Revisiting the Ethics of Urate‐Lowering Therapy Clinical Trials for Gout Management

The early 2000s saw a wave of randomized controlled trials (RCTs) of new urate-lowering therapies (ULTs) used in the management of gout. These trials compared the novel medications with placebo or relatively low doses of allopurinol.1, 2 In 2016, Shmerling raised concerns about the design of these trials, advocating for more ethical gout trials that “i) limit enrolment to individuals with gout refractory to appropriately dosed conventional therapies, ii) eliminate placebo arms, iii) routinely provide anti-inflammatory prophylaxis to reduce gout flares, and iv) allow appropriate up-titration of urate-lowering treatments in comparator arms.”3 In this viewpoint, we revisit ethical principles and standards for contemporary phase III and IV ULT clinical trials. We undertook a rapid literature review4, 5 of RCTs and RCT protocols of ULT for gout published in the last five years. A total of 16 phase III and IV trials were identified (Supplementary Material). Of these, 2 trials (13%) recruited individuals with refractory gout, 12 (75%) had no placebo or placebo-equivalent arm, and 10 (63%) provided routine anti-inflammatory prophylaxis against gout flares. In 10 of 15 trials of oral therapy (67%), ULT was started at a low dose and increased to a set maximum dose rather than to target urate. Shmerling recommended enrollment should be limited to people with gout that is “refractory to appropriately dosed conventional therapies.”3 This recommendation raises several issues. First it assumes that existing ULTs are so good when appropriately dosed and that no other ULT could be used first line. However, a new ULT might have benefits over existing therapies, such as more predictable urate-lowering efficacy, fewer gout flares on initiation, less frequent dosing, better tolerability, or fewer adverse events. Second, comparing a novel therapy with a conventional therapy in those who experienced failure of conventional therapies may undermine the external validity of a study that aims to investigate the efficacy of a treatment for the general gout population. Additionally, the reasons for failure of existing ULTs in real-life clinical practice are complex and may not be solved by changing to a different ULT. Thus, the inclusion criteria for participants in any clinical trial of ULT need to be aligned with the primary research aim, the goals of treatment, and the potential benefits and harms of the agent, rather than restricted to those with refractory disease. Placebos have been used in clinical trials as the comparator against which the efficacy and safety of the medication under investigation is determined. In short-duration, early-phase I and II clinical trials, placebo is justified to determine dosing for efficacy and safety. However, for longer-duration trials and phase III and IV trials, the use of placebo presents greater ethical challenges. The Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Participants6 states that a placebo or no intervention is only acceptable if no proven intervention exists or if there are “compelling and scientifically sound methodological reasons the use of any intervention other than the best proven one(s), the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention; and the participants who receive any intervention other than the best proven one(s), placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.” In the case of gout, there are readily available standard of care therapies that are superior to placebo with respect to urate lowering7; therefore, the use of placebo is not ethically justifiable in most situations. The exceptions are when a urate-lowering medication is being trialed in a situation in which it is not routinely recommended (eg, those with a single flare or very infrequent flares), when all participants receive some form of ULT and are randomized to either a second ULT (investigational product) or placebo, and/or in truly refractory gout when all other ULTs are contra-indicated or have failed. These principles are not aligned with the 2019 European Medicines Agency Guideline on clinical investigation of medicinal products for the treatment of gout, which states that for confirmatory trials “In general, parallel, randomized, double-blind, placebo-controlled trials should be performed for a minimum of 6 months.”8 This guideline may lead to prolonged exposure to hyperuricemia without appropriate ULT. Anti-inflammatory prophylaxis is recommended for up to six months when starting ULT to prevent gout flares.9, 10 Colchicine or nonsteroidal anti-inflammatory drugs are the recommended first line agents with low dose glucocorticoids reserved for those with contra-indications or lack of effect with these agents. Of note, in a retrospective cohort study, fewer cardiovascular events occurred during the six-month period of colchicine anti-inflammatory prophylaxis when commencing ULT.11 These potential benefits need to be weighed against potential harms. All these anti-inflammatory agents can have adverse effects, and there is also an increase in gout flares after discontinuing anti-inflammatory prophylaxis,12 which, for some individuals, will alter the risk–benefit balance. We consider that anti-inflammatory prophylaxis should be offered to every participant in trials commencing ULT. Whether anti-inflammatory prophylaxis is used must be a joint decision between the health care provider and the participant, respecting the participant's autonomy and safeguarding the participant's well-being by balancing the potential risks and benefits of the available agents for the individual. From an ethical perspective, unless the trial is specifically designed to investigate the effects of anti-inflammatory prophylaxis, if the individual has made an informed decision that the potential risks outweigh the potential benefits of anti-inflammatory prophylaxis or if there is prior intolerance or contra-indication to anti-inflammatory prophylaxis medications, there is no obvious reason why they should not be eligible to participate in a ULT trial. Shmerling suggested that participants in the “standard of care” arms of some trials were receiving care that the majority of rheumatologists would consider “suboptimal,” and the failure to up-titrate allopurinol in these trials resulted in loss of equipoise because there was little doubt that fixed dose allopurinol could reasonably be expected to be less effective than the “novel agent,” thereby introducing bias in favor of the “novel agent.”3 This loss of equipoise and positive bias toward the novel agent was illustrated in the phase III febuxostat trials. In the pivotal “Febuxostat compared with allopurinol in patients with hyperuricemia and gout” (FACT) trial, the primary endpoint of serum urate <6.0/dL at the last three monthly measurements was achieved in 53% of participants receiving 80 mg of febuxostat, 62% of those receiving 120 mg of febuxostat, and 21% of those receiving fixed-dose allopurinol (P < 0.001 for the comparison of each febuxostat group with the allopurinol group), leading to claims that febuxostat was more effective than allopurinol.1 However, in the more recent “Comparative effectiveness of allopurinol and febuxostat in gout management” trial, allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, respectively, with maximum titration to 800 and 120 mg, respectively, according to the serum urate target.13 In this trial, there was no significant difference in the proportion of participants achieving target serum urate (81.1% allopurinol and 78.4% febuxostat). Shmerling discussed that the “standard of care” arms in many ULT clinical trials do not reflect best practice. Standard of care in these studies has been based on the treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by health care professionals, for example, fixed low dose allopurinol. In comparison, best practice is recognized in major gout management guidelines as starting ULT at low dose with gradual dose titration, when possible, to achieve target serum urate9, 10 in order to decrease the risk of adverse effects and gout flares in the short term and to improve patient-reported outcomes such as flares and tophi over the long term. From an ethical perspective, modern clinical trials should offer best practice for comparator arms. However, we acknowledge the challenges dose titration creates in clinical trial design, especially for blinded trials that are required for regulatory approval. Gout flares are episodic, are unpredictable, and have a significant impact on patient quality of life. Early institution of gout flare therapy may shorten the flare duration. Like other chronic diseases, a flare action plan with a readily available supply of therapy is important for people with gout. When exiting any gout ULT clinical trial, participants need a defined management plan for ongoing ULT. This provision should be included within trial protocols. In those participants with truly refractory gout, when all other funded ULTs are contra-indicated or have failed, posttrial access to the intervention should routinely be offered if the intervention has been shown to be efficacious and reasonably safe, as outlined in the Declaration of Helsinki.6 Another key concern is whether participants in gout trials represent the general gout population. This is most evident in the exclusion of individuals with comorbidities associated with gout, especially chronic kidney disease,14 and the underrepresentation of Indigenous populations.15 It is imperative in large phase III and IV clinical trials that the trial population is representative of the general gout population. Over the last 15 years, we have considered many of these ethical issues in the design of our own investigator-led clinical trials. The allopurinol dose escalation study16, 17 occurred in the context of standard of care allopurinol prescribing, which restricted allopurinol dose based on renal function. The aim of the allopurinol dose escalation study was to examine the safety and efficacy of nonrenal-based allopurinol dosing. To achieve this, we needed to compare outcomes in a group who received dose-escalated allopurinol (active arm) and a group who remained on allopurinol at a fixed renal-based dose (control arm). However, we considered it unethical to continue fixed allopurinol dose, which rendered individuals above target serum urate for two years, so designed the study so that the control arm began allopurinol dose escalation to achieve target urate at the end of year one. The allopurinol dose escalation trial also highlighted the need to include individuals with comorbidities that are common in gout populations.16, 17 Renal impairment was not an exclusion, and so it provided much-needed evidence about the use of allopurinol in those with renal impairment. The Easy-Allo clinical trial18 examines two different strategies for allopurinol dose escalation with no placebo arm. Blinding treatment strategy trials can present logistical challenges and add a degree of complexity that may risk unintentional unblinding. Although this trial is not blinded, the primary outcome of the percentage of participants achieving target urate at month 12 is less likely to be subject to bias because it is a laboratory measurement and is more resistant to investigators’ biases. In the colchicine prophylaxis study19 and the current Easy-Allo clinical trial,18 all participants have an individualized gout flare management plan, have a best-practice allopurinol dose escalation, and are handed over to their ongoing primary care physician with a gout management plan at the end of the study. Schmerling challenged gout researchers, pharmaceutical companies, and institutional review boards to conduct ethical clinical trials that do not cause harm due to suboptimal ULT, particularly for participants randomized to comparator groups. This remains an imperative in contemporary clinical trial design. We acknowledge the tension between drug approval agency recommendations and the ethical principles we have discussed, particularly around the use of placebo. We challenge the drug approval agencies to consider whether their drug approval processes are ethically fit for purpose for ULT in gout management in 2026 and beyond. We also argue that other aspects of gout trial design should also be considered, as summarized in Table 1, to ensure that participants in trials of ULT receive best-practice gout care and that the results from clinical trials can be generalized to all people with gout. All data used in this research are already included in the article or the Supplementary Material. Open access publishing facilitated by University of Otago, as part of the Wiley - University of Otago agreement via the Council of Australian University Librarians. All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Stamp confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements. Disclosure form. Appendix S1: Supplementary Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.