Study design

FAVORITE is a randomised, placebo-controlled, double-blind, multicentre trial. Patients with minor stroke (National Institute of Health Stroke Scale (NIHSS) ≤3 scores at the time of randomisation) or TIA within 3 months or chronic imaging changes of ischaemic cerebrovascular disease (eg, multiple infarcts, microbleeds or white matter hyperintensities) complicated with mild anaemia or low haemoglobin are randomised with 1:1 to ferrous succinate group or placebo group. All patients will be followed up for 3 months during intervention, and at 1 year after enrolment. The flow of the FAVORITE is displayed in figure 1. The study will recruit patients age ≥18 years with mild ischaemic stroke (NIHSS ≤3 scores) or transient ischaemic attack within 3 months or chronic imaging changes of multiple infarcts (≥2), multiple microbleeds (≥2) or white matter hyperintensities (Fazekas grading ≥2) showed on CT or MR without clinical events, complicated with mild anaemia or low haemoglobin. Patients are diagnosed with mild anaemia or low haemoglobin with haemoglobin concentrations 90–130 g/L for adult males and 90–120 g/L for adult non-pregnant females or serum ferritin <20 µg/L according to WHO criteria.12–14 After randomisation, patients will be administrated with study drugs within 24 hours. The summary of inclusion and exclusion criteria is shown in figure 2. Each hospital has obtained institutional review board approval about the informed consent, protocol and other materials used to enrol patients prior to initiating the study. Patients from 20 centres from China will be screened and recruited in FAVORITE.

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Figure 1

FAVORITE study design. FAVORITE, Ferrous iron on the prevention of Vascular cOgnitive impaiRment in patients with cerebral Infarction or TIA; TIA, transient ischaemic attack.

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Figure 2

Summary of inclusion and exclusion criteria. NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischaemic attack.

Randomisation

Subjects will be randomised (1:1) to receive either ferrous succinate or placebo. A randomisation sequence will be generated centrally using random permuted fixed-size block methods through SAS statistical analysis software V.9.4 (SAS Institute) from the Statistics and Data Centre at the China National Clinical Research Centre for Neurological Diseases. The randomisation computer programme will make the treatment assignment based on the overall balance of treatment assignment. After randomised allocation, the trial intervention will be administered to the participant as soon as possible.

Intervention

Ferrous succinate, as the most commonly used and the most accessible iron supplement for iron-deficiency anaemia in Chinese patients, is selected as the intervention medicine in this study with the conventional therapeutic dose of 0.2 g per day for 12 weeks.

Eligible patients are randomly assigned to each of two groups:

Primary outcomes

The primary efficacy outcome is the incidence of VCI within 3 months after randomisation. The patients were evaluated by the MOCA through face-to-face follow-up in the outpatient clinic at 3 months±7 days. Patients are diagnosed with VCI with the criteria of MOCA<26 scores.15 16 We also identify mild cognitive impairment or vascular dementia with other criteria including Clinical Dementia rating (CDR), Peterson’s diagnostic criteria or DSM-V diagnostic criteria.17 18

Secondary outcomes

Secondary outcomes include (1) Incidence of VCI within 1 year (evaluated by the MoCA through face-to-face follow-up at 1 year±14 days, MoCA<26 scores is diagnosed as VCI); (2) Any new ischaemic stroke, TIA or haemorrhagic stroke events during 3 months and 1 year; (3) Any death during 3 months and 1 year; (4) Incidence of dependence during 3 months and 1 year (modified Rankin Scores≥3) and (5) The change of haemoglobin concentration, serum ferritin, red blood cell indices and the expression of key blood biomarkers including P-tau, amyloid protein β, that is, between the two groups.

The influence on treatment outcome of gender, age, time from index event to randomisation (≤14 days, 14 days ~3months or without ischaemic event but showing ischaemic cerebrovascular imaging changes, aetiology subtype, smoking, diabetes mellitus, dyslipidaemia and different levels of haemoglobin at randomisation will be clarified in the subgroup analyses.

Safety outcomes

The primary safety outcomes are (1) any gastrointestinal adverse event within 3 months, including abdominal pain, nausea, vomiting, diarrhoea, constipation or other gastrointestinal adverse events/serious adverse events (SAEs), excluded those independent of the supplementation protocol and (2) iron overload identified as serum ferritin exceeding 1000 µg/L within 3 months. Iron is deposited excessively in the body and causes structural damage and dysfunction of important organs (such as the heart, liver and joints).

Data safety and monitoring board

The data safety and monitoring board (DSMB) will monitor the progress of the trial and per protocol, ensure patient safety and ethically conduct of the trial. After each meeting, DSMB will provide recommendations in a written statement to the Chairs of trial Steering Committee. The responsibilities of members of DSMB are confirmed by the executive committee. They do not participate in the trial

Training and certification

The executive committee shall ensure that all subcentres investigators have received Good Clinical Practice training. Training should also be conducted on patient screening, follow-up and outcome evaluation for investigators in all subcentres (eg, NIHSS scores, mRS, MMSE, MoCA and CDR). Prior to study initiation, the principal investigators and coordinators of the subcentre will complete training and obtain certification as required.

Sample size

The sample size calculation is based on the risk of primary outcome (3-month risk of VCI). We applied the following assumptions: a significance level of 0.05 for a two-sided test; statistical power of 90%; according to the previous studies, the risk of VCI within 3 months after ischaemic cerebrovascular disease is 21%–70%, it is conservatively estimated that the risk of VCI within 3 months in patients with ischaemic cerebrovascular disease combined with iron deficiency or haemoglobin deficiency is 45% in the control group.1 2 According to the previous studies, the relative improvement rate of iron treatment for cognitive impairment in patients with iron deficiency is about 25%,9–11 and it is conservatively estimated that the 3-month risk of VCI in patients with ischaemic cerebrovascular disease combined with iron deficiency or haemoglobin deficiency treated by iron supplementation is 35%. Proportional risk reduction of 25% (rate ratio=0.75). We estimated that 1006 eligible patients (503 for each arm) are required. As 20% of patients are mild anaemia or low haemoglobin,4 5 we will screen about 5030 patients in total.

Statistical analyses

The intention-to-treat analysis will be performed for all participants randomised to two groups. Subjects will be censored at their last follow-up review, at the time of withdrawal from the trial or experiencing a clinical event. Multivariate analysis of VCI will be performed using a generalised linear model, with relative ratio (RR) and 95% CI calculated. Kaplan-Meier model will be used to evaluate the survival curve of all-cause death and stroke recurrence. The Cox proportional hazards model will be used to analyse all-cause death and stroke recurrence events for HR calculation and 95% CIs. Logistic regression model will be used to analyse outcome of dependence for OR calculation and 95% CIs. Statistical significance for primary outcome will be ascertained as p value of 0.05.

Study organisation

The trial steering committee will meet twice yearly and provides strategic input and oversight. The trial management committee executes the trial on a day-to-day basis and is based at the FAVORITE Trial Coordinating Centre. Trained assessors will analyse the outcomes, SAEs and imaging materials, masked to treatment assignment.

Study current stage

The enrolment had been completed on 1 March 2022. All the 3-month follow-up had been completed on 1 July 2022. All the 1-year follow-up had been completed on 1 June 2023. Now we are in the process of data cleaning and statistical analysis.

Limitation

We acknowledge several limitations of this study. (1) Previous studies on the effects of iron supplementation to correct anaemia on VCI were lacking, and the estimate of the relative proportion of improvement in the incidence of VCI in this study may be inaccurate, which may have a certain impact on the estimate of the sample size of this study. (2) Only patients with ischaemic cerebrovascular disease complicated with mild iron-deficiency anaemia were included in this study, and moderate and severe iron-deficiency anaemia were not included, which may have a certain selection bias on the outcome of improving cognition function with iron supplementation.