participating clinical centres. It must also convince interested colleagues who may wish to participate. Thus, it should use language which is neither too specialised, nor cluttered with unnecessary detail, yet it must provide a clear scientific/clinical motivation for the randomised trial outlined.
3.4 Research objectives
In this section of the protocol, the research objectives of the trial are summarised in broad outline and specifics with regard to the endpoints provided.
3.4.1 Objectives
The objectives need not be lengthy provided they encapsulate the major intentions – essentially stating the hypotheses under test. The examples given below do not refer explicitly to the design chosen, for example whether randomised or not, but do imply they are comparative in nature.
Example 3.3 Protocol SQNP01 (1997): Standard radiotherapy versus concurrent chemo‐radiotherapy followed by adjuvant chemotherapy for locally advanced (non‐metastatic) nasopharyngeal cancer
To compare the clinical response, distant metastases, disease free survival and overall survival of chemo‐radiotherapy and adjuvant chemotherapy using combination chemotherapy comprising CisDDP and 5‐Fluorouracil (5‐FU), with radiotherapy in patients with locally advanced NPC.
This summary indicates the comparisons concerned, although omitting full details of the (complex) chemotherapy regimen under test, and makes it clear the patient are those with a particular form of nasopharyngeal cancer. The statement also identifies the several trial endpoints to be determined, which concern response (and the protocol includes details of how this is to be assessed), measures that require following the patients progress to establish when (if ever) distant metastases or recurrent disease appear, and survival.
Example 3.4 Protocol PRESSURE (2000) Part Section 2: Pressure‐relieving support surfaces: a randomised evaluation
2. RESEARCH OBJECTIVES
2.1 Primary objective
To determine whether there are differences between alternating pressure overlays and alternating pressure replacement mattresses with respect to:
1 The development of new pressure sores
2 Healing of existing pressure sores
3 Patient acceptability of the surfaces
4 The cost‐effectiveness of the different pressure‐relieving surfaces.
2.2 Secondary objective
To investigate the specific additional impact of pressure sores on patients’ wellbeing.
The research objectives of the PRESSURE (2000) trial clearly distinguish between the primary, although it is multiple in nature, and secondary objectives. They also specify the two mattress types, overlay and replacement, that are to be compared.
3.4.2 Outcome measures
The eventual design chosen will have been influenced by the outcome measures, certainly by the primary one, and each endpoint measure must be explicitly defined. The trial structure in terms of, for example, the frequency and timing of the (possibly repeated) assessments should enable the endpoint for each individual subject on the trial to be determined. Thus, in the PRESSURE (2000) trial, in those patients admitted without pressure sores skin conditions were assessed daily by the ward nursing staff using the skin classification scale stipulated within the protocol.
Example 3.5 Protocol PRESSURE (2000) Part Section 9.1: Pressure‐relieving support surfaces: a randomised evaluation
9.1 Primary endpoint
9.1.1 Development of new pressure sores
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.
9.2 Secondary endpoints
9.2.1 Healing of existing pressure sores
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.
9.2.2 Patient acceptability
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.
Example 3.6 Protocol AHCC01 (1997): Randomised trial of tamoxifen versus placebo for the treatment of inoperable hepatocellular carcinoma
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 3.5 requires 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
