I Join an RCT: A View From the Other Side

In ITNS we discuss randomized control trials (RCTs) and I’ve taught about them since whenever. If done well, they should provide gold standard evidence about the benefits and harms of a therapy. So I was particularly interested to be invited to join a large RCT. My wife, Lindy, and I both elected to join and we are now into the daily ritual of taking a little white tablet, each of us not knowing whether we have the dud or the active version. Weird!

The RCT is StaREE, A Clinical Trial of STAtin Therapy for Reducing Events in the Elderly. Yep, I’m officially ‘elderly’ and have been for a couple of years! It’s an enormous multimillion dollar project aiming for 10,000 participants over something like 8 years. It’s publicly funded, no drug company money involved.

StaREE project description and justification (taken from the registration site)

Statin therapy has been shown to reduce the risk of vascular events in younger individuals with manifest atherosclerotic disease or at high risk of vascular events. However, data derived from meta-analyses of existing trials suggests that the efficacy of statins may decline sharply amongst those over 70-75 years of age. Insufficient patients of this age group have been included in major trials to be certain of the benefit. Within this age group part of the benefit of statin therapy may be offset by adverse effects including myopathy, development of diabetes, cancer and cognitive impairment, all of which are more prevalent in the elderly in any event.

The use of statins in the over 70 age group raises fundamental questions about the purpose of preventive drug therapy in this age group. When a preventive agent is used in the context of competing mortality, polypharmacy and a higher incidence of adverse effects its use should be justified by an improvement in quality of life or some other composite measure that demonstrates that the benefit outweighs other factors.

STAREE will determine whether taking daily statin therapy (40 mg atorvastatin) will extend the length of a disability-free life, determined from survival outside permanent residential care, in healthy participants aged 70 years and above.

Background Reading

There’s a big 2016 review in The Lancet on open access here. A more recent review and meta-analysis is here. These seem to me to support the need for StaREE. Atorvastatin, the cholesterol-lowering drug under study seems safe and effective, while being cheap and widely-known. But most research to date has focussed on folks who have already had some cardiac event, or have high risk factors. There is need for evidence specifically about its possible value for healthy older folks.

My Experience So Far

Of course I first read all that the StaREE website had to offer, and what’s public in the registration of the trial at ClinicalTrials.gov and (more or less the same information) the Australian New Zealand Clinical Trials Registry.

I have asked the researchers for any further information they can give me, including information on:

• how the sample size of 10,000 was chosen
• the extent to which the full data and analysis scripts will be open, i.e. on public access
• further details of the data analysis planned, beyond the long list of measures included in the registration (these first 3 dot points are about Open Science good practice)
• details of how the safety committee is to operate and, in particular, what criteria will it use if it decides the trial should be stopped. (Such a committee is independent of the researchers and sees progressive results, without blinding, so can monitor any emerging trends that the therapy is clearly way better, or worse, than placebo. What evidence would lead it to stop the trial?)
• budget

No reply yet–I may report further if I find out more.

At my first appointment a nurse trained in the StaREE protocols explained everything in very simple terms. I signed, including agreement that the researchers could have full access to my medical records, past present and future. I did some cognitive tests, mainly of memory. (One of the aims is to assess the extent dementia risk might be reduced by the medication.) Then I started the one-month lead-in period, during which I had to take a tablet every day. This was stated to be placebo, despite one of the reviews (links above) arguing that it’s more informative to use the active tablets for all participants during the lead-in. There was a long questionnaire about my medical history, and a blood test, including cholesterol, was ordered.

Then I needed to see my regular doctor, who shared with me the blood test results. My LDL (‘bad’ cholesterol) and HDL (‘good’ cholesterol) levels were well within the normal range, as I expected. She signed to say that none of the StaREE exclusion criteria applied to me and that I could join the trial.

It was made clear that my own health care is first priority, so my doctor can, if she judges it necessary, be unblinded and perhaps advise me to leave the trial. Of course it should work that way, but that’s just one more complication for the researchers.

At my second appointment there were more cognitive tests. Quite amusing, given that I was familiar with some, having taught about them way back. Even so, it’s not so easy to remember the long list of words at first go, and to minimise Stroop interference while quickly reading out the ink colour of incongruent colour words. (Say ‘RED’ on seeing BLUE in red ink.)

Then the big pack of my tablets arrived in the post and I confirmed online that I was starting. One more thing to remember when packing for any travels, even overnight.

Blinding–but perhaps not of participants

According to the registration, the blinding (actually referred to as ‘masking’) is: “Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)”. Excellent. At present I’m blinded, but at any stage my doctor might order a blood test, including for cholesterol. A distinct drop in my LDL (and perhaps a boost to my HDL) would strongly suggest that I’m on the statin medication. I would, in effect, be unblinded.

I’ve also read about, and had anecdotal reports of small changes that can sometimes be felt when starting statins–call them minor, short-lived side-effects. These might also unblind a participant, although of course anyone aware of such possibilities might judge them to occur when actually starting placebo!

When I return for my next StaREE appointment after 12 months, there will be more cognitive tests and the researchers will order a blood test, but that will specifically not include cholesterol–so the researchers will remain blinded. However, many older folks have blood tests, including for cholesterol, regularly, even annually. And the documentation about Atorvastatin provided by StaREE states that “your cholesterol… levels need to be checked regularly…”. Therefore many participants could potentially know their cholesterol levels, say a year or so into the trial, and therefore potentially be unblinded. I don’t see any way around this. Just one more complication for researchers, and perhaps for the interpretation of results.

Efficacy or Effectiveness?

Efficacy… under ideal circumstances, e.g. in an ideal RCT. Effectiveness… in the real world. See here for A Primer on Effectiveness and Efficacy Trials.

RCTs are easy to criticise for imposing so many restrictions on who can participate–in the interests of minimising nuisance variability–that estimates of treatment benefits may be overestimated compared with what’s realistic to expect in everyday clinical practice, no doubt with a more diverse set of patients. StaREE does have a list of exclusion criteria (see the 10 dot points at the registration site) but this case is a little different: The research question asks about possible treatment benefits for a wide range of generally healthy folks; the exclusion criteria are actually not very restrictive. Maybe the efficacy estimated by StaREE won’t be all that different from the effectiveness to be expected if statin use becomes widespread among the healthy elderly. (That word again!)

Compliance is often notoriously low, especially I would suspect when a drug is to be taken for ever, and for a not very dramatic–even though worthwhile–reduction in risk of some nasty outcome. In StaREE, volunteers who choose to take part in research may be quite compliant–although perhaps the knowledge that there is only a 50-50 chance that the tablets contain the active ingredient might reduce compliance. Conversely, if StaREE does find evidence that statins are worth taking by healthy older folks, then folks won’t have the special context of a research project, but they will be sure that they are getting the good stuff. I’ll be interested to know StaREE compliance, but I’m unsure how well that will predict real-life compliance.

How Do I Feel?

It’s great that such a study has been funded. My experience so far emphasises what an enormous task it is to plan, set up, and run such a usefully large study. Far more difficult and complex than to write a couple of pages in a textbook about how an RCT should be designed! (A year ago I wrote a post about two enormous and expensive RCTs–the SYNTAX and EXEL studies–that compared stents and coronary grafts as treatments for heart disease. The two very different approaches turn out, overall, to be about equally good.)

I’m keen to know how closely this StaREE study aligns with Open Science practices.

Of course I’ll be 100% compliant! I’ll take my little white tablets every single day, even if it’s a coin toss whether they are all duds or not. Yes, for sure! Well, a couple of years on, will I still feel this way? I hope so. But consider: 10,000 participants, taking tablets daily for an average of 5 years or so, is approx 16 million tablet-taking moments. And all those moments are needed to find out some simple information: by how much is the risk reduced for stroke, heart attack, etc by taking the little white tablets that do contain (what we hope is) the good stuff?

Most of us probably owe our lives to modern medicine, partly thanks to participants who have consented to join past studies. I’m glad to have the chance to join what looks like a well-done and worthwhile study now.

Geoff