Clinical Trials Register

Summary
EudraCT Number:	2017-005060-18
Sponsor's Protocol Code Number:	2016AL002
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-01-09
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-005060-18

A.3

Full title of the trial

The Role of Uric Acid Metabolism in Pathogenesis of Anaphylaxis: the Effect of Allopurinol on Experimentally-induced Allergic Reaction to Peanut in Peanut Allergic Adults- a randomised, double-blind placebo-controlled, cross-over, single centre study.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The Role of Uric Acid Metabolism in Anaphylaxis: the Effect of Allopurinol on Allergic Reactions to Peanut in Peanut Allergic Adults.

A.3.2

Name or abbreviated title of the trial where available

RUPA v1.0

A.4.1

Sponsor's protocol code number

2016AL002

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Manchester University NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Manchester University NHS Foundation Trust
B.5.2	Functional name of contact point	Angela Kelsall
B.5.3	Address:
B.5.3.1	Street Address	Manchester CRF, North West Lung Research Centre, Southmoor Road
B.5.3.2	Town/ city	Manchester
B.5.3.3	Post code	M23 9LT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01612914168
B.5.6	E-mail	Angela.Kelsall@mft.nhs.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Allopurinol
D.2.1.1.2	Name of the Marketing Authorisation holder	Sharp Clinical Services (using overencapsulated Hexal AG)
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Allopurinol
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Allopurinol
D.3.9.1	CAS number	315-30-0
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Determination of the Lowest Observed Adverse Event level dose (LOAEL)of peanut in individual suffering with peanut allergy, after treatment with allopurinol.

E.1.1.1

Medical condition in easily understood language

Allergy to peanut

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001738
E.1.2	Term	Allergy
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10016946
E.1.2	Term	Food allergy
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine whether allopurinol given to peanut-allergic adults increases their tolerance to peanut during a peanut challenge, based on objective symptoms (e.g rash, angioedema, wheeze).

E.2.2

Secondary objectives of the trial

1. To determine whether allopurinol given to peanut-allergic adults increases their tolerance to peanut during a peanut challenge, based on subjective symptoms (e.g itch, stomachache, dizziness).
2. To determine whether allopurinol given to peanut-allergic adults reduces the severity of their symptoms during an open peanut challenge.
3. To determine if the use of allopurinol in peanut-allergic adults will cause more Adverse Events and Serious Adverse Events, compared to the use of placebo.

Exploratory objectives:
4. To identify differences in exploratory mechanistic studies: basophil activation test (BAT) and mast cell assays (Mast Cell Activation test), metabolomics and proteomic analysis.
5. To determine whether there are differences in the blood output of the heart when peanut-allergic adults are experiencing an allergic reaction and when not (positive vs negative challenge)- Exploratory objective depending on equipment availability.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All of the below must apply:
1. Males and females 18-55 years
2. Capable of giving informed consent
3. Previous medical history of allergic reaction to peanut
4. Doctor’s diagnosis of peanut allergy (either reported in the previous medical history or diagnosis of peanut allergy at the screening visit -V1- by a physician other than the study doctor, as described in the trial Case Report Forms).
5. Reaction history should not be solely indicative of oral allergy syndrome (that is, only localised symptoms in and/or around the oral cavity)
6. Positive skin prick test result to peanut > 3mm and/or specific IgE to peanut ≥0.4kUa/L (ImmunoCAP Phadia)
7. Participant able to swallow capsules
8. Baseline systolic blood pressure of equal or over 100mmHg
9. Participant should be able to receive the following rescue medication, if needed (They should not have a contraindication to the use of this medication, as per study doctor’s judgement).
-Inhaled and IV salbutamol;
-inhaled and IM adrenaline;
-oral and IV antihistamines;
-Inhaled, oral or other systemic (e.g parenteral) corticosteroids.
10. Negative HLA-B*5801 status
11. Positive result on the peanut day of the DBPCFC (visits two and three), and the positive result to be on any dose up to and including the 100mg dose of peanut protein.
12. Negative challenge result on the placebo day of the DBPCFC (visits two and three).

E.4

Principal exclusion criteria

Any of the below excludes someone from participating:
1. Females must be non-pregnant with no intention of becoming pregnant during the study.
Women of childbearing potential (<1 year post-menopausal) must agree to use (or are already on) one of the following acceptable birth control methods whilst they are enrolled in the trial:
-True complete abstinence when this is in line with the preferred and usual lifestyle of the participant;
-surgical sterilisation of either the female participant in the study or of her male partner, if he is the sole partner of the participant;
-established hormonal contraception (implantable, patch, oral or intramuscular [IM]) administered for at least one month prior to study medication administration;
-intrauterine device (IUD) or intrauterine system (IUS) with a failure rate of less than 1% per year inserted by a qualified physician, at least one month prior to study medication administration;
-double barrier method: condom and occlusive cap (diaphragm) with spermicidal foam/gel/film/cream/suppository

2. Serum pregnancy test will be conducted at screening, and urine pregnancy tests (sticks) will be conducted at all other visits apart from the two follow-up visits. In the event of a positive test, the participant will be withdrawn from the trial and the pregnancy will be reported to the Sponsor.

3. Females must be non-lactating.
Reports indicate that allopurinol and oxypurinol are excreted in human breast milk. Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxypurinol have been demonstrated in breast milk from a woman taking allopurinol 300 mg/day. There is no data regarding the effects of allopurinol or its metabolites on the breastfed baby.

4. The participants should not be on medication that is contraindicated for the IMP or for the procedures of the trial:
These are:
-(due to interactions with allopurinol): Salicylates (e.g Aspirin), Uricosuric agents (e.g. febuxostat, probenecid), Phenytoin, Theophylline, Ampicillin, amoxicillin (e.g co-amoxiclav), Coumarin Anticoagulants (e.g. warfarin), Immunosuppressant and immunomodulatory drugs (e.g 6-mercaptopurine, azathioprine, cyclophosphamide, cyclosporin), doxorubicin, bleomycin, procarbazine, mechlorethamine, Antiretroviral drugs (e.g Didanosine), diuretics, Chlorpropamide, Captopril, Vidarabine (adenine arabinoside), ACE inhibitors.
-(due to interference with the study design): Beta-blocking agents, ACE inhibitors, Oral or other systemic corticosteroids, anti-IgE (omalizumab), SSRI antidepressant medication.

Also, the participant should not be on allopurinol.

5. Participants should not have participated in other clinical trials involving the use of an Investigational Medicinal Product (IMP) within the past 3 months.
6. There should be no previous history of a severe allergic reaction to peanut with confirmed lower respiratory symptoms or documented hypotension.
7. FEV1 should be no less than 70% predicted for age, gender and height
8. Participants should not be unable or unlikely to follow the trials procedures due to any issue (including communication issues such as language barrier).
9. The participant should not have:
-Uncontrolled asthma, as defined by an Asthma Control Test (ACT) of less than 20 score, unless the failure to reach this threshold is due to consistent scheduled use of short-acting bronchodilators.
-Active chronic urticaria and angioedema
-Uncontrolled atopic dermatitis as defined by an ‘Objective SCORAD’ score of over 40.
-Mastocytosis
-Any medical condition that by study doctors judgement would compromise their safety or the reliability of the findings (including but not restricted to mast cell disorders, immune system disorders, malignancies current or past, and others)
-BMI >30
-Any contraindication to the administration of adrenaline (e.g ischaemic heart disease, poorly controlled hypertension or cardiac arrhythmia)
-History of, or evidence of current use of drugs of abuse.
-Allergy to any excipient of the IMP (These are: Lactose Monohydrate, Colloidal Anhydrous Silica, Maize Starch, Powdered cellulose, Sodium Starch Glycolate (Type A), Sodium Lauryl Sulphate, Povidone (E1201), Magnesium Stearate (E572)
-Food Allergy to the other ingredients (apart from peanut) of the food matrix used for the challenge meal
-Lactose intolerance
-Galactose intolerance
-Glucose-galactose malabsorption
-Lapp lactase deficiency
-Malignant disease
-Myeloproliferative disease
-Lesch-Nyhan syndrome
-Abnormal liver function tests (any of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase, >1.5 x upper limit of normal or < 0.5 lower limits of normal (if applicable); Abnormal renal function (any of urea, creatinine, blood urea nitrogen, uric acid >1.5 upper limit of normal or < 0.5 lower limit of normal (if applicable); and/or eGFR <60 ml/min

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is the mean within-participant change in peanut dose required to induce objective symptoms, during a peanut challenge, which will take place at the end of each treatment period. In more detail, this is the difference in the amount of peanut protein (mgs) that brings about objective symptoms in each participant between the two food challenges carried out at the end of the placebo and allopurinol treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

This endpoint will be evaluated at the end of treatment periods 1 and 2 (visits 5 and 7) after an open peanut challenge that will be conducted during each of these visits.

E.5.2

Secondary end point(s)

Secondary endpoints/outcomes

1. The mean within-participant change in the threshold dose of peanut (LOAEL dose) required to induce subjective symptoms during an open peanut challenge while receiving allopurinol, as compared to placebo.
2. The mean within-participant change in severity of symptoms during an open peanut challenge after treatment with allopurinol and placebo, as assessed by variable severity scores (including Ifaam severity scores).
3. The difference in the number of Adverse Events and Serious Adverse Events between different treatments (allopurinol vs placebo).

Exploratory endpoints/outcomes

1. We will seek to identify novel proteomic/metabolomic markers associated with allergy/tolerance to peanut through an untargeted analysis. Blood will be collected throughout the challenges and analysed to that end.

2. Depending on time and equipment availability, while undergoing the peanut challenge we intend to apply on the chest of the participants the touch electrodes of a CE-licenced device currently used in routine practice for hemodynamic monitoring (Cheetah StarlingTM hemodynamic monitor or equivalent licenced device). These are non-invasive devices that monitor and display a patient’s Cardiac Output (CO) in Ltr/Min, with additional functions that measure and display blood pressure (diastolic, systolic, and mean) and heart rate. These devices display hemodynamic parameters: Cardiac Index, Stroke Volume, Stroke Volume Index, Stroke Volume Variation, Heart Rate, Ventricular Ejection Time, and others. Changes in cardiac output measurements will not be used to define positivity of the challenge or support any clinical decision; the data may be collected and analysed to explore this hypothesis (that cardiac blood output changes are associated with allergic reaction/challenge positivity). The data collection for this output and subsequent analysis will be dependent on the availability of the device. This outcome is expressed as the mean within-participant difference in blood output of the heart when experiencing an allergic reaction or not (positive vs negative challenge). This outcome is expressed numerically in blood volume per time (L x min-1), and it is highly accurate.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints/outcomes

1. This endpoint will be evaluated at the end of treatment periods 1 and 2 (visits 5 and 7) after an open peanut challenge that will be conducted during each of these visits.
2. This endpoint will be evaluated at the end of treatment periods 1 and 2 (visits 5 and 7) after an open peanut challenge that will be conducted during each of these visits.
3. This endpoint will be evaluated at the end of treatment periods 1 and 2 (visits 5 and 7) after receiving the diaries where AEs will be recorded.

Exploratory endpoints/outcomes

1. Blood samples for proteomic and metabolomic analysis will be collected at visits 1, 2, 3, 5, and 7.
2. Nikom monitoring will take place durin the challenges at visits 2,3 5 and 7.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of the trial is defined as the date of the data lock.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1