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3.5 Design
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.
Example 3.7 Protocol PRESSURE (2000): Pressure‐relieving support surfaces: a randomised evaluation
3. DESIGN
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.
3.6 Intervention details
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.
Example 3.8 Protocol PRESSURE (2000): Pressure‐relieving support surfaces: a randomised evaluation
Table 2 Operational mattress definitions
| Alternating pressure mattress overlay | Alternating pressure mattress replacement | |
| Alternating cell height minimum | 3.5 inches/8.5 cm | 8 inches/19.6 cm |
| Alternating Cell Height maximum | 5 inches/12.25 cm | 12 inches/29.4 cm |
| Cell Cycle Time | 7.5–30 minutes | 7.5–30 minutes |
| Cell Cycle | 1 in 2 or 1 in 3 or 1 in 4 | 1 in 2 or 1 in 3 or 1 in 4 |
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.
Example 3.9 Protocol SQNP01 (1997): Standard radiotherapy versus concurrent chemo‐radiotherapy followed by adjuvant chemotherapy for locally advanced (non‐metastatic) nasopharyngeal cancer
| Therapy | Dose | Route | Days |
| CisDDP | i) 25 mg/m2/day for 4 days | IV over 6–8 hours | 1–4 (Week 1) |
| 22–25 (Week 4) | |||
| 43–46 (Week 7) | |||
| ii) Alternatively, 30/30/40 mg/m2/day for 3 days, if patient starts RT on a Wednesday and only for the first cycle | 1–3 (Week 1) | ||
| 22–25 (Week 4) | |||
| 43–46 (Week 7) | |||
| RT | 200 cGy/day | Mega‐voltage with or without electrons | 35 daily treatments |
Example 3.10 Protocol SQOLP01 (1999): Comparison of steroid with cyclosporine for the topical treatment of oral lichen planus
Dose and duration
Steroid (S) – Triamcinolone acetonide 0.1% in oral base (Kenalog)
This is administered by topical application by the patients themselves. Patients are instructed to apply a small dab of the paste (about ½ cm) three times daily after meals. Treatment continues for 8 weeks.
Cyclosporine (C) – Sandimmun Neoral solution 100 mg cyclosporine/ml
