Condition category
Nutritional, Metabolic, Endocrine
Date applied
28/09/2006
Date assigned
28/09/2006
Last edited
08/07/2013
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

http://www.trialregister.nl

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, Cushing’s 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

Sponsor information

Organisation

VU University Medical Center (The Netherlands)

Sponsor details

Van der Boechorststraat 7
Amsterdam
1081 BT
Netherlands

Sponsor type

Hospital/treatment centre

Website

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

  1. 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.

  2. 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.

  3. 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.

Additional files

Editorial Notes