Placebos as comparators

In reviewing TADS we were struck by the small size of the difference between fluoxetine and placebo as compared with the effect of placebo... 

Table 2. Distribution of side effects with placebo as compared to disodium cromoglycate...

Venlafaxine (48) is a stmcturaHy novel phenylethylamine derivative that strongly inhibits both noradrenaline and serotonin reuptake. It lacks anticholinergic, antihistaminergic, and antiadrenergic side effects. As compared to placebo, most common adverse events are nausea, somnolence, dizziness, dry mouth, and sweating. Venlafaxine-treated patients also experienced more headaches and nausea, but less dry mouth, dizziness, and tremor than patients treated with comparator antidepressants. 

The main indication for certain psychostimulants is ADHD in children and adults [4]. Recent research shows that the clinical effect and benefit are dramatic even in adults. About 60% of adult patients receiving stimulant medication showed moderate-to-marked improvement, as compared with 10% of those receiving placebo. The core symptoms of hyperactivity,... 

The natural history of Hymenoptera venom anaphylaxis, that is the risk to develop anaphylaxis again when re-stung, has been analyzed in several prospective studies (table 3) [35-37], and in placebo or whole-body extract treated controls of prospective studies on venom immunotherapy [38-40]. It is higher in patients with a history of severe as compared to mild systemic anaphylactic reactions, and in honey bee than in vespid venom-allergic patients - most likely because of the smaller and less constant amoimt of venom applied by vespids [10,41]. A short interval between two stings increases the risk of anaphylaxis [25], but severe anaphylaxis may occur again even after intervals of 10-20 years or more. 

Small vessel/lacunar strokes have better short- and long-term (1-year) survival as compared to other stroke subtypes. In the NINDS trial of rt-PA within 3 hours of onset, patients classified as small vessel stroke on the basis of their clinical syndrome had a 50% chance of a normal NIHSS score at 3 months if they received placebo, increasing to 70% in the treatment group. In the Lausanne cohort, 95% were independent after their first event, as opposed to only 65% of the cardioembolic strokes and 49% with large vessel atherothrombotic infarctions. Eighty-two percent of patients with small vessel stroke were independent at 1 year. Even at the time of maximal deficit, between 38% and 64% of small vessel/lacunar patients were independent, with motor impairment and extent of white matter disease adversely affecting outcomes. " In TOAST, small vessel/lacunar stroke was the only subtype associated with a favorable outcome, independent of the NIHSS score. ... 

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. 

Kumor K., Haertzen C., Johnson R., Kocher T., Jasinski D. Human psychopharmacology of ketocy-clazocine as compared with cyclazocine, morphine and placebo. J. Pharmacol. Exp. Ther. 238 960, 1986. 

Results of four placebo-controlled comparative trials have not been as favorable, finding no significant clinical or urodynamic effect for oral estrogen compared with placebo. 

Controlled studies demonstrate that tolterodine is more effective than placebo and as effective as oxybutynin IR in decreasing the number of daily micturitions and increasing the volume voided per micturition. However, most studies have not shown a decrease in the number of daily UI episodes as compared with placebo. 

Fig. 10.3. Effect of daily treatment with CEE + MPA on breast cancer incidence as compared to placebo. WHI study, nonhysterec-tomized women. Reproduced with permission from Chlebowski et al. (2003)... 

During the 4 years of the trial 61 cases of breast cancer were reported and confirmed. Of these, 30 were in the placebo group (28 invasive) and 31 were in the raloxifene group (24 invasive). This means a 59% reduction in the incidence of invasive breast cancer in the raloxifene group as compared with women receiving placebo (2.1 vs. 5.2 cases per 1000 woman-years HR = 0.41, Cl = 0.24 to 0.71). Only nine intraductal, noninvasive breast cancers were detected, seven in the raloxifene group and two in the placebo group. The treatment with raloxifene reduced the overall incidence of breast cancer by 50%. The results... 

Kumor KM, Haertzen CA, Johnson RE, Kocher T, Jasinski D. (1986). Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine, and placebo. J Pharmacol Exp Then 238(3) 960-68. 

A double-blind randomised study is recommended for the confirmation study unless there are substantial scientific reasons not to do so. In many cases, an active comparator is preferred to an inactive placebo, as evidence of similar efficacy to the premium priced product will be an advantage for obtaining favourable reimbursement price. Nevertheless, choice of the placebo increasing to demonstrates absolute efficacy of the drug and has been accepted by many study sites. 

QTprolongation In a multicenter, randomized, double-blind trial that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the tiotropium group as compared with placebo. No patients in either group had QT of more than 500 msec. 

Infection An increased proportion of zafirlukast patients older than 55 years of age reported infections as compared to placebo-treated patients. 

Drug abuse and dependence Studies in healthy volunteers, subjects with a history of multiple drug abuse, and depressed patients showed some increase in motor activity and agitation/excitement. In individuals experienced with drugs of abuse, a single dose of 400 mg bupropion produced mild amphetamine-like activity as compared with placebo. 

The results of MADIT II were met with some skepticism, but later confirmed by the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [24]. This study evaluated the benefit of ICD therapy versus amiodarone or placebo as primary prevention in over 2,500 patients with stable NYHA class II or III heart failure and EF < 35%, without the requirement for NSVT or EPS. Patients with both ischemic and nonischemic etiologies for cardiomyopathy were included. Over a follow-up of 4 years, there was no benefit of amiodarone over placebo for overall mortality, but ICD therapy resulted in a significant 23% reduction in overall mortality [p = 0.007] (Fig. 3.5). The benefit of ICD therapy was comparable for ischemic and nonischemic cardiomyopathy. 

Chondroitin Sulfate and Glucosamine in OA therapy have efficacy comparable to placebo as showed by a National Institute of Health study. Intraarticular hyaluronic acid for pain relief is inferior compared to intraarticular corticosteroids. Temporary crepitus reduction or eradication may last several years in radiological stages I and II Knee OA with intraarticular hyaluronic acid. 

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