Randomised, double-blind, placebo-controlled study evaluating the effect of allopurinol on the risk of cardiovascular events in patients with high and very high cardiovascular risk, including the presence of long-COVID-19 syndrome: the ALL-VASCOR study protocol

Abstract

Introduction

Numerous studies, but not all, have suggested a positive effect of allopurinol on the cardiovascular system. The randomised, double-blind, placebo-controlled study evaluating the effect of allopurinol on the risk of cardiovascular events in patients with high and very high cardiovascular risk, including the presence of long-COVID-19 syndrome (ALL-VASCOR) study aims to evaluate the efficacy of allopurinol therapy for improving cardiovascular outcomes in patients at high and very high cardiovascular risk excluding ischaemic heart disease. This is particularly important due to the high cost of cardiovascular disease treatment and its status as one of the leading causes of mortality.

Methods and analysis

The ALL-VASCOR study is a randomised, double-blind, placebo-controlled, multicentre trial that examines the effect of allopurinol therapy (200–500 mg of allopurinol daily) versus an equivalent dose of placebo on the risk of cardiovascular events in 1116 patients aged 40–70 with serum uric acid levels above 5 mg/dL at high and very high risk of cardiovascular disease. The ALL-VASCOR study will also assess the occurrence of long-COVID-19 syndrome. The study will measure primary and secondary as well as additional endpoints and the planned intervention will end on 31 July 2028 unless advised otherwise by the Safe Monitoring Board or other applicable authorities. Participant recruitment is planned to begin in March 2024 in Poland.

Ethics and dissemination

The study was ethically approved by the Bioethics Committee of Poznan University of Medical Sciences (No 03/23, 12 January 2023). The results are expected after 2028 and will be disseminated in peer-reviewed journals and at international conferences.

Protocol version number

01–15 November 2022.

Trial registration number

EudraCT: 2022-003573-32, 27 October 2022, ClinicalTrials: NCT05943821, 13 July 2023.

Correspondence to Katarzyna Lewandowska; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The ALL-VASCOR study is a prospective, randomised, large scale intended to investigate whether allopurinol treatment can improve cardiovascular outcomes in patients at high and very high risk of cardiovascular diseases.

• The study population comprises relatively young patients between 40 and 70 years old without a clinical diagnosis of ischaemic heart disease. This design allows for evaluating the effects of allopurinol in different patient populations than those included in the multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease (ALL-HEART) study.

• One limitation is that patients who will not reach their target serum uric acid levels will have to take multiple tablets which may affect their compliance.

• While the ALL-VASCOR study maintains a double-blinded design, there is a risk of unblinding the investigational therapy due to a reduction in serum urate which would disclose the allocation to the active therapy.

Introduction

The ALL-VASCOR study is a clinical trial investigating the effects of allopurinol therapy on cardiovascular (CV) risk in patients with high and very high CV risk. Allopurinol is a medication that reduces serum uric acid (UA) levels by inhibiting xanthine oxidase (XO) activity.

UA in humans is the final product of purine metabolism due to the action of xanthine oxidoreductase and occurs in two isoforms, XO and xanthine dehydrogenase. UA has antioxidant properties that potentially may protect against oxidative stress¹ but paradoxically, a high UA concentration is related to an increased risk of CV diseases.^2–4 The potential cause for this phenomenon is likely due to increased XO activity under hypoxic conditions, such as atherosclerosis, that generates active oxygen species during UA synthesis disrupting the oxidative–antioxidative balance and potentially contributing to endothelial damage and dysfunction.³ UA is a significant independent risk factor for CV diseases and hyperuricaemia is more frequent in patients with CV diseases. The Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study indicated that an increase in serum UA concentration of 1 mg/dL was associated with a 22% increase in the risk of death from CV and 12% for all-cause mortality. The serum UA concentration best predicting death from CV causes was 5.4 mg/dL with a sensitivity of 61% and specificity of 67% and that of death from all causes was 4.9 mg/dL with a sensitivity of 68% and specificity of 55%.⁵ The Third National Health and Nutrition Examination Survey III revealed that an increase of 1 mg/dL in UA was associated with a 16% increase in total mortality and an 18% increase in mortality from CV causes.⁶ Moreover, Ioachimescu et al observed that an increase in serum UA concentration by 1 mg/dL increased the risk of death by 39% and after adjusting for most recognised CV risk factors, the serum UA level predicted value of the risk of death was still significant. The accuracy of the Framingham risk score model for CV risk assessment was significantly improved considering the UA level.⁷

Allopurinol therapy might benefit patients with high CV risk at doses greater than or equal to 300 mg/day.⁸ MacIsaac et al conducted a retrospective study that indicated that administering 300 mg/day of allopurinol or more to adults aged 65 or over with arterial hypertension was associated with a 42% decrease in the risk of stroke and a 37% decrease in the risk of cardiac-related events.⁸ The European Society of Cardiology/European Society of Hypertension 2018 Guidelines on Hypertension recognised UA as an important, modifiable risk factor for CV diseases.⁹ International experts on the diagnosis and treatment of patients with hyperuricaemia and high CV risk advocated for considering allopurinol treatment in individuals with UA concentrations higher than 5 mg/dL who possess at least two of the following risk factors: arterial hypertension, diabetes, dyslipidaemia, prior stroke, myocardial infarction, or chronic kidney disease and suggested a target UA concentration of less than 5 mg/dL.⁴ The authors of the consensus clearly emphasised that, at that time, there was no large, well-designed study that would confirm their ‘soft’ recommendations.⁴ Most experts in this field believe that there is a need for large randomised controlled trials to determine whether patients with CV diseases benefit from allopurinol therapy before recommendations for the use of XO inhibitors are incorporated into CV prevention and hypertension guidelines.

The recently published ALL-HEART trial was a multicentre, prospective, randomised, open-label, blinded endpoint trial in which allopurinol did not significantly improve CV outcomes in 5721 patients with a mean age of 72±6.8 years and comorbid ischaemic heart disease (IHD).^{10 11} However, this study had several limitations. First, the mean age of the study population was over 72 and the mean duration of IHD was over 10 years, indicating advanced and most likely irreversible vascular damage. Second, adherence to allopurinol therapy was poor, with more than half of the participants stopping taking their drug mainly due to a skin rash likely induced by the high dose of allopurinol. Adverse event reporting was conducted remotely, raising suspicion that these events were not adequately documented and verified. Finally, the UA level was not monitored and the dosage of allopurinol was rigid.^{10 11} Allopurinol may have a pro-oxidant effect in patients without hyperuricaemia as the authors suggest that the possible antioxidant benefits of allopurinol could be demonstrated in patients with high serum UA levels who were not intentionally included in the study per protocol.^{10 11}

The ALL-VASCOR trial excludes patients with IHD and implies the recruitment of younger patients to assess the usefulness of allopurinol in primary and secondary prevention in a different patient group than that included in the ALL-HEART trial. The study logo is shown in figure 1.

Figure 1. The study logo.

Although numerous studies have demonstrated that allopurinol may be capable of favourably impacting the CV risk in patients,^12–14 these studies were not adequately designed.⁴ The ALL-HEART study revealed that allopurinol therapy is not beneficial in those over 60 with IHD^{10 11}; therefore, this patient group is excluded from our study to obtain stronger evidence that will definitively define the role of allopurinol therapy for those at high and very high CV risk and with CV diseases, excluding IHD.

Methods and analysis

This study protocol was written according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.¹⁵ The SPIRIT checklist and the participant consent form are located in the online supplemental files 1 and 2, numbered 1 and 2, respectively. The study preparation commenced on 3 October 2022 and patient recruitment will begin in the second half of March 2024. The study is scheduled to conclude by 31 July 2028.

Objectives

The primary aim of the ALL-VASCOR study is to determine if allopurinol therapy (from 200 mg up to 500 mg/daily) in patients with high and very high CV risk improves their CV outcomes. During the intervention, the target effective and safe daily dose of allopurinol to reduce CV risk will be determined. Additionally, the study will assess the prevalence of long-COVID-19 syndrome in the study population.

Study design

The ALL-VASCOR study is a randomised, double-blind, placebo-controlled trial to evaluate the impact of allopurinol therapy on CV event risk in patients aged 40–70 years with serum UA levels above 5 mg/dL and with high or very high CV risk. Additionally, the presence of long-COVID-19 syndrome will be assessed. The trial is based on primary, secondary and additional endpoints and the duration is limited to the planned intervention time. Therefore, the trial is planned to be completed by 31 July 2028 unless the Safety Monitoring Board or another body decides otherwise.

Study centres

The study will be conducted in 12 reference medical centres throughout Poland, with the main centre being the Clinic of Hypertension, Angiology and Internal Diseases at the Medical University of Poznan (PUMS). The selection of centres is based on specific criteria such as having clinical experience or previous participation in at least one clinical trial.

Number of participants, allocation and randomisation

In total, 1116 patients (93 per centre) including 690 over 60 years old will be recruited. Voluntary consent for participation will be obtained during the first study visit (V0) along with a medical interview, physical examination and laboratory and imaging diagnostics to assess the patient’s CV risk. The intervention will only be applied to patients who meet both the inclusion criteria. Table 1 outlines the inclusion and exclusion criteria. The participants will be informed about the potential side effects of allopurinol therapy at the beginning of the study and their right to withdraw from the study at any time without providing a reason. The participants will be randomly allocated to two groups (allopurinol therapy vs placebo therapy) in a 1:1 ratio. Stratification will consider the following factors: centre, patient age (above and below 60 years old), gender and baseline CV risk (high/very high). Any individual who receives a randomisation code and withdraws from the trial at any stage will not be replaced by another participant. Allocation and randomisation will be conducted through an electronic case report form (eCRF). The study will be double blind, meaning neither the investigators nor the participants will know who is taking allopurinol or a placebo. Identification codes will only be unblinded in exceptional circumstances to ensure the overall study quality with the decision being made by the Safety Data Monitoring Board in consultation with the Scientific Research Committee.

Table 1

Inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

40–70 years of age Providing informed consent to participate in the study Serum UA levels >5 mg/dL within the last 6 months before the screening visit Meeting at least one of the criteria defining high or very high CV risk including: Calculated 10-year cardiovascular mortality risk based on SCORE2 >2.5% for patients under 50 years old or ≥5% for patients 50 years old or older Documented occurrence of CV diseases (cerebrovascular disease: ischaemic stroke, intracerebral bleeding, TIA; heart failure regardless of the aetiology NYHA I–II (without IHD), PAD, atrial fibrillation (de novo or ever) Diabetes or arterial hypertension complicated by organ damage: Increase in vascular stiffness: pulse pressure≥60 mmHg, and/or cervicofemoral PWV >10 m/s; Features of left ventricular hypertrophy on echocardiography or electrocardiography Increased urine albumin-creatinine ratio (30–300 mg/g) Ankle-brachial index <0.9

Taking allopurinol, febuxostat or other hypouricaemic drugs Contraindications to taking allopurinol Pregnant women, breastfeeding or planning pregnancy during the study duration Hormonal therapy containing oestrogens Active cancer process or disease in the last 5 years excluding locally malignant tumours Uncontrolled hypertension (mean value ≥180/110 mm Hg 7 days before screening visit) in home measurements despite using hypotensive drugs Renal insufficiency with an eGFR <45 mL/min/1.73 m2 (according to 2009 CKD-EPI recommendations: stage G3b, G4 and G5). Hypothyroidism or hyperthyroidism not in a state of euthyroidism Confirmed coronary artery disease (defined as prior AMI, revascularisation of the myocardium, confirmed presence of atherosclerotic plaques in coronary arteries on imaging studies) Heart failure in NYHA class III and IV Taking azathioprine, mercaptopurine or ciclosporin. Participation in another clinical trial of a medicinal product or medical device within the last 3 months or 5 half-lives whichever period is longer

AMI, acute myocardial infarction; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CV, cardiovascular; eGFR, estimated glomerular filtration rate; IHD, ischaemic heart disease; NYHA, New York Heart Association; PAD, peripheral artery disease; PWV, pulse wave velocity; SCORE2, Systematic Coronary Risk Evaluation; TIA, transient ischaemic attack.

Interventions

Obligatory intervention

The participants allocated to the first group (G1) will receive allopurinol at an initial daily dose of 200 mg and participants allocated to the second group (G2) will receive a placebo. The placebo will be prepared as tablets with the same shape and appearance as the test drug in the appropriate dose and containing the same excipients. Participants will initially take one tablet daily in the morning. The physicians will dispense the drugs in packs of 30 tablets for the entire interval between visits (therapy 26 weeks ±2 weeks) to patients during visit V1. The drugs will be prepared in identical packages, appropriately sealed, with a number for drug identification.

Optional intervention

Approximately 26 weeks (±2 weeks) after the start of the intervention, treatment efficacy will be evaluated at the follow-up visit V2. Efficacy is defined as achieving a serum UA level below 5.0 mg/dL for those with baseline levels >5.0 to 7.0 mg/dL or below 5.5 mg/dL for those with baseline levels ≥7.0 mg/dL. If insufficient therapy efficacy is noted, the initial allopurinol dose will be increased by 100 mg (up to 300 mg during V2). Similarly, the dose may be increased by 100 mg at visit 3 and by another 100 mg at visit 4 (up to 500 mg during V4). An appropriate preparation will be added so that the number of tablets in the placebo group corresponds to the group with the active substance. Patients will be advised to take the appropriate number of allopurinol or placebo tablets each morning and the treatment will continue until the end of the observation. Patients who meet their UA target concentration at visit V2, V3 or V4, and those who fail to meet their target concentration at visit V4, will not have their dosing changed until the end of the follow-up. Participants will continue to take other medications depending on their diseases per the latest medical knowledge.

Follow-up visits

The second stage will consist of at least five follow-up visits (V2–V6) at approximately 6-month intervals. During each visit, a medical interview and physical examination, laboratory tests, blood pressure control and a re-evaluation of the CV profile will be conducted. A detailed list of examinations at visits V0–V7 is presented in table 2, and for visits V8–V11 in table 3. All tests and procedures will be conducted by trained medical personnel and laboratory tests will be performed in certified laboratories. At each follow-up visit, the medications taken by the patient will be verified, and any contraindications or adverse effects of allopurinol therapy will be identified. Patients will be given sufficient medication at each follow-up visit to continue their treatment until the next scheduled visit, which will be 26 weeks ±2 weeks. During visit 7 (the summary visit), a medical interview and physical examination will be conducted as well as laboratory and imaging diagnostics to assess the patient’s CV risk and the impact of the drug therapy on the primary, secondary and additional endpoints. Participants who have at least 26 weeks between visit V7 and the study end date will continue therapy and be invited for visits V8–V11 during which they will receive medications unless the end of the study is shorter than the next visit. During visits V8–V11, interviews regarding primary and secondary endpoints will be conducted (table 3).

Table 2

A detailed list of examinations and tests at visits V0–V7

	V0	V1	V2	V3	V4	V5	V6	V7
	Up to 3 weeks V1	0	26±2 weeks	52±2 weeks	78±2 weeks	104±2 weeks	130±2 weeks	156±2 weeks
Informed consent	x
Medical interview	x		x	x	x	x	x	x
Physical examination	x		x	x	x	x	x	x
Cardiovascular risk assessment	x		x	x	x	x	x	x
Information on concomitant treatment	x		x	x	x	x	x	x
Evaluation of exclusion criteria			x	x	x	x	x	x
Documentation of COVID-19 history	x
Long-COVID-19 symptoms survey	x	x	x	x	x	x	x	x
Office BP measurement	x		x	x	x	x	x	x
HBPM assessment*	x		x	x	x	x	x	x
ABPM assessment	x							x
ECHO	x							x
12-lead ECG	x							x
Laboratory tests—profile I†	x							x
Laboratory tests—profile II†			x	x	x	x	x
PWV‡	x							x
Abdominal ultrasound and aorta assessment	x							x
Duplex Doppler ultrasound of the carotid arteries	x							x
Ankle-brachial index test	x							x
Assessment of inclusion and exclusion criteria	x
Pregnancy test (strip test)	x
Randomisation		x
Issuance of medication (drug or placebo) for the duration of treatment until the next visit		x	x	x	x	x	x	x
Evaluation of achievement of target uric acid level and decision regarding potential dose increase			x	x	x
Evaluation of side effects			x	x	x	x	x	x
Verification of medication intake			x	x	x	x	x	x
Evaluation of endpoint			x	x	x	x	x	x

Profile I of biochemical tests: complete blood count, full lipid profile, hsCRP, AST, ALT, creatinine, eGFR, TSH, sodium, potassium, glycated haemoglobin, fasting glucose, uric acid concentration in a 24-hour urine collection, general urine test, urine albumin/creatinine ratio, serum uric acid concentration.

Profile II of biochemical tests: AST, ALT, creatinine, eGFR, sodium, potassium, fasting glucose, serum uric acid concentration and uric acid concentration in a 24-hour urine collection.

*HBPM will be performed for participants who agree to it and have an appropriate upper arm device for BP measurement. Patients will receive diaries to record their measurements.

†The visit will be preceded by a laboratory visit up to 5 days before the scheduled date of the visit to collect the necessary blood samples and, in the case of ABPM device insertion.

‡PWV will only be tested at centres with Sphygmocor.

ABPM, ambulatory blood pressure monitoring; ALT, alanine transaminase; AST, aspartate transferase; BP, blood pressure; ECHO, echocardiography; eGFR, estimated glomerular filtration rate; HBPM, home blood pressure monitoring; hsCRP, high-sensitivity C reactive protein; PWV, pulse wave velocity; TSH, thyroid stimulating hormone.

Table 3

A detailed list of examinations and tests at visits V8–V11

	V8	V9	V10	V11
	182±2 weeks	208±2 weeks	234±2 weeks	260±2 weeks
Medical interview	x	x	x	x
Physical examination	x	x	x	x
Cardiovascular risk assessment	x	x	x
Information on concomitant treatment	x	x	x
Evaluation of exclusion criteria	x	x	x
Long-COVID-19 symptoms survey	x	x	x	x
Office BP measurement	x	x	x	x
Issuance of medication (drug or placebo) for the duration of treatment until the next visit	x	x	x
Evaluation of side effects	x	x	x	x
Verification of medication intake	x	x	x	x
Evaluation of endpoint	x	x	x	x

BP, blood pressure.

Treatment duration and observation

The total study will last for 72 months with a minimum observation period for study participants of 3 years (156 weeks) and a maximum observation time of 5 years (260 weeks). After 3 years, only those patients whose next follow-up visit does not exceed the study end date will be invited for follow-up visits (each visit at 26±2 week intervals).

Patient and public involvement

Patients and the public were not actively involved in the study’s design but the study design was discussed with experienced physicians from well-known medical centres who have significant experience in clinical trials and working with patients with CV diseases.

Outcomes

The primary composite endpoint is defined as the occurrence of a major adverse CV event (MACE), all causes of death, cardiac death, stroke, transient ischaemic attack, acute coronary syndrome, coronary angioplasty or revascularisation, peripheral arterial angioplasty, hospitalisation for unstable angina or worsening heart failure (hospitalisation and stay in the emergency department due to heart failure, the need to use intravenous loop diuretics and/or doubling the dose of oral loop diuretics).

The secondary endpoints are defined as individual MACE components alone or in combination, hospitalisation for reasons other than the primary endpoint.

Additional endpoints are defined as follows:

• The assessment of the progression and/or development of organ complications and the development and/or progression of atherosclerosis including echocardiography (assessment of systolic function by calculating the ejection fraction and assessment of left ventricular hypertrophy); the assessment of the incidence of atrial fibrillation in an electrocardiographic examination (documented incident of de novo atrial fibrillation during observation); the assessment of the end-stage kidney disease; assessment of abdominal aorta diameter in ultrasound examination; the assessment of the intima-media complex and atherosclerotic plaques in the Doppler ultrasound of the carotid arteries; the assessment of the ankle-brachial index; the assessment of pulse wave velocity.

• The occurrence of long-COVID-19 symptoms.

• The assessment of treatment efficacy: the attainment of target serum UA levels of 5 mg/dL or 5.5 mg/dL depending on baseline values.

• The assessment of other laboratory parameters: estimated glomerular filtration rate, albumin-to-creatinine ratio, urinary albuminuria; glycosylated haemoglobin A1c; lipid profile; plasma C reactive protein concentrations; activity of aspartate and alanine transaminases.

• The assessment of the frequency of side effects.

• The assessment of changes in participants’ CVs based on the Systematic Coronary Risk Evaluation (SCORE) 2 scale.

Data analysis and statistical methods

Sample size

After evaluating the activity profiles of our partner centres and the aforementioned assumptions, it was estimated that the total CV risk for the Polish population over the 10-year observation period would be approximately 22%. Based on the findings of MacIsaac et al, the capacity of allopurinol versus placebo intervention to reduce CV events was 37%⁸; thus, it was planned to recruit 1116 participants. The sample size was calculated based on the assumption of performing a Kaplan-Meier analysis to assess the occurrence of the primary endpoint. The estimated risk of CV events in the recruited group over a 10-year observation period was approximately 22%. With an average planned observation period of 4.3 years, this value is projected to be 9.5%. Following drug administration, it is expected to decrease to 5.9% (based on results from retrospective studies, it was assumed that the risk of CV events in the tested group would decrease by 37%).

The test power was set to 80% and the confidence level to 0.95 for calculations. Based on log-rank power analysis, the planned sample size was set at 507 people for each group. Since there is potential for loss of power due to participant withdrawal or not completing the study due to adverse events, the size of the groups was increased by 10% yielding a total of 1116 or 558 for each group.

The number of participants over 60 years old was calculated separately to assess the test power accurately. It was assumed that the total CV risk in this subpopulation would be 20 percentage points higher than the general population (based on the Pol-SCORE tables), resulting in an estimated 42%.¹⁶ Similarly, with an average observation period of 4.3 years, the risk is assumed to be 18.1%, which would be reduced during the intervention studied to 11.3%. To achieve 80% test power at a 95% confidence level, the size of this group should be 314 participants. Taking into account potential losses due to withdrawal or adverse events, 345 participants over 60 years old should be recruited for each group with a total of 690 participants.¹⁷

Data analysis plan

The primary and secondary endpoints will be compared between the test and control groups using Kaplan-Meier analysis with the log-rank test and a multivariate Cox model. Defined recurrent CV events will be assessed through the Andersen-Gill model.

The achievement of additional endpoints will be compared at specific time points: after 3 years of treatment and after each subsequent half-year period. All individuals for whom data have been collected during the V0–V2 visits will be assessed. A separate analysis will be conducted for participants over 60 years old and for the entire test population. Further subanalyses will be performed regarding initial UA concentrations, allopurinol doses and the presence of risk factors such as diabetes, hyperlipidaemia, chronic kidney disease or hypertension. Finally, an analysis of changes in the occurrence of long COVID-19 syndrome symptoms between both groups will also be performed. The trial data will be analysed according to the ‘Intention-to-treat’ principle. The planned analyses will determine the following:

• Whether patients with high and very high CV risk benefit from allopurinol therapy and if its use reduces the occurrence of the mentioned endpoints in this group.

• Whether the effectiveness of allopurinol therapy depends on the coexistence of specific diseases.

• If there is a ‘CV profile’ that will determine the best response to allopurinol therapy.

• If the efficacy of allopurinol therapy in the test cohort is dependent on their baseline laboratory parameters.

• The ideal serum UA concentration for patients with high and very high CV risk to benefit from allopurinol.

• How prevalent are side effects during allopurinol therapy in the Polish population and are specific subpopulations of patients more susceptible to them.

• What is the optimal allopurinol dosage for reducing CV risk.

• Does allopurinol therapy affect the course of long-COVID-19 syndrome.

• Whether treatment with XO inhibitors affects the CV profile of the participants.

Project completion

The study will be completed after data have been collected from the final visit of the last participant with an expected completion date of 31 July 2028. However, earlier study termination may occur as a result of a decision by a regulatory institution, Ethical Commission, or the Safety Monitoring Board in the case of a serious adverse event that is deemed to be linked to the intervention. Additionally, the Scientific Research Committee may prematurely terminate the study if there is a significant difference in achieving primary endpoints between the test and the control groups and they deem continued research unethical.

Trial management

The Scientific Research Committee comprises eight independent researchers including the Principal Investigator and National Coordinator from the main research centre—PUMS. Their responsibilities include overseeing the work of the research centres, supervising the project, completing relevant formalities for the study implementation (registration/eCRF/CRO/ethics committee approval/purchase of necessary equipment, etc), providing GCP training for scientists from 12 research centres, organising meetings for researchers from other centres and Safety Data Monitoring Committee meetings, and supplying medicine to research centres. Researchers are required to submit a report on the course and implementation of the research to the Medical Research Agency every 6 months.

The Data Safety Monitoring Board, composed of three members, will supervise the study and all side effect reports will be reported to it. Patients will report adverse events both during control visits (in the HBPM measurement logbook received at the beginning of the study) and electronically via a dedicated email. During follow-up visits, physicians must assess the patient’s condition based on the history, physical examination and additional tests. In the event of significant deviations from their initial state, a decision on further participation in the study will be made by the Data Safety Monitoring Board. Each report will be evaluated individually by the Data Safety Monitoring Board.

Ethics and dissemination

This study will be conducted according to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Poznan University of Medical Sciences. The trial was prospectively registered in ClinicalTrials: NCT05943821, 13 July 2023 and EudraCT (2022-003573-32, 27 October 2022). The ethics committee and regulatory institutions will approve protocol changes. The research team will communicate the changes to the investigators and the main study registry.

Data deposition and curation

Data will be collected by appropriately trained clinical research staff and entered into electronic forms using the eCRF system. Results will be reported in peer-reviewed journals and at international conferences.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors AT conceptualised the study and all authors contributed to the protocol design (substantial contributions to the conception or design of the work: all authors—planning, methodology, conduct and reporting of the work in this paper). KL, DL, PU and AT coauthored the initial draft of the protocol (drafting the work). DL and PU provided statistical expertise in clinical trial design and conducted the primary statistical analyses. All authors further refined the study protocol and approved the final manuscript (revising it critically for important intellectual content), with KL managing all changes and preparing it for publication.

Funding This work was supported by Medical Research Agency (st. Stanisława Moniuszko 1A, 00-014 Warsaw, Poland) grant number (2022/ABM/01/00027) from the state budget (15155388,20 PLN).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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