A small-scale test of the intervention, trial design and methods to explore the cumulative effectiveness of two commonly used prescribing strategies for patients with long COVID: Treatment A - prescribing a specific homeopathic remedy for long COVID, plus or minus Treatment B - a course of individually tailored treatment by a homeopath. Both interventions compared to usual care

We will use Trials within cohorts (TwiCs) methodology to test the cumulative effectiveness of two homeopathic prescribing strategies: Treatment A -the effectiveness of prescribing a specific homeopathic remedy for long COVID, plus or minus Treatment B - a course of individually tailored treatment by a homeopath. We will compare Treatment A, and Treatment A + B, to no homeopathic treatment.

Up to 120 participants with confirmed long COVID will be recruited to an observational cohort (the long COVID POD). Their self-reported symptoms Measure Yourself Medical Outcome Profile (MYMOP) and Wellbeing Health Survey Questionnaire (SF-36) will be measured via on-line questionnaires using the JISC on-line platform. All eligible participants will complete questionnaires monthly for the duration of the study. After completing questionnaires twice, eligible cohort participants will be randomized into two groups: one group will be offered Treatment A. The other group will remain in the observational cohort.

After one month, the Treatment A group will be further randomized into two groups, stratified according to improvement in their self-reported symptoms (MYMOP <> 30%). One group will continue with Homeopathic treatment A. The other group will be offered Homeopathic Treatment B.

Recruitment will continue until at least 60 participants have complied with Treatment A and completed at least 4 questionnaires; and 30 of them have also complied with Treatment B.

Randomisation will be performed by the study statistician and retained on his premises. : Participants will be recruited in cohorts of 15. For each cohort, all 126,126 ways of dividing this into three groups of 5 will be examined; the arrangement which displays the least differences in age, sex distribution, duration of illness and initial symptom severity will be selected, and randomly allocated to either treatment or usual care. One group will be randomly allocated to usual care, and the remaining two merged to comprise the treatment group. For outcome analysis, all cohorts will be combined. A similar procedure will be used for the second randomisation.

Numbers and reason for refusing the offer will be recorded. Participants randomised to Treatment A will be allocated a homeopath who will contact the participant and explain to them that they will be sent a homeopathic remedy. The homeopath will be the first point of call for questions, adverse events or decisions to vary the potency and frequency of the prescription.

The homeopath will order the remedy from Ainsworths Homeopathic Pharmacy to be sent to the participant, and check that it has been received. Ainsworths will send one month's supply of the remedy to participants with instructions on how to take it.

After one month, participants will complete the long COVID questionnaire again (T3). Their MYMOP T3 results will be compared to their baseline (average of T1 & T2) results.

Treatment A group will be randomized again, stratified according to their MYMOP score change (<> 30%) to minimise variance in recorded changes in MYMOP symptoms.

Participants will be randomised to either continue with Treatment A or offered Treatment B.

Delivery of Treatment B Participants will be offered four consultations with their designated homeopath at 4-6 week intervals. The initial consultation will be up to 1½ hours long and follow up appointments 30-40 minutes. Appointments will take place via zoom.

The initial consultation will focus on understanding the history of the participant, considering all aspects including acute COVID-19 and long COVID symptoms, medical history, life events, lifestyle, self-care practices, and personality. Individually tailored homeopathic remedies prescribed by the homeopath after this consultation will be ordered by them from Ainsworths Pharmacy to be sent to the participant.

At follow up consultations, participants will be asked about any changes in symptoms. Depending on this information, the homeopath will either continue with the prescription, or change it if no improvements are reported, in the same way they would in their usual practice.

Data Management The JISC on-line survey platform will host MYMOP, SF36 (8 domains), and additional questions: how long have you had long COVID?; approximate date of onset of acute COVID-19; by whom were you diagnosed with long COVID (a healthcare professional; documentation from an NHS long COVID clinic; equivalent formal medical verification); number and nature of different symptoms; vaccines received; self-help approaches used. Participant will be asked their permission to be: contacted again; for their (anonymized) data to be used; and if they are interested in being offered a treatment. Questionnaires will be requested monthly x 6. It is estimated that they take about 20 minutes to complete.

Participant confidentiality will be ensured by allocating a participant code to each participant as a unique identifier for all data collection. The participants name, address, phone number and email address and unique identifier will be stored separately.

Data will be stored and handled in accordance with the General Data Protection Regulations brought in under the Data Protection Act 2018. All electronic data, including the spreadsheet containing the unique identifier linked to the participant details will be stored in a password protected file on the St Mary's University servers and only accessible by approved research team members. Data collected from the participants will use the unique identifier.

Participants who request to withdraw from the study will have their data removed from the password protected spreadsheet by an approved research team member.

Data management will be via an encrypted excel spreadsheet and SPSS. Each questionnaire will be analysed separately. Data will be retained on the JISC and Meaningful Measures platforms until ready to be analysed.

Return rates and missing items will be documented for the acceptability of the selected outcomes. Responses will be analysed to assess the appropriateness and sensitivity of the measures by identifying any floor or ceiling effects.

Homeopaths Homeopaths are volunteers registered with one of the regulatory bodies. The code of practice consulted for this project is the code of practice and ethics of professional body HINT (Code of Professional Conduct - Homeopathy International (hint.org.uk). They will be regularly supervised by a study supervisor to enable them to discuss treatment experiences; observed characteristics of participants; self-care approaches used; and whether certain patient types are more responsive to treatment (e.g consideration of underlying conditions, age groups, length of time since acute COVID-19, level of health etc.). Emerging themes will be grouped and described.

Homeopaths will complete an on-line form after each consultation and an adverse event form if needed.

Safety Homeopathic treatment is considered a safe intervention. Consultations take place by zoom, neither participants or homeopaths are required to travel.

No change to participant's usual health-care provision is required, and participants advised to retain contact with their usual health-care providers.

Adverse events will be documented according to the Common Terminology Criteria for Adverse Events (CTCAE, 2010) guidelines and European Commission (2011) guidelines. Homeopaths will ask about adverse events and refer any event to the lead researcher within 24 hours. Participants will be referred to either their homeopath, 111/999, or their regular doctor, whichever is most appropriate.

Differences between the three groups (usual care, Treatment A, and Treatment A+B) on the primary outcome measures will be detected by a suitable analysis of variance (parametric for SF-36 total score, nonparametric for MYMOP total score); if significant overall differences appear, suitable pairwise comparisons between the three groups will be carried out to determine where differences lie between the individual treatment regimes.

Demographic data and baseline features will be compared using independent sample t-test and Fisher test for continuous and categorical variables. (Age, sex, duration of long COVID, number of co-morbidities, level of health (SF36) Missing values will be imputed using mean substitution A minimal clinical change score of 0.5-1.0 in the MYMOP scale will be considered clinically significant .Analyses will be performed using SPSS software, version 26. Two-tailed P < 0.05 will be used to denote statistical significance.

Inclusion Criteria:

• Adults who experienced acute COVID-19 at least 12 weeks ago
• A medical diagnosis of long COVID (diagnosis by a healthcare professional, documentation from an NHS long COVID clinic, or equivalent formal medical verification)
• At least one recognized long COVID symptom according to NHS criteria
• Agreement to be contacted again and interest in participating in research.

Exclusion Criteria:

• Those who have not had acute COVID-19
• Those who have not received a medical diagnosis of long COVID
• Those not currently experiencing symptoms (MYMOP average score 1 or less)
• Inability to give informed consent
• Inability to complete online forms and receive zoom calls
• Those currently under homeopathic treatment
• Those who have started a new medication or treatment for long COVID within the past month
• Those suffering from life threatening conditions

Once anonymised, data (but not free-text responses) may be made available to researchers on request.

Once the collection period has been completed the data will be exported and stored on St Mary's University servers securely for a period of 10 years.

Once anonymised, data (but not free-text responses) may be made available to researchers on request