L-carnitine as an Adjunct Treatment for Septic Shock Patients With Acute Kidney Injury (CarniSave)

L-carnitine as an Adjunct Treatment for Septic Shock Patients With Acute Kidney Injury: a Multicentre, Randomized, 2-parallel Group, Superiority Trial

The primary objective of this study is to compare 28 day mortality rates between septic shock patients with acute renal insufficiency treated via L-Carnitine (as an adjunct therapy) versus a similar group of patients not receiving L-Carnitine adjunct therapy.

Study Overview

• Status: Recruiting
• Conditions: Shock, Septic; Acute Kidney Injury; Severe Sepsis
• Intervention / Treatment: Drug: 56 days of weight-adjusted L-Carnitine treatment; Drug: 10 days of intravenous placebo (isotonic saline)

Detailed Description

The secondary objectives of this study are:

A. First secondary objective of this study is to compare 10 day mortality rates of septic shock patients with renal insufficiency treated via L-Carnitine (as an adjunct therapy) for 56 days versus a patients not receiving L-Carnitine adjunct therapy

B. To compare study arms in terms of patient safety.

C. To compare study arms in terms of further clinical outcomes, with special emphasis on nephrological outcomes.

D. To study (and compare between arms) the kinetic curves of free and total serum carnitine. Renal replacement therapy rapidly depletes the body's carnitine levels. Tracking adequate carnitine levels is therefore important for the interpretation of study results.

E. To constitute a bio-bank in association with the study for future ancillary studies (e.g. kidney injury marker studies, carnitine-responders versus non-responders, and other exploratory studies.

• Study Type: Interventional
• Enrollment (Estimated): 272
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Carey Suehs, PhD; Phone Number: +33.(0)4.66.68.67.88; Email: carey.suehs@chu-nimes.fr
• Study Contact Backup: Name: Pascal Reboul, MD; Phone Number: +33.(0)4.66.68.35.56; Email: pascal.reboul@chu-nimes.fr

Study Locations

• France
  • Caen Cedex 9, France, 14033
    • Recruiting
    • CHU de Caen
    • Sub-Investigator: Thierry Lobbedez, MD, PhD
    • Principal Investigator: Damien Ducheyron, MD, PhD
  • Chartres, France
    • Recruiting
    • CH de Chartres
    • Contact: Pierre Kalfon
    • Principal Investigator: pierre kalfon
  • Clermont Ferrand, France, 63003
    • Recruiting
    • CHU de Clermont Ferrand
    • Principal Investigator: Bertrand Souweine, MD, PhD
    • Sub-Investigator: Anne-Elizabeth Heng, MD
  • Dijon, France, 21079
    • Recruiting
    • CHU de Dijon
    • Principal Investigator: Jean-Pierre Quenot, MD
    • Sub-Investigator: Jean-Michel Rebibou, MD
  • Lyon, France
    • Not yet recruiting
    • CHU Lyon
    • Contact: RIMMELE Thomas, MD
  • Marseille, France, 13385
    • Withdrawn
    • APHM - Hôpital de la Conception
  • Marseille, France, 13385
    • Withdrawn
    • APHM - Hôpital de la Timone Adultes
  • Marseille Cedex 20, France, 13915
    • Withdrawn
    • APHM - Hopital Nord
  • Montpellier, France, 34295
    • Recruiting
    • CHU de Montpellier - Lapeyronie
    • Principal Investigator: Kada Klouche, MD, PhD
    • Sub-Investigator: Olivier Jonquet, MD, PhD
    • Sub-Investigator: Georges Mourad, MD, PhD
  • Montpellier cedex 5, France, 34295
    • Recruiting
    • CHU de Montpellier - St Eloi
    • Principal Investigator: Samir Jaber, MD, PhD
  • Nîmes Cedex 09, France, 30029
    • Recruiting
    • CHU de Nimes - Hopital Universitaire Caremeau
    • Sub-Investigator: Olivier Moranne, MD, PhD
    • Principal Investigator: Laurent Muller, MD, PhD
    • Sub-Investigator: Saber Barbar, MD
    • Sub-Investigator: Jean-Yves Lefrant, MD, PhD
    • Sub-Investigator: Serge Lumbroso, MD, PhD
    • Sub-Investigator: David-Paul de Brauwère, MD
  • Poitiers Cedex, France, 86021
    • Recruiting
    • CHU de Poitiers
    • Sub-Investigator: claire DAHYOT-FIZELIER, MD, PhD
    • Sub-Investigator: Frank Bridoux, MD, PhD
    • Principal Investigator: thibaut papet
    • Sub-Investigator: marc bauwens
  • Saint-Priest en Jarez, France, 42270
    • Not yet recruiting
    • CHU de St Etienne
    • Principal Investigator: Eric Alamartine, MD, PhD
    • Sub-Investigator: Christophe Mariat, MD, PhD
  • Toulouse Cedex 9, France, 31059 T
    • Recruiting
    • CHU de Toulouse - Hôpital Rangueil
    • Principal Investigator: stanislas faguer
    • Sub-Investigator: Dominique Chauveau, MD, PhD
    • Sub-Investigator: Olivier Cointault, MD
    • Sub-Investigator: nassim kamar

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • The emergency inclusion procedure was correctly applied according to French law (signature of consent form by a patient-designated trusted person or a family member, or a medical decision to proceed with patient inclusion if the latter two persons are unavailable) ---- OR ---- signature of the consent form by the patient

  • The patient must be insured or beneficiary of a health insurance plan
  • The patient is at least 18 years old
  • The patient was admitted to an intensive care unit (participating in the study) for sepsis or septic shock and presented with acute renal failure requiring, at some point, the use of extra-renal purification.
  • • The patient has sepsis or septic shock according to international criteria SEPSIS 3 (Singer et al, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) ; JAMA. 2016)
  • The patient has acute renal insufficiency with an KDIGO score of 3
  • The patient has started continuous renal replacement therapy (CRRT) or intermittent renal replacement therapy (IRRT) within the previous 72 hours, or will start RRT (CRRT or IRRT) within the next 72 hours.

Exclusion Criteria:

• • The patient is participating in, or has participated in over the past three months, another interventional study that may interfere with the results or conclusions of this study

  • The patient is in an exclusion period determined by a previous study
  • The patient is under judicial protection, or is an adult under guardianship
  • The patient is pregnant, parturient or breastfeeding
  • The patient is susceptible to procreate and does not use methods of effective contraception (contraceptive hormonal ring, surgical contraception, contraceptive implant, contraceptive pill, male or female sheaths, skin patch, intrauterine contraceptive device)
  • If the patient is unable to sign a consent form: the patient-designated trusted person or family member refuses to sign the consent form
  • If the patient is unable to sign a consent form: It is impossible to correctly inform the patient-designated trusted person or family member
  • The patient is able/apt to sign a consent form, but refuses to do so
  • The patient is able/apt to sign a consent form, but cannot be correctly informed
  • Septic shock without associated AKI
  • Patients with a known allergy to L-Carnitine or other component of levocarnil oral solution or for injection
  • Pre-existing chronic disease requiring dialysis
  • The patient has stage 4 CKD with baseline DFG (CDK) if known <30 ml
  • History of seizures or epilepsy
  • Chronic bowel disease or history of chronic diarrhoea
  • Under treatment with sodium valproate

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-Carnitine group; Patients in the experimental arm will receive 10 days of intravenous L-carnitine treatment followed by 46 days of oral L-Carnitine treatment. Intervention: 56 days of weight-adjusted L-Carnitine treatment	Drug: 56 days of weight-adjusted L-Carnitine treatment; Patients in the experimental arm will receive 10 days of intravenous L-carnitine treatment followed by 46 days of oral L-Carnitine treatment. Day 1: a first bolus of 6g of L-Carnitine is administered with a syringe driver of 50 ml. Day 2 to Day 10: Two mini-perfusions are prepared each day, corresponding to 1 administration every 12 hours. 50 mg/kg/day (rounded up to the next gram) L-Carnitine is added to each syringes For the next 46 days, patients will take oral doses of L-Carnitine as follows: < à 60kg : 2g/day > 60kg : 3g/day If the patient leaves the hospital before D10, oral treatment can be initiated at the end of the hospitalization
Placebo Comparator: Placebo then open group; Patients in the placebo arm will receive 10 days of intravenous isotonic saline in a fashion analogous to the experimental arm (they study is thus blinded for the first 10 days and then open there afterwards). Intervention: 10 days of intravenous placebo (isotonic saline)	Drug: 10 days of intravenous placebo (isotonic saline); Patients in the placebo arm will receive 10 days of intravenous isotonic saline in a fashion analogous to the experimental arm (they study is thus blinded for the first 10 days and then open there afterwards). Day 1: 1 50ml syringe driver of 50 ml isotonic saline solution . Day 2 to Day 10 : Two syringe drivers of 50 ml of isotonic saline solution are prepared each day, one during the morning and one during the evening.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mortality	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First secondary objective of this study is to compare 10 day mortality rates of septic shock patients with renal insufficiency treated via L-Carnitine (as an adjunct therapy) for 56 days versus a patients not receiving L-Carnitine adjunct therapy.	Mortality	10 days
Adverse Events per patient		12 months (throughout study)
Survival		12 months (throughout study)
The number of days alive and not on renal replacement therapy		12 months
The number of days alive and free of renal failure		12 months
The number of days alive and free of organ failure		12 months
The number of days alive and not on mechanical ventilation		12 months
The number of days alive and not in Intensive Care Unit (ICU)		12 months
The number of days alive and not in hospital		12 months
The number of days alive and free of (not requiring) catecholamines		12 months
A vector of repeated measures of daily SOFA (Sequential Organ Failure Assessment score) scores available during the ICU stay	Available daily scores will be aggregated into a vector for repeated measures analysis (similar to the agregation required for calculating a slope).	at ICU discharge (expected max of 28 days)
A vector of repeated measures of AKIN (Acute Kidney Injury Network score) score available during the ICU stay	Available daily scores will be aggregated into a vector for repeated measures analysis (similar to the agregation required for calculating a slope).	at ICU discharge (expected max of 28 days)
A vector of repeated measures of serum creatinine	Available measures will be aggregated into a vector for repeated measures analysis (similar to the agregation required for calculating a slope).	at ICU discharge (expected max of 28 days)
A vector of repeated measures of serum creatinine	Available measures will be aggregated into a vector for repeated measures analysis (similar to the agregation required for calculating a slope).	at discharge from the nephrology department (expected max of 60 days)
A vector of repeated measures of lactate levels available during the ICU stay	Available measures will be aggregated into a vector for repeated measures analysis (similar to the agregation required for calculating a slope).	at ICU discharge (expected max of 28 days)
Glomerular filtration rate (EpiCKD)	(if the patient is on dialysis, the glomerular filtration rate is set at 0)	month 1
Glomerular filtration rate (EpiCKD)	(if the patient is on dialysis, the glomerular filtration rate is set at 0)	month 2
Glomerular filtration rate (EpiCKD)	(if the patient is on dialysis, the glomerular filtration rate is set at 0)	month 3
Glomerular filtration rate (EpiCKD)	(if the patient is on dialysis, the glomerular filtration rate is set at 0)	month 6
Glomerular filtration rate (EpiCKD)	(if the patient is on dialysis, the glomerular filtration rate is set at 0)	month 9
Glomerular filtration rate (EpiCKD)	(if the patient is on dialysis, the glomerular filtration rate is set at 0)	month 12
Serum free carnitine level		baseline
Serum free carnitine level		after 48h of renal replacement therapy
Serum free carnitine level		day 7
Serum free carnitine level		day 14
Serum free carnitine level		month 1
Serum free carnitine level		month 2
Serum total carnitine level		baseline
Serum total carnitine level		after 48h of renal replacement therapy
Serum total carnitine level		day 7
Serum total carnitine level		day 14
Serum total carnitine level		month 1
Serum total carnitine level		month 2

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Study Director: Pascal Reboul, MD, Centre Hospitalier Universitaire de Nîmes

Publications and helpful links

General Publications

• Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. doi: 10.1097/01.CCM.0000050454.01978.3B.

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2018
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: January 19, 2016
• First Submitted That Met QC Criteria: January 22, 2016
• First Posted (Estimated): January 27, 2016

Study Record Updates

• Last Update Posted (Estimated): December 14, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Sepsis; Shock, Septic; Wounds and Injuries; Shock; Acute Kidney Injury
• Other Study ID Numbers: PHRC-N/2015/PR-01

Drug and device information, study documents

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