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A Rare Find

To say patient recruitment is hard work is an understatement. It can take up to 30 per cent of the clinical timeline, and problems with recruitment cause delays in 90 per cent of clinical trials (1,2).

For an ultra-rare disease such as alkaptonuria (AKU), patient recruitment can be even tougher due to a limited number of patients and lack of awareness in the medical community. There are only around 1,000 patients with this condition worldwide, and many more remain undiagnosed.

Finding patients to participate is only half of the equation. Keeping them motivated through the duration of a study looks set to become the biggest focus for upcoming trials.

DevelopAKUre Project

AKU, or Black Bone Disease, is a debilitating genetic condition that causes severe early onset osteoarthritis and a range of other symptoms. Prevalence estimates vary from one in 250,000 to one in a million.

The AKU Society, a patient group supporting individuals with this rare disease, is one of 13 organisations involved in the DevelopAKUre consortium – a five-and-a-half-year project that includes three clinical studies taking place in England, France and Slovakia.

The first study, SONIA 1, was a four-week dose response study involving 40 patients. The second, SONIA 2, will be a four-year efficacy study involving 140 patients. If successful, these studies will lead to a marketing authorisation application for the use of nitisinone in AKU. A third cross-sectional study, SOFIA, has been designed to determine when the damage associated with AKU starts and, therefore, at what age treatment should begin.

It is necessary to recruit at least 156 patients for the three studies but, with only 1,000 AKU sufferers worldwide, this presents a challenge. The pool of patients shrinks even further when we remove those who are already being treated with nitisinone off-label.

Good Relationships

So far, our most successful patient recruitment approaches have built on existing relationships with patients, doctors and sister societies, as well as growing a strong online presence.

When the DevelopAKUre project began in November 2012, there was a small but dedicated group of patients who were already interested in taking part in the trials. The society was also in touch with a number of AKU specialists across Europe who were willing to tell their patients about the study. In addition, there are established AKU sister societies in Italy, France, the Netherlands and Germany which informed their patients and put interested individuals in touch with us. Through these contacts, we were able to organise local patient meetings in several countries to discuss the trials.

Using existing relationships ensured there was good initial buy-in to the project. Many individuals had a vested interest in finding a treatment for AKU. The doctors and sister societies have also been very helpful in overcoming the language barrier which exists with many of our interested patients.

Online Presence

Having a strong online presence has allowed patients from around the world to find and contact us. In a recent 2013 study by the Centre for Information and Study on Clinical Research Participation (CISCRP), 46 per cent of participants reported finding information about clinical research online – an increase from 25 per cent in 2004 (3).

A dedicated microsite for the DevelopAKUre project was set up to provide information about the clinical trials. Between June and November 2013, there was a 486 per cent increase in unique monthly visits to the website, from 120 to 820. Every page of the site includes a ‘register your interest’ box which visitors can fill in with their contact details. Since the website launched in May 2013, 40 submissions have been received. Patients are also encouraged to discuss the clinical trials on the society’s Facebook page and via online patient communities.

Alternative Measures

Existing relationships and online means were the most successful avenues for recruiting patients for the first study, SONIA 1. Figure 1 shows where the 15 patients who attended the study site in England found out about the trial.

The approaches mentioned above were successful in recruiting patients for SONIA 1. However, the second, longer trial, SONIA 2, requires a much larger group of patients. Only a limited number of patients could be recruited through existing contacts and online channels. For this reason, a number of other recruitment approaches were tried.

In the first few months of the project, we wrote to hundreds of healthcare specialists in relevant areas such as metabolic medicine and rheumatology, reached out to national groups for those specialities, and contacted national rare disease groups. Alongside this, we asked doctors we were already in communication with to put us in touch with any useful contacts. Finally, we kept an eye out for papers and case studies on AKU and relevant authors to ask for help.

These approaches were time-consuming and produced limited results. However, with such a small group to recruit from, every single patient counts. Reaching out to so many doctors also increases awareness of AKU and, therefore, patients’ chances of diagnosis.

The second study, SONIA 2, has not yet started. Figure 2 shows where 42 patients interested in attending the English study site found out about the trial. The big difference from SONIA 1 is that 11 interested patients were found through contacting new doctors.

Cultural Barriers

Among the patient recruitment challenges, geography and language have been the most prominent. Although the internet helps to overcome geographical barriers in communication, it cannot remove the need for patients to travel to test centres regularly for the trials. Making it clear that all long-distance travel will be arranged and paid for by the test centre has partly addressed this challenge, but many patients are still put off by the travelling required.

The language barrier has been difficult primarily because of the limited budget of the project. We simply cannot afford to use official translation services all the time. To address this, we use Google Translate for quick emails to patients, a network of volunteer translators, and official translation companies only when necessary.

A number of cultural barriers have become apparent during patient recruitment. How open patients are to clinical research or travelling for a clinical trial varies between countries. Involvement in previous research has also affected how likely patients are to take part. Those who have had positive experiences are often more willing to participate; others feel dispirited because they have not seen anything come out of the research they were involved in. This is particularly true for patients who have taken part in more fundamental research.

Patient Motivation

Getting in touch with patients is only the beginning. The next step is to keep them motivated and involved in the trial. Indeed, motivating patients is going to become a much bigger focus when SONIA 2 starts in the next few months.

SONIA 1 was only four weeks long with a small group of patients, 80 per cent of whom received treatment.

In contrast, SONIA 2 will involve a much larger group of patients over a longer period of time, with only 50 per cent of patients receiving treatment. Patients will also know if they are not receiving medication as nitisinone changes the colour of AKU patients’ urine, which is why we have a non-treatment group rather than using a placebo.

Two factors have kept patients motivated and interested in the trial so far: forming a relationship with them, and providing them with a steady stream of information. This is made possible because all three trial sites have a dedicated member of staff for patient recruitment and support.

Building a relationship with patients requires staff to be reliable, honest and accessible. Patients need regular updates about the trial, but it is important to realise that ‘regular’ means a different thing for each patient. Some will need contact several times a week, whereas others only want to be updated when there is significant progress. We also try to be honest about any problems, such as delays or uncertainty about start dates. Finally, patients are aware that they can contact us by email or phone with any concerns or questions. Alongside this one-to-one contact, we provide patients with information through regular blog posts, newsletters and webinars.

Being able to provide patients with regular updates is reliant on us knowing what is going on in the project. With the DevelopAKUre consortium comprising 13 organisations from seven countries, this is no easy feat. In addition to regular email contact, all 13 bodies are also represented at a weekly teleconference to discuss the project’s progress.

Improving Trial Experiences

SONIA 1 has revealed a lot about patient motivation. During the study, a member of the AKU Society spent time with patients during every visit. We were able to talk to patients in-between assessments, building on the relationships formed before the trial. As interpreters were present, this was an ideal opportunity for us to communicate with non-English speaking patients.

Making participation as easy and carefree as possible is also a motivator. In the recent CISCRP survey, 38 per cent of drop-outs from clinical studies found site visits stressful, compared with only 16 per cent of those who completed studies (4). In our studies, long-distance travel and accommodation is arranged and paid for in advance. Other expenses are paid as soon as possible. Where there were delays in SONIA 1, we found this caused unnecessary distress to patients. Our aim in SONIA 2 is to keep these delays to a minimum.

Plans for the future include keeping up a steady flow of information to patients. Some 68 per cent of research participants say receiving regular updates about research they were involved in influenced their choice to participate in future (5). We will continue one-to-one contact, as well as regular blog posts, newsletters and webinars.

We also plan to encourage interaction between patients during and in-between visits. Around 61 per cent of clinical research participants say feeling part of a community was important in their decision to take part (5). Many SONIA 1 patients enjoyed having the opportunity to spend time with other patients. The rarity of AKU means many patients have never encountered anyone else with AKU. This quote from a patient sums up the positive experiences of many when they finally meet another fellow-sufferer: “The first time I met another patient with AKU, it was as if I had found a family member. Finally, someone who understood.”

In-between visits, patients will be encouraged to interact in our online communities. In addition, we are looking to inform patients which topics are best avoided when discussing the trials with other participants. As patients will know whether they are receiving nitisinone or not, we do not need to worry about patients unblinding themselves through discussing the trial; however, we still need to reduce the chances of patients influencing results by discussing side-effects or revealing too much about the inclusion process.

Vital Task

Finding enough patients and motivating them to get involved and stay involved in a trial is a hard but vital task. Some approaches to patient recruitment are easier and more successful than others. However, in a rare disease trial, every single patient recruited is crucial. This means embarking on time-consuming methods, even if results are limited. Motivating patients requires many different methods used together. Most important is building a relationship with the patients involved.

1. Bairu M, and Weiner M, Global Clinical Trials for Alzheimer’s Disease: Design, Implementation and Standardization, Academic Press, San Diego, p207, 2013
2. Online recruitment is streamlining clinical trials, Datamonitor, July 2008. Visit: online_recruitment_is_streamlining_ clinical_trials?productid=62E17CB0- F4C4-4774-A3A2-598600B85247
3. Report on clinical trial information seekers, 2013 Perceptions & Insights Study, CISCRP, p2, 2013
4. Report on ineligible participants and those who terminate participating early, CISCRP, p3, 2013
5. Report on study participant experiences, 2013 Perceptions & Insights Study, CISCRP, p2, 2013

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Hana Ayoob joined the AKU Society in 2012 after completing a BA in Natural Sciences and Management Studies at the University of Cambridge. As Clinical Trials Coordinator, her main role is patient recruitment and support in the DevelopAKUre project.

Hana Ayoob
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