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
The patients are instructed to apply the cyclosporine solution to the lesions with their fingers, three times daily after meals. Treatment continues for 8 weeks.
Application of topical medication
The topical medication is applied three times a day – after breakfast, after lunch and before going to bed. Patients will be advised to brush their teeth, gargle and dry the area/s of the lesion/s before each application. Emphasis will be made to use a mirror to see where the medication is to be applied. Patients will be asked to note each application in a patient diary, to monitor compliance. They are instructed not to eat, drink or smoke for 30 minutes after the application.
Dose modification
Topical application of the test drugs are not expected to produce severe side effects. However, if toxicity occurs following commencement of therapy, the number of applications, of either S or C, should first be reduced from 3 to 2 and then from 2 to 1 per day. Should the patient continue to experience the same, or greater levels of toxicity, S or C therapy should cease.
The design structure of the SQOLP01 (1999) trial in patients with oral lichen planus has been illustrated in Figure 2.1 while the panel above from the protocol describes the treatments given together with dose modifications should they be required. As was the case for the mattress types, the topical treatments concerned and how they should be applied are easily expressed. Clear guidance is given for dose reduction (and possibly cessation) should ‘severe side effects’ occur although none were expected.
On the other hand, in protocol ENSG5 (1990) it was well understood by all the investigators and associated clinical teams that the chemotherapy schedule was indeed highly toxic and that many complex clinical situations could arise as a consequence. However, the teams concerned with treating these children and young adults were all in specialist paediatric oncology centres and there was an established network through which the clinical teams were constantly seeking each other’s advice. Effectively, a ‘virtual’ case review would be established as and when necessary. However, this protocol was launched and completed some time ago and the statement contained within the protocol might be inadequate for current approval processes, which demand greater precision in the specification of details and mechanisms.
Example 3.11 Protocol ENSG5 (1990): Comparison of high dose rapid schedule with conventional schedule chemotherapy for stage 4 neuroblastoma over the age of 1 year
12. MODIFICATION