Vitamin A for viral smell loss
| ISRCTN | ISRCTN13142505 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN13142505 |
| IRAS number | 294741 |
| Secondary identifying numbers | 1.1, IRAS 294741, NIHR201978, CPMS 50043 |
- Submission date
- 23/02/2021
- Registration date
- 10/08/2021
- Last edited
- 03/07/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Ear, Nose and Throat
Plain English Summary
Background and study aims
Loss of smell affects an estimated 5% of people leading to depression, anxiety and isolation as well as changes in weight due to reduced appetite. Viral infections in the nose, including common colds and COVID-19, are the second most common cause of this smell loss. A recent limited study in Germany using vitamin A nasal drops showed that those in the treated group improved twice as much as those in the untreated group, lasting at least 10 months. It is thought that this treatment works to help repair tissues in the nose damaged by viruses. This work will explore whether this is correct. The aim of this study is to find out whether there is an increase in the size and activity of damaged smell pathways in patients’ brains when they are treated with vitamin A nasal drops. This would show recovery of the damage caused by common viral infections in the nose.
Who can participate?
People with smell loss due to a previous viral infection
What does the study involve?
People can join the study when they attend the Norfolk Smell & Taste Clinic, or through Fifth Sense, the UK smell and taste disorders charity. Those able to join will be randomly allocated to one of two groups: 38 patients will receive a 12-week course of nasal vitamin A drops and 19 will receive standard care which is currently no treatment. Both sets of patients will receive brain scans, before and after the 12-week interval. The researchers will look for changes in the size of the olfactory bulb (an area above the nose where the smell nerves join together and connect to the brain), that can be measured. They will also look at activity in areas of the brain linked to recognising smells. The patients will be smelling odours (roses and rotten eggs) while special brain scans are taken that use a magnetic coil to create images. A smell test and a questionnaire will also measure smell loss and its daily impact at the two visits.
What are the possible benefits and risks of participating?
There is a possibility of minor side-effects from using the drops such as irritation of the nose. Some people may also feel claustrophobic inside the MRI scanner; participants who suffer from claustrophobia should discuss this with the research team. Women who are pregnant or planning to become pregnant should not participate in the study as there is a risk of vitamin A causing harm to the unborn child.
Where is the study run from?
University of East Anglia (UK)
When is the study starting and how long is it expected to run for?
February 2021 to August 2024
Who is funding the study?
National Institute of Health Research (NIHR) (UK)
Who is the main contact?
Prof. Carl Philpott
c.philpott@uea.ac.uk
Contact information
Public
University of East Anglia
Norwich
NR4 7TJ
United Kingdom
| Phone | +44 (0)1603591105 |
|---|---|
| C.Philpott@uea.ac.uk |
Study information
| Study design | Mechanistic proof of concept double-blind placebo-controlled randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | 39523_PIS_V1.3_02Aug21.docx |
| Scientific title | A proof-of-concept study for vitamin A nasal drops in post-viral olfactory loss |
| Study acronym | APOLLO |
| Study hypothesis | It is theorised that topical Vitamin A treatment will encourage regeneration of the olfactory epithelium which is damaged by respiratory viruses responsible for the common cold and help to restore the sense of smell in sufferers. |
| Ethics approval(s) | Approved 16/08/2021, West Midlands - Black Country Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; +44 (0)207 104 8010; blackcountry.rec@hra.nhs.uk), ref: 21/WM/0179 |
| Condition | Post-viral (infectious) olfactory loss/dysfunction (PVOL/PIOD) |
| Intervention | The researchers will invite people who have been found to have smell loss due to a previous viral infection to join the study. They can join when they attend the Norfolk Smell & Taste Clinic, or through Fifth Sense, the smell and taste disorders charity. Those able to join will be randomly allocated to one of two groups: 38 patients will receive a 12-week course of nasal vitamin A drops (Vitadral Topfen Oral Drops [Aristo Pharma, Berlin, Germany]) and 19 will receive standard care which is currently no treatment. Both sets of patients will receive brain scans, before and after the 12-week interval. The researchers will look for changes in the size of the olfactory bulb. They will also look at activity in areas of the brain linked to recognising smells. The patients will be smelling odours (roses and rotten eggs) while brain scans are taken that use a magnetic coil to create images. A smell test and a questionnaire will also measure smell loss and its daily impact at the two visits. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Vitadral Topfen Oral Drops (vitamin A) |
| Primary outcome measure | Olfactory bulb volume measured using MRI scan at 3 months |
| Secondary outcome measures | 1. Right orbital sulcus volume measured using MRI scan at baseline and 3 months 2. Blood-oxygen-level-dependant (BOLD) signal in primary olfactory areas (amygdala, piriform, and insula) measured using fMRI scan at baseline and 3 months 3. Olfactory function measured using the psychophysical smell test (TDI) score at baseline and 3 months 4. Olfactory-related quality of life measured using the olfactory disorders questionnaire (ODQ) score at baseline and 3 months |
| Overall study start date | 16/02/2021 |
| Overall study end date | 31/08/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 57 |
| Total final enrolment | 57 |
| Participant inclusion criteria | 1. A partial or total loss of smell due to post-viral olfactory loss as confirmed on history, examination and with a smell test (TDI) score of <31/48 2. Within 3 years of the precipitating viral infection |
| Participant exclusion criteria | 1. Participants with a history of: 1.1. Chronic rhinosinusitis with/without nasal polyposis 1.2. Severe nasal septal deviation 1.3. Major prior head injury 1.4. Congenital olfactory loss 1.5. Use of concurrent intranasal medications or possible medications know to affect olfaction 1.6. Chronic renal disease 1.7. Chronic hepatic disease 1.8. Allergy to peanuts, soy or vitamin A (drops contain peanut oil) 2. Significant medical, surgical or psychiatric disease that in the opinion of the PI would affect subject safety or influence the study outcomes 3. Current taking oral vitamin A supplements 4. Age less than 18 years 5. Pregnant women 6. Depending on the situation with regards to nasal endoscopy and COVID-19 at the time of study commencement we will exclude the following based on the endoscopy or the initial MRI scan: 6.1. Participants with any endoscopic findings of: 6.1.1. Chronic rhinosinusitis with/without nasal polyposis 6.1.2. Severe nasal septal deviation (preventing passage of 4mm endoscope) 6.1.3. Other inflammatory sinonasal disease 6.2. Participants with MRI changes indicating oedema in the sinuses and/or olfactory clefts 7. Participants must not have any metal implants, such as a pacemaker etc, as is standard for MRI scanning. 8. Any participants who move excessively during scanning 9. Any participant with a combined OBV of >85 mm³ as it is unlikely they will demonstrate a significant increase in overall volume based on previous studies of OBV |
| Recruitment start date | 01/02/2022 |
| Recruitment end date | 30/04/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Norwich
NR4 7TJ
United Kingdom
Sponsor information
University/education
Norwich Research Park
Norwich
NR4 7TJ
England
United Kingdom
| Phone | +44 (0)1603 597948 |
|---|---|
| researchsponsor@uea.ac.uk | |
| Website | https://www.uea.ac.uk/ |
"ROR" |
https://ror.org/026k5mg93 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/12/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Specialty specific dissemination: The researchers anticipate dissemination through traditional channels including conference presentations, abstracts and open-access peer-reviewed publications. These will be targeted at specialist ENT and chemosensory experts. As a proof of concept study, the study findings will provide a benchmark for the next stage of the research. Dissemination in the public domain: Beyond informal and specialist publications, the researchers also plan to use wider communication channels and in conjunction with PPI input and they will utilise existing websites such as Fifth Sense to engage the public. Fifth Sense, where Prof. Philpott is the Director of Research and Medical Affairs (and a trustee), has a track record in public engagement, both with its members and the wider public (see https://www.fifthsense.org.uk/fifth-sense-news/). There has recently been heightened interest in smell loss in relation to COVID-19 as evident from the wide uptake of recent articles written by Prof. Philpott (e.g. https://theconversation.com/coronavirus-loss-of-smell-and-taste-reported-as-early-symptoms-of-covid-19-134564) - read by over 370,000 globally). Follow up articles to announce progress in relation to the potential for therapeutic interventions for PVOL will be expected to be popular in light of this. Projected outputs: The researchers expect the outputs of this study to enable a subsequent randomised controlled trial of Vitamin A versus placebo with an internal pilot to establish the place of a suitable placebo. As mentioned at the top of the application. The PPI input will ensure that our outputs are also publicly available in a way that is meaningful and relevant to patients. As aforementioned in the application, the researchers had previously submitted a study proposal to the NIHR EME funding stream to conduct a randomised controlled trial but were asked to provide more proof of concept. They have already prepared a draft RCT proposal in partnership with the Norwich Clinical Trials Unit and would plan to develop this further in light of the findings of this proof of concept study. Expected research outputs: 1. Open access publications in appropriate journals such as Rhinology and Chemical Senses 2. Conference presentations and proceedings 3. Funding proposal for a randomised controlled trial |
| IPD sharing plan | Requests for access to trial data will be considered, and approved in writing where appropriate, after formal application to the trial management group (TMG). Considerations for approving access are documented in the TMG Terms of Reference. The final trial dataset will be held at Norwich Clinical Trials Unit on a secure server and will be accessible by the research team. The University of East Anglia will own the foreground IP (as the employer of the Chief Investigator) and James Paget University Hospitals will have rights via a royalty-free licence to use for their own non-commercial purposes and patient benefit. Any exploitation shall be managed through the University’s Intellectual Property Team who shall put into place appropriate royalty share agreements although it is not anticipated that this will be the case as further research will be required. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 1.3 | 02/08/2021 | 06/08/2021 | No | Yes |
| Protocol file | version 1.2 | 12/05/2021 | 06/08/2021 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 12/10/2023 | 16/10/2023 | Yes | No |
Additional files
Editorial Notes
03/07/2024: The following changes were made:
1. The intention to publish date was changed from 30/09/2024 to 31/12/2024.
2. The overall study end date has been changed from 31/07/2024 to 31/08/2024.
3. The total final enrolment was added.
03/01/2024: The following changes have been made:
1. The recruitment end date has been changed from 30/01/2024 to 30/04/2024.
2. The overall study end date has been changed from 30/03/2024 to 31/07/2024 and the plain English summary updated accordingly.
16/10/2023: Publication reference added.
05/06/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2023 to 30/01/2024.
2. The overall end date was changed from 30/09/2023 to 30/03/2024.
3. The intention to publish date was changed from 31/03/2024 to 30/09/2024.
4. The plain English summary was updated to reflect these changes.
14/02/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 28/02/2023 to 30/06/2023.
2. The overall end date was changed from 30/06/2023 to 30/09/2023.
3. The intention to publish date was changed from 31/12/2023 to 31/03/2024.
4. The plain English summary was updated to reflect these changes.
08/12/2022: The following changes were made to the trial record:
1. The overall end date was changed from 31/05/2023 to 30/06/2023.
2. The plain English summary was updated to reflect these changes.
02/11/2022: The following changes were made to the trial record:
1. The recruitment end date has been changed from 30/11/2022 to 28/02/2023.
2. The overall trial end date has been changed from 31/03/2023 to 31/05/2023.
3. The intention to publish date has been changed from 30/06/2023 to 31/12/2023.
10/08/2022: The following changes have been made:
1. The recruitment end date has been changed from 31/08/2022 to 30/11/2022.
2. The overall trial end date has been changed from 31/12/2022 to 31/03/2023 and the plain English summary updated accordingly.
3. The intention to publish date has been changed from 31/03/2023 to 30/06/2023.
01/02/2022: The following changes have been made:
1. The ethics approval has been added.
2. The trial website has been changed from http://www.uea.ac.uk/rhinology-group to https://rhinology-group.uea.ac.uk/.
3. The recruitment start date has been changed from 02/01/2022 to 01/02/2022.
03/09/2021: Sponsor contact details updated.
06/08/2021: Trial's existence confirmed by the NIHR.
