A New Formulation of Intravenous Paracetamol for Fever Management

A Double-blind, Randomized, Placebo-controlled Phase IV Clinical Study of the Efficacy and Safety of a New Formulation of Paracetamol for the Management of Fever of Infectious Origin

The efficacy of intravenous paracetamol has never been compared with other drugs for the management of fever due to infections. Available data come from clinical studies conducted in healthy volunteers subject to experimental endotoxemia. The present study compares the efficacy of the new ΑPOTEL Μax® formulation versus placebo for the management of fever of infectious origin.

Study Overview

• Status: Completed
• Conditions: Fever
• Intervention / Treatment: Drug: APOTEL max; Drug: Placebo

Detailed Description

A new formulation of paracetamol for intravenous administration has been manufactured in Greece by the industry Uni-Pharma (ΑPOTEL Μax®). According to this new formulation, 1g of paracetamol is provided as a flask diluted into 100ml volume with the possibility of immediate connection with the infusion device of the patient. This formulation provides the advantage of a dilution ready-to-use which equals considerable financial benefit; nursing staff is not pre-occupied with the preparation of dilutions and the amount of consumables required for the preparation of this dilution is significantly decreased. Taking into consideration that the antipyretic effect of intravenous paracetamol has never been studied compared with other agents in patients and available data come from studies in volunteers with experimental endotoxemia, the present study compares the efficacy of the new ΑPOTEL Μax® formulation versus placebo for the management of fever of infectious origin (fever due to infection of the upper respiratory tract, of the lower respiratory tract, acute pyelonephritis or of the skin and soft tissues).

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Greece
  • Chalkida, Greece, 34100
    • General Hospital of Chalkida
  • Haidari/Athens, Greece, 12462
    • Attikon Hospital
  • Herakleion, Greece, 71110
    • University Hospital of Crete
  • Magoula Attikis, Greece, 19018
    • Thriasion Elefsis General Hospital
  • Rion/Patras, Greece, 26504
    • University Hospital of Patras
  • Thessaloniki, Greece, 54642
    • General Hospital of Thessaloniki Ippokratio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent by the patient
2. Patient of either gender
3. Age equal to or greater than 18 years old
4. Fever onset less than 24 hours
5. Body temperature greater than or equal to 38.50C.
6. Infection of the upper respiratory tract or of the lower respiratory tract or acute pyelonephritis or infection of the skin and soft tissues that can explain fever onset.

Exclusion Criteria:

1. Age below 18 years old
2. Denial for written consent
3. Intake of paracetamol for any reason either orally or intravenously or intramuscularly the last 12 hours
4. Intake of any non-steroidal anti-inflammatory drug the last 8 hours
5. Intake of any steroidal anti-inflammatory drug the last 12 hours
6. History of liver cirrhosis
7. Serum creatinine greater than 3 mg/dl
8. Aspartate aminotransferase more than 3 times greater than the upper normal limit for the hospital lab
9. Known allergy to non-steroidal anti-inflammatory drugs or to paracetamol
10. Pregnancy or lactation
11. Active bleeding of the upper or the lower gastrointestinal tract
12. Thrombocytopenia defined as any absolute platelet count below 50000/mm3.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: APOTEL max; Active drug; water for injection at a volume of 100ml with added 1g of paracetamol and inactive ingredients (ΑPOTEL max®), infused within 15 minutes. Available in 100ml bags.	Drug: APOTEL max; The study drug is provided in a form of bag with 100ml final volume and it is directly connected to the infusion device that leads to a catheter already cannulated in one antecubital vein.; Other Names: Paracetamol solution for infusion, 1gram per 100ml bag
Placebo Comparator: Placebo; Placebo; water for injection at a volume of 100ml with added inactive ingredients, infused within 15 minutes. Available in 100ml bags.	Drug: Placebo; Placebo is provided in a form of bag with 100ml final volume and it is directly connected to the infusion device that leads to a catheter already cannulated in one antecubital vein. Placebo contains water for injection and inactive vehicles.; Other Names: Water for injection and vehicles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body temperature as a measure of to compare the efficacy of intravenously administered ΑPOTEL Μax® over placebo for the achievement of defervescence.	The comparative efficacy of intravenously administered ΑPOTEL Μax® over placebo for the achievement of defervescence; defervescence is defined as any body temperature equal to or lower than 37.1 degC.	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for the administration of rescue drug.	The comparison between the two study groups on the frequency and time to administration of rescue drug.	30 hours
Comparison of defervescence with the rescue drug in the paracetamol arm with the placebo arm	The correlation between defervescence with the rescue drug with the efficacy of the initially administered type of study drug (placebo over active drug).	30 hours
Correlation between serum concentrations of free active paracetamol and metabolites with the clinical efficacy of paracetamol	The correlation between the achievement of defervescence and the concentrations of free active paracetamol and its metabolites in the serum of the patients.	30 hours
The administration of other antipyretics by the attending physicians after rescue drug in each study group	The correlation between achievement of defervescence with the rescue drug and the need of further administration of other drugs as antipyretics at the discretion of the attending physicians.	30 hours

Collaborators and Investigators

• Sponsor: Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A.
• Collaborators: University Hospital of Crete; University Hospital of Patras; Attikon Hospital; Thriasion Elefsis General Hospital; General Hospital Of Thessaloniki Ippokratio; General Hospital of Chalkida
• Investigators: Principal Investigator: Charalambos Gogos, MD, PhD, University Hospital of Patras; Principal Investigator: Dimitrios Boumpas, MD, PhD, Attikon Hospital; Principal Investigator: George Samonis, MD, PhD, University Hospital of Crete; Principal Investigator: Styliani Sympardi, MD, Thriasion Elefsis General Hospital; Principal Investigator: Asterios Karagiannis, MD, PhD, University Hospital of Thessaloniki Hippokrateion; Principal Investigator: Nikolaos Tsokos, MD, General Hospital of Halkida

Publications and helpful links

General Publications

• Giamarellos-Bourboulis EJ, Spyridaki A, Savva A, Georgitsi M, Tsaganos T, Mouktaroudi M, Raftogiannis M, Antonopoulou A, Papaziogas V, Baziaka F, Sereti K, Christopoulos P, Marioli A, Kanni T, Maravitsa P, Pantelidou I, Leventogiannis K, Tsiaoussis P, Lymberopoulou K, Koutelidakis IM. Intravenous paracetamol as an antipyretic and analgesic medication: the significance of drug metabolism. J Pharmacol Sci. 2014;124(2):144-52. doi: 10.1254/jphs.13133fp. Epub 2014 Jan 30.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: October 19, 2014
• First Submitted That Met QC Criteria: October 31, 2014
• First Posted (Estimate): November 5, 2014

Study Record Updates

• Last Update Posted (Estimate): March 22, 2016
• Last Update Submitted That Met QC Criteria: March 21, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Infections; Paracetamol; Management of fever
• Additional Relevant MeSH Terms: Body Temperature Changes; Fever; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: APOTEL-02