Short-term Metabolic Effects of Ketosteril® Supplemented Low Protein Diet in Pre-dialysis Chronic Kidney Disease (CKD) Patients

Study Overview
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Brief Summary
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Supplementation of ketoanalogues of essential amino acids improves the protein quality of protein restricted diets without burdening the kidneys. The ketoanalogues are transaminated by aminotransferases to the corresponding amino acids by incorporating nitrogen from amino groups derived from endogenous amino acid degradation. Therefore, less nitrogen needs to be excreted and the kidney's workload is reduced. The purpose of the trial is to investigate the impact of Ketosteril® supplementation on A) nutritional safety and tolerance of a low protein diet (LPD) (0.6 g protein/kg bodyweight (BW)/day)and B) net protein synthesis in pre-dialysis CKD patients. Changes of urea in serum and urine will be assessed under controlled metabolic balance conditions in non-dialysed CKD patients consuming a LPD supplemented with Ketosteril® at 1 tablet/5 kg body weight/day compared to the same, isonitrogenous and isocaloric diet without Ketosteril®. Changes in protein synthesis and degradation at the defined protein intake with or without Ketosteril® supplementation will be investigated - based on nitrogen balance, normalized protein catabolic rates as well as blood levels of defined proteins as surrogate markers for net protein synthesis and anabolic signaling.

Official Title
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Short-term Metabolic Effects of Ketosteril® Supplemented Low Protein Diet in Pre-dialysis CKD Patients - A Randomized, Controlled, Open-labelled Clinical Trial

Conditions
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Renal Insufficiency, Chronic

Intervention / Treatment
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* Drug: Ketosteril®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Non-dialysed male and female CKD patients with expected start of dialysis ≥ 3 months eGFR ≥5 to < 30 ml/min/1.73 m2 Stable renal function at least 12 weeks before enrollment, defined by change in serum creatinine ≤ 80 µmol/L Body mass index (BMI): ≥ 22 kg/m² and ≤ 35 kg/m2 Age: ≥ 40 to ≤ 75 years Eligible physical status of the patient for participation in the study upon assessment of the investigator based on medical history, physical examination and clinical laboratory parameters Exclusion Criteria: Existing gastrointestinal diseases or pathological findings (e.g. heart, liver, or lung failure), which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient (e.g. persistent or frequent episodes of anorexia, vomiting, or diarrhea) Active cancer Diabetes treated with standard pharmacotherapy HbA1c ≥ 48 mmol/mol, and/or fasting blood glucose ≥ 126 mg/dl (≥ 7 mmol/L)) Evidence of chronic infection or chronic inflammation; evidence of acute infection or acute inflammation C-reactive protein (CRP) > 20 mg/L determined at screening examination Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparation Severe allergies or multiple drug allergies if judged as relevant for the clinical trial by the investigator Patients suffering from hypercalcaemia with a serum calcium ≥ 2.9 mmol/L performed on screening examination Major disorder of amino acid metabolism, e.g. hereditary diseases Hospitalization within the previous 1 month Proteinuria > 3 g/day Regular intensive exercise Ingestion of creatine supplements within the previous 1 month Intake of other anabolic or anti catabolic agents within the previous 1 month Any change of the chronic medication within 1 month before screening Autosomal dominant polycystic kidney disease (ADPKD) Positive anti-HIV-test (if positive to be verified by western blot), Hepatitis B surface antigen (HBsAG)-test (if positive to be verified by test for hepatitis B core antigen (HBc)- Immunoglobulin M (IgM)) or anti-hepatitis C virus (HCV)-test Current drug or alcohol dependence Blood donation (including donation of plasma and platelets) or other blood loss of more than 400 ml within the last 2 months prior to individual enrolment of the patient Participation in an interventional clinical trial during the last 2 months prior to individual enrolment of the patient Patients who report a frequent occurrence of migraine attacks (i.e. at least once per month) History of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders Change in habits of physical activity within the last 2 months for at least 7 days (e.g. immobilisation due to bed rest, immobilisation of a leg or other big muscle groups) Positive pregnancy test at screening examination Pregnant or lactating women Not willing to apply highly effective contraceptive methods [i.e. combined (estrogen and progestogen containing) hormonal contraception e.g. oral, intravaginal, transdermal and progestogen-only hormonal contraception e.g. oral, injectable, implantable as well as intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) in combination with male condom; bilateral tubal occlusion, vasectomised partner or sexual abstinence] Patients suspected or known not to follow instructions Patients who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Low protein diet<br>Low protein diet with 0.6 g protein/kg BW/day (20-30% high biological value) and an energy intake of 30-35 kcal/kg BW/day | |
| Experimental: Supplemented low protein diet<br>Ketosteril® supplemented low protein diet (sLPD), (1 tablet/5 kg BW/day) with 0.6 g protein/kg BW/day (20-30% high biological value) and an energy intake of 30-35 kcal/kg BW/day | Drug: Ketosteril®<br>* Patients will be randomised to receive isonitrogenous and isocaloric LPD providing 0.6 g protein/kg BW/day and an energy intake of 30-35 kcal/kg BW/day with (test group) or without (control group) intake of Ketosteril® (1 tablet/5 kg BW/day). The control group will get additional food protein to balance the nitrogen content of Ketosteril® The mainly vegetarian diet will be maintained for 10 days.<br>* Other names: EV product code: PRD1170237;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of Ketosteril® on the generation of nitrogenous waste products | Serum urea | 10 days | 
| Impact of Ketosteril® on the generation of nitrogenous waste products | Urine urea | 10 days | 
| Impact of Ketosteril® on the generation of nitrogenous waste products | Nitrogen balance | 10 days | 
| Impact of Ketosteril® on the generation of nitrogenous waste products | Normalized protein catabolic rate (nPCR) | 10 days | 
| Protein metabolism | Serum total proteins | 10 days | 
| Protein metabolism | Albumin | 10 days | 
| Protein metabolism | Transthyretin | 10 days | 
| Protein metabolism | Transferrin | 10 days | 
| Markers of anabolic signaling | Serum Insulin-like growth factor (IGF)-I | 10 days | 
| Markers of anabolic signaling | Insulin like growth factor (IGF)-II | 10 days | 
| Markers of anabolic signaling | IGF-binding protein 3 | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal function | Proteinuria | 10 days | 
| Renal function | Albuminuria | 10 days | 
| Renal function | Serum and urine creatinine | 10 days | 
| Renal function | Serum and urine urea | 10 days | 
| Renal function | Serum urea nitrogen (SUN) | 10 days | 
| Renal function | Urine nitrogen | 10 days | 
| Renal function | Glomerular filtration rate estimated from serum creatinine (eGFR) | 10 days | 
| Renal function | Albumin-creatinine ratio | 10 days | 
| Renal function | Urea clearance | 10 days | 
| Nutritional status | Body weight | 10 days | 
| Nutritional status | Body Mass Index (BMI) | 10 days | 
| Nutritional status | Body composition (via Bio Impedance Spectroscopy) | 10 days | 
| Nutritional status | SUN-to-creatinine ratio | 10 days | 
| Glucose metabolism | Fasting blood glucose | 10 days | 
| Lipid profile | Triglycerides | 10 days | 
| Lipid profile | Cholesterol | 10 days | 
| Lipid profile | High-density lipoprotein (HDL)/Low-density lipoprotein (LDL)-cholesterol | 10 days | 
| Mineral status | Sodium | 10 days | 
| Mineral status | Calcium | 10 days | 
| Mineral status | Potassium | 10 days | 
| Mineral status | Magnesium | 10 days | 
| Mineral status | Phosphate (serum and urine) | 10 days | 
| Mineral status | Alkaline phosphatase | 10 days | 
| Mineral status | Fibroblast growth factor (FGF)-23 | 10 days | 
| Mineral status | 25-hydroxycholecalciferol (serum) | 10 days | 
| Acid-base balance | Serum bicarbonate | 10 days | 
| Acid-base balance | Arterialized venous blood potential of hydrogen (pH) | 10 days | 
| Acid-base balance | Urine pH | 10 days | 
| Inflammation | Serum C-reactive protein (CRP) | 10 days | 
| Inflammation | Serum albumin/CRP ratio | 10 days | 
| Hematology | Hematocrit | 10 days | 
| Hematology | Hemoglobin | 10 days | 
| Hematology | Red blood cell (RBC) count | 10 days | 
| Hematology | White blood cell (WBC) count total | 10 days | 
| Hematology | WBC count differential (lymphocytes, basophils, monocytes, neutrophils, eosinophils) | 10 days | 
| Hematology | Platelet count | 10 days | 
| Hematology | Mean corpuscular hemoglobin (MCH) | 10 days | 
| Hematology | Mean corpuscular hemoglobin concentration (MCHC) | 10 days | 
| Hematology | Mean corpuscular volume (MCV) | 10 days | 
| Coagulation | Prothrombin time (Quick) | 10 days | 
| Coagulation | Activated partial thromboplastin time (APTT) | 10 days | 
| Coagulation | International normalized ratio (INR) | 10 days | 
| Serum chemistry | Glutamate oxaloacetate transaminase (GOT)/Aspartate aminotransferase (AST) | 10 days | 
| Serum chemistry | Glutamate-pyruvate transaminase (GPT)/Alanine transaminase (ALT) | 10 days | 
| Serum chemistry | Uric acid | 10 days | 
| Serum chemistry | Creatine kinase (CK) | 10 days | 
| Serum chemistry | Troponin T if CK is elevated | 10 days | 
| Serum chemistry | Chloride | 10 days | 
| Adverse Events | Adverse Events | 52 days | 
| Vital signs | Systolic and diastolic blood pressure | 10 days | 
| Vital signs | Pulse rate | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketosteril, keto-acids, ketoanalogues, Chronic kidney disease, CKD