Safety and Efficacy of the Addition of Alanyl-Glutamine-Dipeptide to Dialysis Solution in Peritoneal Dialysis

• Clinical PET-test to measure specific transport kinetics in peritoneal cells (creatinine, urea, sodium, potassium, phosphor, glucose, protein) [ Time Frame: up to 70 days ] [ Designated as safety issue: No ]
  The ratio of solute concentrations in dialysate and plasma (D/P ratio) at specific times (t) during the dwell signifies the extent of solute equilibration. Creatinine, glucose, urea, electrolytes, phosphate, and proteins are the commonly tested solutes for clinical use, in this study alanine, glutamine and alanyl-glutamine-dipeptide also will be measured to allow assessment of the respective resorption kinetics.
• Cell number in peritoneal effluent; [ Time Frame: up to 70 days ] [ Designated as safety issue: No ]
  At the end of PD, total peritoneal cell count of the dialysate is measured; Unit of measurement: cells/µl
• cytokines (IL-6, IL-8, TNFα); [ Time Frame: up to 70 days ] [ Designated as safety issue: No ]
  At the end of PD cytokines contained in the dialysate are being analysed. Unit of measurement: pg/ml
• Cell function (phagocytosis and cytokine production) [ Time Frame: up to 70 days ] [ Designated as safety issue: No ]
  Analysis of cell function in dialysate at the end of PD by declaring the contingent of positive cell function in percent;
• Morphology of peritoneal cells from effluent (cell culture) [ Time Frame: up to 70 days ] [ Designated as safety issue: No ]
  At the end of PD, the cells contained in the dialysate are being differentiated in following categories: ephitelium; non epithelium; mixed.
• Biomarker CA125 [ Time Frame: up to 70 days ] [ Designated as safety issue: No ]
  At the end of PD, the amount of CA125 in the dialysate is measured in U/ml.
• Tolerability/safety endpoints: No. and severity of AEs [ Time Frame: up to 70 days ] [ Designated as safety issue: Yes ]
  During the trial and after signing informed consent, the presence/absence/severity of AEs occurring to patients is being documented. Measurement parameter is no. and severity of AEs (including SAEs and SUSARs).

Peritoneal dialysis (PD) is a cost effective and safe form of renal replacement therapy in patients suffering from end stage renal disease.

However currently available PDF (peritoneal dialysis fluids) are not biocompatible for the peritoneal cavity and its cells. Acute cytotoxic effects of the majority of the current glucose-based PDF are caused by low pH, lactate, high glucose and its degradation products (GDP).

Toxic effects of PDF can thus be extended to suppression of mesothelial HSR (heat shock reactions) following PDF exposure resulting in increased susceptibility of mesothelial cells against PDF exposure: PDF inherent stress factors fail to adequately induce HSP as effectors of the cellular stress response - the adequate HRS rather seems to be blocked.

Hence, therapeutic approaches to activate and enhance the HSR will reduce peritoneal damage and organ failure and improve the survival of organisms.

Preclinical results demonstrated that supplementation of PDF with pharmacological doses of alanyl-glutamine restored HSP expression and increased the resistance of mesothelial cells in in-vitro models of PD and preserved peritoneal integrity in in-vivo models of PD.

After these positive preclinical results, this study shall now clarify, whether the addition of alanyl-glutamine to the most commonly used glucose-based PDF is safe and tolerable. Therefore PDFs will be drained in a randomized cross-over study. Main outcomes measures will be total HSP expression in peritoneal cells and changes of the peritoneal transport kinetics and the presence/absence/severity of side effects.

• Arm A
  Arm A includes 14 patients. In treatment period 1, arm A receives standard PDF with the interventional drug alanyl-glutamine-dipeptide as add-on. As it is a cross-over study design, in treatment period 2, group A receives standard PDF without add-on.
  Intervention: Drug: Dipeptiven (Alanyl-glutamine-dipeptide)
• Arm B
  Arm B includes 14 patients who in treatment period 1 receive standard PDF without the investigational drug. As it is a cross-over study design, in treatment period 2 arm B receives standard PDF with alanyl-glutamine-dipeptide as add-on.
  Intervention: Drug: Dipeptiven (Alanyl-glutamine-dipeptide)

Inclusion Criteria:

• Signed informed consent prior to any study-mandated procedure
• Male and female patients aged ≥ 19 years old
• Chronic renal failure; 2 months stable on PD
• no peritonitis within the previous 2 months
• Without severe concomitant disease
• Negative pregnancy test in female patients of childbearing potential and adequate contraception in female patients of childbearing age

Exclusion Criteria:

• Known hypersensitivity to study medication
• Treatment with another investigational drug within 1 month prior to start of study medication
• Malignancy requiring chemotherapy or radiation
• Pregnancy or nursing,
• Presumed non-compliance
• Limited efficacy of peritoneal dialysis due to anatomical anomalies or severe intra-abdominal adhesions
• Clinical significant inflammatory parameters
• Less than 50 kg body weight
• Immunosuppressive therapy