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Protocol for the STAR (Sheffield Treatments for ADHD) project: An internal pilot study assessing the feasibility of the Trials within Cohorts (TwiCs) design to test the effectiveness of interventions for children with ADHD

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Background Attention deficit hyperactivity disorder (ADHD) is a common and growing problem and a leading cause of child referrals to Child and Adult Mental Health Services (CAMHS). It is a drain on resources across nationally funded support agencies and associated with negative outcomes such as early criminality, school disruption and antisocial behaviour. Mainstream interventions (pharmacological and behavioural) demonstrate effectiveness whilst implemented, but are costly, often have unwanted side effects and do not appear to be affecting long-term outcomes. Development of a robust evidence base for the effectiveness of current and novel interventions and their impact over the long term is required. The aim of the Sheffield Treatments for ADHD Research (STAR) project is to facilitate a rigorous evidence base in order to provide information about the comparative (cost) effectiveness and acceptability of multiple interventions to key stakeholders. Methods The Trials within Cohorts (TwiCs) design was used to build a cohort of children with a diagnosis of ADHD and conduct a three-armed pilot trial of the clinical and cost effectiveness of two novel interventions: (a) treatment by nutritional therapists and (b) treatment by homoeopaths, compared to (c) treatment as usual. Participants are recruited to the STAR long-term observational cohort, and their outcomes of interest (ADHD symptoms, health-related quality of life, school disruption, resource use and criminality) are measured every 6 months by carers and (blinded) teachers. Two promising interventions were identified for the first randomised controlled trial embedded in the cohort. A random selection of eligible participants is offered treatments (a) and (b). The outcomes of those offered treatment are compared to those not offered treatment using intention to treat (ITT) analysis. The feasibility of recruiting to the cohort and the trial, delivering the interventions, the effectiveness of the interventions and the appropriateness, sensitivity and collectability of outcomes is trialled. Discussion The results of this trial will provide information on the feasibility of the TwiCs design to facilitate multiple trials of potential interventions for children with ADHD, and the acceptability, clinical and cost effectiveness of two potential interventions for ADHD to ADHD stakeholders including service providers. Future stages of the STAR project will test other treatments informed by the results in stage 1. Trial registration ISRCTN number 17723526. 10.1186/ISRCTN17723526. Date assigned 27/4/15.
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S T U D Y P R O T O C O L Open Access
Protocol for the STAR (Sheffield Treatments
for ADHD) project: an internal pilot study
assessing the feasibility of the Trials within
Cohorts (TwiCs) design to test the
effectiveness of interventions for children
with ADHD
Philippa Fibert
1*
, Clare Relton
1
, Tessa Peasgood
1
and David Daley
2
Abstract
Background: Attention deficit hyperactivity disorder (ADHD) is a common and growing problem and a leading
cause of child referrals to Child and Adult Mental Health Services (CAMHS). It is a drain on resources across nationally
funded support agencies and associated with negative outcomes such as early criminality, school disruption and
antisocial behaviour. Mainstream interventions (pharmacological and behavioural) demonstrate effectiveness whilst
implemented, but are costly, often have unwanted side effects and do not appear to be affecting long-term outcomes.
Development of a robust evidence base for the effectiveness of current and novel interventions and their impact over
the long term is required. The aim of the Sheffield Treatments for ADHD Research (STAR) project is to facilitate a
rigorous evidence base in order to provide information about the comparative (cost) effectiveness and acceptability of
multiple interventions to key stakeholders.
Methods: The Trials within Cohorts (TwiCs) design was used to build a cohort of children with a diagnosis of ADHD
and conduct a three-armed pilot trial of the clinical and cost effectiveness of two novel interventions: (a) treatment by
nutritional therapists and (b) treatment by homoeopaths, compared to (c) treatment as usual.
Participants are recruited to the STAR long-term observational cohort, and their outcomes of interest (ADHD
symptoms, health-related quality of life, school disruption, resource use and criminality) are measured every
6 months by carers and (blinded) teachers. Two promising interventions were identified for the first randomised
controlled trial embedded in the cohort. A random selection of eligible participants is offered treatments (a) and (b).
The outcomes of those offered treatment are compared to those not offered treatment using intention to treat
(ITT) analysis.
The feasibility of recruiting to the cohort and the trial, delivering the interventions, the effectiveness of the
interventions and the appropriateness, sensitivity and collectability of outcomes is trialled.
(Continued on next page)
* Correspondence: p.fibert@sheffield.ac.uk
1
School of Health and Related Research, University of Sheffield, Regent Court,
30 Regent Street, Sheffield S1 4DA, UK
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Fibert et al. Pilot and Feasibility Studies (2018) 4:61
https://doi.org/10.1186/s40814-018-0250-3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
(Continued from previous page)
Discussion: The results of this trial will provide information on the feasibility of the TwiCs design to facilitate
multiple trials of potential interventions for children with ADHD, and the acceptability, clinical and cost effectiveness
of two potential interventions for ADHD to ADHD stakeholders including service providers. Future stages of the STAR
project will test other treatments informed by the results in stage 1.
Trial registration: ISRCTN number 17723526. https://doi.org/10.1186/ISRCTN17723526. Date assigned 27/4/15.
Keywords: ADHD, Feasibility, TwiCs, Nutrition, Homoeopathy
Background
ADHD is a common and growing problem and a leading
cause of child referrals to Child and Adult Mental
Health Services (CAMHS). It accounts for a sizeable
amount of resource use, is a drain on resources across
nationally funded support agencies [1], and presents a
major, often unmet challenge to services [2]. There is a
need to improve outcomes, where the condition is asso-
ciated with negative outcomes such as early criminality,
school disruption and antisocial behaviour. Mainstream
interventions (pharmacological and behavioural) demon-
strate effectiveness whilst implemented, but are costly,
often have unwanted side effects and do not appear to
be affecting long-term outcomes.
ADHD is associated with a range of negative behav-
iours such as difficulties regulating emotions, particu-
larly anger [3], involvement with violent criminality and
at a young age [4], school disruption, exclusion and low
attainment [5,6]. Children often have few friends [7],
and their experience of school can be one of academic
failure, rejection by peers and low self-esteem [8]. Infor-
mation is required about cost-effective interventions
which can achieve positive changes over the long term.
Current interventions may only be effective whilst im-
plemented [9,10] over the short term [1113] and com-
pliance with medication (the main intervention) can be
poor [14,15]. Furthermore, up to 25% of children may
not respond to stimulant medication [1618] which is
associated with adverse events [19] particularly those
with concomitant ADHD and autism spectrum condi-
tions (ASCs) [2022].
Whilst we have information about the efficacy of main-
stream interventions, it is unclear whether this translates
into real-world effectiveness, acceptability and improve-
ment in long-term outcomes. Pragmatic trials will be help-
ful for a variety of reasons [23]. Measurement of the
acceptability and (cost) effectiveness of interventions over
the long term can provide important information for
stakeholders. Heterogeneity is a feature of ADHD expres-
sion and children often have a wide range of other diagno-
ses such as ASCs [24], conduct disorders [25], sleep
disturbance [26], gut dysbiosis and tics [27]. Information
is required about whether efficacious interventions for
children with single ADHD diagnoses are effective in
populations with additional co-morbidities. Finally, chil-
dren with ADHD and their families can be hard to engage
and treat [28]; therefore, the acceptability of interventions
is an important consideration.
The Trials within Cohorts (TwiCs) design (also known
as the cohort multiple randomised controlled trial
(cmRCT) design) has been developed to help address
some of the limitations associated with existing RCT de-
signs [29]: for example, the tendency for potential treat-
ments to be trialled one at a time, in different populations
by different research teams, yielding trials with heteroge-
neous trial populations between trials and often short-
term and heterogeneous outcomes.
The TwiCs design recruits a large, long-term observa-
tional cohort of people with the condition of interest
and regularly measures their outcomes of interest. For
each trial embedded within this cohort, a proportion
meeting trial inclusion and exclusion criteria are offered
interventions. Those not randomly selected act as a vir-
tual treatment as usual (TAU) control group.
The STAR project aims to facilitate a rigorous evi-
dence base in order to provide information about the
comparative (cost) effectiveness and acceptability of
multiple interventions to key stakeholders about inter-
ventions which might address treatment gaps. This pilot
study addresses the research question: Is the TwiCs de-
sign feasible to assess the effectiveness of treatments for
ADHD? For the study, two interventions with prelimin-
ary indications of effectiveness, considered complemen-
tary and alternative medicine (CAM) [30], have been
selected. Parents of children with ADHD are trying these
interventions, paying for them out of pocket.
CAM use for ADHD has been found to range from
12% [31] to 71% [32]. Its use is increasing, especially
for conditions without effective recommended treat-
ments, where medical treatment is associated with ser-
ious adverse effects [33]andforchildrenwithchronic
conditions [3436]. Patients are using CAM despite
physicians concerns, and in addition to medication,
therefore, development of a robust evidence base is re-
quired. The CAM interventions being used by parents
of children with ADHD include acupuncture, aroma-
therapy, chiropractic, elimination diets, fatty acid sup-
plementation, herbal medicine, homoeopathy, massage,
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speech, physical and occupational therapy, and vitamins
[31,32,36,37].
For this first RCT, we identified two interventions
showing indications of effectiveness and being used by
parents of children with ADHD. Since they are being
tested as experienced in real-life clinical practice as be-
fitting a pragmatic trial, we named them treatment by a
homoeopath and treatment by a nutritional therapist.
The published evidence for homoeopathic treatment
for ADHD consists of seven trials: two RCTs tested the
efficacy of specific homoeopathic formulas [38,39]; four
RCTs tested the efficacy of individualised homoeopathic
medicines [4043]; and one within subjects trial of chil-
dren with ASCs measuring ADHD symptoms tested the
effectiveness of individualised homoeopathic treatment
[44]. All studies but one [42] of individualised homoeop-
athy found significant improvements, but effect size var-
ied, and quality is variable.
Although a healthy diet is recommended by NICE [2],
no trials assessing the effectiveness or acceptability of
this have yet been conducted. There are many studies
exploring the efficacy of individual nutrients, multiple
nutrients, and special diets for ADHD. Systematic re-
views concur that polyunsaturated fatty acids have small
effects on ADHD symptoms [45,46] and that restricted
elimination diets, artificial food colour elimination and
dietary supplements may be efficacious, but more stud-
ies are required before firm conclusions can be reached.
Improvements may be optimised by both eliminating ag-
gravating factors and boosting nutritional deficits in an
individualised way, since sensitivities are found in some
but not all children with ADHD. Treatment by nutri-
tional therapists provides advice about, and support
implementing, individually tailored exclusion, supple-
mentation, and healthy eating.
Aims and objectives
The aim of the STAR project is to provide a facility for
efficiently testing multiple interventions for children
with ADHD.
Stage 1 of the STAR project will test the feasibility of
the Trials within Cohorts (TwiCs) design and conduct a
three-armed pilot trial of the clinical and cost effective-
ness of two interventions: (a) the offer of a course of
treatment by homoeopaths and (b) the offer of a course
of treatment by a nutritional therapist, compared to (c)
treatment as usual.
Stage 1 will test the feasibility of the TwiCs design by
conducting a small-scale test of the methods and proce-
dures and assess the acceptability, deliverability, clinical
and cost effectiveness of treatment by homoeopaths and
nutritional therapists for children with ADHD.
The objectives of stage 1 are to assess the feasibility of
recruiting to time and target a cohort of children with a
diagnosis of ADHD, their carers and teachers; the feasi-
bility and acceptability of the study design; the feasibility,
deliverability, safety and acceptability of the interven-
tions; the suitability, acceptability and deliverability of
the outcome measures; and to inform sample size calcu-
lation for a full trial (stage 2).
Methods
Recruitment
At least 140 children aged 518 with a diagnosis of
ADHD and any accompanying co-morbidities are re-
cruited to an observational cohort and their consent to
participate in the cohort is sought by completion of a
questionnaire with embedded consent to be contacted
again. Their outcomes of interest are measured at re-
cruitment (baseline) and every 6 months, via these ques-
tionnaires, which are completed by carers and blinded
teachers. Carers of children with ADHD were involved
in the selection of items for, design and pilot testing of
the questionnaire, advised about recruitment and sat on
the steering committee.
Randomisation
After recruitment to the STAR cohort, a three-armed in-
ternal pilot trial is subsequently conducted whereby ran-
dom selections of eligible children are offered either
adjunctive treatment by homoeopaths (arm 1) or nutri-
tional therapists (arm 2). Randomisation is computer
generated by an independent statistician from the Uni-
versity of Sheffield and held in the locked drawer of a
different statistician from the University of Sheffield.
Stratifying factors are age (primary 511/secondary 12
18), medication status (yes/no) and ADHD severity
(Conners global ADHD Tscore 80+/under 80) [47]. Par-
ticipants fulfilling inclusion and exclusion criteria who
consent to be contacted again are identified on recruit-
ment to the cohort. Stratifying factors are extracted and
emailed to the statistician holding the randomisation list,
who randomly assigns them to one of the three groups
and gives them a randomly generated three-digit code
by which they are subsequently identified.
Carer and childs consent to try treatments is sought
at this stage. They are sent a letter of invitation for 1 year
of treatment, which includes a statement that partici-
pants can withdraw at any time; a brief description of
the treatment; requests the carer to ask their child if
they are happy to participate; a consent form to treat-
ment to be signed by carer and child and returned in a
pre-paid envelope; and an email address and telephone
number as an alternate means of contact. The PI then
rings the participants up and asks if they have any ques-
tions; if they wish to participate (if their form has not
yet been returned); and if they both consent, to their de-
tails being passed on to the therapist. In the absence of a
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returned consent to treatmentform, carer and childs
wish to participate on the telephone is taken as verbal
consent. Consent forms are then signed at the first ap-
pointment with the therapist, who further explains what
treatment will constitute, as befits usual practice. Appro-
priate marks by young children are taken as signatures.
Those children not selected act as a treatment as usual
control (arm 3).
Sample size
Sample size for the pilot trial is calculated to recruit at
least 30 participants in each arm in order to estimate the
pooled standard deviation of the outcome with a reason-
able degree of precision for the full trial [48,49]. We
have estimated that attrition will be 20% based on a pre-
liminary feasibility-controlled case series [50] and that a
further 20% joining the STAR cohort will either not
meet the first trial inclusion criteria or not accept the
offer of treatment.
Sample size for the full trial will be based upon results
obtained in the pilot. The calculation will be based upon
the obtained effect size (SMD) for the primary outcome,
significance (alpha error) of 0.05 and power of 80% and
adjusted according to the levels of attrition observed. If
an effect size of .4 is obtained in the pilot, then the out-
comes of approximately 100 participants per group will
be required. If estimated attrition of 40% is correct, then
166 participants per group will need to be recruited to
the cohort.
Participants are recruited from registered charities,
schools, word of mouth and support groups. The major-
ity of participants are recruited from the city of Sheffield;
however, participants are also recruited nationally and
the feasibility of on-line treatments assessed.
Inclusion/exclusion criteria
Inclusion criteria for the STAR cohort are children aged
518 (inclusive) with a carer-reported diagnosis of
ADHD (date, venue and diagnosing physician) and a
carer-reported Conners Global Index (CGI) Tscore of at
least 55 (denoting mild atypicality (Table 1). Inclusion
criteria for the trial are a carer-reported CGI score of at
least 65 (indicating a significant problem) (Table 1).
Exclusion criteria to both cohort and trial are children
below the age of 5 or adults over 18; children with ter-
minal, severe, life-limiting conditions; and families where
English is not written or spoken (as the project does not
have funds to provide a translation service). Exclusion
criteria to the trial are children currently receiving treat-
ment by a homoeopath or a nutritional therapist and
children with CGI Tscores below 65.
Outcome measurement
Carers of children with ADHD are asked to complete
carer questionnaires (CQs) sent to them by post or com-
pleted on-line (www.starsheffield.com).The CQ includes
the 10-item ConnersGlobal Index (CGI) [47]; the 18-
item Swanson, Nolan and Pelham Teacher and Parent
Rating Scale (SNAP) [51]; the 9-item Child Health Util-
ity health-related quality of life (CHU-9) measure [52];
and questions about resource use. The last page asks for
consent from carers and children to be contacted again,
for their school to be contacted, personal and school
contact details.
Where consent is given, schools are sent a teachers
questionnaire (TQ) and an information letter. They are
not informed about treatment allocation. The TQ in-
cludes the CGI, SNAP, and questions about school-
specific resource use, attendance, disruption and exclu-
sion. Schools which do not want to participate are not
contacted again.
Control group participants are not informed that they
have not been selected for a treatment but continue to
be sent questionnaires at the same time intervals as
treatment groups. CQs and TQs are sent out every
6 months to all cohort participants. Those refusing the
offer of treatment are still asked to complete outcome
measures as usual every 6 months and considered mem-
bers of the offer group.
The interventions
Homoeopaths are registered with one of the four main
bodies representing homoeopaths in the UK. Nutritional
therapists are registered with the British Association of
Applied Nutrition and Nutritional Therapy and are mem-
bers of the Complementary and Natural Healthcare Coun-
cil. All therapists are CRB checked, complete an on-line
NSPCC child protection course (https://www.nspcc.or-
g.uk/what-you-can-do/get-expert-training), attend a 1-day
training course on risk and receive guidelines in manage-
ment of ADHD and serious adverse events.
Both interventions are offered to participants for a
maximum of 1 year consisting of a maximum of eight
appointments. Consultations take place at Complemen-
tary Medicine Centres, participants homes or on-line.
First consultations last for up to 1½ h and follow-ups
last up to 40 min approximately every 6 weeks for up to
Table 1 Interpretive guideline for ConnersTscores and
percentiles
Tscore Percentile Guideline
70+ 98+ Markedly atypical (significant problem)
6670 9598 Moderately atypical (significant problem)
6165 8694 Mildly atypical (possible problem)
5660 7485 Slightly atypical (borderline)
<3055 < 273 Average (typical: should not raise concern)
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1 year resulting in a total of up to seven contact hours.
Homoeopaths conduct fact-finding consultations on the
basis of which they prescribe homoeopathic medicines,
guided by underlying basic homoeopathic principles
[53]. Treating like with likeis the core principle: that
substances causing certain symptoms in healthy persons
may cure those same symptoms in those who are ill. Nu-
tritional therapists take an initial health history and dis-
cuss and agree with participants an appropriate range of
options such as elimination diets, healthy food and
menu options, reducing aggravators such as food colour-
ings or sugar; improving fluids intake, lifestyle issues
such as sleep; specific dietary intervention for symptoms;
and supplementation.
At each consultation, therapists ask participants and/
or their carer (dependent on age) to complete Measure
Your Own Medical Outcome Profile (MYMOP) [54].
This patient generated outcome measure consists of 4
self-chosen items measured using a Likert-type scale of
0 (as good as it could be) to 6 (as bad as it could be):
two symptoms considered most bothersome, an activity
ADHD limits participation in, and well-being. Dimin-
ution of scores represents improvement. This persona-
lised measure allows participants to select their key
concerns and document how they change over time. It is
a validated outcome measure considered appropriate to
capture non-specific effects.
Therapists also ask about any adverse events experi-
enced by participants which are recorded according
to the Common Terminology Criteria for Adverse
Events guidelines [55]. Therapists are instructed to re-
port adverse events of level 3 or more to the PI
within 24 h, who refers them immediately to the
study Data Management and Ethics Committee for
appropriate action.
Information regarding adverse events for children with
ADHD in response to homoeopathic treatment suggests
that there may be occasional mild transient increases in
symptoms, which are however usually associated with
overall feelings of well-being. Information in response to
nutritional therapy suggests that there may be occasional
minor side effects from supplementation.
Outcomes
Patient-centred outcomes
The primary outcome measured is ADHD symptomatol-
ogy measured using CGI, consisting of a 10-item total
score and two sub-scores measuring restlessness/impul-
sivity (7 items) and emotional lability (3 items). The out-
come is reported by carers (unblinded) and teachers
(blinded), and each intervention is compared to usual
care. Secondary outcomes are carer proxy health-related
quality of life (CHU-9) and sleep. Resource use is col-
lected by asking about medication use; further ADHD
interventions being used; hospital, GP, social worker and
police attendances; levels of absenteeism, exclusion and
criminality; and teaching assistant and other help in
school.
Resource use data is collected to enable an economic
evaluation alongside a clinical trial. Evaluation will include
health-related quality of life assessment, with utility mea-
sures based on the CHU-9D, the cost of consultations,
medications, remedies, supplements and room hire, to en-
able QALY and ICER calculation. The time horizon is
1 year, during which time resource use will be collected
from therapists, who complete therapist forms at each
consultation documenting the time spent, the venue, med-
ications or supplements given.
Feasibility outcomes (Table 2)
Key feasibility criteria are the ability to recruit a cohort
and to recruit to the interventions within the stated time
frame of 2 years, by measuring recruitment rates and
time taken. Numbers recruited in 2 years will be extrap-
olated to estimate the time needed to recruit to a full
trial, and longer than 4 years will not be considered feas-
ible. The feasibility of recruiting a representative cohort
will document ADHD severity, number and type of co-
morbidities, medications taken, resource usage, levels of
exclusion, and criminality, and recruiting from nationally
funded ADHD facilities such as special schools, secure
units, NHS facilities and support services.
Whether suitable homoeopaths and nutritional thera-
pists can be recruited will be assessed, with recruitment of
two therapists for each intervention considered the mini-
mum required. The uptake of treatment will measure the
number of appointments kept and missed; the taking of
homoeopathic medicines; and the implementation of ad-
vice, diets, and the taking of supplements. At least 30%
will need to have accessed treatment, and at least 70% of
those to have attended at least three consultations, to con-
tinue to the full trial. It is anticipated that there may be
high dropout rate and chaotic uptake. The percentage of
participants refusing treatment will be considered to de-
termine acceptable levels of refusal since too many re-
fusers may lead to high chance of a type II error and
inadequate information to estimate critical parameters for
a full trial with reasonable precision.
Adverse events will be documented to measure the
safety of the interventions using the Common Termin-
ology Criteria for Adverse Events (CTCAE, 2010). Any
severe adverse events as a result of treatment will mean
the intervention will not continue to full trial.
The acceptability of the outcome measurements will
assess rates of completion by parents and teachers at
each time point in the study. Collection methods will be
adjusted if necessary. Their suitability will also be
assessed by ascertaining whether information can be
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accurately and usefully collected about ADHD symptoms,
health-related quality of life, criminality, school exclusion,
attendance, extra help, professional resource use, medica-
tion and other intervention use and adjusted as necessary.
Whether CGI and SNAP are appropriate and sensitive
enough to measure therapist- and participant-perceived
change will be assessed and measures adjusted accord-
ingly. The measure will be adjusted if any systematically
missing items are identified. The suitability and appropri-
ateness of statistical analyses to interpret results will also
be assessed.
Statistical analysis
Statistical testing is exploratory since the study is not pow-
ered to detect statistical differences. It will be used to en-
sure that a difference can be seen from the interventions
to proceed to the full trial, to inform sample size calcula-
tion, and to pilot test the statistical analyses selected. Ana-
lysis will focus on confidence interval estimation rather
than hypothesis testing. IBM SPSS 21 statistical software
[56] will be used. All statistical exploratory tests will be
two-tailed with significance level (alpha) set to 5%, and
95% confidence intervals presented. Outcomes will be
measured by parents and teachers at baseline, 6 months
and 1 year. Both interventions tested will be compared
with treatment as usual with parent and teacher measure-
ments reported.
Missing data: post hoc tests will be performed to iden-
tify any differences between groups regarding whether
data is missing completely at random or not at random.
6-month missing data will be imputed using Last Obser-
vation Carried Forward or mean substitution (for base-
line data) according to tool developer recommendations
[47].
Intention to Treat(ITT) analysis is used whereby par-
ticipants offered treatment remain within the treatment
group regardless of whether they take up the offer of
treatment. The method used for statistical analysis of the
outcome data will be regression analysis, with outcome
change score as the dependent variable and group (hom-
oeopathic treatment or nutritional therapy, analysed sep-
arately) as the independent variable. Analysis will
control for the effects of gender, ADHD severity (CGI
baseline score) and age.
The acceptability of the offer of treatment will be re-
ported by presenting numbers for all patients offered
Table 2 Feasibility criteria
Criteria Measurement Criteria for continuation to a full trial
Recruitment to cohort rates Number recruited in 2 years % recruited/sample size estimation. Minimum acceptable to proceed
to a full-scale trial will consider the number of years needed to recruit
the required sample size. Numbers recruited in 2 years will be
extrapolated to determine how long a full trial would need to be. The
required sample size will be divided by the percentage recruited in
2 years. Duration of the full trial of more than 4 years will not be
considered feasible.
Recruitment to treatment rates Percentage accepting offer At least 30%. The percentage of participants refusing treatment will
be considered to determine acceptable levels of refusal. Too many
treatment refusers may lead to a high chance of a type II error and
inadequate information to estimate critical parameters for a full trial
with reasonable precision.
Treatment effects (statistical significance) Standard mean difference (SMD) CGI Mean = < .3. Since neither intervention has been tested in this form
previously, estimation of the effect size cannot consider previous
estimates. Since we need to know that therapies show some
evidence of being helpful, a SMD of 0.3 in those implementing the
therapies will be considered sufficient to proceed to full trial.
Treatment effects (clinical significance) CGI Tscore 5 percentiles. A Tscore change of 5 percentiles is considered
clinically significant, since the child has moved from one level of
severity to another according to Conners (2009) [47].
Attrition: cohort Number of PQs returned at 6 months At least 30%
Attrition: consultations Number of consultations attended Adjustment of intervention provision
Acceptability of TQ and CQ Number of TQs and CQs completed at
baseline and 6 months; number of email/
telephone/ paper responses
Adjustment of measure, collection methods and trial parameters.
Questions reworded or removed dependent on discussion with
carers and teachers, and optimum means of delivering questionnaires
explored
Adverse events Clinicians records No severe adverse events as defined by the Common Terminology
Criteria for Adverse Events guidelines
Appropriate outcome measurement Number of missing items Adjustment of measure
Recruitment of therapists Number recruited fulfilling criteria At least two for each therapy
Statistical analysis ANCOVA Meets assumptions
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treatment. Statistical tests will be carried out to identify
characteristics of those who did and did not accept and
receive treatment. Sub group analysis will explore the ef-
fect of treatment on those accessing that treatment,
those taking/not taking ADHD medication and those
with co-occurring autism.
The clinical effect of treatment will be explored by cal-
culating standardised mean differences [57] for those of-
fered and taking up the offer of each treatment to obtain
sample size estimates.
Discussion
The results of this pilot trial will provide preliminary in-
formation on the feasibility of the TwiCs design to assess
the effectiveness of interventions for children with
ADHD to improve (long-term) outcomes. It will also
provide preliminary information about the acceptability,
clinical and cost-effectiveness of two potential interven-
tions for ADHD. If feasibility criteria are met, then the
study will continue to a full trial of these two interven-
tions subject to reviewers comments and obtaining fur-
ther funding.
Future plans are to develop the STAR cohort as a facil-
ity where interventions can be rigorously evaluated in a
timely and efficient manner. This will entail expanding
and ensuring the representativeness of the cohort and
offering random samples of eligible participants a variety
of mainstream and non-mainstream interventions. Re-
cruitment of a representative cohort will focus on
recruiting at-need populations such as teens, particularly
those involved in criminality; hard to reach families;
those with co-occurring autism; and those with multiple
co-morbidities.
Advantages of the TwiCs design are the speedy re-
cruitment of sufficient numbers. No deception is experi-
enced by participants compared with placebo controlled
trials. Trial conditions are similar to those patients could
expect if consulting therapists in clinical practice and
healthcare assessors might expect were they to commis-
sion treatments. All types of interventions, for example,
complex, therapist-led and/or pharmaceutical treatments
can be compared. Since the TwiCs design is designed to
test multiple interventions, potential biases are equally
distributed across groups.
As a pragmatic trial, a disadvantage is that there is inev-
itable variation (noise), such as participants trying other
interventions, changing medication dosage, or life events.
All interventions are equally subject to such noise. A fur-
ther potential disadvantage is that the offer of treatment,
i.e., its acceptability, is measured, since ITT analysis is the
primary analysis. The effectiveness of undertaking the
treatment (per protocol analysis) is a secondary analysis.
Measuring acceptability is an important issue in ADHD
research where non-compliance is common. However,
assessors may prioritise and require measurement of spe-
cific effects within treatments, such as effect due to ther-
apist, supplement, dietary advice, homoeopathic medicine,
etc. The real-life effectiveness of the two selected interven-
tions has remained untested until now.
The TwiCs approach can be a cheap way to generate
evidence regarding comparative effectiveness and poten-
tial to improve long term outcomes and can provide
useful information to ADHD stakeholders including ser-
vice providers. The current approach is inefficient, ex-
pensive, slow, difficult to compare, and not focused on
improving outcomes for all those with ADHD in the
longer term. If feasible, the STAR approach to testing in-
terventions has the potential to contribute to the re-
search canon and to patient outcomes.
Abbreviations
ADHD: Attention deficit hyperactivity disorder; ASCs: Autism spectrum
conditions; CAM: Complementary and alternative medicine; CAMHS: Child
and Adult Mental Health Services; CGI: Conners Global Index; CHU-9: Child
Health Utility Index (9 items); cmRCT: Cohort multiple randomised controlled
trial; CQ: Carer questionnaire; CTCAE: Common Terminology Criteria for
Adverse Events; ScHARR: School of Health and Related Research;
SNAP: Swanson, Nolan and Pelham Questionnaire; STAR: Sheffield Treatments
for ADHD Research; TAU: Treatment as usual; TQ: Teacher questionnaire;
TwiCs: Trials within Cohorts
Acknowledgements
We would like to acknowledge the contribution of all the families and
therapists involved in this project.
Funding
The STAR project has received funding from the Homeopathic Research
Institute (HRI). They had no role in the design of the study nor will have any
role in the collection, analysis or interpretation of data, or writing of any
manuscripts.
Availability of data and materials
Data storage and retention are in line with the Data Protection Act of 1998
and UK Common Law (duty of confidentiality). Data will be retained for a
period of 5 years after the project ends. Digital data is stored on an encrypted
University of Sheffield google drive accessible by the PI or administrative
assistant. Other patient identifiable information is stored in a locked filing
cabinet. Data is only stored for participants and schools who have given their
informed consent to participate in the project.
The datasets generated and/or analysed during the current study are not
publicly available due to confidentiality concerns, but anonymised data can
be made available from the corresponding author on reasonable request.
The STAR project is monitored by an independent Data Monitoring and
Ethics Committee (DMEC) since it involves a higher risk vulnerable population
of children and oversees safety and adverse event reporting. The following
will be immediately referred to the DMEC for appropriate action: any serious
adverse event, any child considered to be at risk, and any child suspected of
being abused.
Authorscontributions
PF is the principle investigator in the project and wrote the manuscript. CR is
a member of the Management Committee and Steering group and helped
devise the project. TP sits on the steering committee and advised on health
economics. DD chairs the steering committee. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
The study was approved under the University of Sheffields Ethics Review
Procedure by the School of Health and Related Research (ScHARR) Research
Ethics committee (REC) on 30/4/15, application number 003424.
Fibert et al. Pilot and Feasibility Studies (2018) 4:61 Page 7 of 9
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The University of Sheffield is the Research Governance Sponsor (University
Research Management System (UMRS) number: 143647). The project was
classified as a human-interventional study, under the Universitys quality
assurance procedure for such studies, requiring it to be risk assessed, and
was considered to be low risk. They confirmed that a trial measuring
treatment by a homoeopath and a nutritionist did not constitute a Clinical
Trial of a Medicinal Product (CTIMP); therefore, Medicines Regulatory Health
Authority (MRHA) approval was not required.
The study was registered with the ISRCTN Registry (International Standard
Randomised Controlled Trials Number 17723526) on 27/4/2015.
The study is overseen by an independent Steering Committee of academics,
clinicians and patient representatives, who meet every 6 months for the
duration of the trial.
Consent for publication
All data are anonymised. Schools and participants are informed that their
data will be anonymised and kept in a secure location.
Competing interests
The authors declare that they have no competing interests.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
School of Health and Related Research, University of Sheffield, Regent Court,
30 Regent Street, Sheffield S1 4DA, UK.
2
Institute of Mental Health, Jubilee
Campus, University of Nottingham, Wollaton Road, Nottingham NG8 1BB, UK.
Received: 11 May 2017 Accepted: 2 February 2018
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... This article reports the results of Stage 1 of the STAR project, which was to assess the feasibility of the TwiCs trial design to provide suitable information for stakeholders to enable evaluation of the clinical and cost effectiveness of some treatments for ADHD identified as being used by carers. This was done by conducting a small-scale test of the methods and procedures: a three-armed internal pilot trial of the clinical and cost effectiveness of (a) the offer of adjunctive treatment by homoeopaths and (b) the offer of adjunctive treatment by nutritional therapists, compared with (c) treatment as usual [7] (ISRCTN17723526). ...
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Attention deficit hyperactivity disorder (ADHD) is a lifelong condition associated with considerable costs. The long-term effectiveness and acceptability of treatments to improve outcomes remains in doubt. Long-term trials are needed comparing interventions with standard care and each other. The Sheffield Treatments for ADHD Research (STAR) project used the Trials within Cohorts (TwiCs) approach. A cohort of children with ADHD was recruited and outcomes collected from carers and teachers. A random selection was offered treatment by homoeopaths (hom) or nutritional therapists (NT). Their outcomes (Conners Global ADHD Index) were compared with those not offered interventions. The feasibility of the methods and interventions was assessed. The TwiCs approach was feasible with modifications. 144 participants were recruited to the cohort, 83 offered treatment, 72 accepted, and 50 attended 1+ appointments. Results according to carers assessments at 6 months were as follows: t = 1.08, p = .28 (− 1.48, 4.81) SMD .425 (hom); t = 1.71, p = .09 (− .347, 5.89), SMD = .388 (NT). Teachers’ responses were too few and unstable. No serious treatment adverse events occurred. Conclusion: the STAR project demonstrated the feasibility of the TwiCs approach for testing interventions for children with ADHD.What is Known: • Attention deficit hyperactivity disorder (ADHD) is a lifelong condition associated with considerable costs to ADHD stakeholders. Children are at risk of negative outcomes and in need of pre-emptive strategies • The long-term effectiveness and acceptability of recommended treatments to improve outcomes remains in doubt What is New: • A small-scale test of the design demonstrated that the Trials within Cohorts (TwiCs) approach is feasible and can make a useful contribution regarding testing the effectiveness of interventions for children with ADHD to improve long-term negative outcomes • Treatment by homoeopaths and nutritional therapists may offer novel opportunities to improve outcomes.
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Unlabelled: 20 consecutively enrolled children age 5-16 with Attention Deficit Hyperactivity Disorder (ADHD) received treatment by a homeopath (8 consultations and individualized remedies) for one year. Ten subsequently enrolled children received similar time and attention for 4 months. The study explored optimum treatment protocols; the effectiveness, deliverability and acceptability of treatment; and the feasibility of outcome measurement and recruitment. Parents completed Conners' Parent Rating Scale, Revised Long Version ( Cprs-r: L) every 4 months, from which DSMIV total scores were extracted; and Measure Your Own Medical Outcome Profile (MYMOP) every consultation. An interaction between time (baseline/4 months) and group (treatment/non-treatment) was found .756 F (1,28)=9.06, p=0.005. The intervention was associated with statistically significant improvements in treated children over the year: Cprs-r: L (t (18)=4.529, p≤0.000); MYMOP (t (18)=6.938, p≤0.000). Mean DSMIV total t scores decreased at each time point: baseline: 85 (SD 5.1); 4 months 76.2 (SD 10.9); and 12 months 71.5 (SD 12.77). Recruitment of control participants was problematic. Recruitment to treatment was feasible via ADHD support groups, charities, police support agencies and social services, not schools or NHS services. Attending appointments was problematic for some participants, but home visits did not improve uptake. The best venue was a familiar clinic. Some participants took medicines inappropriately, but generally taking homeopathic remedies was acceptable and well implemented. Cprs-r: L (80 items) was problematic for some parents. MYMOP was preferred by parents but not acceptable to stakeholders. In this small consecutive sample the intervention was associated with improvements in criminality, anger and children with a concomitant diagnosis of Autism Spectrum Disorder ASD. Treatment by a homeopath was associated with sustained, increasing improvements and the intervention was acceptable to participants. More methodically rigorous research is warranted. "We recommend that future research in this area uses comparative effectiveness randomised controlled trial designs. We also recommend that these trials measure outcomes of relevance to stakeholder needs - the people and services who care for those with ADHD - parents, teachers and social workers and the criminal justice system".
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Childhood attention-deficit/hyperactivity disorder (ADHD) has been associated with reduced health and well-being of patients and their families. The authors undertook a large UK survey-based observational study of the burden associated with childhood ADHD. The impact of ADHD on both the patient (N = 476) and their siblings (N = 337) on health-related quality of life (HRQoL) and happiness was quantified using multiple standard measures [e.g. child health utility-9D (CHU-9D), EuroQol-5D-Youth]. In the analysis, careful statistical adjustments were made to ensure a like-for-like comparison of ADHD families with two different control groups. We controlled for carers' ADHD symptoms, their employment and relationship status and siblings' ADHD symptoms. ADHD was associated with a significant deficit in the patient's HRQoL (with a CHU-9D score of around 6 % lower). Children with ADHD also have less sleep and were less happy with their family and their lives overall. No consistent decrement to the HRQoL of the siblings was identified across the models, except that related to their own conduct problems. The siblings do, however, report lower happiness with life overall and with their family, even when controlling for the siblings own ADHD symptoms. We also find evidence of elevated bullying between siblings in families with a child with ADHD. Overall, the current results suggest that the reduction in quality of life caused by ADHD is experienced both by the child with ADHD and their siblings.
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Background: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. Objectives: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. Search methods: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. Selection criteria: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. Data collection and analysis: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. Main results: The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). Secondary outcomes: Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). Authors' conclusions: The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.