Plain English Summary
Not provided at time of registration
Trial website
Contact information
Type
Scientific
Primary contact
Dr M Diamant
ORCID ID
Contact details
VU University Medical Center
Department of Endocrinology
Diabetes Center
De Boelelaan 1117
P.O. Box 7057
Amsterdam
1081 HV
Netherlands
+31 (0)20 4440534
m.diamant@vumc.nl
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
Scientific title
Acronym
PRESERVE TRIAL
Study hypothesis
Type two diabetes is cause by progressive beta-cell dysfunction against a background of obesity and insulin resistance in susceptible individuals.
Peroxisome Proliferator-Activated Receptor (PPAR) gamma-mediated mechanisms are involved in the regulation of important processes that may protect the pancreatic beta-cell. Local pancreatic and systemic activation of the Renin-Angiotensin System (RAS), as frequently observed in people with obesity/insulin resistance, may be harmful to the pancreatic beta-cell causing beta-cell dysfunction and beta-cell apoptosis.
Treatment of subjects at high risk to develope type two diabetes, including those with impaired fasting glucose and/or impaired glucose tolerance (with/without a familiy history of diabetes) with a PPAR gamma agonist and/or an angiotensin II receptor blocker may improve beta-cell function.
Ethics approval
Ethics approval received from the local medical ethics committee
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Impaired glucose metabolism
Intervention
Participants will be randomised into one of the following four treatment groups for a 52-week intervention:
1. Rosiglitazone 8 mg daily and valsartan-placebo
2. Valsartan 320 mg daily and rosiglitazone-placebo
3. Rosiglitazone 8 mg daily and valsartan 320 mg daily
4. Rosiglitazone-placebo and valsartan-placebo
Further information as of 10/07/12: The decision was made not to initiate the rosiglitazone arm because of the reported potential cardiovascular risks associated with rosiglitazone.
Intervention type
Drug
Phase
Not Specified
Drug names
Rosiglitazone and Valsartan
Primary outcome measures
To compare beta-cell function, as reflected by the first phase insulin secretion corrected for insulin sensitivity and/or the arginine-stimulated insulin secretion, both co-primary endpoints as measured during the eu-hyperglycemic clamp procedure, following 52 weeks of rosiglitazone, valsartan or rosiglitazone combined with valsartan in subjects with IFG (with and without a family history of DM2) and/or IGT.
Secondary outcome measures
To compare the effects of 52 weeks of rosiglitazone, valsartan or rosiglitazone combined with valsartan in subjects with IFG (with and without a family history of DM2) and/or IGT with respect to:
1. Fasting plasma glucose
2. Second phase insulin secretion in response to hyperglycemia during the hyperglycemic clamp test
3. All the above-mentioned beta-cell function parameters at 12 weeks after discontinuation of therapy to assess durability/disease modifying effects
4. The conversion from Normal Glucose Tolerance (NGT) to IGT or diabetes (as evaluated by an oral glucose tolerance test)
5. HbA1c, fasting blood glucose and lipid/lipoprotein concentrations
6. Insulin sensitivity assessed during the euglycemic clamp test
7. Safety and tolerability, including assessments of hypoglycemic events, blood pressure, and urinary albumin excretion rate
Overall trial start date
01/10/2006
Overall trial end date
01/01/2010
Reason abandoned
Eligibility
Participant inclusion criteria
1. Male and female subjects (aged 35 to 70 years)
2. Impaired Fasting Glucose (IFG): fasting plasma glucose 6.1 or higher and less than 7.0 mmol/l, or fasting plasma glucose 5.6 or higher and less than 7.0 mmol/l) and a family history of Diabetes Mellitus type two (DM2) (i.e. first and second degree [i.e. grandparents] relatives)
3. Impaired Glucose Tolerance (IGT): two hour plasma glucose during 75 g oral glucose tolerance test 7.8-11.1 mmol/l
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
144
Participant exclusion criteria
Drug use:
1. Current use of Angiotensin-Converting Enzyme Inhibitors (ACE-I), Angiotensin Receptor Blockers (ARB) and/or Thiazolidinediones (TZDs) and inability to discontinue these drugs
2. Known hypersensitivity to any of the study drugs
3. Prior use of blood glucose lowering medications except during pregnancy
4. Use of systemic glucocorticoids or niacin
Cardiovascular co-morbidities:
1. Ejection fraction known to be less than 40% or congestive heart failure, or existing clinical Cardio-Vascular (CV) disease:
a. previous Myocardial Infarction [MI] or stroke
b. angina with either more than 50% stenosis in more than or equal to two major coronary arteries, or ST depression of more than or equal to 2 mm, or a positive nuclear test, or previous coronary angioplasty, stent or bypass
c. previous limb bypass or vessel angioplasty or angiographic evidence of more than 50% stenosis, or intermittent claudication with an ankle/arm pressure less than or equal to 0.8
2. Uncontrolled hypertension requiring ACE-I or ARB
Other Criteria:
1. History of diabetes (except gestational DM) or on anti-diabetic medication
2. Renal or Hepatic Disease:
a. renal artery stenosis
b. creatinine clearance less than 40 ml/min or serum creatinine 200 umol/l or higher
c. clinical proteinuria (one or above, positive proteinuria on dipstick or 300 mg and above albuminuria/day, in the absence of urine)
d. measured Alanine Transferase (ALT) 2.5 or more times the upper limit of normal
e. active liver disease including jaundice, chronic hepatitis, previous liver transplant
3. Major illness with life expectancy of less than five years or that may interfere with participation
4. Use of another experimental drug
5. Pregnant or unwilling to use reliable contraception (fertile women will have a pregnancy test prior to randomisation)
6. Major psychiatric disorder
7. Diseases and medications that affect glucose tolerance (e.g. pheochromocytoma, Cushings syndrome, acromegaly, steroid-dependent asthma, protease inhibitors, anti-psychotics)
8. Unwillingness to be randomised or sign informed consent)
9. Known uncontrolled substance abuse
10. Inability to understand study information and/or communicate with clinic staff
Recruitment start date
01/10/2006
Recruitment end date
01/01/2010
Locations
Countries of recruitment
Netherlands
Trial participating centre
VU University Medical Center
Amsterdam
1081 HV
Netherlands
Funders
Funder type
Industry
Funder name
Novartis Pharma B.V. (The Netherlands)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
GlaxoSmithKline (The Netherlands)
Alternative name(s)
GlaxoSmithKline plc., GSK
Funding Body Type
private sector organisation
Funding Body Subtype
corporate
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary
1. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22768174
2. 2012 further results in http://www.ncbi.nlm.nih.gov/pubmed/21712806
3. 2013 results in http://www.ncbi.nlm.nih.gov/pubmed/23553863
Publication citations
-
Results
Goossens GH, Moors CC, van der Zijl NJ, Venteclef N, Alili R, Jocken JW, Essers Y, Cleutjens JP, Clément K, Diamant M, Blaak EE, Valsartan improves adipose tissue function in humans with impaired glucose metabolism: a randomized placebo-controlled double-blind trial., PLoS ONE, 2012, 7, 6, e39930, doi: 10.1371/journal.pone.0039930.
-
Further results
Moors CC, van der Zijl NJ, Diamant M, Blaak EE, Goossens GH, Impaired insulin sensitivity is accompanied by disturbances in skeletal muscle fatty acid handling in subjects with impaired glucose metabolism., Int J Obes (Lond), 2012, 36, 5, 709-717, doi: 10.1038/ijo.2011.123.
-
Results
Moors CC, Blaak EE, van der Zijl NJ, Diamant M, Goossens GH, The effects of long-term valsartan treatment on skeletal muscle fatty acid handling in humans with impaired glucose metabolism., J. Clin. Endocrinol. Metab., 2013, 98, 5, E891-6, doi: 10.1210/jc.2012-4067.