The Therapy Pill: Achieving Treatment

Dose Within a Rehabilitation Trial

Janice M. Collier1 and Julie Bernhardt1,2
1
2

National Stroke Research Institute (NSRI), Australia

La Trobe University, Australia

ackground: Developing high quality clinical trials within rehabilitation

research is achievable and should be pursued wherever possible. One of the
greatest challenges rehabilitation trialists face is defining experimental and control interventions and ensuring that the intervention dose is delivered as planned.
Aim: We describe procedures employed within a pilot randomised controlled trial
of a rehabilitation intervention to monitor therapy dose. Method: The trial setting
was two acute stroke units in large teaching hospitals in Melbourne, Australia.
The design was a randomised controlled trial of very early mobilisation (commenced within 24 hours of stroke onset) plus standard care (VEM) versus standard care alone. Assessors were blinded to group and analysis was intention to
treat. All therapy data (both intervention and control) were acquired using personal digital assistants. Monitoring of therapy dose and feedback to trial staff was
given 6 months into the trial by a researcher independent of the trial team.
Results: Before feedback, therapists were barely meeting intervention protocol
minimum targets. Following feedback, compliance with trial protocol was
achieved. Conclusion: Monitoring of the therapy dose within a clinical trial is
important to achieve trial quality. This article shows how monitoring including
feedback leads to improved delivery of the therapy pill.

Keywords: stroke, rehabilitation, randomised controlled trial, methods

Randomised controlled trials are widely

accepted as the most reliable way in which we
can determine whether one treatment is more
effective than another (Wade, 1999). A randomised controlled trial is not the only method
that can be employed to answer important clinical questions. Indeed, it would not be sensible to
propose that all, or even half, of the research
questions that need answering in the field of neurological rehabilitation are open to testing within
the context of a randomised controlled trial.
However, they do represent gold standard trial
design, and developing high quality clinical trials
within rehabilitation research is achievable and
should be pursued wherever possible.
The challenge for rehabilitation researchers is
that many rehabilitation treatments that require

testing in clinical trials involve complex interactions between a patient and a clinician, within a
multifaceted treatment environment. Defining the
parameters of treatment and checking adherence
to treatment is one of the greatest challenges rehabilitation researchers face. Just as medical
researchers must be able to define a chemical
structure, dose or route of administration of a
drug, we must be able to define our planned control and experimental interventions at the start of
the trial, and also provide details of the actual dose
delivered to the patients within the trial.
It is useful to think of our rehabilitation treatments as a therapy pill. How much must an individual have, and at what schedule (e.g., 30 minutes,
3 times a day, 6 days a week, for 6 weeks) to
achieve the desired benefit? Who can deliver the

Address for correspondence: Dr Janice Collier, National Stroke Research Institute, Level 1, Neurosciences Building,
300 Waterdale Rd, Heidelberg Heights VIC 3081, Australia. E-mail: jcollier@nsri.org.au
BRAIN IMPAIRMENT
VOLUME

9 NUMBER 2 SEPTEMBER 2008 pp. 191197

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JANICE M. COLLIER AND JULIE BERNHARDT

dose? Will the dose chosen be acceptable to the

patient and clinician? What should happen if a
patient misses a dose? How important is it to
receive the whole dose or just part? Equally important to consider is whether a particular dose of therapy causes harm. Defining the active ingredient at
the core of a therapeutic intervention is important,
but not necessarily simple. Given the relatively low
theoretical base of many rehabilitation interventions, it is likely that what we expect the active
ingredient to be may not actually be the case
(Whyte, 2003). In the context of stroke rehabilitation trials, monitoring of the intervention dose
according to protocol is rarely, if ever reported.
Unlike a pharmaceutical pill, a therapy intervention involves not just the patient, but also the clinician. Once the therapy pill is defined we need to
consider how to make sure the clinician and patient
comply with the treatment regime. The challenge of
ensuring compliance with the therapy pill is considerable and some treatment environments are more
difficult to monitor than others. In this article we
describe the procedures employed within a pilot randomised controlled trial of a rehabilitation intervention to monitor and improve compliance with
therapy dose. Although we will outline the process
that we have taken to define the intervention within
our trial, the details of the intervention itself will not
be fully disclosed as the final phase of the trial is currently underway. The primary trial outcomes are
reported elsewhere (Bernhardt, Dewey, Thrift,
Collier, & Donnan, 2008).

Methods

Study Design
We used a prospective, open randomised controlled trial blinded outcome assessment
(PROBE) design, (Hansson, Hedner, & Dahlor,
1992) to test the hypothesis that a protocol of
very early mobilisation (commenced within 24
hours of stroke symptom onset) in addition to
standard care (VEM) was both safe and feasible,
compared with standard stroke care (SC). The
ethics committees of both institutions approved
the study and informed consent was obtained
from all participants or their representative. The
approval allowed concealment of group allocation from patients.

Study Setting
The clinical trial took place in two geographically
located acute stroke units at large teaching hospitals in metropolitan Melbourne, Australia. These
acute stroke units employed multidisciplinary

192

teams with an interest in stroke and had regular

team meetings as well as access to 24-hour brain
imaging (CT and MRI) and intensive care units.

Inclusion Criteria
The inclusion criteria for this trial were broad.
Patients over 18 years of age with first or recurrent
stroke, as defined by the World Health
Organisation, (Hatano, 1976) were eligible.
Patients had to be admitted within 24 hours of
symptom onset, needed to react to verbal commands (but did not need to be fully alert), have a
systolic blood pressure between 120220 mmHg,
an oxygen saturation of > 92% (with or without
supplementation), a heart rate between 40 and 100
beats per minute and a temperature < 38.5 C.

Exclusion Criteria
Patients with significant premorbid disability
rated using a retrospective modified Rankin Scale
(de Haan, Limburg, Bossuyt, van der Meulen, &
Aaronson, 1995; score > 3) neurological deterioration within the first hour of admission to the
stroke unit or those directly admitted to intensive
care were excluded. Patients with a concurrent progressive neurological disorder, acute coronary syndrome, severe heart failure, confirmed or suspected
lower limb fracture preventing mobilisation and
those receiving palliative care were also excluded.

Randomisation
Computer generated blocked randomisation procedures were used with stratification by stroke
severity and clinical site. We aimed to recruit
equal numbers of patients with mild, moderate
and severe stroke. The National Institutes of
Health Stroke Scale (NIHSS) administered by
trained assessors was used to determine stroke
severity with the following cut points used: mild
(NIHSS < 8), moderate (NIHSS, 816) and severe
(NIHSS > 16; Brott et al., 1989). Opaque
envelopes concealed group allocation.

Blinding
Patients were advised that if they consented they
would be randomised to one of two styles of rehabilitation: A or B. Trial therapists and nursing staff
(recruited from existing hospital staff) could not
be blinded to intervention group. To limit knowledge of experimental intervention to other ward
staff, interventions were conducted by dedicated
trial staff behind closed curtains wherever possible. The importance of maintaining blinding was
emphasised to trial staff. No experimental interventions provided by trial staff were recorded in

THE THERAPY PILL

the medical record. Trial therapists recorded the

details of all interventions on personal digital
assistants (PDAs). All outcomes were assessed by
a blinded assessor located off site. If the patient
was still in the acute hospital at the 7- and 14-day
assessments, trial staff were informed of an
impending visit so that the blinded assessor would
not inadvertently view an intervention.

Intervention
An intervention protocol was developed following
a number of preliminary observational studies that
(1) determined the patterns of physical activity of
acute stroke patients in a number of hospitals in
Melbourne, Australia (Bernhardt, Dewey, Thrift, &
Donnan, 2004); (2) determined the amount and
nature of therapy delivered to acute stroke patients
(Bernhardt, Chan, Nicola, & Collier, 2007); and (3)
detailed the activity patterns and therapy delivered
in an acute stroke unit in Trondheim, Norway
already delivering very early mobilisation as part of
its standard care package (Bernhardt, Chitravas,
Lidarende, Thrift, & Indredavik, in press). We
believe that a reduction in the amount of bed rest
throughout the day may be the active ingredient
of the intervention, leading to a reduction in post
stroke complications. As stated previously, we do
not intend to detail the intervention protocol; however, the following description serves to help readers understand the fundamentals.
Patients were randomised to standard care
(SC), or to standard care and a very early mobilisation (VEM) protocol that commenced mobilisation as soon as possible after recruitment with the
goal of first mobilisation within 24 hours of stroke
symptom onset. VEM continued daily for the first
14 days poststroke or until discharge (whichever
was sooner) and was delivered by a nurse and
physiotherapist team. The VEM protocol included
physiological monitoring of blood pressure, heart
rate, oxygen saturation and temperature prior to
each mobilisation within the first 3 days of stroke.
The emphasis of VEM was to assist the patient to
be upright and out of bed at least twice per day; in
addition to their usual care, 6 days per week. This
was expected to double the standard care dose previously identified (Bernhardt et al., in press). The
intervention protocol states minimum, target and
maximum dose according to stroke severity for
SC and VEM patients. Dose includes (a) minutes
of therapy per session, and (b) number of sessions
per day.
No special equipment was used, and staff followed hospital occupational health and safety
guidelines for the manual handling of patients.
Mobilisation therefore included the use of hoists,

where necessary. Both groups received usual

(standard) care from ward therapists and nurses.

Trial Staff Training

Training in VEM by the principle investigator
(JB) took place on the ward over several hours. A
main investigator was nominated at each site. This
person took responsibility for screening and
recruitment of patients, and was also responsible
for helping all other trial staff to follow the intervention protocol. Small laminated reminder cards
containing the key features of the intervention
protocol and safety monitoring procedures were
carried by the trial staff.

Therapist Data Recording

Trial therapists and ward therapists recorded all
therapy delivered using Pendragon Forms Version
4.0 (Pendragon Software Corporation, 2002) on
PDAs (Palm OneTM Zire 21TM). Data was transferred daily via hotsych to a computer database at
the local site. Electronic forms were based on
paper treatment forms created and validated by
Wittwer et al. (2000). Therapists recorded the time
(minutes) spent with the patients in each pre-specified activity category.

AVERT Intervention Protocol Monitoring

Only one monitoring episode was possible due to
limited funding. To maintain blinding of the trial
investigators, an independent research assistant
was employed to review intervention data. The
aim of intervention monitoring was to provide
AVERT staff with unblinded summary data that
outlined whether intervention protocol targets
were being met. The emphasis of feedback was on
meeting VEM protocol targets, rather than protocol minimums. We also sought informal feedback
from trial staff regarding any concerns or difficulties with the protocol delivery and data recording.
Trial therapists providing VEM were given a 1hour feedback session. Standard care therapists
were not provided feedback, with monitoring of
standard care described elsewhere (Bernhardt et
al., 2008). Monitoring and feedback was provided
6 months into the 212-year trial (data described as
before feedback) and data were reviewed at trial
end (data described as after feedback).
Feedback summary data was provided in
graphic form using Microsoft Power Point
2002 Version 5.1. Data were summarised according to patient group (VEM: SC) and baseline
stroke severity using the NIHSS: mild (07),
moderate (816) or severe (> 16). The median minutes per therapy session and number of sessions per

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JANICE M. COLLIER AND JULIE BERNHARDT

Results
Seventy-one stroke patients were recruited (n = 60,
site 1; n = 11, site 2). Participants were 74.7 years,
54% male, 75% first stroke with a baseline NIHSS
of 10 (Bernhardt et al., 2008). The majority of
patients were recruited from site 1 and the trial was
closed prior to monitoring at site 2. Six months
after trial commencement at site 1, 36 patients were
recruited. The independent research assistant summarised very early mobilisation data from 18
patients. Figure 1 illustrates a bar graph of summary patient data similar to that presented to therapists. Actual graphs provided explicit data, with
target lines to indicate distance from targets.
Patient VEM data before (n = 18) and after
the feedback session (n = 19) are shown in
Figures 2 and 3. Median and interquartile ranges
(IQRs) are presented as data were not normally
distributed. Prior to feedback, VEM patients
received near the minimum protocol dose of 10
minutes of therapy per session (mild: 12.9, IQR
10.714.5; moderate: 13.7, IQR 11.416.0;
severe: 8.8, IQR 4.99.7). VEM patients also
received near the minimum protocol frequency
which was 50% of target sessions per day (mild:
26%, IQR 2135; moderate: 47%, IQR 1775;
severe: 60%, IQR 4282).
Patient SC dose data before (n = 16) and after
(n = 15) the monitoring sessions did not systematically increase or decrease. Standard care minutes per therapy session were of the order of 20
to 30 minutes (Before feedback: mild: 30.0, IQR
19.236.5; moderate: 22.8, IQR 10.530.2;
severe: 17.3, IQR 17.317.3; After feedback:
mild: 20.8, IQR 18.023.5; moderate: 20.0, IQR
14.134.3; severe: 15.7, IQR 13.718.1). The
number of daily therapy sessions typically
ranged from 0.5 to 1.0 (Before feedback: mild:
0.9, IQR 0.51.0; moderate: 0.7, IQR 0.21.0;
severe: 0.5, IQR 0.50.5; After feedback: mild:

194

120

% sessions/day of target

day were presented as tables and figures. Actual

therapy delivered was compared to intervention
protocol targets. We calculated days of therapy and
assumed that therapy was delivered between
Monday to Friday (regardless of public holidays or
staffing), with admission and discharge days
counted as one therapy day. For all data on frequency of sessions per day, we report compliance
with protocol as a percentage of target.
Data were summarised, but statistical analyses
were not performed as results were concerned
with meeting protocol targets. SPSS Version
12.0 was used for data analysis.

Target

100
80
60
40
20

Mild
n = 12

Moderate
n=2

Severe
n=4

FIGURE 1
Feedback on very early mobilisation sessions per day
(median) as a percentage of target according to stroke
severity.

0.6, IQR 0.50.7; moderate: 0.9, IQR 0.41.5);

severe: 0.7, IQR 0.51.3).
Review of intervention at the end of the study
found that marked improvements in compliance
with protocol had taken place following feedback.
Session length for mild patients reached target for
mild patients (10.2, IQR 7.010.9), and was close
to target of 20 minutes per session for moderate
(16.2, IQR 14.817.3) and severe (17.0, IQR
16.817.4) patients. The number of sessions provided each day increased from 25% to 62% of
target sessions per day for mild patients (62%,
IQR 2266) and from less than 25% to almost
100% target sessions per day for moderate (90%,
IQR 8298) and severe (90%, IQR 90117)
patients. Most importantly, dose differences (separation) between standard care and intervention
patients were maintained.
Three patients did not receive any therapy sessions (before feedback; SC, n = 1; VEM, n = 1:
After feedback SC, n = 1; VEM, n = 0). Two SC
patients did not receive therapy, and one VEM
patient deteriorated and was palliated prior to
commencement of therapy.
Feedback from trial staff indicated that the
frequency and length of sessions proposed for
mild patients within the trial protocol was not
realistic. As a consequence, targets for mild
patients were changed and the intervention protocol was updated. No issues were raised regarding
recording of therapy sessions on PDAs.

THE THERAPY PILL

Minutes/session

20.0

15.0

10.0

5.0

0.0

Mild

n = 12

Moderate
n=2

Severe
n=4

Mild
n=3

Before feedback

Moderate
n = 11

Severe
n=5

After feedback

FIGURE 2
Boxplots for minutes of very early mobilisation per session according to stroke severity: before and after feedback.

Discussion

% sessions/day of target

We have shown that monitoring of dose and the

provision of feedback to the trial therapist
improved compliance with an intervention protocol in a clinical trial.
Intervention dose improved following feedback, shifting from meeting protocol minimums

to more frequently meeting protocol targets.

Importantly, the intervention therapists delivered
enough therapy to achieve a significant dose difference from that of the standard care group
(Bernhardt et al., 2008).
Whether the dose delivered in the intervention
arm of this study is sufficient to lead to improved

120

100

80

60
W
W

40

20

0
Mild
n = 12

Moderate
n=2

Before feedback

Severe
n=4

Mild
n=3

Moderate
n = 11

Severe
n=5

After feedback

FIGURE 3
Boxplots of very early mobilisation sessions per day as a percentage of target according to stroke severity: before
and after feedback.

195

JANICE M. COLLIER AND JULIE BERNHARDT

outcome for patients is the focus of the larger

Phase III study currently underway.
Being able to detail the intervention delivered
within a clinical trial is important for reasons that
go beyond the immediate scientific and pragmatic
needs of the trial. First, it is important that the trial
have sufficient detail to allow it to be replicated in
future studies by other investigators. Efficacy is
rarely established within a single trial. Second, if
the intervention is found to be effective, the next
logical step, particularly in rehabilitation research,
is to implement the intervention into clinical practice. To do this, clinicians require detail about the
treatment package. We found that our data collection tools (PDAs and pendragon forms) allowed
the collection of not only the dose but the timing,
rest intervals and content of the therapy delivered
to both standard care and intervention participants
in this study. Furthermore, we were able to review
these data and provide feedback to therapists in a
relatively simple manner. However, due to cost
constraints we were unable to provide more than a
single episode of feedback. The trial therapists
indicated that had feedback been provided earlier
and more often, this would have helped them
ensure that protocols were being adhered to. We
believe that more frequent monitoring is essential,
particularly in larger trials with multiple sites and
multiple therapists and have built a weekly feedback system into the larger Phase III study.
The feedback approach described in this study
is not the only method that might be considered to
monitor delivery of the intervention. Audiotaping
or videotaping of interventions can be used.
Traditional supervision of intervention staff, intermittent refresher training sessions with feedback
may also be employed (Medical Research
Council, 2000). One of the challenges within a
clinical trial context is that the individual(s) who
perform this monitoring need to be independent of
the clinical trial team. The need for independence
stems from the potential to introduce bias into the
trial, if investigators are aware of the intervention
group. In our pilot trial, we employed a research
assistant to act as the independent monitor. This
provided a low cost and therefore feasible solution
to the problem of monitoring.
Striking the right balance between placing
emphasis on compliance with the trial intervention protocol and the need for real and accurate
trial data is important. It would be harmful to the
trial if the intervention team felt so compelled to
meet the target (that may or may not be practical)
that the data provided were no longer accurate.
Ensuring that the planned intervention within a
trial is acceptable to the patient and staff who

196

deliver it, and feasible within the treatment setting

during the pilot phase of trial development, should
alleviate this problem. We have amended our own
trial protocol in the light of the pilot findings from
this study. Trial staff should be rewarded for compliance, however the reward should not be sufficiently large to encourage falsification of data.
Rewards can be as simple as a phone call to offer
thanks, reporting good performance in the trial
newsletter, or providing small incentive rewards.
We have learnt much during the conduct of
this trial that has helped us prepare for the large
efficacy trial currently underway. In A Very Early
Rehabilitation Trial (AVERT) phase III, we aim to
determine whether very early mobilisation
reduces death and disability at 3 months poststroke, reduces number and severity of complications, improves quality of life at 12 months and is
cost-effective, compared with standard care. The
trial commenced in July 2006 and will take over 5
years to complete, with a sample size of 2,104
patients (Bernhardt et al., 2007). In a trial of this
size, we expect to have over 20 different trial
intervention teams, and the importance of monitoring intervention dose becomes even more critical. We plan to provide automated weekly
feedback to trial staff. This will be achieved
through the use of a sophisticated web-based data
entry and feedback system developed specifically
for the trial. Intermittent training updates will also
be scheduled for each site throughout the trial and
at periods of high staff changeover. These systems
will help to provide the intervention teams with
the feedback they need to monitor dose throughout the trial.

Acknowledgments and Funding

We appreciate the participation and support of
stroke survivors and their carers in this study. We
gratefully acknowledge assistance from the following people:

Austin Hospital: Tara Sharpley, Mark

Hindson, Lia Augoustakis
St. Vincents Hospital: Kim Brock, Bernadette
Dornom, Carolyn Luke, Paul Ilett
National Stroke Research Institute: Clara Fu,
Marcus Nicol.

This trial was supported by grants from the

National Heart Foundation of Australia (Grant
Number G 04M 1571), Affinity Health and an
equipment grant from the Austin Health Medical
Research Fund. Dr Bernhardt was supported by a
National Health and Medical Research Council
(Australia) fellowship (157305).

THE THERAPY PILL

Conflicts of Interest Disclosure

No potential conflicts of interest relevant to this
article were identified.

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