Myocardial Protection With Phosphocreatine in High-RIsk Cardiac SurgEry Patients (PRISE)

Myocardial Protection With Phosphocreatine in High-RIsk Cardiac SurgEry Patients: a Single-center Randomised Double-blind Placebo-controlled Exploratory Pilot Clinical Trial

There is evidence on the role of the phosphotransfer system in the energy metabolism of the heart, with altered energetics playing an important role in the mechanisms of heart failure. Phosphocreatine plays an important part in the energy heart system. The investigators have just performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and matched studies that compared phosphocreatine with placebo or standard treatment in patients with coronary artery disease or chronic heart failure or in those undergoing cardiac surgery. Patients receiving phosphocreatine had lower all-cause mortality as well as improved cardiac outcomes when compared to the control group, however, the quality of the included studies was low. Thus, the investigators plan to conduct an exploratory high quality RCT to investigate whether providing phosphocreatine compared to placebo improves the myocardial protection in high-risk patients scheduled for cardiac surgery and to determine the best research endpoint for future trials.

Study Overview

• Status: Completed
• Conditions: Cardiac Surgical Procedures; Heart Valve Prosthesis Implantation
• Intervention / Treatment: Drug: Phosphocreatine sodium tetrahydrate after anaesthesia induction; Drug: Phosphocreatine sodium tetrahydrate added to cardioplegia; Drug: Phosphocreatine sodium tetrahydrate after heart recovery; Drug: Phosphocreatine sodium tetrahydrate after ICU admission; Drug: 5% Glucose after anaesthesia induction; Drug: 5% Glucose; Drug: 5% Glucose after heart recovery; Drug: 5% Glucose after ICU admission

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Novosibirsk, Russian Federation, 630055
    • Evgeny Fominskiy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Double/triple valve lesion that required cardiac surgery with CPB
• Aged 18 years or older
• Signed informed consent

Exclusion Criteria:

• Emergency surgery
• Concomitant coronary artery bypass grafting surgery (CABG) or procedure on any part of the aorta
• Chronic kidney disease of G3-G4-G5 categories according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria (at least one of the following present for > 3 months: glomerular filtration rate ≤ 60 ml/min/1.73 m2, history of kidney transplantation) or solitary kidney (by any reason)
• Known allergy to PCr
• Pregnancy
• Current enrollment into another RCT (in the last 30 days)
• Previous enrollment and randomisation into the PRISE trial
• Administration of PCr in the previous 30 day
• Concomitant radiofrequency/cryo- ablation procedure
• Structural abnormalities or genetic trait point to kidney disease including glomerulonephritis and gout.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Phosphocreatine; Participants randomly assigned to the phosphocreatine arm receive: after anaesthesia induction 2 g of Phosphocreatine (PCr) prepared in 50 mL of glucose 5% during 30 min intravenous (IV);; together with cardioplegia 2.5 g of PCr prepared in 50 mL of glucose 5% and added to every 1 L of cardioplegic solution (Custodiol, Dr. F. KOHLER CHEMIE, GmbH, Germany; concentration = 10 mmol/L);; immediately after heart recovery (spontaneous or paced myocardium contraction) after aorta declamping 2 g of PCr prepared in 50 mL of glucose 5% during 30 min IV;; immediately after ICU admission 4 g of PCr in 100 mL of glucose 5% during 60 min IV	Drug: Phosphocreatine sodium tetrahydrate after anaesthesia induction; after anaesthesia induction 2 g of Phosphocreatine (PCr) prepared in 50 mL of glucose 5% during 30 min intravenous (IV); Other Names: Neoton; Drug: Phosphocreatine sodium tetrahydrate added to cardioplegia; together with cardioplegia 2.5 g of PCr prepared in 50 mL of glucose 5% and added to every 1 L of cardioplegic solution (Custodiol, Dr. F. KOHLER CHEMIE, GmbH, Germany; concentration = 10 mmol/L); Other Names: Neoton; Drug: Phosphocreatine sodium tetrahydrate after heart recovery; immediately after heart recovery (spontaneous or paced myocardium contraction) after aorta declamping 2 g of PCr prepared in 50 mL of glucose 5% during 30 min IV; Other Names: Neoton; Drug: Phosphocreatine sodium tetrahydrate after ICU admission; immediately after ICU admission 4 g of PCr in 100 mL of glucose 5% during 60 min IV; Other Names: Neoton
PLACEBO_COMPARATOR: Control; Participants randomly assigned to the placebo arm receive: after anaesthesia induction 50 mL of glucose 5% IV delivered by an identical infusion pump during 30 minutes;; together with cardioplegia 50 mL of glucose 5% is added in every 1 L of cardioplegic solution (Custodiol, Dr. F. KOHLER CHEMIE, GmbH, Germany);; immediately after heart recovery (spontaneous or paced myocardium contraction) after aorta declamping 50 mL of glucose 5% IV delivered by an identical infusion pump during 30 minutes;; immediately after ICU admission 100 mL of glucose 5% IV delivered by an identical infusion pump during 60 minutes	Drug: 5% Glucose after anaesthesia induction; after anaesthesia induction 50 mL of glucose 5% IV delivered by an identical infusion pump during 30 minutes; Other Names: Dextrose; Drug: 5% Glucose; together with cardioplegia 50 mL of glucose 5% is added in every 1 L of cardioplegic solution (Custodiol, Dr. F. KOHLER CHEMIE, GmbH, Germany); Other Names: Dextrose added to cardioplegia; Drug: 5% Glucose after heart recovery; immediately after heart recovery (spontaneous or paced myocardium contraction) after aorta declamping 50 mL of glucose 5% IV delivered by an identical infusion pump during 30 minutes; Other Names: Dextrose; Drug: 5% Glucose after ICU admission; immediately after ICU admission 100 mL of glucose 5% IV delivered by an identical infusion pump during 60 minutes; Other Names: Dextrose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Peak concentration of Troponin I	From the randomization to the postoperative day 3 (POD 3)

Secondary Outcome Measures

Outcome Measure	Time Frame
Peak serum creatinine concentration	through study completion, an average of 4 weeks
The incidence of acute kidney injury	through study completion, an average of 4 weeks
Duration of mechanical ventilation	through study completion, an average of 4 weeks
Duration of ICU stay	through study completion, an average of 4 weeks
Duration of hospital stay	through study completion, an average of 4 weeks
The need for (yes/no), and dosage (inotropic score) of, inotropic agents	through study completion, an average of 4 weeks
The need for (yes/no), the number of and the dosage of, defibrillation	through study completion, an average of 4 weeks
The incidence of new-onset moderate and severe arrhythmias or cardiac arrest	through study completion, an average of 4 weeks
Cardiac index	at 6 h after ICU admission, and at the beginning of POD 1
Left ventricular ejection fraction	At the beginning of POD 1
Sequential Organ Failure Assessment score	through study completion, an average of 4 weeks
30-day all-cause mortality	30 days after randomisation

Collaborators and Investigators

• Sponsor: Meshalkin Research Institute of Pathology of Circulation
• Investigators: Principal Investigator: Evgeny V. Fominskiy, MD PhD, Academician EN Meshalkin Novosibirsk Research Institute of Circulation Pathology

Publications and helpful links

General Publications

• Horjus DL, Oudman I, van Montfrans GA, Brewster LM. Creatine and creatine analogues in hypertension and cardiovascular disease. Cochrane Database Syst Rev. 2011 Nov 9;2011(11):CD005184. doi: 10.1002/14651858.CD005184.pub2.
• Strumia E, Pelliccia F, D'Ambrosio G. Creatine phosphate: pharmacological and clinical perspectives. Adv Ther. 2012 Feb;29(2):99-123. doi: 10.1007/s12325-011-0091-4.
• Landoni G, Zangrillo A, Lomivorotov VV, Likhvantsev V, Ma J, De Simone F, Fominskiy E. Cardiac protection with phosphocreatine: a meta-analysis. Interact Cardiovasc Thorac Surg. 2016 Oct;23(4):637-46. doi: 10.1093/icvts/ivw171. Epub 2016 Jun 17.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2016
• Primary Completion (ACTUAL): April 1, 2021
• Study Completion (ACTUAL): May 1, 2021

Study Registration Dates

• First Submitted: April 13, 2016
• First Submitted That Met QC Criteria: April 27, 2016
• First Posted (ESTIMATE): May 2, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 1, 2021
• Last Update Submitted That Met QC Criteria: June 28, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Phosphocreatine; Creatine Phosphate; Neoton; Phosphate, Creatine; Phosphorylcreatine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Protective Agents; Cardiotonic Agents; Anesthetics; Phosphocreatine
• Other Study ID Numbers: PCr-in-CS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES