Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 2040-2046 (doi:10.1542/peds.2005-1328)
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An n-of-1 Trial Service in Clinical Practice: Testing the Effectiveness of Stimulants for Attention-Deficit/Hyperactivity Disorder

C. Jane Nikles, MBBSa, Geoffrey K. Mitchell, PhDa, Chris B. Del Mar, MDb, Alexandra Clavarino, PhDc and Norma McNairn, BSNa

a Discipline of General Practice
c School of Population Health, The University of Queensland, Herston, Queensland, Australia
b Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, Australia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. We sought to describe the clinical use of n-of-1 trials for attention-deficit/hyperactivity disorder in publicly and privately funded family and specialized pediatric practice in Australia.

METHODS. We used a within-patient randomized, double-blind, crossover comparison of stimulant (dexamphetamine or methylphenidate) versus placebo or alternative stimulant using 3 pairs of treatment periods. Trials were conducted from a central location using mail and telephone communication, with local supervision by the patients’ clinicians.

PATIENTS. Our study population included children with clinically diagnosed attention-deficit/hyperactivity disorder who were aged 5 to 16 years and previously stabilized on an optimal dose of stimulant. They were selected because treatment effectiveness was uncertain.

MAIN OUTCOME MEASURES. Our measures included number of patients recruited, number of doctors who used the service, geographic spread, completion rates, response rate, and post–n-of-1 trial decisions.

RESULTS. Forty-five doctors across Australia requested 108 n-of-1 trials, of which 86 were completed. In 69 drug-versus-placebo comparisons, 29 children responded better to stimulant than placebo. Immediately posttrial, 19 of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 of 24 nonresponders ceased or switched stimulants. In 40 of 63 for which data were available, posttrial management was consistent with the trial results. For all types of n-of-1 trials, management changed for 28 of 64 children for whom information was available.

DISCUSSION. Attention-deficit/hyperactivity disorder n-of-1 trials can be implemented successfully by mail and telephone communication. This type of trial can be valuable in clarifying treatment effect when it is uncertain, and in this series, they had a noticeable impact on short-term management.

Key Words: n-of-1 trials • attention-deficit/hyperactivity disorder

Abbreviations: ADHD—attention-deficit/hyperactivity disorder • DSM-IV—Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

Attention-deficit/hyperactivity disorder (ADHD) affects >7% of all children (especially boys)1 and may cause poor school performance, family distress, impaired social relationships, low self-esteem, accidental injury, lower perceived quality of life, and difficulties with independent life skills and general functioning.2,3 It may go on to cause antisocial behavior, substance abuse, leaving school early, and unemployment4 and costs the US community approximately US $1 billion annually.5

The stimulants dexamphetamine and methylphenidate reduce inattentiveness in children with a definitive diagnosis of ADHD and provide short-term improvements in behavior and academic performance.6 Currently, 1% of all Australian children are prescribed stimulants.7 However, only ~80% respond to dexamphetamine,2 although 92% do respond to either dexamphetamine or methylphenidate used at maximum doses.8 It is not possible to predict which children will respond.9 Stimulant use for children is a concern because of the huge increase in its use since 1988,10,11 and it is frightening for many Australian parents and their doctors because these stimulants are classified as drugs of dependence.

We have developed n-of-1 trials into clinical tests for several conditions, designing them to assist clinicians to identify whether a specific patient responds to a particular drug for chronic stable conditions in which individual response to treatment is variable.12,13 This formalizes the "trial of therapy" frequently used in clinical practice, which has several shortcomings, mostly related to the placebo effect and regression-to-the-mean effect.

The ADHD n-of-1 trial provides an objective means of answering questions about whether stimulants continue to provide benefit after long-term use. They also can be useful when starting a patient on stimulants after the dose has been stabilized. Our service has improved on previous ADHD n-of-1 trials9,14–19 by allowing flexible dosing (rather than fixed dosing by patient weight, which makes no allowance for differing tolerances) and using multiple crossovers (instead of just 1).15,16 The original purpose of the service was to evaluate individual responses to stimulants.

The usefulness of n-of-1 trials in general is well accepted,20 but there have only been 2 previous reports of n-of-1 trial services.20,21 Both offered n-of-1 trials on a face-to-face basis. However, we also were able to provide a national service throughout Australia using mail, telephone, and electronic communication.

A means of delivering n-of-1 trials at a distance is particularly important in Australia. It has a land mass approximately the size of the continental United States but has only 20 million people. Most of these people live in a few large cities, with the rest distributed in small- to medium-sized settlements. Access to health services poses particular problems, with most specialist services being located in the major population centers and medical services in many areas provided solely by family practitioners and occasionally visiting specialists. Waiting times are long, and some services are simply not available.22

The purposes of this article are to report on the service and its deployment in clinical practice, describe the methods we used, and report on the feasibility of the mail and telephone delivery. We also describe our response rates and the management decisions taken immediately after the n-of-1 trial.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The Clinical n-of-1 Service
Our service to clinicians was similar to those previously described,20,21 evolving from December 1999 (in a single academic family practice and face to face23,24) to May 2005 (by which stage it was offered nationwide with communication by mail, telephone, fax, and e-mail25,26). It went through a short transition period of local delivery by mail, telephone, fax, and e-mail as a trial for national delivery. The service was designed to mimic requesting pathology tests (Fig 1). The planning process has been described previously.24 We supplied request and consent forms and prepaid postal envelopes to interested doctors. Doctors could explain the process to interested patients (and parents) and obtain informed consent. We organized postage of the exact number of tablets required (listed on the request form) to an accredited manufacturing pharmacy for encapsulation of individualized doses and randomization according to a computer-generated randomization schedule. Kits containing the correct sequence of randomized doses, behavioral-symptom diaries, and instructions were posted back to doctors to dispense to the patients’ parent and provide usual clinical care. We tracked all steps involving postage of medication to comply with regulated-medications laws.


Figure 1
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  		FIGURE 1 Instructions for doctors.

 
Initially, one part-time research assistant and a part-time research officer ran the service entirely through The University of Queensland; subsequently, to test its transferability, it was delivered by a private pathology company (for 40) and a public children’s hospital (for 29), both with the university analyzing the results. A part-time academic family practitioner provided clinical input.

The service provided follow-up for patients by telephone to maximize compliance with the protocol. Patients completed a diary (which was analyzed by the service) once or twice weekly, and a report was sent to the doctor. The doctor and patient could then make informed clinical choices based on this information.

We promoted the service to doctors through newsletters, professional media, a Web site, and clinical meetings and to patients through support groups, brochures in doctors’ rooms, newspapers, television, radio, and a Web site.

Patients
Children were eligible if they had a clinical diagnosis of ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria, were stable on an apparently optimal dose of stimulant, had parental and schoolteacher informed consent (children >12 years provided assent), were aged 5 to 16 years (ensuring that teachers were available to provide observations), and had uncertainty about treatment effectiveness. If teachers did not agree to participate, the n-of-1 trial was not conducted (only 1 patient withdrew because of teacher nonparticipation). Children came from family practice and public (hospital-based, free care) and private (patients must pay for the service) pediatric practices.

Randomization
The possible comparisons (set by the particular clinical question posed by the doctor and parents) were dexamphetamine or methylphenidate with placebo or each other or different doses (such as 10 vs 15 mg of dexamphetamine per day). There were 3 pairs of treatment periods in each trial. Each pair contained the stimulant and the comparator stimulant or placebo (Fig 2). The child’s doctor individualized the dosing. The order of drugs was randomly assigned within each pair. Patients, parents, doctors, and the research assistant were all blinded to medication order. A hospital pharmacy encapsulated the medication (crushing of tablets and production of identical capsules containing either medication or placebo).


Figure 2
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  		FIGURE 2 Flowchart for ADHD n-of-1 trial. In this example, "week 1" is a treatment period (5 days of active treatment and 2 rest days). Weeks 1 and 2 combined are the first pair of treatment periods. The whole n-of-1 trial consists of the 3 pairs of treatment periods. Later n-of-1 trials used 2-day cycles.

 
Initially, the n-of-1 trials were 6 weeks long, but after 48 patients, we reduced the drug-versus- placebo ones to 3 weeks to reduce behavior problems in responders while they were on placebo. Because both stimulants have short half-lives (4–6 hours), full washout occurs within 24 to 30 hours of the last dose (usually before 4 PM); thus, we could conduct 2 treatment periods in a school week with 2 days per treatment period, not including Wednesdays and weekends in the trials. For drug-versus-drug comparisons, with smaller between-arm variation, we used longer treatment arms (all 5 school days without weekends). The between-arm variation was postulated to be smaller for drug-versus-drug n-of-1 trials than for drug-versus-placebo trials, and small differences would be more likely to be evident if each treatment period was longer.

Data Collection
The child (if aged >12 years), parent, and teacher completed diaries containing behavioral problem rating scales, assessment of adverse effects, and treatment preferences during and at the end of each treatment period. Initially, we used the Conners’ Teacher and Parent self-reported revised short form and the Conners-Wells Adolescent Rating Scales.27 These comprise 27 to 28 items evaluating 4 domains: oppositional/conduct problems, cognitive problems/inattention, hyperactivity, and ADHD index, which is a global rating of the function of the child with ADHD. The scales correspond with symptoms used in the DSM-IV as criteria for a diagnosis of ADHD.

After the 41st patient, we used ADHD du Paul Rating Scale-IV parent and teacher questionnaires because they were less expensive but adequately reliable and valid for monitoring response to treatment.28 The scale consists of 18 items; it closely corresponds to DSM-IV diagnostic criteria for ADHD and is relatively uninfluenced by symptoms of other disorders.28 However, we continued using the Conners-Wells Adolescent Rating Scales for children >12 years, because there is no du Paul ADHD Rating Scale for adolescents.

We collected information about medication history, demographic variables, the treatment decision immediately after the n-of-1 trial, and patient assessment of the utility of the service. Doctors gave feedback in a small written questionnaire survey.

Data Analysis
For stimulant-versus-placebo n-of-1 trials, we categorized individual adjusted Conners’ or du Paul scores into "responder" (more favorable response to stimulant on the measure by any quantity in all 3 treatment pairs), "possible responder" (in 2 of 3 treatment pairs), or "nonresponder." For the drug-versus-drug comparison, we arbitrarily defined as responders those in whom the pretrial drug performed best (Fig 3).


Figure 3
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  		FIGURE 3 Example of a responder and a nonresponder to dexamphetamine. The responder’s parent report shows clear differences between weeks 1, 4, and 5 (placebo) and weeks 2, 3, and 6 (dexamphetamine). Higher scores indicate worse behavior.

 
The University of Queensland Medical Research Ethics Committee, the Mater Misericordiae Hospital Medical Research Ethics Committee, and the Therapeutic Goods Administration gave approval for this study.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Forty-five doctors (17 family physicians, 26 pediatricians, and 1 child psychiatrist) in 4 states of Australia, mostly nonrural areas, used the service. They requested between 1 and 19 n-of-1 trials each, for a total of 108 trials in 21 girls and 85 boys (with 2 boys repeating). Twenty-two (20%) of the trials were not completed.

Here we briefly report the key results of the first 86 of the 108 n-of-1 trials commenced. Forty doctors in 4 states of Australia requested these trials for 18 girls and 66 boys (2 boys repeated the trial, one because he withdrew the first time and the other repeated the trial at a lower dose). Ages ranged from 5 to 16 years (median: 10 years). Patients had had ADHD for 2 to 12 years. Thirty-six patients were taking methylphenidate, and 47 were taking dexamphetamine (for 3 patients, whose questionnaires were never received and who became lost to follow-up, the pretrial medication was unknown). Treatment effect was uncertain for a number of reasons, including: stimulant thought not to be working, stimulant thought to be working but child may have grown out of it; and parents worried about long-term use.

Although the results from the children who used the service are not generalizable, a brief description of their initial results is necessary to put the post–n-of-1 trial management decisions into context.

Seventy-six patients completed 3 pairs of periods. Of those in drug-versus-placebo comparisons, 29 were responders, 28 were nonresponders, and 12 were possible responders. Of those in drug-versus-drug comparisons, 3 did better on methylphenidate than dexamphetamine, 1 did better on dexamphetamine than methylphenidate, and 1 was possibly better on dexamphetamine.

Ten (12%) trials were not completed: 7 because of deterioration on placebo (2 of these were obviously responders but were not counted as such because they did not complete their n-of-1 trial), 1 because of adverse effects (insomnia and depression), 1 from lack of teacher participation, and for 1 the reason was unknown.

In the following description, the denominator is the number of patients with complete information. The n-of-1 trial had a marked effect on management. Medication immediately posttrial changed for 28 (44%) of 64 of those completing the trial: 21 patients ceased their stimulant, 7 switched to another stimulant, and 36 (56%) of 64 stayed on the same medication.

Doctor/family groups used the trial results to varying extents. In 40 (63%) of 63 patients for whom data were available, posttrial management was consistent with the trial results; in 23 (37%) of 63 patients, the management was not consistent. For example, immediately posttrial, when data were available, 19 (76%) of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 (54%) of 24 nonresponders ceased or switched stimulants. Three of 4 patients who responded better to either methylphenidate or dexamphetamine remained on stimulants (Table 1).


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  		TABLE 1 Management Changes Immediately Post–n-of-1 Trial

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have successfully implemented n-of-1 trials as a diagnostic test in both clinical family medicine and pediatric practice, using for the first time a mail and telephone communication process that simulates pathology testing. We previously showed that the service was accepted by patients.29 Most clinicians declared that the service was useful: in a small survey of 13 family physicians, >80% would order more ADHD n-of-1 trials, thought them worth the time commitment, and found them useful, and 30% said ADHD n-of-1 trials changed their prescribing.30

In other studies, 31 (72%) of 43 children had a good response to methylphenidate,9 and 48 (68%) of 70 children showed improvement on methylphenidate in one of two 2-week periods.15 Of 94 children treated with methylphenidate, 70 (74%) demonstrated a positive response.16 Five (50%) of 10 children with ADHD and IQs ranging from 48 to 77 responded positively to methylphenidate.31 Our placebo-controlled response rates are lower than these, probably because of our different selection criteria and more strict criteria for response. We also tested both methylphenidate and dexamphetamine against each other and placebo, which none of the other studies did.

In our study, only 20% of the patients withdrew, which is much lower than the withdrawal rates previously reported for n-of-1 trials in Australia (40%12 and 37%32). This may be related to our ability to shorten the trials because stimulants are eliminated so quickly from the body.

It is important to note that 63% of patient/family/doctor groups used the n-of-1 trial results to guide management, and 21 (28%) of the patients who had been on regular stimulants ceased them. This indicates that n-of-1 trials can have at least a short-term impact on management for a sizeable number of patients. A subsequent article will describe management 3, 6, and 12 months later.

However, doctors used the service comparatively little. We can only speculate why. Perhaps we only slightly penetrated doctors’ awareness; the process requires considerable input from doctors (although we tried to minimize this). Others have also found similar issues with uptake (G. Guyatt, MD, verbal communication, 2000). In addition, long-acting stimulants were introduced to Australia partway through the trial, which slowed down our recruitment rate because many of our potential patients were switched to this more convenient formulation. However, in the last few months, we did offer n-of-1 trials of long-acting methylphenidate compared with placebo using encapsulation (the long-acting preparation is a biphasic release form of the normal drug and the half-life is unchanged). In the future it would be possible to conduct n-of-1 trials for other newer drugs for ADHD.

Although we did not collect relevant data, others have examined predictive factors for stimulant response. Neurologic status, inattention, and overactivity were found to be most likely to predict good response to psychostimulants, but the strength of the predictive associations suggested only minimal clinical usefulness.33 History and physical findings were not helpful in predicting methylphenidate response.15,34 As knowledge increases about the role that genetics plays in ADHD,35 we may be able to use genetic studies to assist in identifying responders in the future.

Increasing use of ADHD n-of-1 trials may not only result in more considered, rational, and cost-effective prescribing of these drugs but also may improve outcomes such as educational and occupational achievements. They should be used more often.


   ACKNOWLEDGMENTS
 
We thank the General Practice Evaluation Program, the Department of Health and Aged Care, Queensland Medical Laboratory, and the Royal Australian College of General Practitioners for funding. C.J.N. holds a National Health and Medical Research Council medical postgraduate research scholarship (210364).

We thank Paul Glasziou for co-initiating and overseeing the initial n-of-1 trial project; Queensland Medical Laboratory for delivering the attention-deficit/hyperactivity disorder n-of-1 trial service from 2001–2003; the Centre for Clinical Studies, Mater Misericordiae Health Service, in particular Dr Peter Steer, Dr Michael O’Callaghan, and Sue Jenkins-Manning, for delivering the service to hospital outpatients; Cate Duggan, Tina Janamian, Peter Coxeter, Kate Del Mar, Sharyn Herzig, Julie King, Jacob Carter, Donna-Marie Preston, Robyn Brown, Brenda Rosser, Norma McNairn, and Grace McBride for research assistance; and the children, caregivers, teachers, and doctors who participated.


   FOOTNOTES
 
Accepted Nov 15, 2005.

Address correspondence to C. Jane Nikles, MBBS, Discipline of General Practice, The University of Queensland, Herston Road, Herston, Queensland 4006, Australia. E-mail: uqjnikle{at}uq.edu.au

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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