The Trial design, e.g. individual patient versus cluster


The appropriate design of clinical trials,
particularly randomized controlled trials (RCT), allows the production of
quality evidence for the assessment of healthcare interventions. The
appropriateness is essentially related with methodological issues,
transparency, and the complete descriptions of how studies are conducted so
they can be reproduced and fully assessed.

The design of an effectiveness trial, which is the
purpose of this assessment, is usually simpler than the design of efficacy
trials, because effectiveness trials tend to accept more wide inclusion
criteria, include flexible regimens, and allow participants to accept or reject
the interventions offered to them. Typically, these trials evaluate effective interventions
provided to heterogeneous participants under ordinary clinical circumstances.

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The current recommendations for the design of a clinical
effectiveness evaluation through an RCT, for a novel lifestyle intervention
including motivational interviewing, activity pacing and aerobic exercise for
people complaining of long-standing low back pain (LBP), considered several
reference from the literature, particularly the CONsolidated Standards Of
Reporting Trials (CONSORT) statement (Schulz, 2010) and the SPIRIT 2013
checklist (Chan, 2013). These two standards
are consensual and generally accepted for planning such trials.



       Trial design, e.g. individual patient versus cluster
RCT. 4
       The choice of comparator 5
       The method of randomisation and allocation
concealment 6
       The choice of primary outcome measure. 7
       Methods to promote blinding. 8
       Methods of recruitment 9
       Methods to maximise retention. 10



Trial design, e.g. individual patient versus cluster

For the purpose of the required study, a comprehensive
cohort study design might be ideal (multicenter, pragmatic, single-blind,
parallel-group, non-inferiority), comparing a novel lifestyle intervention and
standard of care (usual physiotherapy care) for people with long-standing low
back pain. The main reasons are the following:

design allows to recruit all patients fulfilling the clinical eligibility
criteria regardless to their consent to randomization;

be performed an assessment of external validity by comparing the randomized
study sample to the population of patients who met the eligibility criteria but
did not consent to randomization;

prioritize random allocation of treatment against patient preferences. This
should avoid subversion bias. In this type of studies, the individual will know
in which arm is included;

design avoids the risk of massive drop outs due to consent previous to
randomization, which the opposite could lead to bias;

of pragmatic trial, which includes individuals who do not consent to be
randomized, reducing selection bias and improving generalizability of results;

is no need to fully understand the concept of randomization by the individuals,
which avoids additional anxiety and promotes confidence between patient and

expectations and resentful demoralization.

Nevertheless, there are some issues, such as
information denial of trial options prior to randomization and a denial of
patient choice between interventions, which is not a major issue due to the
fact that all individuals will receive care (standard or novel);


not other designs?

Not needed multiple RCTs over time, so cohort multiple
RCT is not necessary, since the population will be randomized for each arm
(standard or novel care);

A cluster design wouldn’t be recommended, because it
is more important to have a baseline population, rather than a randomization of
time, place, or clinicians. This methodology could also lead to less
statistical significant conclusions and loss of allocation concealment, which
is fundamental to prevent randomization bias. This design could be interest if,
for instance, the purpose was to assess effectiveness of the novel intervention
performed in a different primary care unit, or delivered by a different type of
health professional.

Explanatory trials, on the opposite of pragmatic
trials, assess if an intervention has an effect under optimal conditions, while
pragmatic trials evaluate effectiveness of an intervention in real-life
conditions, which is more appropriate for this purpose.

For this purpose is not ideal to receive both
treatments (novel and standard care) in random sequences (crossover or
factorial trials), neither clustering, as previously mentioned. Parallel-group
(each participant is randomly assigned to a group, and all the participants in
the group receive the novel intervention or standard care) is the recommended

A standard clinical RCT design could result in
measures of clinical effectiveness, but there is a risk of low recruitment
rates, poor generalizability and low external validity.


The choice of comparator


The purpose is to assess clinical effectiveness of a
novel intervention, which means there is a comparator (current standard care)
to the novel care. The estimated effect of intervention should clearly
distinguish between standard and novel care, for a similar baseline population.

The choice of the comparator must be related to the
trial population, and local context of practice and decision-making.

The potential comparators should rely on all
technically feasible, acceptable, and relevant alternatives for the purpose of
care. In the current case, for people complaining of long-standing low back

In this particular situation, the comparator should be
based on noninvasive pharmacologic and nonpharmacologic treatments for low back
pain, since the intervention is nonpharmacological and noninvasive.

The suggested comparator should be Exercise Therapy,
because it is classified as recommended in the NICE recommendations REF?
and American Guidelines REF
Exercise Theraphy already proved, with moderate-quality evidence, to have small
improvements when compared with no exercise and with usual care in a systematic
review for chronic low back pain REF 2: Since there is no evidence that one particular type
of exercise therapy is clearly more effective than others, the Exercise Therapy
should include the most frequent type of exercise plan, or a mix of common
exercise plans. REF. ref. DOI:

For this comparator, a non-inferiority RCT would fit
the purpose of assessing clinical effectiveness for the novel intervention.

An alternative could be a comparison with usual care.
In this case, probably a superiority RCT might be more appropriate to assess
clinical effectiveness. Nevertheless, usual care might consist in a mix of
interventions, and an appropriate identification of what might be the usual
care in a particular context should be identified.

Other alternatives, according to the Clinical
Guidelines Committee of the American College of Physicians, could be multidisciplinary
rehabilitation, acupuncture, or mindfulness-based stress reduction, since all
of them have proved a moderate reduction in short-term pain intensity with
moderate-quality evidence. Nevertheless, these options are not recommended by

Other recommended pathway treatments such as
pharmacological and psychological are not suitable for the purpose of this
study, since the clinical effectiveness of the novel intervention is not yet
proven. The first step should be to prove the clinical effectiveness among the
same type of treatments in order to include the novel intervention in the
treatment pathway.

Comparator should address the appropriateness, in
order to ensure no overestimated effectiveness of the novel intervention.



The method
BM1 of randomisation and allocation concealment


If the standard of care consist of only one type of
physiotherapy care, then the trial should be randomized through an equal
assignment of 1:1 in a 2-arm RCT (novel intervention-arm and control-arm).

The selection of patients should be based in clear
inclusion and exclusion criteria, in order to ensure concealment of allocation.
It is essential that the allocation is not known, knowable, or guessable prior
to recruitment. Random allocation to the novel intervention or comparator
groups will occur after confirmation of eligibility and baseline assessment.

The method used should be a stratified block
randomization. The stratification should be by region, since it’s a multicenter
trial and it is expected some heterogeneity between regions. The blocking will
allow to assess whether the severity of low back pain over the treatment arms
conduces to a difference in response.

The most suitable method should be a randomization
after consent, due to a risk of subversion (only opened when the patient has
consented) and bias (higher possibility of drop outs due to the fact that
individuals will not undergo the novel lifestyle plan). Selection bias is
avoided through this method, because allocation is purely by chance, and the
chance of getting the observed effects is completely and absolutely free from
any confounding effects.

After the selection of patients (inclusion and
exclusion criteria), the randomized allocation can be processed either by local
randomization using a pre-prepared sequence or by remote randomization. The most
suitable way could be a remote allocation, blinded and performed using a
computer-generated random allocation schedule operated by a remote researcher.
The allocation of participants should then be concealed by using sequentially
numbered, sealed and opaque envelopes. These envelopes, sealed using
tamper-proof security tape and impermeable to intense light, should be
sequentially numbered and opened sequentially only after participant details
are written on the envelope.

After randomization, patients would be included in the
trial-arm (novel lifestyle intervention) and control-arm (standard of
physiotherapy care). During this process, all the participants, including the
ones who drop out after randomization, should be recorded.

This process guarantees compliance. This process
should be clear in the report, to provide minimal criteria judgement of
adequate concealment of allocation, complying with Cochrane systematic review
recommendations REF and the concealment mechanism from SPIRIT statement


Group allocation Allocation will be. Source:





The choice
BM2 of primary outcome measure

The primary outcome should aim to evaluate the
clinical effectiveness of a novel lifestyle intervention, based on whether
individuals in the novel lifestyle arm report significant improvement,
comparing with those allocated for current standard of physiotherapy care.

Since the novel lifestyle intervention includes
motivational interviewing, activity pacing and aerobic exercise for people
complaining of long-standing low back pain, and the study purpose is to assess
clinical effectiveness, an appropriate measure of quality of life (patient
related outcome measure – PROM), that produces numerical information that
describes the well-being of patients, should be identified that answers, at
least, eight concepts: appropriateness, acceptability, feasibility, validity,
reliability, responsiveness, precision and interpretability.

In this particular situation, a multi-dimensional and
generic PROM measure is recommended to measure pain disability as primary
outcome and there are robust and validated PROM measures available. There’s no
need to develop an entire new PROM measure.

When checking the PROM instruments available, Roland-Morris
Disability Questionnaire (RMDQ) could be recommended as an example BM3 to better measure outcomes for effectiveness
evaluation, since is adequate to measure health changes due to novel care, it
contains 24 items relating to a range of functions commonly affected by LBP,
allows to assess overall effectiveness through a score, and its generally used
for non-specific low back pain quality of life measures REF Since there are some limitations with RMDQ, particularly
ceiling effect (at some point, the variation of scores doesn’t reflect a
condition improvement or declining), Ref:, the Modified Von Korff Scale would also be
recommended as complementary and valid for low back pain, because it assesses
disability and its impact on daily activities, recreation, and ability to work
Ref: A multicentred randomised controlled trial of a primary care-based cognitive

Also, the Aberdeen Back Pain Scale, Örebro
Musculoskeletal Screening Questionnaire (OMSQ or OMSQ-12), Osteoporosis
Functional Disability Questionnaire, Psychosocial Functioning Questionnaire for
Patients with Low Back Pain, Quebec Back Pain Disability Scale, and Oswestry
pain disability index could also be used. Other non-specific back pain PROMs
could also be used, such as Brief Pain Inventory, Short Form 36 physical
functioning subscale and McGill present pain index.

These are appropriate because they answer the question
of the study; they are acceptable, because it only requires a few time and
non-invasive procedures; they are feasible, easy to process and requires few
time from professionals and participants; they are valid, since they were
already tested and published; they are reliable, because the validity process
already showed internal validity and consistency; they are responsive, since
allows to detects changes over time in the quality of life for patients with
LBP; they are precise since the scores result from several dimensions of care;
and the interpretability is high, because the score result is associated with a
degree of health state associated with patient preferences.

The suggestion of these PROMs doesn’t mean that literature
should not be consulted to detect other possible PROM measures, as well as the
consultation of ePROVIDE resources. Depending on the setting where the study
will be used for decision-making, the authority guidelines should be consulted,
as well as patients and clinicians, for the same reason.



Methods BM4 to promote blinding


Blindness is recommended in order to avoid the
subversion risk (e.g. the allocation of the next envelope, if not blinded,
could be performed only when a suitable patient appears, which is not

Blinding of the treating physiotherapists and
participants will not be possible because they will know the intervention arm
to which they have been allocated.

The blinding should be performed for outcome
assessment, and is achieved if neither patients nor those involved in the trial
have any means to discover which arm a patient is in.

When considering the risk of bias from lack of
blinding of outcome assessment it is important to consider specifically
who is assessing the outcome, and the risk of bias in the outcome
assessment (considering how subjective or objective an outcome is).

Questionnaires at all time points will be
self-completed by the patient. A valid method could be to inform patients not
to tell outcome assessor the treatment they received and fill the questionnaire
in a centralized research facility, where the assessor had no contact with the
intervention procedure. In this case, a letter should be sent to participants
before any assessment stating that they should make no mention of their
intervention. Ref. methods:

In this way, blinding will be achieved by having an
independent blinded assessor performing the follow-up assessments after 6 and
12 months. The blinded assessor will not be treating any of the participants,
nor be aware of their group allocation.

The statistician conducting the primary data analysis
will also be blinded to group allocation.

Authors should consider to group outcomes with similar
risks of bias.

This method follows the CONSORT and SPIRIT statements,
and The Cochrane Collaboration’s tool for assessing risk of bias. ref?



MethodsBM5  of recruitment


Participants meeting the eligibility criteria previously
defined will be recruited.

Potential participants can be identified through
searching general practice records, and from direct referrals from general
practitioners. Treating physiotherapists will screen (all) potential
participants from the outpatient clinics, and inform them about the study.

Potential participants interested in participating in
the study will receive an information statement and be referred to the research

Patients with chronic LBP who meet the inclusion
criteria will be invited to participate in the trial. A research assistant will
discuss the study and offer participation to those who meet the inclusion
criteria, including a participation fee. If they agree to participate a signed
consent form will be recorded and baseline data will be collected.


Each potential participant goes through an eligibility

Telephone reminders to non-respondents, opt-out
procedures requiring potential participants to contact the research team if
they do not want to be contacted about the trial, and the financial incentives
with the trial invitation are the key features for recruiting REF..


The patients will provide written informed consent
prior to randomisation. The participants providing written consent are
consecutively included and randomized.




Fonte: Methods to
improve recruitment t oRCT: Cochrane …




Methods BM6 to maximise retention


The comprehensive cohort study design is useful to
improve recruitment rates, because it does not exclude from the RCT
participants with strong preferences.

At the beginning, patient preferences are elicited
before randomisation occurs, and the study design recruits all patients that
are eligible regardless of their consent to randomisation. Those who do not
consent to randomisation are kept in the study but their treatment choice is
made based on preference. Patients who consent are randomized to the two
treatment choices.

A method to maximize retention should address
participants motivation and the maintenance of the participants and site
clinicians engaged with the trial. It is proven that providing incentives can
improve retention REF..

Loss of participants must not exceed 5%. In the worst
case scenario, 20% or greater loss of participants might threaten the trial
validity. Despite the possibility of solving some issues by statistical
methods, the risk of bias will remain.

For this particular study, it is recommended to:

monetary incentives to the participants who consent to randomization and remain
in the attributed arm (no more than 10 euros, so it won’t be perceived as
coercion for data). The incentive should be given after the reception of a
fully answered questionnaire.

the questionnaire short. Nevertheless, this aspect should not be considered as
a priority since there is no sufficient evidence that it would provide an
increase of responses;

people before sending the questionnaires.

Non-monetary incentives are not proven to be effective
ways of maximizing retention, because they don’t increase response rates

This method might increase retention, providing
greater generalizability, validity and reliability to the trial results.

Source: “strategies to improve retention in randomized
trials: a Cochrane systematic review and meta-analysis”, Brueton, et al. (




 BM3The Roland Morris Questionnaire
(RMQ) is the most widely used measure of LBP disability in primary-care trials.

contains 24 items relating to a range of functions commonly affected by LBP.102
It takes less than 5 minutes to complete. It has good reliability101 but there
are concerns that it does not conform to many of the assumptions that underpin
its use in statistical analysis (scaling and normality of distribution). Data
from the Oxfordshire Low Back Pain Trial suggested that it had a marked ceiling
effect, failing to capture important clinical information on improvement in
participants with subacute or chronic LBP attending NHS physiotherapy. It has
been shown to be differentially sensitive at low, mid and high ranges, with
(not unsurprisingly) better sensitivity in the middle range.108,109 In the low
to mid range, the RMQ is less sensitive to within-group changes than the
Aberdeen Low Back Pain Score, but better at detecting between-group


Modified Von Korff Scale (MVK)103 assesses two dimensions – pain and disability
associated with back pain in the last 4 weeks. It is made up of six items, each
of which is scored on a scale of 0 (no pain/disability) to 10 (worst
pain/disability). The first three of these items relate to disability and ask
about how back pain interferes with (1) daily activity, (2) recreation and (3)
ability to work. The last questions relate to pain and assess the (1) worst
pain, (2) average pain and (3) rating of back pain today. The questionnaire was
administered at baseline, 3, 6 and 12 months.





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