Clinical trial NCT00565318: Benfotiamine in Diabetic Nephropathy
Official title: A Double-Blind Clinical Trial of Benfotiamine Treatment in Diabetic Nephropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetic Nephropathy
Keywords: Benfotiamine
Diabetes
Nephropathy
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Isala
name: Wörwag Pharma GmbH & Co. KG
name: Predictions Network
First posted: 2007-11-29
Enrollment: 86
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate the effect of benfotiamine supplementation in patients with diabetic nephropathy, and to determine whether it will slow down the progression to end-stage renal disease (ESRD).

Detailed description: There is a worldwide increase in prevalence in type 2 diabetes mellitus, which is being paralleled by an increasing number of patients reaching dialysis because of diabetic nephropathy. Much of the fivefold increase in patients receiving dialysis treatment that occurred over the past two decades is attributable to type 2 diabetes and diabetic nephropathy. Diabetes is now the leading cause of end-stage renal disease (ESRD), with more than 40% of all new cases of ESRD occurring in patients with diabetes.

Benfotiamine has been shown to reduce diabetic nephropathy and retinopathy in animal experimental models. We hypothesize that benfothiamine supplementation in patients with diabetic nephropathy will ameliorate the effects of both albuminuria/proteinuria and hyperglycaemia on oxidative stress and advanced glycation end-products (AGEs) accumulation in renal tissue, and thereby decrease inflammatory responses and fibrotic responses, causing slowing down of progression to ESRD as a consequence.

Intervention:

The intervention duration is 12 weeks for each group.

* Group A: Benfotiamine (300 mg) 3x 1 film coated tablet daily (900 mg daily dose benfotiamine)
* Group B: Placebo 3x 1 film coated tablet daily

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes mellitus
* Patients are on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin II antagonists (AIIA) in an unchanged dose for at least 3 months
* Active diabetic nephropathy as indicated by presence of microalbuminuria (15-300 mg/24 h urine) in at least two samples within 2-6 weeks in advance of inclusion in the trial
* HbA1c \< 8.5%, a higher HbA1c \< 9.5% is acceptable if the treating physician and the patient have accepted that striving for lower values is an unreachable goal (patients with high HbA1c values are the ones that one would expect to be benefit most from treatment with benfotiamine)
* eGFR (estimated by MDRD formula) \> 30 ml/min
* Males and postmenopausal females
* Written informed consent

Exclusion Criteria:

* Renal impairment by other causes than diabetes
* Stage of the disease more severe than indicated in Inclusion criteria (macroalbuminuria or renal insufficiency)
* Severe hypoglycemia during the last 3 months, needing help from another person
* Severe hepatopathy (laboratory values about three times higher than normal
* Endocrine disorders, e.g. hyper/hypothyroidism
* Blood pressure \> 160/90 mmHg
* Severe cardiac function disturbances and severe heart rhythm disturbances
* Neoplasm's (excluding history of treated skin cancer of the type basal cell carcinoma BCC or squamous cell carcinoma SCC)
* Severe general diseases or mental disorders making the participation in the study impossible
* Drug abuse
* Female patients during pregnancy and lactation period and female patients with active menses during the past year
* Hypersensitivity to benfotiamine
* HbA1c \> 9.5%
* Use of thiamine containing supplements during the last 3 months
* Participation in another study within one month before joining the benfotiamine study

Primary outcomes:
measure: Change in urinary excretion of: - Kidney injury molecule-1 (KIM-1) - Albumin
timeFrame: 12 weeks
Secondary outcomes:
measure: Change in urinary excretion of: β2 microglobulin, macrophage inhibiting factor (MIF), monocyte chemo-attractant protein-1 (MCP-1), and other advanced glycation end-products (AGEs).
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Zwolle
country: Netherlands
facility: Isala Klinieken Hospital
Study officials:
affiliation: University Medical Center Groningen
name: G J Navis, MD, PhD
role: STUDY_DIRECTOR
affiliation: Isala
name: H JG Bilo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9. doi: 10.1038/nm834. Epub 2003 Feb 18.
citation: Bakker SJ, Heine RJ, Gans RO. Thiamine may indirectly act as an antioxidant. Diabetologia. 1997 Jun;40(6):741-2. No abstract available.
citation: Thornalley PJ, Babaei-Jadidi R, Al Ali H, Rabbani N, Antonysunil A, Larkin J, Ahmed A, Rayman G, Bodmer CW. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia. 2007 Oct;50(10):2164-70. doi: 10.1007/s00125-007-0771-4. Epub 2007 Aug 4.
citation: Alkhalaf A, Kleefstra N, Groenier KH, Bilo HJ, Gans RO, Heeringa P, Scheijen JL, Schalkwijk CG, Navis GJ, Bakker SJ. Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy. PLoS One. 2012;7(7):e40427. doi: 10.1371/journal.pone.0040427. Epub 2012 Jul 6.
citation: Alkhalaf A, Klooster A, van Oeveren W, Achenbach U, Kleefstra N, Slingerland RJ, Mijnhout GS, Bilo HJ, Gans RO, Navis GJ, Bakker SJ. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care. 2010 Jul;33(7):1598-601. doi: 10.2337/dc09-2241. Epub 2010 Apr 22.