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International Journal of Molecular Sciences
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6 January 2024

Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities

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1
Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
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Odames Library, Victoria Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci.2024, 25(2), 747;https://doi.org/10.3390/ijms25020747
This article belongs to the Special Issue The Potential Health Benefits of Resveratrol
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Abstract

Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current ‘state-of-play’ and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol’s potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic.

1. Introduction

There have been over 13,000 publications featuring resveratrol (RSV) in the title since the seminal paper by Jang et al. that demonstrated its potential cancer preventive effects in 1997 []. Resveratrol has been pursued for a vast array of clinical indications and health benefits, but the majority of research in this context has been at the preclinical level in simple cellular and animal models. In the laboratory, resveratrol has been reported to exert cardioprotective, neuroprotective, antitumour, antidiabetic, antibacterial, and anti-ageing effects; common to some of these effects is an ability to modulate glucose metabolism, oxidative stress, cell death, and inflammation, amongst numerous potential mechanisms of action. However, to ascertain the potential value of resveratrol as a supplement for humans, clinical studies, and ultimately randomised controlled trials (RCTs), are essential to provide critical evidence that may justify its recommendation.
Conducting meaningful RCTs with dietary-derived compounds is fraught with challenges, particularly around the lack of financial incentives and long-term returns for nutraceutical companies that would justify funding large expensive trials, akin to the model of drug development followed by the pharmaceutical industry. Additional barriers arise from lack of patentability, manufacturing difficulties, and differences in regulatory requirements, as well as the type of health claims that can be made for nutraceuticals versus investigational medicinal products, product consistency, and quality control.
Trials using dietary-derived compounds typically have to be grant-funded through charitable or government organisations and, as such, they are often limited to small-scale early-phase studies. Consequently, it can be difficult to build up a body of evidence for any one clinical indication or health application that would be sufficient to warrant the investment needed for further development or implementation. To maximise the chances of advancing resveratrol, it is important to evaluate the quality, design, and findings of the many trials that have been conducted at both an individual level and when considered collectively.
The aim of this exercise was to systemically review every clinical trial reported to date that involved the administration of a defined dose of resveratrol in a purified form (i.e., not as part of a mixture) across all possible indications. We aimed to summarise the progress made and current state of knowledge, whilst identifying gaps and opportunities for future clinical research, to help advance the use of resveratrol in situations where efficacy can be demonstrated.

2. Methods

2.1. Database Screening and Inclusion/Exclusion Criteria

This systematic review was conducted according to PRISMA guidelines. Searches were conducted by a librarian across Medline, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov, from database inception to 24 February 2023. Relevant reference lists were also searched to ensure complete capture. No limits were applied for date, publication type, or language, but records were limited to human studies. The full search strategies are available in the Supplementary Materials. All articles were imported into the Covidence web-based systematic review software (https://www.covidence.org/, accessed on 30 November 2023), which allows independent dual screening of titles, abstracts, full-text articles, and data extractions. At all stages, any conflicts in screening were resolved by discussion between the lead authors (KB and LH) until the final extracted data set was established. This review and protocol have not been registered on PROSPERO. The PRISMA diagram is shown in Figure 1.
Figure 1. PRISMA diagram showing study flow and reasons for exclusion.
The inclusion criteria were a clinical trial or study on humans; which could be any phase, randomised or non-randomised; studies must involve the administration of pure RSV; different formulations are acceptable, an RSV dose must be specified; and the full publication must be available in the English language. The exclusion criteria were the administration of RSV-containing extract or mixture, including red wine enriched with RSV and use of RSV in combination with another agent, unless there was a comparator group with pure RSV alone; ex vivo, in vitro, and non-human studies; trials examining RSV products for cosmetic purposes; studies in which RSV metabolites were administered as opposed to the parent RSV; review papers; population or observation studies; commentaries; correspondence; and conference abstracts.

2.2. Data Extraction

For data extraction, where articles were not readily available online or through library services, the authors were contacted via email, with follow-up reminders where necessary. Data collection for extraction consisted of the following: sponsorship source; country of origin; clinical setting; type of patients or volunteers; author’s name and institution; year of publication; trial registration identification; study design and groups; whether outcomes were patient-reported; primary outcome/s; whether the study was prospective, retrospective, or a reanalysis of samples/data from a previous study; inclusion/exclusion criteria; adverse event number and type; whether RSV was given with standard of care; total and male/female numbers in each intervention group; mean BMI and mean age of each group; description of the intervention, dosing schedule, total daily dose, and duration of dosing for each group; and for each primary outcome, a change from baseline and between groups. Non-numerical outcomes were also recorded as free text.

2.3. Quality Assessment

Each RCT and associated study was assessed for quality by evaluating the risk of bias in reporting clarity for the following areas: randomisation generation; allocation concealment; blinding of participants; blinding of outcome assessment; incomplete outcome data; selective reporting; and RSV formulation reporting. Each risk of bias was initially judged to be low, high, or unclear, with those reported as unclear by both reviewers subsequently classed as high risk.

3. Results

3.1. Number and Geographical Location of RSV Trials

Since 2004, when the first RSV clinical trial was published by Walle et al. [], an additional 154 individual trials have been reported, with a further 39 published studies describing additional analyses of samples or participant data from these trials (Figure 2A). During this period, a total of 6126 individuals have received RSV under trial conditions at various doses. There has been a general annual trend for increasing numbers of RSV studies, up to a peak in 2018, when 22 unique studies were reported. Since 2011, RCTs have consistently accounted for the majority of RSV studies published during each full year with a smaller proportion of non-RCTs. Interest in RSV is worldwide, as evidenced by the fact trials have been completed in thirty-one countries across five continents (Figure 2B), with the greatest number to date performed in Iran (20), followed by the USA (16), China (15), and Brazil (12). Ten separate trials have been performed in the UK and Australia. The key features of all 194 RSV studies, including details on the participants, dosing regimen, primary objectives, and main outcomes, are summarised in Table 1 (for RCTs) and Supplementary Table S1 (for non-RCTs).
Figure 2. Overview of RSV trials conducted to date. (A) The number of clinical studies published on RSV (including reanalyses of participant data or samples) separated into randomised controlled trials (RCTs) and non-RCTs conducted each year since 2004. The graph also shows the cumulative number of participants that took RSV within these studies. (B) Geographical spread of all RSV clinical trials, showing the number of unique trials (excluding subsequent studies/reanalyses on the same trial population) performed in each country. Data presented were extracted from all the references cited in Table 1 and Table S1.
Table 1. Summary of all randomised controlled trials (RCTs) identified through the search strategy that involved the administration of resveratrol (RSV) in a purified form. Also listed under each numbered primary RCT publication are any associated studies that used samples and/or data from the original trial, as well as any interim reports that described outcomes. These linked studies are shown with the same background colour (white or grey) and are separated by dashed lines. Trials are grouped according to the clinical indication for which RSV is being investigated in the primary study; in some cases, the associated or follow-up studies may be focussed on a different type of indication but in this table, they have been presented together with the primary trial, for clarity.

3.2. Quality Assessment—Risk of Bias

Each published RCT (and associated reanalysis) was assessed for risk of bias against seven specified quality criteria (Figure 3). Almost half (43%) of the studies fulfilled all seven quality requirements and, in total, 86% (118/137) met at least five of the requirements, suggesting that the vast majority of studies had reasonably high reporting standards (Figure 3A). Analysis of the individual responses for each quality indicator revealed that information was mainly lacking on the method of randomisation generation, with 56/137 publications presenting insufficient detail (Figure 3B). Poor reporting of the RSV formulation, in terms of the source or manufacturer, was also apparent in ~23% of studies.
Figure 3. Quality assessment for risk of bias in each randomised controlled trial, including associated reanalysis. Publications were assessed against seven quality criteria, as shown in (B). (A) The number of quality requirements reached, expressed as the percentage of studies with each score out of 7. (B) Breakdown of the risk of bias, defined as high or low, across each of the seven quality criteria for all the RCTs (and reanalyses). The results presented relate to all references cited in Table 1.

3.3. Clinical Indication and Trial Participants

The first suggestion that RSV might impact human health emanated from the ‘French paradox’, a term that described the 1992 observation by Renaud and de Lorgeril that people in France experienced a relatively low incidence of coronary heart disease despite consuming a diet rich in saturated fats []. It was postulated that the moderate wine intake of people in France may explain this finding and RSV, as a constituent of red wine, was proposed to account for the beneficial effects []. The validity of the French paradox is still a matter of significant debate; a number of confounders and limitations have been identified within the epidemiology data, but there seems to be evidence of a J-shaped relationship between wine consumption and vascular events and cardiovascular mortality []. The underlying mechanisms and protective factors have yet to be defined, but the initial article certainly helped spark interest in RSV and probably contributed to the emphasis that persists today around the cardiovascular and cardiometabolic effects of RSV.
As of the year 2023, RSV has been investigated for health maintenance, disease prevention, and treatment across a wide range of conditions, which have been broadly grouped in Figure 4 (also see Table 1 and Table S1). The greatest number of studies (30) have been conducted for the fundamental purpose of characterising pharmacokinetics (PK), distribution, metabolism, and the bioavailability of RSV formulations, whilst often simultaneously evaluating safety as an endpoint. The next most common application is in the management of type 2 diabetes mellitus (T2DM) and glucose control (23 studies), followed by cardiovascular disease (21). Considerable preclinical research has focused on the metabolic effects of RSV and, in addition to the T2DM/glucose studies, this has led to a total of 39 investigations across a spectrum of cardio-metabolic disease, metabolic syndrome, NAFLD, obesity, and, more recently, type 1 diabetes. The general anti-inflammatory and anti-oxidant effects of RSV in humans have also received attention, and its potential for activity in this context has led to trials for conditions, such as ulcerative colitis and arthritis-related diseases. Ten studies have addressed the effects of RSV on cognitive function, and three have explored its ability to modulate biomarkers of Alzheimer’s disease, including one of the most promising larger-scale trials conducted to date in patients with mild to moderate dementia [,]. Cancer-related endpoints have been less well studied in humans, particularly considering the wealth of preclinical publications in the area of prevention and treatment across many malignancies, but this may be partly due to the lack of easily accessible and/or surrogate biomarkers of cancer that can be analysed to provide a short-term measure or prediction of efficacy [].
Figure 4. Range of clinical indications investigated in RSV trials and breakdown of the types of participants involved. Each study (including reanalyses) was classified according to its main purpose, such as the treatment or prevention of a particular disease according to the headings shown, or to establish more fundamental characteristics such as pharmacokinetics, ADME, or drug interactions. The studies are further classified according to the participants involved and whether they are healthy volunteers, healthy overweight/obese individuals, or patients with an underlying pathology/disease. Data presented were extracted from all the references cited in Table 1 and Table S1.
Interestingly, 35% of all RSV studies recruited healthy volunteers; a further 9% specifically involved overweight or obese individuals who were classed as otherwise healthy (Figure 4). Overall, the mean body mass index (BMI) of participant groups recruited to RCTs was higher than individuals in non-RCTs (28.9 versus 26.0), which probably reflects the links between being overweight and risk of developing the types of conditions explored in the RCTs (Figure 5A). Just over half of all RSV studies (56%) involved patients with an underlying disease or pathology (Figure 4). The near-even split between healthy individuals and patients with a diagnosed pathology reflects a focus on health maintenance and prevention, as well as using RSV as a potential treatment. Furthermore, the safety profile of RSV means it has been possible to conduct many of the studies addressing PK, metabolism, and bioavailability in healthy people [,,,,].
Figure 5. Characteristics of participants in RSV trials. (A) Comparison of the mean BMI value of participants taking RSV in RCTs versus non-RCTs. Where there is more than one group receiving RSV, the mean BMI has been calculated for the trial. Values are available from 78 of the 104 RCTs and 19 of the 51 non-RCTs. The graph shows the median value for each group, with the box indicating the 25th to 75th percentiles and the whiskers corresponding to the 10th and 90th percentiles. (B) Shows the mean age distribution of RSV-treated participants across all trials where this has been reported. In trials involving multiple groups receiving RSV, the mean age of each group has been included. Mean age data were not available for 39 out of 155 trials. The data presented relate to all references cited in Table 1 and Table S1.
RSV has been investigated in adults of all ages including elderly populations over 70 years, as illustrated by the frequency distribution of mean age per group for individuals that received RSV in each trial (Figure 5B). Furthermore, four separate trials have been conducted in children, assessing the ability of RSV to affect symptoms associated with attention-deficit/hyperactivity disorder [], autism spectrum disorder [,], and fast breathing pneumonia [].

3.4. Duration and Size of Trials

One of the limitations associated with RSV clinical data is that the vast majority of studies conducted have been relatively small, with the median group size for participants who received RSV across all trials being just 22 (Figure 6A). Only a handful of trials (5% of the total) have involved over 100 people taking RSV, which is probably a reflection of the fact RSV is still at a relatively early stage of development for most therapeutic indications. Similarly, most trials have involved a short duration of RSV intervention (median 8 weeks), with the most frequently employed dosing regimen, in 19% of studies, being a single dose, followed by 8 weeks of daily administration (Figure 6B). Six trials involved participants consuming RSV for 12 months [,,,,,] and in a recent small open-label dose–escalation study in 11 patients with muscular dystrophy, RSV was taken for 2 years []; this represents the longest reported intervention with RSV within the context of a clinical trial.
Figure 6. Overview of trial size, duration, and dose used across RSV studies for both RCTs and non-RCTs. (A) Frequency distribution of group size across all individual trials. Data represent the number of participants that received RSV; when this equates to multiple groups in a single trial, the average was used. (B) Frequency distribution of trial duration in terms of the length of time RSV was taken. The dashed vertical line separates studies involving a single dose given on one occasion from those with repeated dosing lasting more than one day. (C) Overview of the different doses used in trials that involved the oral administration of RSV. Results are shown as a frequency distribution for the total daily dose and the inset highlights the range of low doses investigated. Data presented were extracted from all the primary trials listed in Table 1 and Table S1.

3.5. RSV Dose

RSV has been administered orally at daily doses ranging from 5 to 5000 mg; this represents a 1000-fold difference in daily intake across clinical trials and reflects that the optimum efficacious dose of RSV has not yet been defined for any indication. The most commonly used dose is 500 mg (median is 490 mg), followed by 1 g per day, which were investigated in 32 and 26 trials, respectively. Of all the groups of participants that received RSV in clinical trials, 88% were assigned a dose of 1 g or lower. The trend towards lower doses may have been influenced by relatively early reports that high-dose RSV can modulate the expression/activity of drug metabolising enzymes, together with recommendations not to exceed 1 g per day in healthy populations due to the potential for gastrointestinal side effects, which may affect compliance [,]. However, it should be recognised that the choice of the dose is dependent on the balance of risks and benefits; hence, patients undergoing treatment for a particular disease or condition may tolerate a higher degree of toxicity than a healthy person using RSV for health maintenance or prevention. Consequently, an appreciable number of trials have investigated high doses of RSV, with six studies utilising 5 g per day, including two trials in cancer patients involving SRT501, a formulation with significantly enhanced bioavailability compared to standard RSV [,].
It is notable that only a small number of trials (24 out of a total of 155) included more than one RSV dose to enable direct comparisons of endpoints following the ingestion of different doses. Of these trials, ten were conducted with the primary purpose of establishing ADME/PK or safety, four were classed as pilot studies, and ten were RCTs, meaning less than 10% of all RSV RCTs sought to examine any kind of dose–response relationships. A further eight trials compared different RSV formulations or products, which may also have involved different doses.

3.6. Safety Reporting

Of the 104 individual RCTs conducted to date, 27 listed adverse events occurring in the participants, and another 42 studies specifically stated that no adverse events were reported (Table 1). For the remaining 35 trials, there was no mention of adverse events in the associated publications. There was a similar split for the non-RCTs, where the types of adverse events experienced were detailed in publications from 14 trials; 18 trials stated there were no adverse events, and the remaining 19 failed to report anything on side effects or safety, which may suggest that no obvious or significant AEs occurred within these trials (Supplementary Table S1). It is worth noting that the first dose escalation and multiple dosing studies conducted with RSV fall within this non-RCT group; these trials provided the earliest indication of the adverse events associated with oral RSV in volunteers and patients, and the favourable safety profile reported in these trials has been reinforced in subsequent RCTs.
Of the twenty-seven RCTs that provided detail on the adverse events experienced, four trials involved administering RSV in combination with standard-of-care drugs that have established toxicity profiles, and there were no significant differences in side effects between groups in all of these studies (Table 1). Of the remaining twenty-three trials, eight specifically reported that there were no differences in the incidence of side effects between the the RSV and placebo groups, whilst a further two studies stated that similar numbers of participants reported AEs across the groups. These trials, citing similar adverse event frequencies, used a range of RSV doses, up to a maximum of 3 g daily.
Across all the trials that reported side effects associated with RSV use, the most common were gastrointestinal in nature, comprising diarrhoea, constipation, nausea, abdominal cramps, vomiting, steatorrhoea, heartburn, reflux, and bloating. In general, studies have shown that RSV is well-tolerated at once-daily doses of ≤1 g, and one of the longest published trials in elderly Alzheimer’s patients has demonstrated an excellent safety profile in doses of up to 1 g taken twice daily for one year []. The high acceptability of RSV as a preventive therapy in healthy people is illustrated by the two-year RCT crossover study RESHAW, which examined the effect of 12-month daily RSV supplementation on brain health in post-menopausal women []. Of the 146 individuals originally randomised, 86% completed the study, and the most frequent reasons for leaving the trial were lack of time to commit, relocation, and change in pre-existing medical conditions, as opposed to being related to RSV. Furthermore, in the exit survey, 88% of women reported that they would continue with RSV supplementation after the conclusion of the study [].

3.7. Types of Trial Outcomes

Ultimately, to justify the recommendation of RSV for any indication, evidence of clinical efficacy is required; however, the ability to obtain such data is highly dependent on the clinical setting, target population, and whether the intention is prevention, health maintenance, or treatment. Consequently, in many scenarios, studies addressing biomarker changes will be an essential precursor to trials designed to assess efficacy. To provide an overview of how far along the development pipeline RSV has advanced, the outcomes of each published study were classified according to the categories in Figure 7A. There was a tendency for many reports to list multiple primary outcomes with no apparent hierarchy; in this situation, the most robust endpoint has been used to classify the study (i.e., clinical efficacy > clinical biomarkers > exploratory biomarkers).
Figure 7. Summary of the types of outcomes evaluated in RSV trials. (A) For all studies, including associated reanalyses, the primary outcomes were assigned into one of six categories to provide an overview of the extent of RSV clinical development. Where multiple primary outcomes have been listed in publications with no apparent hierarchy, the most robust endpoint has been used to classify the study where clinical efficacy > clinically used markers > exploratory markers. The figures in parentheses represent the number of studies in each category. (B) Proportion of RCTs and associated reanalyses that reported a benefit, or lack of benefit, against the primary outcomes. N/A means that the assessment of benefit was not applicable. Data presented relate to all references cited in Table 1 and Table S1.
Thirty out of 194 studies had a primary goal of assessing the safety, pharmacokinetics, bioavailability, or metabolism of RSV, whilst just four addressed drug interactions specifically. The majority (34%) of studies listed the measurement of established markers in routine clinical use, such as insulin resistance, serum oestradiol, liver fat content, and C-reactive protein, as the primary outcome measure (Figure 7A, Table 1 and Table S1). Another 26% focussed on exploratory markers; these are typically mechanistically driven studies where the marker has not been validated to the point that it is in clinical use for the indication under investigation. Examples include the expression of SIRT in tissues and VEGF protein in muscle, mitochondrial density, serum malondialdehyde as a marker of oxidative stress, and the quantitation of AMPK activation (pAMPK/AMPK ratio) [,,,].
A slightly smaller proportion (22%) of studies had primary outcomes relating to clinical efficacy, such as the healing rate of foot ulcers in people with T2DM, blood pressure changes in pregnant women with pre-eclampsia, the level of endometriosis-related pain, and clinical scores of knee osteoarthritis [,,,].
To provide a broad overview of the potential biological activity of RSV in humans, we evaluated the results from all RCTs, which equates to 137 published studies. RSV was reported as having a significant benefit on the primary outcome in ninety-two studies (67%) (Figure 7B); there was no significant benefit on the primary outcome in forty-two studies (31%), whilst for the remaining three studies, the assessment of benefit was not relevant; for example, in cases where the primary outcome was listed as a safety rather than a pharmacodynamic or clinical endpoint [].

4. Discussion

RSV has been used within a trial setting in ~6000 people across the world, over a wide age range, including children and the elderly. Moreover, evidence indicates it is well-tolerated with relatively few side effects recorded and no serious adverse events that can definitively be attributed directly to RSV. There is potential for drug interactions with medications that affect the activity of certain cytochrome P450s (e.g., CYP3A4 and 2E1), but the clinical relevance of these interactions is not yet known, as patients on concomitant medications would have been excluded from many of the trials [,]; however, this will need to be considered if the use of RSV becomes more widespread.
RSV pharmacokinetics and metabolism have been well characterised, although there is still a need for the assessment of different dosing schedules and a greater understanding of the potential role of RSV metabolites, both human- and bacteria-derived, in contributing to any clinical efficacy. Recently, it has been proposed that variability in response to RSV may be partly explained by differences in the pattern of metabolites generated. Two metabotypes have been observed, associated with the transformation of RSV by gut microbes, namely lunularin producers and non-producers []. Out of 195 healthy volunteers that consumed 150 mg RSV daily for one week, 74% were classed as lunularin producers, and there was a greater prevalence of females in the remaining 26% of participants designated as non-producers. The impact of these metabotypes on the efficacy of RSV remains to be determined, but the findings highlight a need for further studies interrogating the biological activity of individual RSV metabolites, as well as a more comprehensive metabolic profiling of participants in trials to assist in the interpretation of study outcomes.
Given that RSV has been tested within RCTs alone at doses ranging from 5 mg to 5 g, it is likely that vastly different doses may be required for the management of different therapeutic indications. Few trials have attempted to systematically assess dose–response relationships, beyond those establishing safety or characterising pharmacokinetics/metabolism [,], but it is important that a better understanding of this issue is gained with respect to key biological effects and efficacy, particularly considering the demonstration of non-linear dose–response relationships for RSV [], to enable an evidence-based approach to the selection of the optimal dose for future trials.

4.1. Challenges and Knowledge Gaps

Current limitations of the collective clinical data on RSV are the short duration and small size of most trials and the fact that relatively few studies have assessed defined health outcomes that measure whether RSV provides a clinical benefit to patients, using validated surrogate markers for performance, function, morbidity, or mortality from disease. A further weakness is that often the primary endpoint and outcome are not clearly stated or there are multiple listed, with no hierarchy given; this makes it difficult to assess whether a trial has reached its predetermined primary objective. In assessing the risk of bias across RCTs, the quality was generally good overall, but there are areas where the reporting of information was lacking, such as the method of randomisation employed and the precise RSV formulation used and manufacturer, which is needed so that other researchers (and potentially members of the public wishing to use supplements) may access the same products for future trials.
Well-recognised regulatory and financial challenges make it difficult to conduct trials with agents produced and marketed as nutraceutical supplements. There is significantly less economic incentive to fund studies with compounds that often cannot be patented; furthermore, manufacturers do not typically have the level of infrastructure of a pharmaceutical company, financial backing, or appropriate regulatory licences to produce products with evidence-backed health claims. Consequently, the majority of clinical research on RSV is funded by charitable or government organisations and is academic-led, which can limit opportunities for making significant advances.
The challenges of conducting clinical trials with RSV may be compounded by the sheer breadth of conditions it is being investigated for; this could conceivably dilute the resources available and appetite for funding research on the compound. A strategy to help ameliorate this possibility, which may be particularly relevant in the prevention setting, may be to design trials that assess composite endpoints across multiple conditions with overlapping risk factors, such as obesity-driven cancers, T2DM, and cardiovascular disease, to derive an estimation of wider health benefits.
As a naturally occurring polyphenol, RSV presents potential pharmaceutical challenges that are common across phytochemicals. Rapid metabolism and subsequent low systemic bioavailability are frequently cited limitations of RSV; however, it is difficult to assess the true impact of its poor bioavailability without better knowledge of the concentrations and doses that are required for clinical efficacy. As alluded to above, these are likely to differ depending on the indication; for example, low oral doses may be sufficient where the aim is to target the gastrointestinal tract since relatively high concentrations of parent RSV have been detected, along with changes in biomarkers associated with oxidative stress, in colorectal tissue of patients that took as little as 5 mg daily []. In contrast, in situations where high systemic concentrations are required, doses over 200-fold higher may be required. In these cases, the need to consume large numbers of capsules or tablets is likely to reduce acceptance and uptake by patients/populations whilst also increasing the risk of adverse events, which are dose related. Consequently, the poor bioavailability of RSV may necessitate the use of more advanced oral formulations that delay or prevent metabolic transformation to less or inactive derivatives, with the aim of increasing and prolonging higher systemic concentrations of parent RSV. There is much ongoing research and development in this area, although few formulations have been tested in humans to date [,,,]. Another consideration that may be more of an issue for aqueous or liquid-based dosage forms is the photosensitivity of RSV, which causes it to isomerise under UV light to the cis-isomer, which appears to have limited, if any, biological activity []. This will need to be taken into account as more diverse dosage forms are developed, such as gels for topical application and oral dispersions [,].

4.2. Encouraging Findings and Opportunities

Analysis of the types of endpoints utilised in clinical studies and the primary outcomes reported in RCTs (Figure 7) has revealed that the clinical effects and biomarker changes detected in RSV trials are generally in a positive direction, with a benefit reported in two-thirds of cases. Evidence of promising activity was described across a range of indications and since many of the modes of action of RSV are relevant to multiple conditions, results from one clinical setting may have utility in another. As such, despite the small size of the majority of trials conducted to date, recent systematic reviews and meta-analyses are beginning to reveal some reproducible effects of RSV, which may be important across multiple pathologies and conditions. RSV appears to consistently downregulate inflammatory markers, such as C-reactive protein and tumour necrosis factor-α, in a number of disease states, including T2DM, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD) [,,]. Furthermore, meta-analyses have revealed consistent decreases in plasma glucose and insulin, as well as the regulation of lipid metabolism and improvements in insulin sensitivity with RSV treatment [,,]. Overall, these effects may have benefits in the management of T2DM and other metabolic diseases, and also certain cancers since prolonged inflammatory responses and high circulating glucose play an important role in the promotion of carcinogenesis. In designing future trials, it may be pertinent to note that whilst meta-analyses have shown that RSV does not appear to have a direct effect on weight loss [], many of the beneficial metabolic outcomes described above are more pronounced in, or even exclusive to, people that are obese or overweight or have a diagnosis of T2DM []. Initial early evidence of this differential activity stemmed from a study by Timmers et al. in which RSV at a dose of 150 mg/day was found to mimic the effects of calorie restriction in obese men by lowering energy expenditure and improving their metabolic profile [], whereas a comparable dose had no effect in non-obese women with normal glucose tolerance [].
As well as the emerging data from meta-analyses, there have also been encouraging findings from several of the larger studies with longer intervention periods, such as the RESHAW trial involving post-menopausal women, which demonstrated that RSV supplementation significantly improved overall cognitive performance, menopausal symptoms, and measures of general well-being []. The biomarker changes observed in the one-year intervention trial in patients with mild to moderate dementia due to Alzheimer’s disease also suggest that RSV is worth pursuing in this indication []. We are now at the point where a greater number of larger-scale trials with longer durations that assess meaningful health outcomes are needed to advance RSV in areas where it has shown promise. The emphasis of future trials should be on evaluating changes in validated surrogate markers for performance, function, morbidity, and mortality from diseases or conditions rather than changes in biochemical measures in blood or unvalidated surrogate markers. However, such studies can become extremely costly, particularly in situations where regulatory requirements stipulate that RSV is an investigational medicinal product, which must be manufactured to the corresponding regulatory standards. It is, therefore, imperative to ensure that any trials conducted are of high quality and seek to maximise the information gained from every participant, including through the collection of clinical samples for translational research to further mechanistic understanding and ultimately decipher which individuals are likely to benefit from taking RSV.
Despite the barriers described above, the worldwide interest in RSV shows no signs of abating, with 17 trials currently listed on www.clinicaltrials.gov (accessed on 30 November 2023) as actively recruiting across diverse indications ranging from the prevention of recurrent respiratory tract infections in children to treatment of primary ovarian insufficiency. In addition, in the UK, the cancer-preventive effects of RSV are currently being examined in a phase 2 colorectal polyp prevention trial conducted within the English and Welsh National Health Service Bowel Cancer Screening Programme (BCSP) []. The COLO-PREVENT trial will recruit individuals who have attended a screening colonoscopy, at which they are found to have colorectal polyps that are classed as high-risk according to the BCSP standard criteria. Participants (477 in total) will be randomised equally to placebo, low (5 mg), or high (1 g) dose RSV daily for one year, and the primary outcome is the mean number of polyps per participant. The study encompasses a large programme of integrated translational work, including the assessment of circulating and tissue pharmacodynamic biomarkers and repeated metabolic phenotyping and gut microbiome analysis to ascertain whether baseline metabolic status or microbiome profile influences response to RSV and/or whether changes in these parameters may contribute to meditating RSV efficacy. The forward-thinking design parameters of COLO-PREVENT are aimed specifically at bridging the noted gaps in trial quality, size, duration, and use of clinically applicable end-point biomarkers for RSV.

5. Conclusions

This review provides a comprehensive summary of all clinical trials conducted on RSV, including the promising evidence of efficacy that has emerged over the past two decades. Despite there being 104 individual RCTs incorporating over 4800 participants on RSV intervention (67% of which have indicated a positive effect when including any reanalyses), there are clear limitations to the studies, both individually and collectively, which have hindered the advancement of RSV towards clinical utility. The existing evidence warrants future clinical studies, preferably ones that are large and have a sufficiently long duration, in patients experiencing multiple conditions, particularly the metabolic diseases that have been described here as being ameliorated by RSV intervention. Such studies should be designed to measure meaningful health outcomes using clinical endpoints or validated surrogate markers of disease. A detailed description of the formulations and randomisation methods employed should be provided to help demonstrate quality and low risk of bias. Additionally, both the potential link between individual patterns of metabolites and treatment outcomes and the evaluation of potential drug interactions deserve close attention.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijms25020747/s1. References [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,] are cited in the supplementary materials.

Author Contributions

Conceptualization, K.B; study design, K.B., C.P. and L.H.; publication Screening and data extraction, K.B., R.G.B., L.H., G.A., D.T., S.S.U. and C.P.; data collation, interpretation, and analysis, K.B. and L.H.; writing—original draft preparation, K.B., R.G.B., C.P. and L.H.; writing—review and editing, K.B., R.G.B., L.H., G.A., D.T., S.S.U. and C.P.; funding acquisition, K.B. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a Clinical Trial Award from Cancer Research UK (29542) and the UK Department of Health and Cancer Research UK through Experimental Cancer Medicine Centre awards (C10604/A25151). The research was carried out at the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC).

Conflicts of Interest

The authors declare no conflict of interest.

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