Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome

Study Overview
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Brief Summary
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The goal of this non-commercial clinical trial is to assess efficacy and safety of ketoanalogues of essential amino acids in the prevention of protein-energy wasting in nephrotic syndrome.

Detailed Description
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Adult patients with new diagnosis or relapse of nephrotic syndrome and glomerular filtration rate of ≥ 30 mL/min/1.73m2 will be included in the study. Exclusion criteria will be a secondary cause of nephrotic syndrome, morbid obesity and severe diseases affecting nutritional status. Participants will be randomly assigned to the intervention group (KA+MPD) or control group (MPD); randomization will be stratified by type of glomerular disease (podocytopathy or other type) and investigational site. The control group will follow the diet recommended in nephrotic syndrome - a medium protein diet (MPD) - under the care of a dietitian. Intervention group will receive Ketosteril (1 tablet for every 5 kg of ideal body weight) as an addition to the diet. All patients will also receive treatment for underlying glomerular disease in accordance with current guidelines and local practice. The main objective is to assess the efficacy of Ketosteril as an add-on therapy in preventing the loss of lean tissue mass (LTM) over 6 months compared to a standard diet. The additional aims include the assessment of muscle function parameters, nephrotic syndrome severity and laboratory indicators of catabolism.

Official Title
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FORMA - a Multicenter Randomized-controlled Trial to Evaluate the Efficacy and Safety of Ketoanalogues of Essential Amino Acids in Prophylaxis of Protein-energy Wasting in Nephrotic Syndrome

Conditions
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Nephrotic Syndrome

Intervention / Treatment
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* Drug: Ketosteril
* Other: Medium Protein Diet (MPD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nephrotic syndrome with serum albumin < 3.0 g/dL and daily proteinuria of > 3.5 g/day or > 50 mg/kg; New diagnosis or relapse of nephrotic syndrome (defined as: proteinuria of < 2.0 g/day or uPCR < 2000 mg/g in the last 6 months prior to relapse and prednison dose equal to or less than 10 mg/day in the last 3 months prior relapse); Glomerular filtration rate qual to or higher than 30 mL/min/1.73m2 based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Exclusion Criteria: Diabetic kidney disease; Small vessels vasculitis; Systemic lupus erythematosus; Positive antinuclear antibodies, anti-dsDNA or antineutrophil cytoplasmic antibodies (ANCA); Positive anti-HIV or anti-hepatitis C antibodies, HBsAg; HbA1c >7%; Monoclonal gammopathy; Pregnancy; Body mass index >= 40 kg/m2; Severe acute or chronic disease affecting nutritional status; Neoplasm; Contraindication to Ketosteril; Alcohol or drug abuse; Mental disorders; Failure to comply with medical recommendations, lack of cooperation; Participation in other clinical trial or the use of Ketosteril in the last 1 year prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization in 1:1 ratio with stratification by the type of glomerular disease (podocytopathy versus other type) and investigational site
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KA+MPD<br>Ketosteril + Medium Protein Diet (MPD) for 12 months | Drug: Ketosteril<br>* Daily dose = 1 tabl / 5 kg of ideal body weight<br>Other: Medium Protein Diet (MPD)<br>* MPD: daily protein intake of 0.8-1.0 g/kg of ideal body weight + up to 5 g based on daily proteinuria<br>|
| Active Comparator: MPD<br>Medium Protein Diet (MPD) for 12 months | Other: Medium Protein Diet (MPD)<br>* MPD: daily protein intake of 0.8-1.0 g/kg of ideal body weight + up to 5 g based on daily proteinuria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum loss of lean tissue mass | The difference between the initial lean tissue mass (LTM) and the lowest LTM measured within 6 months, expressed in percentage. The non-inferiority hypothesis of Ketosteril use will be tested as the primary endpoint. LTM will be measured with bioimpedance spectroscopy. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum loss of lean tissue mass | The difference between the initial lean tissue mass (LTM) and the lowest LTM measured within 6 months, expressed in percentage. The superiority hypothesis of Ketosteril use will be tested as the secondary endpoint. | 6 months | 
| Neph-PEW diagnosis | The percentage of patients meeting criteria of nephrotic syndrome-associated protein-energy wasting (neph-PEW): reduction of LTM by 3% within 3 months or by 5% within 6 months. | 6 months | 
| 6-minute walk test distance | Change in distance walked in the 6-minute walk test from baseline value; expressed in meters. | 6 months | 
| Handgrip strength (HGS) | Change in HGS value from baseline; expressed in kg. | 6 months | 
| Serum albumin | Change in serum albumin level from baseline value; expressed in g/dL. | 6 months | 
| Urinary protein/creatinine ratio (uPCR) | Change in uPCR value from baseline; expressed in mg/g. | 6 months | 
| Low density lipoprotein (LDL) | Change in serum LDL level from baseline; expressed in mg/dL. | 6 months | 
| Triglycerides | Change in serum triglycerides level from baseline; expressed in mg/dL. | 6 months | 
| Uric acid | Change in serum uric acid level from baseline; expressed in mg/dL. | 6 months | 
| Unfavorable disease course | The percentage of patients who experienced the unfavorable disease course including: glomerular disease related death; venous or arterial thromboembolic event; infection requiring hospital admission; acute kidney injury in the stage 2 or 3; sustained glomerular filtration rate reduction over 50% or initiation of kidney replacement therapy; unplanned hospital admission due to complications of nephrotic syndrome treatment. | 12 months | 
| Glomerular filtration rate | Change in glomerular filtration rate from baseline; expressed in mL/min/1.73m2. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neph-PEW, nephrotic syndrome, protein-energy wasting, lean tissue mass, Ketosteril, ketoanalogues