Study on the effectiveness of a low histamine diet and diamino oxidase enzyme supplementation in patients with histamine intolerance
| ISRCTN | ISRCTN64888465 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN64888465 |
| ClinicalTrials.gov (NCT) | Nil known |
| Clinical Trials Information System (CTIS) | Nil known |
| Protocol serial number | DAO/311776 |
| Sponsor | DR Healthcare España, S.L.U |
| Funder | DR Healthcare España, S.L.U |
- Submission date
- 25/07/2022
- Registration date
- 06/09/2022
- Last edited
- 04/07/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Other
Plain English summary of protocol
Background and study aims
Histamine intolerance is due to an inability to metabolize histamine from the diet, mainly due to reduced activity of the enzyme diamine oxidase (DAO) in the intestine, which causes an increase in the blood concentration of this amine and the appearance of clinical symptoms such as abdominal pain, diarrhea, vomiting, constipation, skin problems (urticaria, dermatitis or pruritus), respiratory problems (sneezing, rhinitis, nasal congestion and asthma), cardiovascular problems and/or headache. Many patients with this disorder often have more than one of these symptoms at a time. The aim is to study the effectiveness of the low-histamine diet and/or DAO enzyme supplementation in the treatment of symptoms associated with histamine intolerance due to DAO deficiency.
Who can participate?
Adults over 18 years of age with two or more symptoms associated with histamine intolerance (headache, dermatological, respiratory, and digestive) and altered plasma DAO enzyme activity and/or have any of the genetic variants of DAO deficiency
What does the study involve?
Participants are randomly divided into eight treatment groups:
1. Placebo group: participants will receive a gastro-resistant mini tablet (placebo) (three times/day, 20 minutes before each meal) and follow a Mediterranean style diet.
2. Diet group: participants will receive a gastro-resistant mini tablet (placebo) three times/day (20 minutes before each meal) and will follow a low histamine diet.
3. Pig DAO supplement + Mediterranean diet: participants will receive a gastro-resistant mini tablet with the animal DAO enzyme (4.2 mg) three times/day (20 minutes before each meal) and will follow a Mediterranean style diet.
4. Pig DAO supplement + low histamine diet: participants will receive a gastro-resistant mini tablet with the animal DAO enzyme (4.2 mg) three times/day (20 minutes before each meal) and will follow a low histamine diet.
5. Vegetable DAO supplement + Mediterranean diet: participants will receive a gastro-resistant mini tablet with the vegetable DAO enzyme (4.2mg) three times/day (20 minutes before each meal) and will follow a Mediterranean style diet.
6. Vegetable DAO supplement + low histamine diet: participants will receive a gastro-resistant mini tablet with the vegetable DAO enzyme (4.2 mg) three times/day (20 minutes before each meal) and will follow a low histamine diet.
7. High dose of vegetable DAO supplement + Mediterranean diet: participants will receive a gastro-resistant mini tablet with the high-dose vegetable DAO enzyme (8.4 mg) three times/day (20 minutes before each meal) and will follow a Mediterranean style diet.
8. High dose of vegetable DAO supplement + low histamine diet: participants will receive a gastro-resistant mini tablet with the high dose DAO enzyme (8.4 mg) three times/day (20 minutes before each meal) and will follow a diet low in histamine.
The maximum duration of the intervention will be 3 months from the beginning until the end. The researchers will check whether or not the activity of the DAO enzyme is altered, and a blood sample will be taken to perform a genetic study. After signing the general consent of the study, participants will have a total of four visits (V1, V2, V3 and V4). At the V1 visit (at baseline) participants will be given an information collection notebook and assigned to one of the two groups: DAO or placebo. They will also receive dietary recommendations that may include:
1. Low histamine diet (DAO-DIET group and DIET group)
2. Standardized Mediterranean-style diet (PLACEBO group and DAO group)
In addition, at baseline, the following information will be collected: symptom assessment and quality of life questionnaires, dietary questionnaire (weekly registration). Blood, urine, and feces samples will be also collected.
At the remaining visits (V2, V3 and V4) the researchers will collect the same information as in the V1 visit although the determination of the DAO activity and microbiota will only be carried out in V1 and V4. Before all of these visits participants must fast, with a minimum fasting time of 10 hours.
What are the possible benefits and risks of participating?
Participation will allow the researchers to evaluate:
1. The effect of diet and DAO supplementation in the treatment of symptoms associated with histamine intolerance
2. The validity of urinary determination of histamine metabolites as a marker of histamine intolerance
3. The role that the gut microbiota may have in histamine intolerance.
4. The validity of single nucleotide polymorphisms (SNPs) as genetic markers of histamine intolerance due to DAO deficiency
In addition, the study can help participants to better understand their state of health, although it is also possible that they may not get any direct benefit from participating. In any case, participants will contribute to a better understanding of the effect of a food supplement on the improvement of the symptoms of histamine intolerance.
The study does not pose any risk to the participants' health since the amount of blood extracted will be slightly higher than the amount extracted when performing a complete analysis. The removal of the blood sample can cause a burning sensation at the point where the needle is inserted into the skin and can cause a small bruise that disappears within a few days. More rarely it can cause brief dizziness.
Where is the study run from?
Hospital Clínic de Barcelona (Spain)
When is the study starting and how long is it expected to run for?
June 2022 to June 2027
Who is funding the study?
DR Healthcare España, S.L.U (Spain)
Who is the main contact?
1. Dr Ramon Estruch Riba, restruch@clinic.cat
2. Dra. M. Carmen Vidal Carou, mcvidal@ub.edu
Contact information
Principal investigator
Department of Internal Medicine
Hospital Clinic
Villarroel 170
Barcelona
08036
Spain
 ORCID ID |
0000-0003-1260-4445 |
|---|---|
| Phone | +34 (0)93 2275745 |
| restruch@clinic.cat |
Principal investigator
Campus de l’Alimentació de la Universitat de Barcelona
Avda. Prat de la Riba, 171
Santa Coloma de Gramenet
08921
Spain
| ORCID ID |
0000-0002-7269-8626 |
|---|---|
| Phone | +34 (0)93 4033786 |
| mcvidal@ub.edu |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Prospective single-centre double-blind randomized placebo-controlled trial |
| Secondary study design | Randomised controlled trial |
| Participant information sheet | 42124_PIS_V3.pdf |
| Scientific title | Low histamine diet and diamino oxidase enzyme supplementation |
| Study acronym | DAO |
| Study objectives | The effectiveness of a low-histamine diet and diamino oxidase (DAO) supplements has been demonstrated in small clinical studies published in recent years, most of them reporting favourable results in terms of improvement or total remission of symptoms. However, these dietary studies have certain limitations, mainly in involving a small group of patients and/or a short intervention period. Therefore, current dietary management strategies for histamine intolerance still require more controlled, randomized, double-blind, and more ambitious, well-designed clinical trials to definitively confirm their effectiveness. |
| Ethics approval(s) | Approved 07/07/2022, Institutional Review Board of the Hospital Clinic of Barcelona (Hospital Clínic De Barcelona, Villarroel, 170 – 08036 Barcelona, Spain; +34 (0)93 227 54 00; CEIC@clinic.cat), ref: HCB/2022/0437 |
| Health condition(s) or problem(s) studied | Symptoms associated with histamine intolerance due to DAO deficiency |
| Intervention | A total of 400 patients divided into eight treatment groups (50 individuals per group) will be assigned randomly using a computer-generated random number table: 1. PLACEBO GROUP: 50 participants will receive a gastro-resistant mini tablet (placebo) (three times/day, 20 minutes before each meal) and follow a Mediterranean-style diet. 2. DIET GROUP: 50 participants will receive a gastro-resistant mini tablet (placebo) three times/day (20 min before each meal) and will follow a low histamine diet. 3. PIG DAO SUPPLEMENT + MEDITERRANEAN DIET: 50 participants will receive a gastro-resistant mini tablet with the animal DAO enzyme (4.2 mg) three times/day (20 min before each meal) and will follow a Mediterranean-style diet. 4. PIG DAO SUPPLEMENT + LOW HISTAMINE DIET: 50 participants will receive a gastro-resistant mini tablet with the animal DAO enzyme (4.2 mg) three times/day (20 min before each meal) and will follow a low histamine diet. 5. VEGETABLE DAO SUPPLEMENT + MEDITERRANEAN DIET: 50 participants will receive a gastro-resistant mini tablet with the vegetable DAO enzyme (4.2 mg) three times/day (20 min before each meal) and will follow a Mediterranean-style diet. 6. VEGETABLE DAO SUPPLEMENT + LOW HISTAMINE DIET: 50 participants will receive a gastro-resistant mini tablet with the vegetable DAO enzyme (4.2 mg) three times/day (20 min before each meal) and will follow a low histamine diet. 7. HIGH DOSE OF VEGETABLE DAO SUPPLEMENT + MEDITERRANEAN DIET: 50 participants will receive a gastro-resistant mini tablet with the high-dose vegetable DAO enzyme (8.4 mg) three times/day (20 min before each meal) and will follow a Mediterranean-style diet. 8. HIGH DOSE OF VEGETABLE DAO SUPPLEMENT + LOW HISTAMINE DIET: 50 participants will receive a gastro-resistant mini tablet with the high-dose DAO enzyme (8.4 mg) three times/day (20 min before each meal) and will follow a diet low in histamine. The interventions will last for a period of 3 months, after which they will be re-evaluated by the medical team to assess the degree of effectiveness of the administered intervention. The combination of these groups will allow: 1. The comparison of the PLACEBO and DAO groups will allow the researchers to determine the effect of DAO supplementation on the reduction of symptoms. 2. The comparison of the PLACEBO and DIET groups will allow the researchers to determine the effect of diet on the reduction of symptoms. 3. The comparison of the DAO and DAO-DIET groups will allow the researchers to determine the synergistic effect between diet and DAO supplementation. 4. The comparison of the DAO and DIET groups will allow the researchers to determine the effect of the two treatments separately. 5. The comparison of the PIG DAO and VEGETABLE DAO groups will allow the researchers to determine which of the two types of DAO is more effective. 6. The comparison of the groups DAO VEGETAL and DAO VEGETAL IN HIGH DOSE will allow the researchers to determine which of the two doses is more effective. |
| Intervention type | Mixed |
| Primary outcome measure(s) |
1. Plasma DAO enzyme activity measured using radioimmune assay (REA-HIT test) at the recruitment visit and 3 months |
| Key secondary outcome measure(s) |
1. Metabolomic markers in urine (histamine, methylhistamine, imidazole acetic acid, methyl-imidazole acetic acid) measured using ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) (untargeted) at baseline, 1, 2 and 3 months |
| Completion date | 07/06/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | All |
| Target sample size at registration | 400 |
| Key inclusion criteria | 1. Adults over 18 years of age 2. Recent history of two or more symptoms associated with histamine intolerance (headache, dermatological, respiratory, and digestive) 3. Present altered plasma DAO enzyme activity and/or have any of the genetic variants of DAO deficiency: 3.1. SNP-type variants associated with reduced levels of DAO activity (oral mucosal smear or blood) 3.2. rs10156191 3.3. rs1049742 3.4. rs1049793 3.5. rs2052129 4. Not having started dietary treatment (low histamine diet/DAO enzyme supplementation) before starting the study |
| Key exclusion criteria | 1. Food and/or environmental allergies 2. Have taken pharmacological treatment with antibiotics or probiotic supplements in the last month before the start of the study 3. Being pregnant |
| Date of first enrolment | 19/09/2022 |
| Date of final enrolment | 07/03/2027 |
Locations
Countries of recruitment
- Spain
Study participating centres
Barcelona
08036
Spain
Barcelona
08921
Spain
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Available on request |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Ramon Estruch (restruch@clinic.cat) and Dr Mari Carmen Vidal (mcvidal@ub.edu). There are restrictions on the availability of data due to the signed consent agreements around data sharing, which only allow access to external researchers for studies following the project's purposes. Requestors wishing to access the DAO trial data used in this study can make a request to restruch@clinic.cat and mcvidal@ub.edu. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 3 | 26/07/2022 | No | Yes | |
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Protocol file | version 3 | 26/07/2022 | No | No | |
| Study website | Study website | 11/11/2025 | 11/11/2025 | No | Yes |
Additional files
- 42124_PROTOCOL_V3.pdf
- Protocol file
- 42124_PIS_V3.pdf
- Participant information sheet
Editorial Notes
04/07/2025: The following changes were made to the trial record:
1. The date of final enrolment was changed from 07/03/2025 to 07/03/2027.
2. The completion date was changed from 07/06/2025 to 07/06/2027.
3. The plain English summary was updated to reflect these changes.
26/07/2022: Trial's existence confirmed by the Institutional Review Board of the Hospital Clinic of Barcelona.
