PIMAT: Pharmacokinetics of Intramuscular Adrenaline in Food--Allergic Teenagers

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT03366298
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arms: 4
• Actual Duration (Months): 10.3
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Food allergy affects up to 2% of adults and 8% of children in the United Kingdom (UK), and is a major public health issue. It is the commonest cause of life-threatening allergic reactions (anaphylaxis), which can be fatal. Adrenaline (epinephrine) auto-injector (AAI) devices are the first-line treatment for anaphylaxis, yet in a UK survey, over 80% of 245 teenagers experiencing anaphylaxis did not use their AAI. Delays in, or lack of adrenaline (epinephrine) administration during anaphylaxis are risk factors for fatal anaphylaxis.

In 2010, a coroner's investigation into the death of a food-allergic teenager in the UK raised several questions around AAI safety and efficacy, since the teenager died despite administering her auto-injector device. This prompted a review by the Medicines and Healthcare products Regulatory Agency (MHRA) in 2014 into the clinical and quality considerations of AAIs. Two recommendations which came from the review was that companies 'should be encouraged to develop a 0.5mg [dose] AAI.' In the UK currently only Emerade, one of the three companies selling AAIs, manufactures a 0.5mg (500mcg) version. Emerade also has a longer needle length (23mm) compared to other AAIs (typically 15mm).

The investigators plan to formally assess the pharmacokinetics (PK) and pharmacodynamics (PD) of self-injection with intramuscular adrenaline (epinephrine) in teenagers at risk of anaphylaxis due to food allergy, and have been prescribed AAI.

1. The investigators will compare self-injection with 300mcg vs 500mcg in teenagers of body weight >40kg. In a 40kg person, an adrenaline dose of 300mcg results in an effective UNDER-dosing of 30% by body weight.

2. The investigators will also assess the impact of needle length on injection, by comparing two different devices, both of which deliver 300mcg, but one via a 15mm needle and the other with a 23mm needle.

Condition or Disease	Intervention/Treatment	Phase
Anaphylaxis	Combination Product: Epipen 0.3mg; Combination Product: Emerade 300mcg; Combination Product: Emerade 500mcg	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics of Intramuscular Adrenaline in Food--Allergic Teenagers: Does Dose Matter?
• Actual Study Start Date: Nov 24, 2017
• Actual Primary Completion Date: Oct 2, 2018
• Actual Study Completion Date: Oct 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Visit 1: Emerade 300mcg then Epipen 0.3mg Visit 2: Emerade 500mcg	Combination Product: Epipen 0.3mg; Epipen 0.3mg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 300mcg; Emerade 300mcg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 500mcg; Emerade 500mcg auto-injector; Other Names: Epinephrine
Active Comparator: 2 Visit 1: Epipen 0.3mg then Emerade 300mcg Visit 2: Emerade 500mcg	Combination Product: Epipen 0.3mg; Epipen 0.3mg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 300mcg; Emerade 300mcg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 500mcg; Emerade 500mcg auto-injector; Other Names: Epinephrine
Active Comparator: 3 Visit 1: Emerade 500mcg Visit 2: Emerade 300mcg then Epipen 0.3mg	Combination Product: Epipen 0.3mg; Epipen 0.3mg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 300mcg; Emerade 300mcg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 500mcg; Emerade 500mcg auto-injector; Other Names: Epinephrine
Active Comparator: 4 Visit 1: Emerade 500mcg Visit 2: Epipen 0.3mg then Emerade 300mcg	Combination Product: Epipen 0.3mg; Epipen 0.3mg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 300mcg; Emerade 300mcg auto-injector; Other Names: Epinephrine ; Combination Product: Emerade 500mcg; Emerade 500mcg auto-injector; Other Names: Epinephrine

Outcome Measures

Primary Outcome Measures

1. Plasma Catecholamine Levels (Maximum Concentration, Cmax) [3 hours]

   Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

2. Plasma Catecholamine Levels (Time to Maximum Concentration, Tmax) [3 hours]

   Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

3. Plasma Catecholamine Levels (Maximum Concentration, Area-under-curve (AUC)) [3 hours]

   Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. Baseline corrected.

Secondary Outcome Measures

1. Change in Heart Rate Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions. [3 hours]

   Pharmacodynamics (heart rate) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

2. Change in Blood Pressure Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions. [3 hours]

   Pharmacodynamics (blood pressure) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

3. Change in Stroke Volume Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions. [3 hours]

   Pharmacodynamics (stroke volume) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

4. Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: Cmax) [3 hours]

   Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.

5. Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: Tmax) [3 hours]

   Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.

6. Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: AUC) [3 hours]

   Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.

7. Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Heart Rate) [3 hours]

   The pharmacodynamics (cardiovascular parameters: heart rate) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.

8. Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Blood Pressure) [3 hours]

   The pharmacodynamics (cardiovascular parameters: blood pressure) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.

9. Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Stroke Volume) [3 hours]

   The pharmacodynamics (cardiovascular parameters: stroke volume) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.

10. Adverse Events Following Self-administration of Adrenaline Via Autoinjector Device [1 day]

    Adverse events following self-administration of adrenaline via autoinjector device defined as in protocol

11. Change in Health-related Quality of Life (HRQL) as Measured Using FAQLQ [1 month]

    The impact of self-administration of adrenaline autoinjectors (in a non-reaction setting) on health-related quality of life (HRQL) measures in food-allergic teenagers and their parents.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 13 - 18 years inclusive

• Body mass >40kg

• Prescription of AAI due to physician diagnosis of Immunoglobulin E-mediated food allergy.

• Written informed consent from parent/guardian together with patient assent, for participants under 16 years of age. For young people age 16+ years, consent will be obtained from the participant themselves.

Exclusion Criteria:

• Known cardiac comorbidity (including hypertension, structural or electrophysiological diagnoses) or prescribed a medicine to control cardiovascular disease/hypertension.

• Known endocrine or renal disease

• Poorly controlled asthma requiring daily rescue treatment with a bronchodilator.

• Pregnancy

• Unwilling or unable to comply with study requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Imperial College London / Imperial College Healthcare NHS Trust	London		United Kingdom	W2 1NY

Sponsors and Collaborators

• Imperial College London

Investigators

• Principal Investigator: Paul J Turner, FRACP PhD, Imperial College London

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 29, 2017

More Information

Publications

None provided.

• Responsible Party: Paul Turner, MRC Clinician Scientist, Imperial College London
• ClinicalTrials.gov Identifier: NCT03366298
• Other Study ID Numbers: 17SM4137; 2017-003239-13; 232931
• First Posted: Dec 8, 2017
• Last Update Posted: Apr 5, 2021
• Last Verified: Mar 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Anaphylaxis; Epinephrine; Racepinephrine; Epinephryl borate

Study Results

Participant Flow

Arm/Group Title	Emerade 300 / Epipen 0.3mg / Emerade 500	Epipen 0.3mg / Emerade 300 / Emerade 500	Emerade 500 / Emerade 300 / Epipen 0.3mg	Emerade 500 / Epipen 0.3mg / Emerade 300
Arm/Group Description	Visit 1: Emerade 300mcg then Epipen 0.3mg Visit 2: Emerade 500mcg Epipen 0.3mg: Epipen 0.3mg auto-injector Emerade 300mcg: Emerade 300mcg auto-injector Emerade 500mcg: Emerade 500mcg auto-injector	Visit 1: Epipen 0.3mg then Emerade 300mcg Visit 2: Emerade 500mcg Epipen 0.3mg: Epipen 0.3mg auto-injector Emerade 300mcg: Emerade 300mcg auto-injector Emerade 500mcg: Emerade 500mcg auto-injector	Visit 1: Emerade 500mcg Visit 2: Emerade 300mcg then Epipen 0.3mg Epipen 0.3mg: Epipen 0.3mg auto-injector Emerade 300mcg: Emerade 300mcg auto-injector Emerade 500mcg: Emerade 500mcg auto-injector	Visit 1: Emerade 500mcg Visit 2: Epipen 0.3mg then Emerade 300mcg Epipen 0.3mg: Epipen 0.3mg auto-injector Emerade 300mcg: Emerade 300mcg auto-injector Emerade 500mcg: Emerade 500mcg auto-injector
Period Title: Overall Study
STARTED	3	3	3	3
COMPLETED	3	3	3	3
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall Cohort
Arm/Group Description	Overall study cohort
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	15.4
Sex: Female, Male (Count of Participants)
Female	5 41.7%
Male	7 58.3%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	12 100%
Body Mass Index (kg/m2) [Median (Full Range) ]
Median (Full Range) [kg/m2]	20

Outcome Measures

1. Primary Outcome

Title	Plasma Catecholamine Levels (Maximum Concentration, Cmax)
Description	Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Emerade 300mcg Injection	Emerade 500mcg Injection	Epipen 0.3mg
Arm/Group Description	Self-injection with Emerade 300mcg adrenaline auto-injector	Self-injection with Emerade 500mcg adrenaline auto-injector	Self-injection with Epipen 0.3mg adrenaline auto-injector
Measure Participants	12	12	12
Mean (95% Confidence Interval) [pg/ml]	218	394	290

2. Primary Outcome

Title	Plasma Catecholamine Levels (Time to Maximum Concentration, Tmax)
Description	Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Emerade 300mcg Injection	Emerade 500mcg Injection	Epipen 0.3mg
Arm/Group Description	Self-injection with Emerade 300mcg adrenaline auto-injector	Self-injection with Emerade 500mcg adrenaline auto-injector	Self-injection with Epipen 0.3mg adrenaline auto-injector
Measure Participants	12	12	12
Mean (95% Confidence Interval) [minutes]	9.6	8.5	5.9

3. Primary Outcome

Title	Plasma Catecholamine Levels (Maximum Concentration, Area-under-curve (AUC))
Description	Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. Baseline corrected.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Emerade 300mcg Injection	Emerade 500mcg Injection	Epipen 0.3mg
Arm/Group Description	Self-injection with Emerade 300mcg adrenaline auto-injector	Self-injection with Emerade 500mcg adrenaline auto-injector	Self-injection with Epipen 0.3mg adrenaline auto-injector
Measure Participants	12	12	12
Mean (95% Confidence Interval) [hr.pg/ml]	174	387	203

4. Secondary Outcome

Title	Change in Heart Rate Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions.
Description	Pharmacodynamics (heart rate) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Change in Blood Pressure Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions.
Description	Pharmacodynamics (blood pressure) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Change in Stroke Volume Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions.
Description	Pharmacodynamics (stroke volume) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: Cmax)
Description	Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: Tmax)
Description	Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: AUC)
Description	Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Heart Rate)
Description	The pharmacodynamics (cardiovascular parameters: heart rate) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Blood Pressure)
Description	The pharmacodynamics (cardiovascular parameters: blood pressure) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Stroke Volume)
Description	The pharmacodynamics (cardiovascular parameters: stroke volume) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg.
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Adverse Events Following Self-administration of Adrenaline Via Autoinjector Device
Description	Adverse events following self-administration of adrenaline via autoinjector device defined as in protocol
Time Frame	1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Emerade 300mcg Injection	Emerade 500mcg Injection	Epipen 0.3mg
Arm/Group Description	Self-injection with Emerade 300mcg adrenaline auto-injector	Self-injection with Emerade 500mcg adrenaline auto-injector	Self-injection with Epipen 0.3mg adrenaline auto-injector
Measure Participants	12	12	12
Pain at injection site	8 66.7%	6 NaN	7 NaN
Systemic AE (any)	4 33.3%	9 NaN	8 NaN
Palpitations	3 25%	4 NaN	3 NaN
Tremor	3 25%	7 NaN	8 NaN

14. Secondary Outcome

Title	Change in Health-related Quality of Life (HRQL) as Measured Using FAQLQ
Description	The impact of self-administration of adrenaline autoinjectors (in a non-reaction setting) on health-related quality of life (HRQL) measures in food-allergic teenagers and their parents.
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Within 24h of injection
Arm/Group Title	Emerade 300mcg Injection		Emerade 500mcg Injection		Epipen 0.3mg
Arm/Group Description	Self-injection with Emerade 300mcg adrenaline auto-injector		Self-injection with Emerade 500mcg adrenaline auto-injector		Self-injection with Epipen 0.3mg adrenaline auto-injector
All Cause Mortality
	Emerade 300mcg Injection		Emerade 500mcg Injection		Epipen 0.3mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)
Serious Adverse Events
	Emerade 300mcg Injection		Emerade 500mcg Injection		Epipen 0.3mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Emerade 300mcg Injection		Emerade 500mcg Injection		Epipen 0.3mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/12 (33.3%)		9/12 (75%)		8/12 (66.7%)
Cardiac disorders
Palpitations	3/12 (25%)	3	4/12 (33.3%)	4	3/12 (25%)	3
Nervous system disorders
Tremor	3/12 (25%)	3	7/12 (58.3%)	7	8/12 (66.7%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.