Mycophenolate Mofetil, Carnitine and PDE5 Inhibitor, Three Potential Treatments for Resistant Proteinuria Slowing Diabetic Nephropathy Deterioration (Myridian)

Study Description

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Brief Summary:

Diabetes mellitus (DM) is a growing disease and it is a public health concern, and projections of its future effect are alarming. About one third of those affected will develop diabetic nephropathy at 20 years after diagnosis. Of these patients, 20% will develop clinically end-stage renal disease ESRD, requiring renal replacement therapy (RRT). Patients with type 2 diabetes account for most patients with end stage renal disease (ESRD) and RRT.

To the best of the investigators knowledge, the effects of MMF on diabetic nephropathy in patients with DM type II were not studied so far. Therefore, the purpose of this pilot study is to evaluate the effects of Mofetil Mycophenolate (MMF) on proteinuria and progression of kidney disease of diabetic origin, in patients at high risk for progressive renal failure in whom other treatment modalities are insufficient or had failed.

Condition or disease	Intervention/treatment	Phase
Diabetic Nephropathy; Chronic Kidney Disease	Drug: Mycophenolate Mofetil (MMF) ,phosphodiesterase 5 inhibitors , CARNITINE	Not Applicable

Detailed Description:

The pathophysiology of the diabetic nephropathy was initially considered to be merely secondary to a non-immune mechanism, specifically due to metabolic (hyperglycemia) and hemodynamic (glomerular capillary hypertension - mechanical stretching) factors. However, our understanding of the pathophysiological processes that lead to diabetic nephropathy and its progression is now clearer and involved not only a non immune mechanism, but also immune-mediated and inflammatory mechanism. Activation of the immune system, with the participation of a chronic inflammatory state, plays a central role in the pathogenesis of diabetic nephropathy. Evidence for the involvement of the immune system in the pathogenesis of diabetic nephropathy was derived from the elevated levels of proinflammatory cytokines such as IL-1, IL-6, IL-18, and TNF-α. These factors are important predictors of the development of diabetic nephropathy, and recently it was shown that these inflammatory cytokines play a determinant role in the development and progression of the microvascular diabetic nephropathy. The first published study that showed the implication of the inflammatory cytokines in the pathogenesis of the diabetic nephropathy was in 1991. Mycophenolate Mofetil (MMF) is an immunosuppressant drug, used to prevent rejection, especially acute rejection in various organ transplantations, mainly kidney transplantation since 1995. In the last decade there are increasing reports describing the beneficial use of MMF in immune- mediated and auto-immune disorders such as Systemic Lupus Erythematosus, IGA nephropathy and other glomerulopathies.

Unfortunately, the potentially beneficial effects of MMF on diabetic nephropathy were not examined in clinical DM and is limited to diabetic rats. In a recent study, Utimura et al. have demonstrated that MMF largely prevented the development of albuminuria and glomerular injury in experimental diabetic nephropathy. The beneficial effect of MMF was not related to its action on glomerular hemodynamic or improvement of metabolic control, but probably related directly to its immunosuppressive and anti-inflammatory properties.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Mycophenolate Mofetil (MMF) ,Carnitine and Phosphodiesterase Type 5 Inhibitor, Three Potential Treatments for Resistant Proteinuria and for Slowing the Deterioration of Diabetic Nephropathy in Patients With Type II Diabetes Mellitus
Study Start Date :	April 2012
Estimated Primary Completion Date :	June 2013
Estimated Study Completion Date :	August 2013

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
No Intervention: control group; group receiving the conventional treatment for DN	Drug: Mycophenolate Mofetil (MMF) ,phosphodiesterase 5 inhibitors , CARNITINE; effect of MMF on diabetic nephropathy patients by evaluating its effect on proteinuria and progression of kidney disease of diabetic origin
Experimental: cellcept group; additional to the conventional treatment patients will receive cellcept	Drug: Mycophenolate Mofetil (MMF) ,phosphodiesterase 5 inhibitors , CARNITINE; effect of MMF on diabetic nephropathy patients by evaluating its effect on proteinuria and progression of kidney disease of diabetic origin
Experimental: carnitine group; aside to the conventional treatment patients will receive carnitine	Drug: Mycophenolate Mofetil (MMF) ,phosphodiesterase 5 inhibitors , CARNITINE; effect of MMF on diabetic nephropathy patients by evaluating its effect on proteinuria and progression of kidney disease of diabetic origin
Experimental: PDE5 group; aside to the conventional treatment patients will receive PDE5 inhibitor	Drug: Mycophenolate Mofetil (MMF) ,phosphodiesterase 5 inhibitors , CARNITINE; effect of MMF on diabetic nephropathy patients by evaluating its effect on proteinuria and progression of kidney disease of diabetic origin

Outcome Measures

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Primary Outcome Measures :

1. proteinuria [ Time Frame: before beginging of the treatment - baseline, after 1,2,3,4 weeks, after 1,2,3,4,5,6,7,8,9,10,11,12 months of the beginning of the treatment ]
   16 time points over 1 year.

Eligibility Criteria

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Ages Eligible for Study:	30 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. T2 DM at age ≥18 y with at least 10 years duration of diabetes.
2. Proteinuria due to diabetic nephropathy of ≥ 2 gram/d treated with ACEi or ARBs at maximal tolerated dose or both of them.
3. CKD grade 1-3
4. Diabetic retinopathy (discuss with Zaid)

Exclusion Criteria:

1. Proteinuria of non diabetic origin
2. Overlap Proteinuria with diabetic nephropathy
3. Other intercurrent illness (fever due to infection ….) that can interfere with the urine protein secretion.
4. Acute Kidney Injury.
5. CKD stage 4-5.
6. New renoprotective treatment in the last 6 months before enrollment.
7. Changes in dosage of one of the renoprotective drugs in the last 6 months before enrollment.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: najla hamati	04-6028888	nana@nazhosp.com

Locations

Israel
Nazareth hospital (EMMS)	Not yet recruiting
Nazareth, Israel
Contact: Zaher Armaly, MD zaherarmaly@nazhosp.com

Sponsors and Collaborators

The Nazareth Hospital, Israel

Western Galilee Hospital-Nahariya

Investigators

Principal Investigator:	Zaher Armaly, MD	Nazareth Hospital (E.M.M.S)

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	The Nazareth Hospital, Zaher armaly , M.D, Head of Nephrology Department, The Nazareth Hospital, Israel, The Nazareth Hospital, Israel
ClinicalTrials.gov Identifier:	NCT01566006 History of Changes
Other Study ID Numbers:	nazh8827ctil
First Posted:	March 29, 2012
Last Update Posted:	March 29, 2012
Last Verified:	March 2012

Keywords provided by The Nazareth Hospital, The Nazareth Hospital, Israel:

Mycophenolate mofetil (MMF); Diabetic Nephropathy; proteinuria; Diabetic Nephropathy in Chronic Kidney Disease patients stages 2-4

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Diabetic Nephropathies; Proteinuria; Urologic Diseases; Renal Insufficiency; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Urination Disorders; Urological Manifestations; Signs and Symptoms	Mycophenolic Acid; Phosphodiesterase 5 Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Phosphodiesterase Inhibitors