Pancreatic beta-cell dysfunction REStorEd by Rosiglitazone and Valsartan Effects: a 52-week randomised controlled factorial study in subjects with impaired fasting glucose and/or impaired glucose tolerance

ISRCTN	ISRCTN42786336
DOI	https://doi.org/10.1186/ISRCTN42786336
Secondary identifying numbers	N/A

Submission date: 28/09/2006
Registration date: 28/09/2006
Last edited: 08/07/2013

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Study website

Contact information

Dr M Diamant
Scientific

VU University Medical Center
Department of Endocrinology
Diabetes Center
De Boelelaan 1117
P.O. Box 7057
Amsterdam
1081 HV
Netherlands

Phone	+31 (0)20 4440534
Email	m.diamant@vumc.nl

Study information

Study design	Randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Not specified
Study type	Treatment
Scientific title
Study acronym	PRESERVE TRIAL
Study objectives	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(s)	Ethics approval received from the local medical ethics committee
Health condition(s) or problem(s) studied	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
Pharmaceutical study type(s)
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Rosiglitazone and Valsartan
Primary outcome measure	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 study start date	01/10/2006
Completion date	01/01/2010

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	144
Key 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
Key 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
Date of first enrolment	01/10/2006
Date of final enrolment	01/01/2010

Locations

Countries of recruitment

Netherlands

Study participating centre

VU University Medical Center

Amsterdam
1081 HV
Netherlands

Sponsor information

VU University Medical Center (The Netherlands)
Hospital/treatment centre

Van der Boechorststraat 7
Amsterdam
1081 BT
Netherlands

"ROR"	https://ror.org/00q6h8f30

Funders

Funder type

Industry

Novartis Pharma B.V. (The Netherlands)

No information available

GlaxoSmithKline (The Netherlands)
Government organisation / For-profit companies (industry)

Alternative name(s): GlaxoSmithKline plc., GSK plc., GSK
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Peer reviewed?	Patient-facing?
Results article	further results	01/05/2012	Yes	No
Results article	results	01/09/2012	Yes	No
Results article	results	01/05/2013	Yes	No