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

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

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.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency, Chronic
• Intervention / Treatment: Drug: Ketosteril®

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia, 140 59
    • Thomayer Hospital Clinical - Pharmacology Unit (CPU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent
2. Non-dialysed male and female CKD patients with expected start of dialysis ≥ 3 months
3. eGFR ≥5 to < 30 ml/min/1.73 m2
4. Stable renal function at least 12 weeks before enrollment, defined by change in serum creatinine ≤ 80 µmol/L
5. Body mass index (BMI): ≥ 22 kg/m² and ≤ 35 kg/m2
6. Age: ≥ 40 to ≤ 75 years
7. 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:

1. 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)
2. Active cancer
3. Diabetes treated with standard pharmacotherapy
4. HbA1c ≥ 48 mmol/mol, and/or fasting blood glucose ≥ 126 mg/dl (≥ 7 mmol/L))
5. Evidence of chronic infection or chronic inflammation; evidence of acute infection or acute inflammation
6. C-reactive protein (CRP) > 20 mg/L determined at screening examination
7. Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparation
8. Severe allergies or multiple drug allergies if judged as relevant for the clinical trial by the investigator
9. Patients suffering from hypercalcaemia with a serum calcium ≥ 2.9 mmol/L performed on screening examination
10. Major disorder of amino acid metabolism, e.g. hereditary diseases
11. Hospitalization within the previous 1 month
12. Proteinuria > 3 g/day
13. Regular intensive exercise
14. Ingestion of creatine supplements within the previous 1 month
15. Intake of other anabolic or anti catabolic agents within the previous 1 month
16. Any change of the chronic medication within 1 month before screening
17. Autosomal dominant polycystic kidney disease (ADPKD)
18. 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
19. Current drug or alcohol dependence
20. 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
21. Participation in an interventional clinical trial during the last 2 months prior to individual enrolment of the patient
22. Patients who report a frequent occurrence of migraine attacks (i.e. at least once per month)
23. History of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders
24. 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)
25. Positive pregnancy test at screening examination
26. Pregnant or lactating women
27. 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]
28. Patients suspected or known not to follow instructions
29. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Low protein diet; 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; 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®; 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.; Other Names: EV product code: PRD1170237

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fresenius Kabi
• Collaborators: EastHORN Clinical Services in CEE; MLM Medical Labs GmbH; ALS Czech Republic, s.r.o.; PCG Clinical Services AB

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2017
• Primary Completion (Actual): April 27, 2018
• Study Completion (Actual): May 2, 2018

Study Registration Dates

• First Submitted: March 1, 2017
• First Submitted That Met QC Criteria: March 6, 2017
• First Posted (Actual): March 10, 2017

Study Record Updates

• Last Update Posted (Actual): May 14, 2018
• Last Update Submitted That Met QC Criteria: May 11, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: CKD; Chronic kidney disease; Ketosteril; keto-acids; ketoanalogues
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Renal Insufficiency
• Other Study ID Numbers: Keto-022-CP1; 2016-003854-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No