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Ct-toolkit.ac.uk
Trial Scenarios for Monitoring
Pilot randomised trial of streptokinase, aspirin and heparin in acute myocardial infarction1 Background: Several small trials have been undertaken of IV streptokinase in acute MI,
often followed by an anticoagulant, but there was considerable heterogeneity of effect and use of these treatments is very variable.
Design: 2x2x2 factorial RCT to gain experience with the treatments and to collect
information on common adverse effects prior to conducting a very large-scale trial
Setting: 8 hospitals (7 in UK and one in Australia) Study population: 600 patients with suspected MI Eligibility criteria: Physician diagnosis of suspected MI; <24 hours of onset of symptoms; no
clear indication for or contra-indication to trial drugs and not other life-threatening condition
Interventions: IV streptokinase infused over 1 hour or matching placebo
IV heparin infused over 48 hours or matching placebo Alternate day oral aspirin 325mg or matching placebo in 28 day calendar pack
Randomisation: 4 hour central telephone randomisation service which allocated the Trial supplies: Treatment pack containing allocated treatments Outcomes: Adverse events during hospital stay – drug reactions, bleeding, stroke,
arrhythmias, heart block, cardiogenic shock, cardiac arrest, reinfarction, death Deaths for up to one year fol owing randomisation (from ONS flagging).
Data management: Data collected on paper CRFs by investigators at each site. Experience: Coordinating centre experienced in clinical trials.
Variable experience at the clinical sites.
What are the particular hazards of the trial?
Vulnerable population, some of which may not be capable of giving informed consent Complex design and double blind trial, therefore it is particularly important to ensure that the
patients receive the allocated treatment
1 This scenario was largely based on the ISIS pilot study (European Heart Journal, 1987; 8:634-642), but some of the details have been altered. Suggested Approaches to Monitoring:
1. Trial Oversight:
An independent Data Monitoring Committee (essential) A
2. Before the start of recruitment:
Investigators meeting to review the trial procedures and discuss consent
Written assurance from each investigator that the setup was complete and
Most panel members would also consider a site visit to review setup and trial
supply arrangements desirable, particularly for inexperienced sites
3. During the trial
Depending on whether or not site visiting is undertaken, one of the following plans is suggested:
Without site visiting With site visiting
consent form at coordinating centre (with patient consent)
over the telephone) prior to randomisation
Unique identifier on label in each treatment pack to be attached to CRF as a
Testing of drugs in some packs to ensure accuracy of pack assembly Centralised
4. At the end of the trial
Drug reconciliation by return of unused treatment packs to coordinating centre or
Written confirmation from each site regarding archiving
Trial of prescribing strategies in managing sore throat2
Background: The management of sore throats in primary care is controversial Design: Open randomised trial of 3 prescribing strategies Setting: 11 general practices in one regional primary care research Study population: Patients aged 4 years or more presenting with sore throat to GP Eligibility criteria: ≥4 yrs. old; sore throat + local sign of infection (inflamed tonsils
or pharynx, exudate, or cervical adenopathy).
Intervention: Group 1 - immediate prescription for 10 day course of standard
antibiotics - penicillin V (or erythromycin if allergic)
Group 2 - no antibiotic prescription Group 3 – prescription (as in Group 1) to be collected if symptoms are not starting to settle in 3 days
Randomisation: Sealed envelopes in GP surgery containing advice sheet for the Trial supplies: Prescriptions dispensed by high street chemist Outcomes: Patient assessed (duration of symptoms recorded by patient
diary) Duration of time off work/school Patient satisfaction
Data management: Paper CRF - data entry at coordinating centre. Experience: Coordinating centre and network practices have undertaken a 2 This scenario was based in part on a trial report by Little P, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL Open randomised trial of prescribing strategies in managing sore throat(BMJ, 1977; 314:722), but some of the details have been altered or invented. What are the particular hazards of the trial? This is a very low-risk trial – a comparison of commonly-used treatment strategies in a patient population that is not seriously ill undertaken by an experienced group of investigators. The particular concerns are:
Randomisation process – use of sealed envelopes in an open trial makes the
study vulnerable to the random allocation of treatment being compromised – either through ignorance or intentionally. Centralised process should be used if at all possible.
Although not a vulnerable population, the inclusion of children introduces the
issue of providing information about the trial for different levels of capacity to understand.
An open trial with patient-assessed outcomes introduces the hazard of
differential and biased outcome assessment. Complete fol ow-up and a robust data collection instrument for the primary outcome are important.
Suggested Approaches to Monitoring:
1. Trial Oversight:
A trial management group that includes the col aborators. An independent DMC is unnecessary
2. Before the start of recruitment:
Investigators’ meeting that includes all those who will be involved in obtaining patient consent, the randomisation procedure, and follow-up for discussion/training plus written assurance from each investigator that the practice is prepared and setup complete;
or
3. During the trial
Because the trial is being conducted in a small network of practices in the same region, site visiting may pose few logistical or financial difficulties, and in view of the concern over the randomisation process may be the best way to monitor the conduct of the trial. Depending on whether or not site visiting is undertaken, one of the following plans is suggested:
Without site visiting With site visiting
centre (with patient consent) Alternatively, ONS flagging would be possible but generally considered unnecessary
Centralised classification of outcomes blind to treatment group is recommended.
4. At the end of the trial
Local PCT arrangements for archiving of documents should be followed.
Trial of preoperative chemotherapy in oesophageal cancer
Background: It has been reported that preoperative chemotherapy improves survival
in oesophageal cancer, but there is little randomised evidence.
Design: Open simple pragmatic RCT Setting: 42 hospitals across Europe Study population: 800 patients with oesophageal cancer due to have surgery Eligibility criteria: Microscopically confirmed oesophageal cancer without lymph node
involvement or metastatic disease; no other malignancy; normal renal function, white-cell count and platelets
Intervention: Group 1 – immediate chemotherapy with 2 cycles of cisplatin and
fluorouracil (commonly used chemotherapies in long-standing use) followed by surgical resection Group 2 – immediate surgical resection
Randomisation: Central telephone randomisation Trial supplies: From routine hospital stock Main outcomes: Survival time (primary) and dysphagia (secondary) recorded by Follow-up: 3-monthly for first year, then 6-monthly until death Data management: Paper CRFs Experience: Coordinating centre and clinical sites all experienced in conducting
What are the particular hazards of the trial? The main concern in this trial is whether pre-operative chemotherapy increases the peri- 3 This scenario was based on a trial report by the MRC Oesophageal Cancer Working Party, Surgical resection with or without preoperative chemotherapy in oesophageal cancer. (Lancet 2002;359:1727), but some of the details have been altered or invented. Suggested Approaches to Monitoring
1. Trial Oversight:
2. Before the start of recruitment: Minimum Written assurance from each investigator that setup complete and ready to start.
Investigator questionnaire to check appropriate training and skills Optimal Investigators’ meeting(s) to review trial and al procedures (it might be
possible to organise a meeting in conjunction with a scientific conference)
3. During the trial
Depending on whether or not site visiting is undertaken, one of the following plans is suggested:
Without site visiting With site visiting
Collect pathology reports Central registry (e.g.
Centralised classification of outcomes blind to treatment group is recommended.
4. At the end of the trial
Written confirmation from each site regarding archiving.
Trial of aspirin and heparin in acute ischaemic stroke Background: Anticoagulants are widely used in ischaemic stroke to facilitate clot
lysis and to inhibit clot propagation but there is little randomised evidence on the balance of risks and benefits.
Design: Open 2x2 factorial RCT with an additional randomisation of dose Setting: Multi-centre, international (467 hospitals in 36 countries) Study population: 20,000 patients with acute stroke (some comatose) Eligibility criteria: Onset of stroke <48hours previously; CT scan to confirm absence
of intracranial haemorrhage (unless severe delays and physician considered stroke very likely to be ischaemic); no contraindications to aspirin or heparin
Interventions: Group 1: low dose subcutaneous heparin + 300mg aspirin daily
Group 2: medium dose subcutaneous heparin + 300mg aspirin daily for 14 days
Group 3: low dose subcutaneous heparin + avoidance of aspirin
daily for 14 days Group 4: medium dose subcutaneous heparin + avoidance of aspirin daily for 14 days Group 5: 300 mg aspirin daily + avoidance of heparin for 14 days Group 6: avoidance of aspirin and heparin for 14 days
Randomisation: Central telephone randomisation Trial supplies: From routine hospital stock Main outcomes: Death from any cause within 14 days; death or dependency at 6
months (collected from patient or proxy)
Data management: Paper CRFs. Data entry at coordinating centre. Experience:
Experienced coordinators; some sites had participated in pilot; some were completely inexperienced in participating in clinical trials.
What are the particular hazards of the trial?
Vulnerable population, many of whom may not be capable of giving informed
Very large number of centres in many different countries of very variable
Potentially hazardous interventions, although considerable clinical experience of
4 This scenario was based on the International Stroke Trial (Lancet 1997; 349:1569), but some of the details have been altered or invented. Suggested Approaches to Monitoring: 1. Trial Oversight: 2. Before the start of recruitment:
Written assurance from each investigator that setup is complete and they are
Investigators meeting(s) to review the trial procedures and discuss consent
3. During the trial
The size of the trial and large number of sites makes it particularly suitable for
central statistical monitoring, with targeted visits if indicated
Depending on whether or not site visiting is undertaken, one of the following
Without site visiting With site visiting
Annual investigator meetings Annual site visits
adherence to protocol and trial procedures Verification of
form at coordinating centre (with patient consent)
Collect CT scan Central registry (e.g.
chart to check what chart to check what patients were prescribed
Outcome/adverse events Collect death certificates Check completeness and
accuracy of adverse event reports against clinic records in sample
Centralised classification of outcomes blind to treatment group
4. At the end of the trial
Written confirmation from each site regarding archiving.
Trial of fish oil supplementation in normal pregnancy Background: Gestational age and birth weight are strong predictors of a baby’s
survival. Observational evidence suggests that women with a high dietary intake of oily fish have long pregnancies and babies with high birth weights.
Design: RCT Setting: A single large antenatal clinic Study population: 600 healthy pregnant women attending routine week 30 Eligibility criteria: Normal pregnancy at 30 weeks gestation based on ultrasound
or LMP Exclusions – multiple pregnancy, bleeding in pregnancy, previous placental abruption, allergy to fish, regular fish oil supplementation.
Intervention: Randomisation: Sealed opaque envelopes in antenatal clinic containing a number
corresponding to a treatment pack or indicating no supplementation.
Trial supplies: Pre-numbered boxes of oil capsules given to women at each visit Outcomes: Duration of pregnancy, birth weight and length Other data: Participant interviews about lifestyle factors relevant to pregnancy
outcome, compliance, food frequency questionnaire
Data management: Paper CRF. Data entry at coordinating centre. Experience: Experienced coordinators; clinic staff little trial experience What are the particular hazards of the trial? This is a low-risk trial – a single-centre trial to assess of the impact of two different oils present in a normal diet on the outcome of normal, low-risk pregnancies. The particular concerns are:
Randomisation process – use of sealed envelopes in an open trial makes the
Study vulnerable to the random allocation of treatment being compromised – either through ignorance or intentionally. Centralised process should be used if at all possible.
Although the women are not a vulnerable population, their babies are and their
safety is of particular concern – both the risks and benefits of treatment should be carefully monitored.
5 Scenario was based on a trial report by Olsen S, Sorensen N, Hedgaard M, Henriksen T, Hansen H, Grant A, Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. (Lancet 1992; 339:1003), but some of details have been altered or inventedSuggested Approaches to Monitoring: 1. Trial Oversight:
A Trial Management Group, An independent Data Monitoring Committee (unless the recruitment phase will
be so short that no information on pregnancy outcomes would be available on the first patients randomised in time to prevent some of the patients being recruited unnecessarily should a benefit be detected).
2. Before the start of recruitment:
As it is a large antenatal clinic a large number of midwives and obstetricians will be involved in the study and they may have little experience of trials. An investigators’ meeting or a site visit is recommended to ensure that all staff are clear about the trial procedures, in particular the randomisation process.
3. During the trial
Because the trial is being conducted in a single hospital, visiting the clinics periodical y is likely to be an efficient way of monitoring the trial. The following could be checked
Signed consent forms Adherence to randomisation process Patient eligibility (most of the panel would do this in a small sample)
Outcomes data could be checked either against the clinic records or by collecting a copy of the birth record.
4. At the end of the trial
Record of destruction of unused treatment packs
CHAPTER 30 Pharmaceutical Products 1. This Chapter does not cover: (a) Foods or beverages (such as dietetic, diabetic or fortified foods, food supplements, tonic beverages and mineral waters)other than nutritional preparations for intravenous administration (Section IV); Plasters specially calcined or finely ground for use in dentistry (heading 2520); Aqueous distillates or aqueou
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