Placebo arm

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

Patients infected with HBeAg-negative chronic hepatitis B have a significant response while on adefovir dipivoxil, but the response is not sustained after treatment discontinuation. Serum ALT levels normalized in 72% of patients treated for 48 weeks compared to 29% who received placebo. Additionally, 51% had undetectable HBV DNA levels with adefovir dipivoxil, whereas none achieved this in the placebo arm.20,27,32... 

Wagner etal. (1998) investigated the ethnic differences in antidepressant response to fluoxetine or placebo in 118 depressed, predominantly male, HIVpositive patients (White n = 79, Hispanic n = 17, African American n = 22). Nine Hispanic subjects (53%) dropped out of treatment making the results difficult to interpret. Among completers in the placebo arm, 80% (four out of five) of Hispanic subjects were responders as compared to 36% of African American subjects and 43% of White subjects. 

The second study, which included 2924 postmenopausal women with osteoporosis, had to be cancelled after 10 months due to a marked increase in adverse uterine effects induced by the two doses of levormeloxifene under study in comparison with the placebo arm leukorrhea (30% versus 3%),... 

In comparison, physical activity may not have the same "catch-up" capacity. The case has been made that exercise when yoimg is likely to provide lifelong benefits to bone structure and strength (Warden et al, 2007). It is possible that comparisons of "catch-up" with diet and physical activity are not yet possible until we have comparable ranges of deficiency and timing of deficiency prior to a period of adequacy. To generalize from the Matkovic study, dietary Ca intakes in the United States in placebo arms of randomized controlled trials are only moderately deficient compared to the very low Ca intakes of children in certain regions of Oriental (Lee et al, 1993, 1995) and Third World coimtries (Dibba et al, 2000), for example, who consume little or no milk. 

Each trial that is to be included in the meta-analysis will provide a measure of treatment effect (difference). For continuous data this could be the mean response on the active treatment minus the mean response in the placebo arm. Alternatively, for binary data the treatment effect could be captured by the difference in the cure rates, for example, or by the odds ratio. For survival data, the hazard ratio would often be the measure of treatment difference, but equally well it could be the difference in the two-year survival rates. 

In general, the use of placebos in psychopharmacology trials requires additional justification, particularly with very disturbed children. The public health responsibility of publicly funded scientific studies is paramount, and this responsibility implies that only issues of genuine importance be targeted for such studies (Hyman, 1999). There may be times, however, when, for scientific reasons, the use of placebo arms may be ethically justified (Roberts et ah, 2001), in part because there are so few psychopharmacology treatments that... 

However, if the use of a placebo is impractical, or inappropriate for ethical or technical reasons, a multiple fixed-dose study without a placebo arm may be an acceptable option. This approach involves comparison of responses to a range of doses of the test drug in comparison with a standard compound. When significant differences between treatment groups are observed, some positive conclusions regarding efficacy can be derived from the data. However, a multiple fixed-dose study design also has some disadvantages ... 

Another meta-analysis of placebo-controlled trials in depression published between 1980 and 2000 showed an increase in the response rates in the placebo arms of trials with a variety of antidepressants (Walsh et al.y 2002). Responses to placebo increased significantly in recent years, as shown by the high positive correlation with the year of publication. The association between response rate and year of publication was more statistically robust for placebo than for active medication. The change in placebo response rate did not appear to be explained directly by changes in study characteristics such as patient age, placebo lead-in or minimum required Hamilton Rating Scale for Depression score. A potential explanation could be the changing awareness of patients and the fact that many patients in recent clinical trials had been exposed to several previous treatments and thus expected to improve (see Box 5.4). 

Active comparators are used in placebo-controlled trials primarily to validate the study results. In addition, the effect size seen with an active comparator provides guidance concerning the effect size of the new treatment in comparison with an established treatment. In studies without a placebo arm and not demonstrating a significant difference, it is often not possible to determine whether the lack of difference was due to equal effectiveness of the treatments or the result of a type II error, i.e., the erroneous assumption that there was no difference between treatments (although in fact there was a difference). 

E. Therapeutic response The primary end point of one randomized, placebo-controUed trial was whether the patient required one or more platelet transfusions in the subsequent chemotherapy cycle. More patients avoided platelet transfusion in the Neumega arm (28%) than in the placebo arm (7%). 

In contrast, patients in the placebo arm of the double-blind continuation study done with venlafaxine had responded to placebo and then remained on placebo under double-blind conditions. Whereas a sizable percentage of the patients switched to placebo in the crossover studies likely required active drug treatment to experience a response, that is not necessarily true for placebo-treated patients in the double-blind continuation studies. Thus, the nature and the course of the illness in these two types of studies may not be the same, accounting for the difference in relapse rates. 

The PACT study was designed to examine the efficacy of pravastatin given within 24 hours of the onset of unstable angina or Ml. The aim was to recruit 10,000 patients, but the study was stopped early by the sponsor after 3408 patients had been enrolled, thus it was underpowered. In the early phase of the study, pravastatin 20 mg daily was compared with placebo, although the dose of pravastatin was later increased to 40 mg daily. There was no statistical difference in the primary endpoint of death, recurrent Ml, or rehospitalization for unstable angina at one month (I 1.6% pravastatin arm vs. 12.4% placebo arm P = 0.48). 

Neuhouser ML, Patterson RE, Thornquist MD, et al, Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET). Cancer Epidemiol Biomarkers Prev 2003 12 350-358. 

Randomized controlled trials (RCTs) compare active therapy with placebo. Placebo should be as similar to the active therapy in appearance and feel as to be indistinguishable. This means that RCTs involving topical therapy are compared to the cream base, and the cream base most often has an independent function as a moisturizer. The potential effects of the cream base must be made explicit, as they may influence the efficacy of the product tested. By explicating the effect of the placebo arm of... 

RCTs it is therefore possible to gain information about the efficacy of moisturizers as monotherapy. The effect of the cream base varies. In a stable, dry, and scaly dermatosis such as psoriasis, active treatment with calcipotriol reduces disease severity as assessed by PASI scores by 56%, whereas the use of the cream base reduces it 35%.1 Dry skin is also a key diagnostic element in atopic dermatitis and moisturizers are therefore extensively used in this disease. Looking at the placebo-arm in RCTs of topical treatment of atopic dermatitis the placebo effect appears to be in the range of 20%.2 6 The disease is however also more dynamic, and it waxes and wanes more frequently than psoriasis, which may explain the difference seen between the two disseases. 

Looking at the placebo arm of RCTs the data therefore suggest that moisturizers have a small but independent biological/medical effect, which may be estimated at 20 to 35% depending on the underlying condition. 

Other aspects of trial design including randomization, acceptability of sham operation in a placebo arm, appropriate statistical approaches, as well... 

However, there is only one report specifically on which patients with a previous TIA or stroke and NRAF are at high (and low) risk, based on 375 patients with NRAF and TIA or non-disabling stroke treated in the placebo arm of the European Atrial Fibrillation Trial (van Latum et al. 1995). Independent risk factors for vascular death, stroke and other major vascular events included increasing age, previous thromboembolism, ischemic heart disease,... 

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