The study was led by Professor Guo Jianwen's team from the National Key Laboratory of Chinese Medicine, Professor Song Lili and Professor Craig Anderson's team from Fudan University, and jointly completed by 26 large hospitals in China, with Professor Xia Zhangyong as the senior author, which marks a new breakthrough in the field of cerebral haemorrhage research in our hospital, and the cooperation with renowned hospitals and experts at home and abroad entered into a new stage.

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I. Background of the study

Acute spontaneous cerebral haemorrhage is the most serious type of stroke, but effective treatments are scarce and limited to the early stage of onset with the aim of reducing haematoma volume.The Chinese medicine FYTF-919 (Zhong Feng Wake Up Brain Liquid), an oral preparation made from four Chinese herbs, is believed to promote haematoma resorption and regulate immunity in Chinese medicine theory, and has many years of clinical experience in the treatment of cerebral haemorrhage in China.The CHAIN study aims to use a standard randomised controlled trial methodology to assess the clinical efficacy andsafety.

Study design

The CHAIN study is a multicentre, randomised, placebo-controlled, double-blind trial conducted in 26 large hospitals in China.Adult (≥18 years old) patients with spontaneous moderate-to-severe cerebral haemorrhage (NIHSS ≥8 or GCS 7-14) confirmed by imaging within 48 hours of onset were randomly assigned to either the FYTF-919 group or the placebo group in a 1:1 ratio.Randomisation was block randomised (block size 4 or 6) and stratified by study centre, degree of neurological deficit (NIHSS score) and haematoma location.Placebo and FYTF-919 were consistent in appearance, odour, taste and other aspects.On the basis of standardised treatment and care in both groups, patients began treatment with either the trial drug or placebo immediately after randomisation, with 33 ml orally three times a day (changed to 25 ml four times a day for patients on nasal feeds), and treatment continued for 28 days.The primary study endpoint was a 90-day utility-weighted mRS (uw-mRS, the mRS is a seven-level ordinal scale ranging from 0 [asymptomatic] to 6 [death], where the utility weights for the seven levels are 0.97, 0.88, 0.74, 0.55, 0.20, -0.19, and 0.00, with higher scores denoting better outcomes).The primary analyses were performed using extensive linear models and adjusted for baseline parameters.We performed multiple corrections and sensitivity analyses for the primary outcome.The primary outcome was performed in the intention-to-treat population.This study is registered with ClinicalTrials.gov under registration number NCT05066620.

III. Study results

Between November 24, 2021 and December 28, 2023, 9,000 patients were screened in the CHAIN study, which included 1,648 patients with acute cerebral haemorrhage. 817 patients were randomly assigned to the FYTF-919 group and 831 patients were randomly assigned to the placebo group. two patients in the FYTF-919 group and five patients in the placebo group received treatment before theywithdrew informed consent, so 1641 patients with primary outcome data were included in the intention-to-treat set, comprising 815 patients in the FYTF-919 group and 826 patients in the placebo group.1242 (75.7%) patients took more than 80% of their medication, and 994 (60.6%) patients were fully compliant with the regimen, taking all their medication within 28 days.This large, randomised, placebo-controlled, double-blind trial did not show that Stroke Awakening Formula improved functional prognosis, survival and quality of life in patients with moderate-to-severe cerebral haemorrhage, but confirmed the safety of the drug, with no significant difference in adverse effects between the two groups.In the preset subgroup analysis, two subgroups of cerebral haemorrhage greater than 15 ml and lobar haemorrhage showed potential benefit of TCM, suggesting that further clinical trials of TCM treatment of patients with larger haematomas should be conducted to confirm efficacy.

Highlights of the study

The highlights of this study are now on the double-blind design of test drug and placebo. The project team ensured the stability of the fingerprint profiles of 30 major chemical components in different batches by purchasing the same batch number of Chinese herbal medicines at one time.And it breaks through the bottleneck of double-blind research on oral liquid of Chinese medicine by adopting food additives to simulate the traits of colour, odour, taste, sweetness and so on, and undergoes the electronic nose and tongue test, which is able to prevent bias and blindness breaking in the double-blind, placebo-controlled clinical trial to the maximum extent, so as to ensure the quality of the clinical trial.Study highlight number two reflects the choice of outcome indicators. The modified Rankin Scale (mRs) is a seven-category scale used to assess the degree of disability in stroke patients, ranging from asymptomatic (0 points) to death (6 points).This scale has been widely accepted and used by the stroke research community for more than 30 years.The utility-weighted modified Rankin Scale (uw-mRS), which was used in this study, further integrates patients' subjective perception of their own health status on top of the traditional assessment, thus making the results more comprehensive.This new assessment method measures not only the patients' functional ability, but also their perception of their own functioning, thus providing a more comprehensive understanding of the patients' recovery and overall health.