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Efficacy and Safety of Penthrox® Combined With a Standard Analgesia (SoC) in Adult Patients Admitted to the Emergency Department With Moderate to Severe Pain Associated With Trauma (Pen ASAP)

Primary Purpose

Pain, Acute

Status
Completed
Phase
Phase 4
Locations
France
Study Type
Interventional
Intervention
Methoxyflurane
Normal Saline
Sponsored by
Mundipharma SAS
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pain, Acute

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men and women aged 18 or older
  • Patients (in an emergency, parent or relative) who dated and signed their informed consent to participate in the study
  • Patients admitted to the emergency department due to a trauma
  • Patients having a pain score ≥ 4 measured using a numerical scale (NRS) at the time of admission to emergency departments.
  • Patients having a pain score ≥ 40 measured using the VAS at the time of randomisation.

Exclusion Criteria:

  • Life-threatening conditions requiring immediate admission to the operating theatre or the intensive care unit;
  • Impaired consciousness according to the investigator regardless of the cause, including head trauma or drug or alcohol consumption;
  • Acute medicinal or alcohol intoxication, according to the investigator;
  • Pregnant woman or woman at risk of pregnancy and not using highly effective contraception methods or known lactation;
  • Analgesic treatment within 5 hours (8 h for sodium diclofenac) prior to admission, except for paracetamol, which is allowed;
  • Treatment with nitrous oxide within 5 hours before presentation at the emergency department;
  • Use of analgesics for chronic pain;
  • Prior use of Penthrox®;
  • Use of an investigational product one month before presentation at the emergency department;
  • Hypersensitivity to Penthrox® or any other fluoridated anesthetic;
  • History of signs of hepatic lesions after use of methoxyflurane or after anaesthesia by a halogenated hydrocarbon;
  • Malignant hyperthermia: Known malignant hyperthermia or patient genetic predisposition or patient or family history of serious adverse reactions;
  • Clinical evidence of respiratory depression according to the investigator;
  • Clinical evidence of cardiovascular instability according to the investigator;
  • Clinical renal or hepatic damage, according to the investigator, pre-existing or known;
  • Presence of any other clinical condition that can, according to the investigator's opinion, have an impact on the patient's ability to participate in the study or the results of the study.
  • Individuals protected by law

Sites / Locations

  • CH Annecy Genevois
  • GH Carnelle Porte de l'Oise
  • Hôpital Avicenne - APHP
  • CHRU Lille
  • Hôpital Edouard Herriot
  • Hospice civil de Lyon
  • CH René Dubos
  • CHU Purpan

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Penthrox® (Methoxyflurane)

Normal Saline

Arm Description

Patients will be asked to inhale Penthrox® intermittently or continuously to obtain adequate analgesia. Penthrox® or placebo will be administered in combination with standard analgesic treatments usually used according to the emergency department protocol (SoC). Duration of treatment: 1 administration (with a maximum of 2 inhalers) during passage to emergency.

Patients will be asked to inhale Penthrox® intermittently or continuously to obtain adequate analgesia. Penthrox® or placebo will be administered in combination with standard analgesic treatments usually used according to the emergency department protocol (SoC). Duration of treatment: 1 administration (with a maximum of 2 inhalers) during passage to emergency.

Outcomes

Primary Outcome Measures

time until pain relief defined by the duration between the start of the study treatment (T0) and pain relief
Measured on Pain intensity visual analogue scale (PI-VAS) 0-100 where 100 is the highest pain

Secondary Outcome Measures

Duration between the start of study treatment (T0) and pain relief reported by the patient
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Absolute Pain Intensity Difference (PID) measured using the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
PID for a given assessment time is equal to the VAS score at T0 minus the VAS score at each assessment time provided in the study. Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Relative Pain Intensity Difference measured using the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Relative pain intensity difference for a given assessment time is equal to the VAS score at T0 minus the VAS score at each assessment time provided in the study divided by the VAS score at T0. Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Pain relief defined by pain intensity < 40 mm on the PI-VAS scale at 5, 10, 15, 20 and 30 minutes after T0
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Response defined by pain reduction of 20 mm on the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Response defined by pain reduction of 30% mm on the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Summed Pain Intensity Difference (SPID) measured on the PI-VAS at 5, 10, 15, 20 and 30 minutes
SPID will be calculated by using the pain intensity difference (PID) at each of these assessment times provided in the study. SPID is the sum of the PID at each study assessment time, weighted by using the time elapsed since the previous assessment, and approaches the area under the curve for the PID over time. Relative to the VAS score, the SPID measurement has the advantage of considering individual differences at the level of initial pain intensity (baseline) as well as time.
Proportion of patients attaining an SPID of at least 33%
The proportion of patients attaining an SPID of at least 33% of the maximum possible SPID will be calculated (maximum possible SPID is the the value that would be obtained if the patient was pain free (VAS=0) for the entire study period); this will be considered as corresponding to the responder rate. A % SPID of 33% was previously established as being a clinically significant measurement in pain results.
Quantity of opioids received (in milligrams of morphine)
Description of the Standard of Care and concomitant analgesic treatments
Descriptions from the World Health Organization (http://www.who.int/cancer/palliative/painladder/en/): Type of drug, doses, administration periods, and treatment duration
Sedation score (Ramsay scale)
Measured using the Ramsay sedation scale
Patient satisfaction score (Likert 0-5 scale)
Satisfaction is rated by patient as Poor, Fair, Good, Very Good or Excellent
Physician satisfaction scale (Likert 0-5 scale)
Satisfaction is rated by Physician as Poor, Fair, Good, Very Good or Excellent
Nurse satisfaction scale (Likert 0-5 scale)
Satisfaction is rated by Nurse as Poor, Fair, Good, Very Good or Excellent
Length of stay (LOS) in emergency
Assess the time until medical decision to discharge
Incidence of adverse events (AE) not associated with the underlying trauma and occurring during treatment
Change in blood pressure
The Blood Systolic and Diastolic pressure (mmHg) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Change in oxygen saturation
Oxygen saturation (%) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Change in respiration rate
Respiration rate (breaths/min) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Change in heart rate
Heart rate (beats/min) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Incidence of tachycardia, hypotension, hypertension and respiratory depression
Incidence of premature withdrawal of patients for safety or tolerability reasons

Full Information

First Posted
November 9, 2018
Last Updated
January 7, 2019
Sponsor
Mundipharma SAS
Collaborators
AXONAL, Exystat
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1. Study Identification

Unique Protocol Identification Number
NCT03798899
Brief Title
Efficacy and Safety of Penthrox® Combined With a Standard Analgesia (SoC) in Adult Patients Admitted to the Emergency Department With Moderate to Severe Pain Associated With Trauma
Acronym
Pen ASAP
Official Title
Multicentre, Randomised, Double-blind Study Assessing the Efficacy and Safety of Penthrox® Combined With a Standard Analgesia (SoC) in Comparison to a Placebo Combined With a Standard Analgesia (SoC) in Adult Patients Admitted to the Emergency Department With Moderate to Severe Pain Associated With Trauma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
May 14, 2018 (Actual)
Primary Completion Date
December 20, 2018 (Actual)
Study Completion Date
December 20, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mundipharma SAS
Collaborators
AXONAL, Exystat

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
A phase 4 randomised, double-blind study to assess the efficacy and safety of Penthrox® used from the outset in multimodal analgesia, in combination with the standard analgesic protocol used in the department, for conscious adult patients presenting in an emergency department with moderate to severe pain associated with a trauma
Detailed Description
On admission, the patient pain score will be measured using a numerical scale (NRS-11) to verify the eligibility of the patient in the study (NRS ≥ 4). At the time of randomisation, the patient's pain score will be measured using a VAS in order to verify the patient's eligibility for randomisation (VAS ≥ 40). Admissible patients will be randomised by IWRS (Interactive Web Response System) to receive: Either Penthrox® + SoC Or placebo + SoC (Figure 1). Randomisation will be stratified by sex, site and according to the baseline pain score (NRS 4-5 for a moderate-intensity pain versus NS 6-10 for a severe-intensity pain). The IWRS system will be based on the fact of including 50% patients with moderate pain and 50% patients with severe pain. Close weekly monitoring of this ratio will be set up. The decision to no longer include patients in one of the study subgroups according to pain, if necessary, or to change this ratio, will be made by the Study Sponsor and in agreement with the study investigator-coordinator and the study scientific committee. A minimum of 150 patients will be included in the severe pain subgroup (EN 6-10). The treatment (preparation of two inhalers, the second only being given to the patient on request) will only be administered once intermittently or continuously to patients on admission to the study (D0, T0). The pain score will be assessed using the VAS every 5 minutes up to 20 minutes, then at 30, 60, 90, and 120 minutes after the start of study treatment (T0). Patients will be assessed until their discharge from the emergency departments (hospitalization, transfer home, transfer to the operating room) or up to 120 minutes after the initial administration. A telephone interview will take place 14 (± 2) days after the first treatment administration to assess the medium-term safety of the product.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pain, Acute

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
360 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Penthrox® (Methoxyflurane)
Arm Type
Experimental
Arm Description
Patients will be asked to inhale Penthrox® intermittently or continuously to obtain adequate analgesia. Penthrox® or placebo will be administered in combination with standard analgesic treatments usually used according to the emergency department protocol (SoC). Duration of treatment: 1 administration (with a maximum of 2 inhalers) during passage to emergency.
Arm Title
Normal Saline
Arm Type
Placebo Comparator
Arm Description
Patients will be asked to inhale Penthrox® intermittently or continuously to obtain adequate analgesia. Penthrox® or placebo will be administered in combination with standard analgesic treatments usually used according to the emergency department protocol (SoC). Duration of treatment: 1 administration (with a maximum of 2 inhalers) during passage to emergency.
Intervention Type
Drug
Intervention Name(s)
Methoxyflurane
Other Intervention Name(s)
Penthrox®
Intervention Description
PENTHROX 3mL inhalation vapour, liquid
Intervention Type
Drug
Intervention Name(s)
Normal Saline
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
time until pain relief defined by the duration between the start of the study treatment (T0) and pain relief
Description
Measured on Pain intensity visual analogue scale (PI-VAS) 0-100 where 100 is the highest pain
Time Frame
through study completion, maximum of 2 hours
Secondary Outcome Measure Information:
Title
Duration between the start of study treatment (T0) and pain relief reported by the patient
Description
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Time Frame
through study completion, maximum of 2 hours
Title
Absolute Pain Intensity Difference (PID) measured using the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Description
PID for a given assessment time is equal to the VAS score at T0 minus the VAS score at each assessment time provided in the study. Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Time Frame
baseline to 5, 10, 15, 20 and 30 minutes
Title
Relative Pain Intensity Difference measured using the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Description
Relative pain intensity difference for a given assessment time is equal to the VAS score at T0 minus the VAS score at each assessment time provided in the study divided by the VAS score at T0. Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Time Frame
baseline to 5, 10, 15, 20 and 30 minutes
Title
Pain relief defined by pain intensity < 40 mm on the PI-VAS scale at 5, 10, 15, 20 and 30 minutes after T0
Description
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Time Frame
baseline to 5, 10, 15, 20 and 30 minutes
Title
Response defined by pain reduction of 20 mm on the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Description
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Time Frame
baseline to 5, 10, 15, 20 and 30 minutes
Title
Response defined by pain reduction of 30% mm on the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0
Description
Pain measured on PI-VAS, 0-100 where 100 is the highest pain
Time Frame
baseline to 5, 10, 15, 20 and 30 minutes
Title
Summed Pain Intensity Difference (SPID) measured on the PI-VAS at 5, 10, 15, 20 and 30 minutes
Description
SPID will be calculated by using the pain intensity difference (PID) at each of these assessment times provided in the study. SPID is the sum of the PID at each study assessment time, weighted by using the time elapsed since the previous assessment, and approaches the area under the curve for the PID over time. Relative to the VAS score, the SPID measurement has the advantage of considering individual differences at the level of initial pain intensity (baseline) as well as time.
Time Frame
baseline to 30 minutes
Title
Proportion of patients attaining an SPID of at least 33%
Description
The proportion of patients attaining an SPID of at least 33% of the maximum possible SPID will be calculated (maximum possible SPID is the the value that would be obtained if the patient was pain free (VAS=0) for the entire study period); this will be considered as corresponding to the responder rate. A % SPID of 33% was previously established as being a clinically significant measurement in pain results.
Time Frame
through study completion, maximum of 2 hours
Title
Quantity of opioids received (in milligrams of morphine)
Time Frame
through study completion, maximum of 2 hours
Title
Description of the Standard of Care and concomitant analgesic treatments
Description
Descriptions from the World Health Organization (http://www.who.int/cancer/palliative/painladder/en/): Type of drug, doses, administration periods, and treatment duration
Time Frame
through study completion, maximum of 2 hours
Title
Sedation score (Ramsay scale)
Description
Measured using the Ramsay sedation scale
Time Frame
through study completion, maximum of 2 hours
Title
Patient satisfaction score (Likert 0-5 scale)
Description
Satisfaction is rated by patient as Poor, Fair, Good, Very Good or Excellent
Time Frame
through study completion, maximum of 2 hours
Title
Physician satisfaction scale (Likert 0-5 scale)
Description
Satisfaction is rated by Physician as Poor, Fair, Good, Very Good or Excellent
Time Frame
through study completion, maximum of 2 hours
Title
Nurse satisfaction scale (Likert 0-5 scale)
Description
Satisfaction is rated by Nurse as Poor, Fair, Good, Very Good or Excellent
Time Frame
through study completion, maximum of 2 hours
Title
Length of stay (LOS) in emergency
Time Frame
through study completion, maximum of 2 hours
Title
Assess the time until medical decision to discharge
Time Frame
through study completion, maximum of 2 hours
Title
Incidence of adverse events (AE) not associated with the underlying trauma and occurring during treatment
Time Frame
through study completion, maximum of 2 hours
Title
Change in blood pressure
Description
The Blood Systolic and Diastolic pressure (mmHg) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Time Frame
baseline to 30 minutes
Title
Change in oxygen saturation
Description
Oxygen saturation (%) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Time Frame
baseline to 30 minutes
Title
Change in respiration rate
Description
Respiration rate (breaths/min) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Time Frame
baseline to 30 minutes
Title
Change in heart rate
Description
Heart rate (beats/min) will be measured at baseline and 30 minutes. The difference between the values will be calculated.
Time Frame
baseline to 30 minutes
Title
Incidence of tachycardia, hypotension, hypertension and respiratory depression
Time Frame
through study completion, maximum of 2 hours
Title
Incidence of premature withdrawal of patients for safety or tolerability reasons
Time Frame
through study completion, maximum of 2 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women aged 18 or older Patients (in an emergency, parent or relative) who dated and signed their informed consent to participate in the study Patients admitted to the emergency department due to a trauma Patients having a pain score ≥ 4 measured using a numerical scale (NRS) at the time of admission to emergency departments. Patients having a pain score ≥ 40 measured using the VAS at the time of randomisation. Exclusion Criteria: Life-threatening conditions requiring immediate admission to the operating theatre or the intensive care unit; Impaired consciousness according to the investigator regardless of the cause, including head trauma or drug or alcohol consumption; Acute medicinal or alcohol intoxication, according to the investigator; Pregnant woman or woman at risk of pregnancy and not using highly effective contraception methods or known lactation; Analgesic treatment within 5 hours (8 h for sodium diclofenac) prior to admission, except for paracetamol, which is allowed; Treatment with nitrous oxide within 5 hours before presentation at the emergency department; Use of analgesics for chronic pain; Prior use of Penthrox®; Use of an investigational product one month before presentation at the emergency department; Hypersensitivity to Penthrox® or any other fluoridated anesthetic; History of signs of hepatic lesions after use of methoxyflurane or after anaesthesia by a halogenated hydrocarbon; Malignant hyperthermia: Known malignant hyperthermia or patient genetic predisposition or patient or family history of serious adverse reactions; Clinical evidence of respiratory depression according to the investigator; Clinical evidence of cardiovascular instability according to the investigator; Clinical renal or hepatic damage, according to the investigator, pre-existing or known; Presence of any other clinical condition that can, according to the investigator's opinion, have an impact on the patient's ability to participate in the study or the results of the study. Individuals protected by law
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
A Ricard-Hibon, Dr
Organizational Affiliation
CHG Pontoise / SAMU 95
Official's Role
Principal Investigator
Facility Information:
Facility Name
CH Annecy Genevois
City
Annecy
ZIP/Postal Code
74374
Country
France
Facility Name
GH Carnelle Porte de l'Oise
City
Beaumont-sur-Oise
ZIP/Postal Code
95260
Country
France
Facility Name
Hôpital Avicenne - APHP
City
Bobigny
ZIP/Postal Code
93000
Country
France
Facility Name
CHRU Lille
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Hôpital Edouard Herriot
City
Lyon
ZIP/Postal Code
69437
Country
France
Facility Name
Hospice civil de Lyon
City
Pierre Bénite
ZIP/Postal Code
69495
Country
France
Facility Name
CH René Dubos
City
Pontoise
ZIP/Postal Code
95300
Country
France
Facility Name
CHU Purpan
City
Toulouse
ZIP/Postal Code
31059
Country
France

12. IPD Sharing Statement

Learn more about this trial

Efficacy and Safety of Penthrox® Combined With a Standard Analgesia (SoC) in Adult Patients Admitted to the Emergency Department With Moderate to Severe Pain Associated With Trauma

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