syndrome undergoing elective surgery for their condition. Pain was assessed postoperatively with the short‐form McGill Pain Questionnaire (SF‐MPQ) at four days. A total of 64 patients were randomised to the three groups resulting in median scores of 16.0 (range 0–69), 10.5 (0–76) and 15.0 (0–82) for the respective groups. From these results, the authors suggest that homoeopathic arnica has no advantage over placebo in reducing levels of postoperative pain.
Key features include the following:
Design: Single‐centre, randomised double‐blind, placebo‐controlled, three‐group dose response,
Endpoint: Pain using the SF‐MPQ,
Size: 64 patients undergoing hand surgery for carpal tunnel syndrome,
Analysis: Kruskal–Wallis test,
Conclusion: Irrespective of dose homoeopathic arnica has no advantage over placebo.
Example 1.5 Large dose–response design – HER2‐positive breast cancer
Smith, Procter, Gelber, et al. (2007) showed that 1 year of treatment with Trastuzumab (T) after adjuvant therapy in HER2‐positive patients with breast cancer was superior to Observation (O) alone. They reported a hazard ratio, HR = 0.66 (95% CI 0.47 to 0.91, p‐value = 0.0115) for overall survival in favour of adjuvant treatment. This comparison was from two arms of a three‐arm large multicentre international randomised trial comprising 1698 patients randomised to O, 1703 to T for 1 year (T1) and 1701 to T for 2 years (T2): a total of 5102 patients.
Key features include the following:
Design: Randomised, multicentre, observation versus active treatment,
Size: Part of a large trial of 5102 women with HER2‐positive breast cancer,
Endpoint: Overall survival,
Analysis: Comparison in 3404 women from the O and T1 groups using survival curves,
Conclusion: Treatment with T1 after adjuvant chemotherapy has a significant overall survival benefit.
Example 1.6 Non‐inferiority trial – uncomplicated falciparum malaria
Zongo, Dorsey, Rouamba, et al. (2007) conducted a randomised non‐inferiority trial to test the hypothesis that the risk of recurrent parasitaemia was not significantly worse with artemether–lumefantrine (AL) than with amodiaquine plus sulfadoxine–pyrimethamine (AQ + SP). A total of 826 patients were screened of which 548 were found to have uncomplicated malaria and were randomised (273 to AQ + SP and 275 to AL). A primary endpoint was the risk of treatment failure within 28 days of randomisation. The authors concluded that AQ + SP, with a recurrent malaria rate of 1.7% (4/233), was more effective than AL, with a rate of 10.2% (25/245) and representing a difference of 8.5% (95% CI 4.3–12.6%). These results suggest that the hypothesis of ‘non‐inferiority’ should not be accepted as the CI included the non‐inferiority limit of 3% set by the investigators.
Key features include the following:
Design: Multicentre, two‐group, non‐inferiority trial,
Endpoint: Time to recurrent malaria,
Size: Large – 548 patients with uncomplicated falciparum malaria,
Analysis: Comparison of Kaplan–Meier survival curves,
Conclusion: AL was less effective than (inferior to) AQ + SP.
Example 1.7 Repeated measures – atopic eczema
Meggitt, Gray and Reynolds (2006) randomised 63 patients with moderate‐to‐severe atopic eczema to receive either Azathioprine or Placebo in a double‐blind formulation to ascertain the relative reduction in disease activity determined by the six‐area six‐sign atopic dermatitis (SASSAD) score between the groups. One patient in each group subsequently withdrew from the trial before treatment was initiated. The investigators reported a 5.4 unit advantage with Azathioprine. In this trial, patients were randomised using a minimisation procedure, in the ratio of 2 to 1 in favour of Azathioprine in order to.
… encourage recruitment, to reduce the numbers receiving pharmacologically inactive systemic treatment, and to increase the likelihood of identifying infrequent adverse events.
Key features include the following:
Design: Single‐centre, randomised double‐blind, placebo‐controlled, randomised 2 : 1 allocation ratio using minimisation,
Endpoint: SASSAD,
Size: 63 patients with moderate‐to‐severe atopic eczema,
Analysis: Comparison of mean group regression slopes over a 12‐week period,
Conclusion: Azathioprine produces a clinically relevant improvement.
Example 1.8 Cross‐over trial – known or suspected hypertension
Kerley, Dolan, James and Cormican (2018) describe a randomised placebo (P) controlled, two‐period cross‐over trial of dietary nitrate (N) in 20 patients with known or suspected hypertension. The P and N interventions were delivered in beetroot juice in a nitrogen‐depleted or nitrogen‐enriched form, respectively. Thirteen of the individuals were randomised to receive the sequence NP, that is N in Period I of the trial followed by P in Period II, and the other seven were allocated the sequence PN. Amongst the many endpoints, plasma nitrate and ambulatory blood pressure were recorded prior to randomisation, then 7 days later following the start of treatment in Period I and a further 7 days following Period II. The authors concluded:
Our results support … an anti‐hypertensive effect of dietary nitrate … .
Key features include the following:
Design: Single‐centre, randomised placebo‐controlled, two‐period cross‐over trial,
Size: 20 patients with known or suspected hypertension, unequal numbers assigned to the sequences,
Washout: None included,
Endpoints: Plasma nitrate and ambulatory blood pressure,
Analysis: Complex methodology described. All statistical tests were conducted at the two‐sided 0.05 significance level,
Conclusion: Nitrogen‐enriched has an anti‐hypertensive effect.
