Placebo comparisons

Although some of these arguments against the use of a placebo involve questions of ethics, the use of a placebo treatment is often preferable to the continued use of treatments of unproven or dubious efficacy or safety. Some old remedies that are still in current use have never been subjected to a placebo-controlled trial, and the opportunity to include them in a placebo comparison may only be during the development of a new medicine. 

Table 4.4 Active/pLacebo comparison, binary outcome survival (hypothetical)...

The effect size of a continuous variable is frequently expressed as the difference between the mean of the experimental minus the mean of the control group divided by the pooled standard deviation. For example, in Chapter 5, data from the National Institute of Mental Health collaborative study demonstrated that antipsychotic-treated patients averaged a 4.2-point increase on a 6-point improvement scale, whereas the placebo patients averaged only a 2.2-point increase (i.e., an average difference of 2 points). The standard deviation of these data was approximately 1.7, so in effect size units, the improvement was approximately 1.2 (i.e., 2.0 1.7) SD units. For discontinuous data, the effect size for a drug-placebo comparison is usually expressed as the difference between the percent improvement with the experimental drug and the percent improvement with placebo. 

Adverse events are sometimes termed type A (usually pharmacologically predictable, relatively frequent, seldom fatal and usually identified during clinical trials) or type B (unpredictable idiosyncratic reactions which are usually infrequent but can be very serious or fatal) (Rawlins and Thompson, 1977 Venning, 1983). Postmarketing ADR monitoring usually identifies the more serious, type B reactions. The sample size needed in clinical trials to detect differences between an incidence rate of 1/10 000 and 2/10 000 is about 306 000 patients (e.g. for a placebo comparison of chloramphenicol-induced aplastic anemia, which occurs in 1/30 000 Lasagna, 1983). Clinical trials at this scale are simply impractical. 

Initially, the IRT mandated blinding of the positive control, but this requirement was later dropped based on an internal IRT review of TQT smdies presented in 2008 (Garnett et al. 2008) and subsequent discussions in the E14 Implementation Working group [Question 7 in ICH E14 Questions Answers (2012)]. Exceptions exist when the nested crossover moxifloxacin/placebo comparison is used in parallel-designed TQT studies, moxifloxacin has to be blinded to protect the blinding of placebo. 

In the Treatment of SSRl-Resistant Depression in Adolescents (TORDIA) study [7 ], 334 depressed adolescents, who had not responded to a previous trial with an SSRl antidepressant, were randomized to either another SSRl or venlafaxine, with or without cognitive behavioral therapy. There were no significant differences between the groups in the rates of suicidal and non-sui-cidal self-injury, although the significance of this was limited by the lack of a placebo comparison group [8 J. 

DalNegro R, Pomari C, Turco P et al (1994) Gastroesophageal reflux and bronchial asthma a cross-over omeprazole vs placebo comparison. Respir Grit Care Med 149 4... 

Griffiths RR, Bigelow GE, Liebson I, et al Drug preference in humans double-blind choice comparison of pentobarbital, diazepam and placebo. J Pharmacol Exp Ther 215 649-661, 1980... 

Orzack MH, Cole JO, lonescu-Pioggia M, et al A comparison of some subjective effects of prazepam, diazepam, and placebo. NIDA Res Monogr 41 309-317, 1982... 

Vermeeren A, Jackson JL, Muntjewerff ND, et al Comparison of acute alprazolam (0.25, 0.50 and 1.0 mg) effects versus those of lorazepam 2 mg and placebo on memory in healthy volunteers using laboratory and telephone tests. Psychopharmacology (Berl) 118 1-9, 1995... 

Montoya ID, Levin FR, Fudala PJ, et al Douhle-blind comparison of carbamazepine and placebo for treatment of cocaine dependence. Drug Alcohol Depend 38 213— 219, 1995... 

Hurt RD, Sachs DP, Glover ED, et al A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337 1195—1202, 1997 Jorenby DE, Leischow SJ, Nides MA, et al A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Eng J Med 340 685— 691, 1999... 

Grant JA, Riethuisen JM, Moulaert B, DeVos C A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo sup- 59 pression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. 

The interventions compared need to be relevant to the health and social care choices faced by decision-makers. Unless do nothing is a valid management strategy, comparison of a new intervention with placebo is not appropriate for an economic evaluation. Since there are a number of dmg therapies and non-pharmacological approaches to the management of people with dementia, the relative cost-effectiveness of these needs to be... 

The Interventional Management of Stroke (IMS I) Study was a multicenter, open-labeled, single-arm pilot study in which 80 patients (median NIHSS 18) were enrolled to receive IV rt-PA (0.6 mg/kg, 60 mg maximum, 15% of the dose as a bolus with the remainder administered over 30 minutes) within 3 hours of stroke onset (median time to initiation 140 minutes). " Additional rt-PA was subsequently administered via a microcatheter at the site of the thrombus in 62 of the 80 patients, up to a total dose of 22 mg over 2 hours of infusion or until complete recanalization. Primary comparisons were with similar subsets of the placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. The 3-month mortality in IMS I subjects (16%) was numerically lower but not statistically different than the mortality of the placebo (24%) or rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic ICH (6.3%) in IMS I subjects was similar to that of the rt-PA-treated subjects (6.6%) but higher than the rate in the... 

The European Stroke Prevention Study 2 (ESPS-2) trial examined four treatment arms—extended-release dipyridamole (ER-DP) 200 mg twice daily alone, aspirin 25 mg twice daily alone, ER-DP 200 mg twice daily + aspirin 25 mg twice daily, or placebo. In comparison with placebo the overall reduction in stroke risk was 16% with ER-DP alone and 18% with aspirin alone. The combination of ER-DP and aspirin led to a 37% reduction in stroke risk compared to placebo. Compared with aspirin alone, the combination of ER-DP with aspirin reduced the risk of stroke by 23%. 

Often there is a desire to compare responses to multiple treatments rather than simply evaluate active against a placebo control. For instance, it may be useful to evaluate several doses or to assess a product against another marketed product. Increasing the number of treatments will increase the sample size required overall, but will also increase the number of subjects required per treatment arm because the number of statistical comparisons is larger. If all between-group comparisons are to be made, the number of statistical tests increases dramatically as the number of treatment arms increases. With two groups, only one comparison is possible. With three groups, the number... 

Essential hypertension, whose prevalence is increased nearly two-fold in the diabetic population, may be another source of free-radical activity. The vascular lesions of hypertension can be produced by free-radical reactions (Selwign, 1983). In the recent Kuopio Ischaemic Heart Risk Factor Study in Finnish men, a marked elevation of blood pressure was associated with low levels of both plasma ascorbate and serum selenium (Salonen etal., 1988). A few studies report a hypotensive effect of supplementary ascorbate in patients with hypertension, but the actual changes in both systolic and diastolic pressure after ascorbate were not statistically significant in comparison with placebo (Trout, 1991). 

Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001 345 631-637. 

Race is handled precisely as gender was, with the exception that Fisher s exact test is used for the therapy comparison between Active and Placebo. ... 

Comparison of Kaplan-Meier survival estimates is often called for in clinical trial analysis. With survival analysis, you are trying to determine which treatment group displays a better time-to-event distribution than another. Part of this analysis is the production of Kaplan-Meier estimates plots that show the probability of a given event over time for each treatment group. In the following example you see that New Drug displays better survival estimates over time than either Old Drug or Placebo. ... 

For the purpose of our research, Sapirstein and I were not particularly interested in the effects of the antidepressants or psychotherapy. What we were interested in was the placebo effect. But since we had the treatment data to hand, we looked at them as well. And, as it turned out, it was the comparison of drug and placebo that proved to be the most interesting part of our study. 

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