Superiority studies, clinical trials

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

Thus, the tetravalency, anti-inflammatory properties and molecular stability of slgA make it particularly suitable for protective passive immunity when applied to mucosal surfaces. To date, the clinical evaluation of slgA protection in humans and animal models has been very limited. Indeed most studies have employed monomeric IgA monoclonal antibodies [3,15]. Hence, differences in IgA and IgG protective activities at the mucosal level have often not been observed [15]. Only a few studies have demonstrated the superior activity of polymeric IgA or slgA compared with monomeric IgG or IgA [16]. In order to determine the efficacy of slgA, future animal experiments and clinical trials are needed to compare the activities of IgG monoclonal antibodies and their slgA counterparts. The ability to engineer slgAs in plants will allow these comparisons to be made [17]. 

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development. 

Captopril (Capoten) was the original prototype product, and it was administered three times a day. A once-a-day preparation was subsequently patented and marketed. Prospective multicenter double-blind placebo-controlled clinical trials have repeatedly demonstrated an early and persistent survival benefit with ACE inhibitors in CHE patients. ACE inhibitors were found superior to hydralazine and nitrates in a direct comparison. ACE inhibitors are now clearly the agents of first choice in the pharmacological management of CHE There are also a number of additional reasons to use ACE inhibitors. The HOPE trial and other studies demonstrated additional survival and renal protective benefits of ACE inhibition in diabetic and/or hypertensive patients long before they develop CHE. 

Because a therapeutic window has been hypothesized to exist for neuroleptics, its existence for risperidone is a reasonable supposition. Indeed, evidence to support such a window was established in the North American Clinical Trial and the International Collaborative Study, both of which found doses of 4, 6, and 8 mg superior to higher or lower doses of risperidone. 

There have been five double-blind studies comparing the antidepressant efficacy of different SSRIs versus different TCAs in patients with HDRS scores of 25 or more (122, 123,124, 125 and 126). Three of these studies permitted inclusion of both inpatients and outpatients ( 122, 123 and 124), whereas the other two were solely done in outpatients (125, 126). Three were placebo-controlled (1.23, 125,126). In these three studies, the SSRI (i.e., fluvoxamine, paroxetine, or sertraline) was either superior to both the f CA and placebo or was comparable with the TCA and superior to placebo. In the other two studies, the SSRI was not different from the TCA and there was no placebo control. There have also been four studies and one metaanalysis of European clinical trials which found no difference in antidepressant efficacy between several different SSRIs and several different tertiary amine TCAs in patients hospitalized for major depression ( 127,128, 129,130 and 131). Finally, there have been two relatively small studies showing that fluoxetine and fluvoxamine both had antidepressant efficacy superior to placebo in patients with melancholia ( 132, 133). Another larger study failed to find a difference between paroxetine and amitriptyline in treating such patients ( 134). 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

A number of clinical trials have found clonidine to be superior to placebo in treating ADHD ( 101, 102,103 and 104). However, these studies were generally not as methodologically rigorous as those with either psychostimulants or antidepressants. Clonidine has been used as monodrug therapy and in combination with methylphenidate. Hunt (101) did a crossover study of clonidine alone, methylphenidate alone, and the combination in 25 children with ADHD and conduct disorder. 

Phase 1 clinical trials demonstrated that Herceptin is safe and confined to the tumor. However, phase 2 trials indicated that the efficacy of the antibody is superior when given with chemotherapy (Pegram et al., 1998). Phase 3 trials have indicated that Herceptin, when added to conventional chemotherapy, can benefit patients with metastatic breast cancer that overexpresses HER-2, prolonging relapse and overall survival (Slamon et al., 2001). Similarly, extensive studies by Menden et al. (2001) support the weekly Docetaxel... 

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