Determination of the Lowest Observed Adverse Event level dose (LOAEL)of peanut in individual suffering with peanut allergy, after treatment with allopurinol. MedDRA version: 20.0 Level: LLT Classification code 10001738 Term: Allergy System Organ Class: 10021428 - Immune system disorders MedDRA version: 20.0 Level: PT Classification code 10016946 Term
Conditions
Interventions
Trade Name: Allopurinol
Product Name: Allopurinol
Pharmaceutical Form: Capsule
INN or Proposed INN: Allopurinol
CAS Number: 315-30-0
Sponsors
Manchester University NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
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). Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
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 s
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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).; Secondary Objective: 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. ;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.;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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
United Kingdom
Contacts
Public ContactAngela Kelsall
Manchester University NHS Foundation Trust
Outcome results
None listed