals). If a meal was missed, the patient was not to take a tablet. After 2 weeks, patients were uptitrated to 60 mg nateglinide ac. Patients also received placebo matching valsartan capsules identical to the active valsartan capsules.
Placebo	Patients took 3 placebo tablets identical to nateglinide tablets 3 times daily ac and 1 placebo capsule identical to valsartan capsule once daily in the morning.

Participant Flow: Overall Study

	Valsartan 160 mg od + Nateglinide 60 mg ac	Valsartan 160 mg od + Placebo Nateglinide	Nateglinide 60 mg ac + Placebo Valsartan	Placebo
STARTED	2316 ^[1]	2315	2329	2346
Complete FU for Progression to Diabetes	1709	1712	1734	1762
Complete Follow-up for Extended CV EPs	1969	1985	1987	2015
Complete Follow-up for Core CV EPs	1948	1963	1966	1988
COMPLETED	2020 ^[2]	2023	2016	2036
NOT COMPLETED	296	292	313	310
lost to follow-up for all-cause death	296	292	313	310

[1]	"Started" indicates Full Analysis Set (FAS) population. Initially enrolled 9518, 212 excluded.
[2]	"Completed" means completed follow up for all cause death.

Baseline Characteristics

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Reporting Groups

	Description
Valsartan 160 mg od + Nateglinide 60 mg ac	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 uptitrated to nateglinide 60 mg ac and valsartan 160 mg od.
Valsartan 160 mg od + Placebo Nateglinide	For the first 2 weeks of treatment, patients took valsartan 80 mg once daily (od) once in the morning. After 2 weeks, patients were uptitrated to 160 mg valsartan od. Patient also received placebo matching nateglinide tablets identical to the active nateglinide tablets (ac, before meals).
Nateglinide 60 mg ac + Placebo Valsartan	For the first 2 weeks of treatment, patients took one 30 mg tablet of nateglinide with a glass of water 1-30 minutes before each main meal of the day, ie, 3 times daily ante cibum (ac, before meals). If a meal was missed, the patient was not to take a tablet. After 2 weeks, patients were uptitrated to 60 mg nateglinide ac. Patients also received placebo matching valsartan capsules identical to the active valsartan capsules.
Placebo	Patients took 3 placebo tablets identical to nateglinide tablets 3 times daily ac and 1 placebo capsule identical to valsartan capsule once daily in the morning.

Baseline Measures

	Valsartan 160 mg od + Nateglinide 60 mg ac	Valsartan 160 mg od + Placebo Nateglinide	Nateglinide 60 mg ac + Placebo Valsartan	Placebo	Total
Number of Participants [units: participants]	2316	2315	2329	2346	9306
Age ^[1] [units: years] Mean ± Standard Deviation	63.7 ± 6.75	63.7 ± 6.91	63.8 ± 6.82	63.9 ± 6.88	63.8 ± 6.84
Gender ^[1] [units: participants]
Female	1174	1140	1194	1203	4711
Male	1142	1175	1135	1143	4595

[1]	Originally 9518 patient were enrolled and 212 excluded. So this baseline measure is based on Full analysis Set(FAS)population.

Outcome Measures

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1. Primary:

Percentage of Patients Reaching the Endpoint: Progression to Diabetes - Valsartan Versus Non-valsartan [ Time Frame: Mean patient duration of 4.2 years ]

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2. Primary:

Percentage of Patients Reaching the Endpoint: Extended Morbidity and Mortality Event - Valsartan Versus Non-valsartan [ Time Frame: Mean patient duration of 5.6 years ]

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3. Primary:

Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Valsartan Versus Non-valsartan [ Time Frame: Mean patient duration of 5.8 years ]

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4. Primary:

Percentage of Patients Reaching the Endpoint: Progression to Diabetes - Nateglinide Versus Non-nateglinide [ Time Frame: Mean patient duration of 4.2 years ]

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5. Primary:

Percentage of Patients Reaching the Endpoint: Extended Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide [ Time Frame: Mean patient duration of 5.6 years ]

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6. Primary:

Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide [ Time Frame: Mean patient duration of 5.8 years ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862 778-8300

No publications provided by Novartis

Publications automatically indexed to this study:

NAVIGATOR Study Group; McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010 Apr 22;362(16):1477-90. Epub 2010 Mar 14.

NAVIGATOR Study Group; Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010 Apr 22;362(16):1463-76. Epub 2010 Mar 14.

Krum H, McMurray JJ, Horton E, Gerlock T, Holzhauer B, Zuurman L, Haffner SM, Bethel MA, Holman RR, Califf RM. Baseline Characteristics of the Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial population: comparison with other diabetes prevention trials. Cardiovasc Ther. 2010 Apr;28(2):124-32. Epub 2010 Feb 23.

Bethel MA, Deedwania P, Levitt NS, Schmitz O, Huntsman-Labed A, Califf RM, Haffner SM, Diem P; NAVIGATOR Study Group. Metabolic syndrome and alanine aminotransferase: a global perspective from the NAVIGATOR screening population. Diabet Med. 2009 Dec;26(12):1204-11.

Bethel MA, Holman R, Haffner SM, Califf RM, Huntsman-Labed A, Hua TA, McMurray J. Determining the most appropriate components for a composite clinical trial outcome. Am Heart J. 2008 Oct;156(4):633-40. Epub 2008 Jul 31.

Responsible Party:	Study Director, Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00097786 History of Changes
Other Study ID Numbers:	CDJN608B2302
Study First Received:	November 30, 2004
Results First Received:	January 14, 2011
Last Updated:	June 27, 2011
Health Authority:	United States: Food and Drug Administration