Taking into account the information about Xamoterol, outline the main features of your phase 3 trial for Xidolol explaining their importance

Introduction

As a rule, phase 3 trials seek to confirm the therapeutic observations made in Phase 2 trials, allowing an assessment of the drug’s value in clinical practice. Furthermore, additional research goals conventionally associated with earlier phases of the trial can be incorporated into phase 3 trials; these include further observations regarding drug interactions as well as the different effects of various doses. Figure 1 outlines the potential for overlap in research goals throughout the various phases of a clinical trial, highlighting the need for researchers to remain attentive to the broad range of factors which may impact on trial subjects during each phase.     

Figure 1: See footnote¹

Through the course of this essay, the key design features of a robust phase 3 clinical trial for a fictional partial beta-1-selective agonist ‘Xidolol’ will be explicated. Phase 2 trials showed symptomatic relief of breathlessness and few adverse effects. It should be noted that a partial beta-1-selective agonist ‘Xamoterol’ was shown to be associated with adverse outcomes when administered to patients with ‘severe’ cardiac failure after its introduction in 1988 (2). With this in mind, this essay will proceed with reference to the following 3 key considerations when developing this phase 3 trial:

1. Methodology
2. Ethics
3. Finance

Prior to commencing any clinical research, it is necessary to hold all of the regulatory approval documentation, ensure that all staff are competent to perform their tasks and the facilities and equipment that will be used are available and in full working order. Only when all permissions have been secured and the trial protocol is fully developed can the trial commence.

Methodology

The category of trial that would be best suited to the investigation of Xiodolol would be a comparative efficacy trial. Comparative efficacy trials, also known as “placebo-controlled” or “superiority” trials are the most common type of phase 3 trial. They observe the differences in effects between the trialled drug and either a placebo or a standard therapy respectively. If the size of the local patient population allows, it would be sensible for it to be a “single-centre” trial to allow untroubled communication between members of the trial team. 

NICE (3) provides guidelines for pharmacological treatment of chronic heart failure with reduced ejection fraction; this includes an angiotensin-converting enzyme (ACE) inhibitor and an approved B-blocker, plus or minus a mineralocorticoid receptor antagonist. While adjunctive medications are discussed in this guideline, there is no mention of partial beta-1-selective agonists. Digoxin could be considered a suitable comparator and has been used before in a randomised, double-blind comparative study of Xamoterol (4). However, digoxin has a completely different mechanism of action to Xiodolol and is only recommended for use in “worsening or severe heart failure despite first-line treatment.”

Another potential comparator is Xamoterol: it has shown positive results in mild-to-moderate heart failure (4), but it would not be prudent to use it as a comparator as it is not considered a standard treatment. An additional reason to avoid Xamoterol is the aforementioned less favourable outcomes associated with this medication in severe heart failure (3). Therefore, this phase 3 trial will compare Xiodolol to a placebo only, as there is no current standard therapy which is similar enough to Xiodolol to allow for a safe and clinically relevant comparator.

National Institute for Health Research (NIHR) states that “crossover trials are only possible in trials of chronic conditions.” (5) There could be some benefit in designing this trial as a ‘crossover study’; for example, one of the potential benefits is that it could reduce the number of subjects required for statistically significant results by allowing the subjects to act as their own controls. This would be cheaper and quicker, as well as ensuring that the two subject-groups are comparable in every way, minimising the potential for bias. However, Xiodolol is a long-term treatment intended for use in subjects with a life-threatening chronic disease. Therefore, it is not simply symptomatic improvement but also any impact on mortality which needs to be measured as an endpoint. This is particularly pertinent because the pharmacologically similar drug Xamoterol demonstrated an increase in mortality in severe heart failure and as such, it is vital that the subjects are observed for long enough to reveal any significant differences in lifespan between the two groups. Therefore, Xiodolol will be trialled using a parallel group study design over a period of 6 months to allow any impacts from continuous long-term use to become apparent.

Blindedness & randomisation are measures to minimise bias. Blindedness can be single (subject only) or double (subject and investigator) with double-blinded trials minimising the potential for bias to a greater extent than single-blinded ones. Assuming that Xiodolol is an orally administered preparation without a distinctive taste, colour or smell, it will be straightforward to blind both the subjects and the investigators involved in this trial by having the placebo precisely resemble the active medication. Since this trial will only involve two groups of subjects, it will be relatively simple to randomly allocate patients to ‘group A’ (active) or ‘group B’ (placebo). These groups should be of approximately the same size which will be achieved by having subjects draw their tablet regimens from a ‘hat’. This method of randomisation is only possible if enough subjects are recruited to create an even balance of patient characteristics across both groups; to achieve this, recruitment for the study should begin early, with clear recruitment milestones in consultation with a statistician to ensure adequate numbers of subjects.

There is a risk that the blindness of the subjects will not be maintained if the medication produces a palpable effect such as slowing of the heart rate; however, there are no palpable physiological effects mentioned in the information available about Xidolol, so we will proceed assuming that there are none. To further minimise the potential for bias, it is vital that both groups are treated identically in every possible way such as length/regularity of appointments and lifestyle advice.

Thus we can see, in order to minimise the potential for bias and maximise the chance of demonstrating significant results, the phase 3 trial for Xiodolol will be a single-centre double-blinded randomized control trial (RCT). In order to create the opportunity for adverse events such as those associated with Xamoterol to exhibit themselves, the trial will last 6 months. In order to maximise the chance of demonstrating clinical effectiveness, Xiodolol will be administered in the dose shown in the phase 2 trials to provide the most symptomatic relief.

Ethics

Before the start of the trial, the trial protocol must be approved by an independent ethics committee. While individual consent from subjects is of course necessary in the trial, it is particularly important that subjects are fully aware of the study’s background and the history of poor outcomes in moderate-to-severe heart failure with Xamoterol. Without this knowledge, the subjects cannot be said to have made a fully informed decision, so it is of paramount importance that the information is conveyed in a clear, sensitive and open manner allowing subjects time to consider the information and the opportunity to express concerns at any juncture.

Beta-blockers have been shown to be haemodynamically and clinically beneficial for patients with heart failure (6), but as the research into beta-blockers evolved, it became apparent that around 20% of patients were symptomatically worse (7). This was thought to be due to reduced cardiac output associated with reduced heart rate, so interest developed in a B1-selective agent called Xamoterol which acts to ‘stabilise’ the heart rate by decreasing it during the day and increasing it at night. The results from a placebo-controlled RCT in mild-to-moderate heart failure were promising (8) demonstrating an increase in exercise tolerance without significant withdrawals due to adverse experiences and no increase in mortality over 3 months. However, the results from a placebo-controlled RCT in moderate-to-severe heart failure showed that by an intention-to-treat analysis, within 100 days of randomisation 9.2% of the xamoterol group and 3.7% of the placebo group died (2). This led to UK Health Authorities issuing recommended restrictions of use aimed at ensuring that Xamoterol is given only to patients with mild heart failure (9).

Since Xiodolol has the same mechanism of action and therefore could be expected to have the same cardiovascular effects as Xamoterol, it would not be ethical to trial Xiodolol on subjects with moderate-to-severe heart failure. Therefore, this phase 3 trial must be conducted only on subjects with mild-to-moderate heart failure; they should be closely observed throughout and the Xiodolol should be stopped if they show signs of crossing over into the moderate-to-severe category during the trial. A robust reporting scheme should also be in place to identify side effects and interactions, and the data gathered should be assessed at regular intervals for any signs of major differences between the two groups.

Due to concerns about teratogenicity, most clinical studies are carried out in men only, reducing the potential sample population and limiting the generalisability of the results. However, since most people suffering from heart failure have exceeded child-bearing age (10), this will not be a significant concern in this trial and a balanced mix of men and women can be recruited into both groups. Nonetheless, every female subject should be asked about the possibility of child-bearing and informed that teratogenicity of Xiodolol is not yet known. 

Finance

There are significant costs involved in any clinical trial, particularly a phase 3 trial of between 1000-3000 patients. Since research is a core function of the NHS, some funding is available via The Department of Health (11). In determining what funding is available for research, costs associated with clinical trials are divided into three categories: research costs, NHS treatment costs and NHS support costs. If an activity is not directly contributing to an NHS patient care services, then it is attributed as a ‘research cost’ and is not typically funded by the normal commissioning process or The Department of Health. Therefore, this cost will need to be met by a research grant or privately funded.

While it is possible that research grants are available for Xiodolol since developing novel agents for the management of heart failure is a high research priority (12), it is inevitable that some costs will need to be covered by the group conducting the trial themselves. If the trial is successful a licence may be granted, and marketing can commence to allow income to be generated by the sale of the drug. However, this should not be counted on as many drugs are refused a licence and some are withdrawn later due to safety concerns.

Another consideration to take into account when planning a trial is affordability of the drug that is being developed for the health service. Since calculations about which drugs to recommend are determined in some part by their cost, a highly expensive drug is less likely to be recommended. Quality-adjusted life years (QALYs) are the currency most frequently used to compare the cost-effectiveness of certain interventions and NICE currently uses the threshold range of £20,000-£30,000 per QALY gained to guide recommendations of treatment (13). Therefore, the overall cost of the trial must allow for the drug to be sold at a price which makes it affordable for the NHS, underlining the need for robust financial planning prior to commencing the trial.

Conclusion

Thus we can see, the main features of a phase 3 trial for Xiodolol include robust methodology to minimise bias, appropriate consent of subjects prior to the study, clear-headed financial planning to render the study viable and a robust reporting system to protect subjects from avoidable adverse reactions. Since one of the key goals of all phase 3 trials is to evaluate safety in longer-term use, subjects should be monitored closely throughout with regular surveillance appointments. However, achieving this while remaining within a specified budget will be a significant achievement. 

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References

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