David Machin - Randomised Clinical Trials

For each patient, the development of a Grade 2 or above pressure sore after randomisation and before discharge or trial completion due to improved mobility/activity, transfer to non‐participating centre, or 60 days from randomisation. This will include Grade 2 sores that develop from Grade 1a and 1b skin changes that were present at randomisation. For patients with existing Grade 2 sores, only sores developing at new sites will be considered as a new pressure sore. The surface area of new pressure sores will be recorded.

Healing will be assessed in two ways:

1 Changes on grade.

2 Changes in surface area. The area encompassed by the acetate film tracings will be measured by computerised planimetry using standardised technique to minimise error.

Two endpoints will be used to assess patient satisfaction:

1 Amongst patients who remain eligible: patient request to be moved to a ‘standard’ mattress because they are dissatisfied with the alternating pressure device.

2 The recording on discharge of whether or not (‘yes’ or ‘no’) patients experienced the following: excessive noise, interference with sleep, motion sickness, difficulty moving in bed, temperature, and overall comfort.

The primary endpoint for Protocol AHCC01 (1997) in patients with inoperable hepatocellular carcinoma was their survival time, which is unfortunately usually very short in such patients. Because of the multinational and multi‐lingual nature of this trial, assessing the secondary objectives with a quality of life instrument was not stipulated as mandatory for all participating centres.

The primary endpoint is survival from the date of randomisation. In addition, although these measures will be optional, Child‐Pugh score and quality of life as assessed by the EORTC QLQ‐C30 will be recorded immediately prior to randomisation and monthly thereafter. Changes in these scores over time will also be compared between the patients in the three treatment groups.

We emphasise that whenever possible all trials should explicitly declare one, or possibly two, so‐called primary outcomes. Thus, for what appears as a several component primary objective, the PRESSURE (2000) trial in Example 3.5requires a more precise definition to be included somewhere in the protocol. We also note in AHCC01 (1997) that the use of EORTC QLQ‐C30 implies 15 outcomes (scales), each outcome measured at multiple time points potentially resulting in a myriad of cross‐sectional or longitudinal analyses. Again, a more specific indication as to how this information will be summarised would be a necessary addition somewhere in the protocol.

The choice of statistical design will reflect the (major) hypotheses under test and the options for design will need to be discussed thoroughly amongst the design team and with other colleagues as appropriate. If not already included elsewhere, a schema of the trial is a useful addition to this section.

The important features here will include the number of interventions under test and the type of design, for example, parallel group or cross‐over trial with a superiority or non‐inferiority objective. If a parallel group design, then the allocation ratio should be specified and if this implies unequal numbers in the intervention groups, then a brief rationale for this should be included if not explained elsewhere. As appropriate, the standard (or control) intervention should be clearly identified. Further, if the design is to be stratified for one or more major prognostic factors this should be indicated. In addition, reference to the degree of blinding should be made with specific mention of ‘open’ trial if there are no masking mechanisms included. Importantly it should be made very clear that the trial is randomised and when assessments are to be made.

This has been designed as a multi‐centre, randomised, controlled, open, fixed sample, parallel group trial with equal randomisation. Patients will be allocated an alternating pressure mattress overlay or an alternating pressure mattress replacement.

The main trial design will be supplemented with a qualitative study involving a purposive sample of 20–30 patients who develop pressure sores, in order to assess the impact of the pressure sores on their well‐being.

Here the design is clearly laid out as, for example, comparative and randomised and specifically refers to a ‘fixed sample’ as opposed to a ‘sequential’ (see Chapter 20) design. They also indicate a supporting study to assess the impact of pressure sores that may develop. It might have been easier for the reader of the protocol if acronyms were given for ‘alternating pressure mattress overlay’ and ‘alternating pressure mattress replacement’ as each have a common three‐word stem. Perhaps simply ‘Overlay’ and ‘Replacement’ with the capitals R and O could have been used.

The alternative interventions or therapeutic options should be carefully described within the protocol, with details of what to do if these require modification or discontinuation for an individual participant. Interventions may be terminated for many reasons ranging from refusal of individuals to remain in the trial, or a clinical team’s concern that the next stage in the intervention is no longer appropriate for the patient in question. Early stopping is of particular concern in trials where the interventions could result in serious untoward consequences. In some situations, such events would not be anticipated whereas in other circumstances they may be expected and are a known consequence of the treatments under test. There will always be occasions when the unanticipated occurs, and patient safety and well‐being should be paramount in clinical trials just as in daily clinical practice.

Table 2 Operational mattress definitions

The Overlay and Replacement mattresses are easy to distinguish, if by no other feature, then by their maximum height. This requires little explanation to busy ward teams although their physical size would no doubt bring some difficulties. Nevertheless, elderly patients may be more likely to fall from the bed with the thicker mattress, which may cause some concern.

In most situations, the interventions are likely to be more complex than a choice of mattresses and hence need a detailed description. An example of part of a more complicated intervention is the concurrent therapy component of the concurrent chemo‐radiotherapy and adjuvant chemotherapy of protocol SQNP01 (1997) for non‐metastatic patients with nasopharyngeal cancer. For those familiar with the disease and its management in this single centre trial, the tabular format highlights the main components of what is involved.