The Effect of phoSPHocreatine on mEdical Emergency Team (Met) tREated Patients (SPHERE)

The Effect of phoSPHocreatine on mEdical Emergency Team (Met) tREated Patients: a Randomized Clinical Trial Protocol

Unexpected deaths and unplanned intensive care unit (ICU) admissions are common during hospital stay and are often preceded by warning abnormalities in patients' vital signs. These abnormalities trigger Medical Emergency Team (MET) activation and up to 15% of patients visited by the MET is admitted to the ICU with an overall hospital stay after the MET intervention of approximately 2 weeks. Phosphocreatine (PCr) is a natural energy-buffering molecule associated with signals of mortality reduction in patients with acute cardiac conditions (according to meta-analytic finding from our group) and with encouraging beneficial effects on other acute organ failures (e.g. brain). The investigators designed a multi-center, randomized, placebo-controlled trial to confirm the promising beneficial effects of PCr in hospitalized patients. The investigators expects a reduction in hospital stay (measured as an increase in days alive and out of hospital at 30 days) when PCr is added to standard treatment in patients requiring MET intervention.

Study Overview

• Status: Recruiting
• Conditions: Respiratory Failure; Bradycardia; Tachycardia; Hypotension; Cardiac Arrest; Tachypnea; Cardiac Failure; Airway Disease; Consciousness, Level Altered; Bradypnea
• Intervention / Treatment: Drug: Phosphocreatine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Giovanni Landoni, Prof.; Phone Number: 6151 +39022643; Email: landoni.giovanni@hsr.it

Study Locations

• Italy
  • Milan, Italy, 20132
    • Recruiting
    • IRCCS San Raffaele Scientific Institute
    • Contact: Giovanni Landoni, Prof; Email: landoni.giovanni@hsr.it
    • Principal Investigator: Silvia Ajello, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Admitted in hospital (but outside ICU)
2. Age>=18 years
3. Written informed consent
4. Serum creatinine <=2 mg/dl

5. Patient with impending or underlying cardiac failure or cardiac arrest, irrespectively of the primitive organ failure, and the Medical Emergency Team (MET) is called upon at least one of the following:

   1. Threatened airways;
   2. Respiratory arrest;
   3. Respiratory rate <5 or >36 breaths per min;
   4. Pulse rate <40 or >140 beats per min;
   5. Systolic blood pressure < 90 mm Hg;
   6. Sudden fall in level of consciousness;
   7. Fall in Glasgow coma scale of > 2 points.

Exclusion Criteria:

1. Age < 18 years;
2. Ongoing cardiac massage;
3. Current hospital admission from a care nursing facility;
4. Planned discharge to a care nursing facility;
5. Reasons for withdrawal of life-sustaining therapy;
6. History of kidney transplantation;
7. Solitary kidney (by any reason);
8. Serum Creatinine > 2 mg/dl;
9. Immediate need for ICU admission;
10. Known allergy to PCr;
11. Pregnancy;
12. Previous enrollment and randomization into this trial;
13. Administration of PCr in the previous 30 day.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phosphocreatine; Patients randomized to the phosphocreatine group will receive the drug for a maximum of 3 days.; Patients without renal failure: At the time of randomization (day 0), 4 grams of phosphocreatine will be administered, followed by an additional 4 grams on the same day, with a minimum interval of 20 minutes and a maximum of 4 hours. On day 1 and day 2, after 8 AM, 2 grams of phosphocreatine will be administered twice a day, with a 6-hour interval between doses.; Patients with history of renal failure: On day 0, patients will receive a single dose of 4 grams of phosphocreatine. On day 1 and day 2, after 8 AM, 2 grams of phosphocreatine will be administered twice a day, with a 6-hour interval between doses.; Patients with acute kidney injury, without chronic kidney disease: Single dose of 4 grams of phosphocreatine on day 0. No further doses of the drug are planned.	Drug: Phosphocreatine; Administration of Phosphocreatine
Placebo Comparator: Placebo; Patients randomized to the placebo group will receive saline solution for a maximum of 3 days.; Patients without renal failure: 200 ml of saline solution twice a day from day 0 to day 2. On day 0, the second bolus should be administered between 20 minutes and 4 hours after the first bolus; on day 1 and day 2, the saline solution should be administered after 8 AM, with the second bolus given 6 hours later.; Patients with history of renal failure: On day 0, a single infusion of 200 mL of saline solution will be administered. On day 1 and day 2, 200 mL of saline solution will be administered twice a day, after 8 AM, with a 6-hour interval between doses.; Patients with acute kidney injury, without chronic kidney disease: A single infusion of 200 mL of saline solution on day 0. No further administrations are planned.	Drug: Placebo; Saline solution of NaCl 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
days alive and out of hospital at 30 days.	To compare the effect of phosphocreatine (PCr) (experimental group), versus placebo (saline solution-control group) on the number of days alive and out of hospital at 30 days.	day 30 or hospital discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive function	Evaluation of cognitive function using the Cognitive Telephone Screening Instrument (COGTEL). The COGTEL is a test that evaluates the cognitive performance of survived patients 30 days after randomization. This scale has a minimum of zero points and a maximum of 100.	day 30
Rate of arrhythmia needing treatment	Clinically relevant arrhythmias will be recorded and confirmed by an ECG. Rate of major arrhythmias divided into supraventricular arrhythmias, ventricular arrhythmias, bradyarrhythmias, and need for antiarrhythmics will be registered.	hospital discharge (which usually occurs in the 30days after randomization)
Rate of ICU admissions or criteria for ICU admission	ICU admission	hospital discharge (which usually occurs in the 30days after randomization)
Death at 30 days	Death	day 30
Death at 90 days	Death	90 days

Collaborators and Investigators

• Sponsor: Università Vita-Salute San Raffaele
• Collaborators: Silvia Ajello

Publications and helpful links

General Publications

• 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.
• Mingxing F, Landoni G, Zangrillo A, Monaco F, Lomivorotov VV, Hui C, Novikov M, Nepomniashchikh V, Fominskiy E. Phosphocreatine in Cardiac Surgery Patients: A Meta-Analysis of Randomized Controlled Trials. J Cardiothorac Vasc Anesth. 2018 Apr;32(2):762-770. doi: 10.1053/j.jvca.2017.07.024. Epub 2017 Jul 24.

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: July 5, 2024
• First Submitted That Met QC Criteria: July 13, 2024
• First Posted (Actual): July 16, 2024

Study Record Updates

• Last Update Posted (Actual): August 6, 2025
• Last Update Submitted That Met QC Criteria: August 5, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Neurologic Manifestations; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Heart Diseases; Respiratory Tract Diseases; Arrhythmias, Cardiac; Neurobehavioral Manifestations; Neurocognitive Disorders; Respiration Disorders; Signs and Symptoms, Respiratory; Heart Failure; Respiratory Insufficiency; Hypotension; Tachycardia; Bradycardia; Consciousness Disorders; Tachypnea; Physiological Effects of Drugs; Protective Agents; Cardiotonic Agents; Phosphocreatine
• Other Study ID Numbers: GR-2021-12375001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No