Efficacy of Chinese herbal medicine Jiangniaosuan formula for treatment of hyperuricemia: study protocol for a double-blinded non-inferiority randomized controlled clinical trial

Rapid economic development and improvement in living standards over the past few decades have resulted in an increase in the prevalence of hyperuricemia across countries [1]. In China, the overall prevalence of hyperuricemia is 13.3%, with a higher prevalence reported in coastal areas (34.05%) and in men than in women (41.53% vs. 26.14%) [2‐4].

Hyperuricemia results from an imbalance between the endogenous production of urate and its excretion. The most common mechanism is decreased excretion of urate. Studies show that hyperuricemia is an independent risk factor for chronic kidney disease (CKD), hypertension, cardiovascular and cerebrovascular diseases, and diabetes, as well as an independent predictor of premature death [5]. Hyperuricemia has been found to be significantly more common in individuals with above-normal serum triglyceride level [6] and to increase the risk for atherosclerosis as well as heart failure [7‐9]. A study that followed up 177,570 patients for 25 years found that patients with high serum uric acid levels had 2.14 times higher risk for CKD than patients with normal serum uric acid [10]. Hyperuricemia has an independent adverse effect on renal function [11], and one prospective study from Japan that followed up individuals without CKD found that those with higher uric acid levels at baseline had a higher CKD incidence and a more rapid rate of decline in renal function [12].

In Western medicine, the commonly used serum uric acid–lowering drugs are allopurinol, febuxostat, and topiroxostat. Allopurinol, which is the most widely used, effectively lowers serum uric acid level in patients with or without gout, but is contraindicated in patients with renal dysfunction. Exfoliative dermatitis is the most serious adverse effect of allopurinol. Febuxostat is associated with a higher risk of cardiovascular events according to the US Food and Drug Administration. Meanwhile, topiroxostat, a novel nonpurine selective inhibitor of xanthine oxidoreductase that was developed as an alternative to conventional XOD inhibitors, has shown renoprotective effects, as demonstrated by the reduction of urinary albumin excretion, and thus can be used without dose reduction in patients with mild to moderate renal dysfunction [13, 14]. However, there is accumulating evidence that it may not be advisable in patients with concurrent chronic heart failure.

In China, compliance with uric acid–lowering treatment is poor. In one study that followed up patients for 4 weeks after a gout attack, only 20.7% adhered to the prescribed treatment, and only 18.9% achieved target serum uric acid levels [15]. A telephone follow-up of 539 patients with gout found that 40.9% of those in whom urate-lowering therapy was indicated had not taken the treatment in the past 12 months; medication adherence was only 21.6% [16]. Furthermore, a survey conducted during the current coronavirus pandemic found that a large proportion (41%) of gout patients were reluctant to go to hospitals for review [17]. Thus, it is obvious that hyperuricemia treatment is often less than satisfactory.

In China, Chinese herbal medicine (CHM) is often used to treat hyperuricemia. One popular medicine is Jiangniaosuan formula (JNSF), proposed by Professor Zheng Pingdong of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM). Over nearly 20 years of clinical observation, Professor Zheng found that phlegm dampness and blood stasis are the key to the pathogenesis of hyperuricemia. JNSF therefore was formulated to prevent blood stasis by stimulating blood circulation and to dissipate phlegm and descend the turbid. Over the past years, JNSF has been found to be safe and effective [18, 19].

Hyperuricemia is currently a major public health problem in China, where TCM is often used for symptom relief and quality of life improvement. This study aims to examine the efficacy and safety of CHM in the management of hyperuricemia. Outcomes assessed during follow-up will include mortality rate and adverse events. These outcomes can be easily assessed with only a few questions. The physicians who will be performing the follow-up are familiar with the patients and are experienced interviewers. Therefore, the quality of the follow-up is guaranteed.

Western medicine is widely used for the treatment of hyperuricemia, but many side effects are reported. In China, the combination of TCM and Western medicine has been successfully used for the treatment of hyperuricemia for many years. However, there is little research evidence to support the efficacy of TCM and no clarity on its mechanism of action in hyperuricemia.

JNSF is a herbal preparation formulated by Professor Pingdong Zheng, a reputed TCM nephropathy expert. Professor Zheng believes that hyperuricemia results from impaired function of the spleen and stomach due to improper diet. In TCM theory, the spleen and stomach govern the transportation and transformation of water and nutrients. An improper diet adversely affects the physiological functioning of the spleen and stomach; the consequent accumulation of dampness and production of phlegm inhibits qi movement and leads to blood stasis, the end result being a syndrome of phlegm–dampness–blood stasis. Professor Zheng sought a way to resolve dampness, fortify the spleen, and stimulate blood circulation and came up with JNSF.

JNSF contains seven herbal ingredients (Table 1). All seven herbal constituents can drain dampness, resolve phlegm, activate blood, and dredge collaterals. The potential mechanism of JNSF in the treatment of hyperuricemia needs to be further explored. Some of the herbs in JNSF have proven pharmacological effects. Emodin has been shown to reduce serum uric acid level in rat models of hyperuricemia by inhibiting xanthine oxidase (XOD) generation [22]. Rheum palmatum L can reduce acute gout arthritis symptoms [23]. Calycosin and ethanol extract of Semen plantaginis can inhibit the activity of liver XOD in hyperuricemic mice, reduce the generation of oxygen free radicals, reduce kidney damage, and promote renal uric acid excretion [24]. Experimental studies have found that Clematis chinensis Osbeck can significantly reduce the deposition of urate crystals in renal tubulointerstitium in rats with uric acid nephropathy [25]. Total flavonoids of hawthorn leaves can regulate the activity of XOD and thus decrease serum uric acid level, raise nitric oxide level, and reduce endothelin level, and thereby minimize uric acid–induced damage to vascular endothelial cells [26]. Its main components steroid saponins have been shown to have strong uric acid–lowering, kidney protective, and immunomodulatory effects [27‐29 ]. JNSF has been used for more than 20 years in China and has proved to be safe and well tolerated. However, there is still a dearth of research-based evidence on the benefits of TCM in hyperuricemia. The results of this trial will be useful for researchers, practitioners, and patients.

This study has some limitations. First, this study will focus on short-term outcomes and, therefore, we will be unable to comment on the downstream effects of the intervention. Second, this will be a single-center study; the results may not be applicable to other hospitals or regions. Third, JNSF is a composite preparation; which components provide the therapeutic effect will have to be clarified in future research. Fourth, this study is single-blinded which is a source of bias.

The study protocol and research strategy were developed from January 2021 to December 2022. Participant enrollment will occur from March 2022 to December 2022, and follow-up and data analysis will be conducted from December 2022 to December 2023. The protocol version number is V3.0, 20210301.