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

• ClinicalTrials.gov Identifier: NCT03077048
• Recruitment Status: Completed
• First Posted: March 10, 2017
• Last Update Posted: May 14, 2018
• Sponsor: Fresenius Kabi
• Collaborators: EastHORN Clinical Services in CEE; MLM Medical Labs GmbH; ALS Czech Republic, s.r.o.; PCG Clinical Services AB
• Information provided by (Responsible Party): Fresenius Kabi

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Renal Insufficiency, Chronic	Drug: Ketosteril®	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Short-term Metabolic Effects of Ketosteril® Supplemented Low Protein Diet in Pre-dialysis CKD Patients - A Randomized, Controlled, Open-labelled Clinical Trial
• Actual Study Start Date: March 30, 2017
• Actual Primary Completion Date: April 27, 2018
• Actual Study Completion Date: May 2, 2018

Arms and Interventions

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 Name: EV product code: PRD1170237

Outcome Measures

Primary Outcome Measures :

1. Impact of Ketosteril® on the generation of nitrogenous waste products [ Time Frame: 10 days ]
   Serum urea
2. Impact of Ketosteril® on the generation of nitrogenous waste products [ Time Frame: 10 days ]
   Urine urea
3. Impact of Ketosteril® on the generation of nitrogenous waste products [ Time Frame: 10 days ]
   Nitrogen balance
4. Impact of Ketosteril® on the generation of nitrogenous waste products [ Time Frame: 10 days ]
   Normalized protein catabolic rate (nPCR)
5. Protein metabolism [ Time Frame: 10 days ]
   Serum total proteins
6. Protein metabolism [ Time Frame: 10 days ]
   Albumin
7. Protein metabolism [ Time Frame: 10 days ]
   Transthyretin
8. Protein metabolism [ Time Frame: 10 days ]
   Transferrin
9. Markers of anabolic signaling [ Time Frame: 10 days ]
   Serum Insulin-like growth factor (IGF)-I
10. Markers of anabolic signaling [ Time Frame: 10 days ]
    Insulin like growth factor (IGF)-II
11. Markers of anabolic signaling [ Time Frame: 10 days ]
    IGF-binding protein 3

Secondary Outcome Measures :

1. Renal function [ Time Frame: 10 days ]
   Proteinuria
2. Renal function [ Time Frame: 10 days ]
   Albuminuria
3. Renal function [ Time Frame: 10 days ]
   Serum and urine creatinine
4. Renal function [ Time Frame: 10 days ]
   Serum and urine urea
5. Renal function [ Time Frame: 10 days ]
   Serum urea nitrogen (SUN)
6. Renal function [ Time Frame: 10 days ]
   Urine nitrogen
7. Renal function [ Time Frame: 10 days ]
   Glomerular filtration rate estimated from serum creatinine (eGFR)
8. Renal function [ Time Frame: 10 days ]
   Albumin-creatinine ratio
9. Renal function [ Time Frame: 10 days ]
   Urea clearance
10. Nutritional status [ Time Frame: 10 days ]
    Body weight
11. Nutritional status [ Time Frame: 10 days ]
    Body Mass Index (BMI)
12. Nutritional status [ Time Frame: 10 days ]
    Body composition (via Bio Impedance Spectroscopy)
13. Nutritional status [ Time Frame: 10 days ]
    SUN-to-creatinine ratio
14. Glucose metabolism [ Time Frame: 10 days ]
    Fasting blood glucose
15. Lipid profile [ Time Frame: 10 days ]
    Triglycerides
16. Lipid profile [ Time Frame: 10 days ]
    Cholesterol
17. Lipid profile [ Time Frame: 10 days ]
    High-density lipoprotein (HDL)/Low-density lipoprotein (LDL)-cholesterol
18. Mineral status [ Time Frame: 10 days ]
    Sodium
19. Mineral status [ Time Frame: 10 days ]
    Calcium
20. Mineral status [ Time Frame: 10 days ]
    Potassium
21. Mineral status [ Time Frame: 10 days ]
    Magnesium
22. Mineral status [ Time Frame: 10 days ]
    Phosphate (serum and urine)
23. Mineral status [ Time Frame: 10 days ]
    Alkaline phosphatase
24. Mineral status [ Time Frame: 10 days ]
    Fibroblast growth factor (FGF)-23
25. Mineral status [ Time Frame: 10 days ]
    25-hydroxycholecalciferol (serum)
26. Acid-base balance [ Time Frame: 10 days ]
    Serum bicarbonate
27. Acid-base balance [ Time Frame: 10 days ]
    Arterialized venous blood potential of hydrogen (pH)
28. Acid-base balance [ Time Frame: 10 days ]
    Urine pH
29. Inflammation [ Time Frame: 10 days ]
    Serum C-reactive protein (CRP)
30. Inflammation [ Time Frame: 10 days ]
    Serum albumin/CRP ratio
31. Hematology [ Time Frame: 10 days ]
    Hematocrit
32. Hematology [ Time Frame: 10 days ]
    Hemoglobin
33. Hematology [ Time Frame: 10 days ]
    Red blood cell (RBC) count
34. Hematology [ Time Frame: 10 days ]
    White blood cell (WBC) count total
35. Hematology [ Time Frame: 10 days ]
    WBC count differential (lymphocytes, basophils, monocytes, neutrophils, eosinophils)
36. Hematology [ Time Frame: 10 days ]
    Platelet count
37. Hematology [ Time Frame: 10 days ]
    Mean corpuscular hemoglobin (MCH)
38. Hematology [ Time Frame: 10 days ]
    Mean corpuscular hemoglobin concentration (MCHC)
39. Hematology [ Time Frame: 10 days ]
    Mean corpuscular volume (MCV)
40. Coagulation [ Time Frame: 10 days ]
    Prothrombin time (Quick)
41. Coagulation [ Time Frame: 10 days ]
    Activated partial thromboplastin time (APTT)
42. Coagulation [ Time Frame: 10 days ]
    International normalized ratio (INR)
43. Serum chemistry [ Time Frame: 10 days ]
    Glutamate oxaloacetate transaminase (GOT)/Aspartate aminotransferase (AST)
44. Serum chemistry [ Time Frame: 10 days ]
    Glutamate-pyruvate transaminase (GPT)/Alanine transaminase (ALT)
45. Serum chemistry [ Time Frame: 10 days ]
    Uric acid
46. Serum chemistry [ Time Frame: 10 days ]
    Creatine kinase (CK)
47. Serum chemistry [ Time Frame: 10 days ]
    Troponin T if CK is elevated
48. Serum chemistry [ Time Frame: 10 days ]
    Chloride
49. Adverse Events [ Time Frame: 52 days ]
    Adverse Events
50. Vital signs [ Time Frame: 10 days ]
    Systolic and diastolic blood pressure
51. Vital signs [ Time Frame: 10 days ]
    Pulse rate

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Czechia

Thomayer Hospital Clinical - Pharmacology Unit (CPU)

Prague, Czechia, 140 59

Sponsors and Collaborators

Fresenius Kabi

EastHORN Clinical Services in CEE

MLM Medical Labs GmbH

ALS Czech Republic, s.r.o.

PCG Clinical Services AB

Investigators

• Study Chair: John F Stover, M.D.; Fresenius Kabi

More Information

• Responsible Party: Fresenius Kabi
• ClinicalTrials.gov Identifier: NCT03077048
• Other Study ID Numbers: Keto-022-CP1; 2016-003854-34 ( EudraCT Number )
• First Posted: March 10, 2017
• Last Update Posted: May 14, 2018
• Last Verified: May 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fresenius Kabi:

CKD; Ketosteril; keto-acids; ketoanalogues; Chronic kidney disease

Additional relevant MeSH terms:

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases