Clinical trial NCT03415074: Could Ketoanalogue-supplemented Low Protein Diet Defer Dialysis in Advanced Diabetic Kidney Disease? (K-DDD)
Official title: Ketoanalogue-supplemented Low Protein Diet and Deferring Dialysis in Patients With Severe Proteinuria and Advanced Diabetic Kidney Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: CKD Stage 4
Keywords: low protein diet
Diabetic Kidney Disease
Lead sponsor: Anemia Working Group Romania
Sponsor class: OTHER
First posted: 2018-01-30
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible patients will enter a run-in phase (3 mo), when mild protein diet (0.8g/kg dry ideal bw) will be initiated and compliance will be evaluated twice monthly.

Those who will prove compliant during the run-in phase and still fulfill the selection criteria will be randomized 1:1 (computer-generated numbers) to receive the low protein diet (0.6 g/kg-day, mainly vegetarian) supplemented with ketoanalogues of essential amino-acids (Ketosteril 1 tb/10 kg dry bw) or to continue the mild protein restriction (0.8 g/kg-day).
Primary purpose: PREVENTION

Brief summary: This is a prospective single center open label randomized controlled trial aiming to assess the effectiveness and safety of a low protein diet (0.6 g/kg-day, mainly vegetarian) supplemented with ketoanalogues of essential amino-acids (sLPD) as compared to a mild protein restriction (0.8 g/kg-day, MPD) in reducing Chronic Kidney Disease (CKD) progression, with a planned total duration is of 18 months.

Adult diabetic patients with CKD stage 4+ \[estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease 4-variable (MDRD4) formula \<30 mL/min per year\], with stable renal function (historical reduction of eGFR of \< 10 ml/min-year) , proteinuria \> 3g/g creatininuria and good nutritional status (SGA A) will be enrolled.

Detailed description: Adult diabetic patients with Chronic Kidney Disease (CKD) stage 4+ (estimated GFR using the Modification of Diet in Renal Disease 4-variable, MDRD4, formula \<30 mL/min per year), with stable renal function (historical reduction of eGFR of \< 10 ml/min-year), proteinuria \> 3g/g creatininuria and good nutritional status (SGA A) will be enrolled. Patients with evidence of active kidney disease (except proteinuria), with indication of etiological or pathogenic treatment, those with poor control of diabetes (HbA1c \>8%), those with uncontrolled high blood pressure (≥155/85 mmHg), those with significant co-morbidities (heart failure, active liver disease, malabsorption, active infections, inflammatory diseases requiring corticosteroids), those with uremic symptoms (pericarditis, digestive disorders ) or malnutrition (SGA B or C, serum albumin \< 3.5 g/dl) will be excluded.

Eligible patients will enter a run-in phase (3 mo), when mild protein restriction (0.8g/kg dry ideal bw) will be initiated and compliance will be evaluated twice monthly.

Those who will prove compliant during the run-in phase and still fulfill the selection criteria will be randomized 1:1 (computer-generated numbers) to receive the low protein diet (0.6 g/kg-day, mainly vegetarian) supplemented with ketoanalogues of essential amino-acids (Ketosteril 1 tb/10 kg dry bw) or to continue the mild protein restriction (0.8 g/kg-day).

The total recommended energy intake is of 30 kcal/kg of ideal dry body weight per day in all patients.

The primary composite endpoint is the need for RRT initiation or a more than 50% reduction in the initial eGFR any time during the assessment phase. The decision to initiate RRT will be made by the Ethical Committee of the Hospital, based on the clinical and laboratory data.

The need for RRT initiation, the quality of life \[assessed by the Short Form-36 (SF-36) Questionnaire\], the decline in GFR and the correction of metabolic complications of CKD \[serum levels of urea, calcium, phosphates, serum parathyroid hormone levels, bicarbonate, potassium\] will be secondary efficacy parameters.

Parameters of nutritional status (SGA, anthropometric and biochemical parameters), compliance to the diet, occurrence of any adverse event and the number of withdrawals will be safety variables.

All the parameters will be assessed at baseline, throughout the intervention phase and at end of the study.

Eligibility criteria: Inclusion Criteria:

* diabetic patients
* CKD stage 4+ (estimated GFR using the Modification of Diet in Renal Disease 4-variable, MDRD4, formula \<30 mL/min per year)
* stable renal function (historical reduction of eGFR of \< 10 ml/min-year)
* proteinuria \> 3g/g creatininuria
* good nutritional status (SGA A)

Exclusion Criteria:

* evidence of active kidney disease (except proteinuria)
* indication for etiological or pathogenic treatment
* poor control of diabetes (HbA1c \>8%)
* uncontrolled high blood pressure (≥155/85 mmHg)
* significant co-morbidities (heart failure, active liver disease, malabsorption, active infections, inflammatory diseases requiring corticosteroids)
* uremic symptoms (pericarditis, digestive disorders
* or malnutrition (SGA B or C, serum albumin \< 3.5 g/dl)

Primary outcomes:
measure: CKD progression
timeFrame: 15 months
Secondary outcomes:
measure: Need for renal replacement therapy (RRT)
timeFrame: 15 months
measure: Patients' Quality of life
timeFrame: at baseline and than every 3 months up to 15 months
measure: Decline in eGFR
timeFrame: monthly up to 15 months
measure: Correction of nitrogen balance
timeFrame: monthly up to 15 months
measure: Correction of metabolic acidosis
timeFrame: monthly up to 15 months
measure: Correction of calcium metabolism abnormalities
timeFrame: monthly up to 15 months
measure: Correction of mineral metabolism abnormalities
timeFrame: monthly up to 15 months
measure: Serum level of intact Parathyroid Hormone (iPTH)
timeFrame: monthly up to 15 months
measure: Nutritional status - Subjective Global Assessment (SGA)
timeFrame: monthly up to 15 months
measure: Body Mass Index (BMI)
timeFrame: monthly up to 15 months
measure: Tricipital Skin Fold (TSF)
timeFrame: monthly up to 15 months
measure: Middle arm muscular circumference (MAMC)
timeFrame: monthly up to 15 months
measure: Serum albumin
timeFrame: monthly up to 15 months
measure: Serum cholesterol
timeFrame: monthly up to 15 months
measure: Inflammatory status
timeFrame: monthly up to 15 months
measure: Compliance to the protein intake
timeFrame: twice-a-month during the run-in phase, weekly for the first month after randomization, every 4 weeks during the next 6 months, and then every 3 months up to 15 months
measure: Compliance to the energy intake
timeFrame: twice-a-month during the run-in phase, weekly for the first month after randomization, every 4 weeks during the next 6 months, and then every 3 months up to 15 months
measure: Occurence of the adverse events
timeFrame: twice-a-month during the run-in phase, weekly for the first month after randomization, every 4 weeks during the next 6 months, and every 3 months up to 15 months
Other outcomes:
Locations:
city: Bucharest
country: Romania
facility: "Dr Carol Davila" Teaching Hospital of Nephrology
Study officials:
affiliation: Carol Davila University of Medicine and Pharmacy
name: Gabriel Mircescu, Prof
role: STUDY_CHAIR
References:
citation: Mihalache A, Garneata L, Mocanu CA, Simionescu TP, Mircescu G. Low-salt low-protein diet and blood pressure control in patients with advanced diabetic kidney disease and heavy proteinuria. Int Urol Nephrol. 2021 Jun;53(6):1197-1207. doi: 10.1007/s11255-020-02717-2. Epub 2021 Jan 2.