Diseases progression trials

Pharmacogenomic studies are often carried out in the context of clinical trials which, by virtue of having both a treatment and placebo group, are able to assess the association between a gene and disease progression independent of therapy as well as interactive effects of genotypes and therapy on disease. Several of the phar-... 

If there is no evidence of interaction, and yet there is evidence of an association between genotype and disease progression, the SNP still may be useful. Identifying fast disease progressors up front may be a mechanism to enrich clinical trials, decreasing the time needed to reach progression-related endpoints. 

The above data demonstrate an important, possibly even critical role of oxidative stress in AD pathogenesis. Therefore, it is reasonable to suggest that antioxidant administration could be useful for the treatment of AD patients. Grundman [320] recently summarized the results of clinical trial, in which vitamin E was administrated to AD patients with moderately severe disease. It has been concluded that the treatment with vitamin E may delay and slow disease progress in these patients. 

Clinical trials have produced unequivocal evidence that ACE inhibitors improve symptoms, slow disease progression, and decrease mortality in patients with HF and reduced LVEF (stage C). These patients should receive ACE inhibitors unless contraindications are present. ACE inhibitors should also be used to prevent the development of HF in at-risk patients (i.e., stages A and B). 

There is overwhelming clinical trial evidence that certain /J-blockers slow disease progression, decrease hospitalizations, and reduce mortality in patients with HF. 

Natalizumab was approved by the U.S. FDA for the treatment of MS in November 2004, and is being evaluated in Phase 3 clinical trials for IBD and CD.105 Based on Phase 3 clinical trials in MS patients, natalizumab appeared to be safe, since an increased rate of infection was not observed after 1 year of treatment.106 The safety of combined treatment with immunosuppressants, other than short courses of corticosteroids, was not evaluated and was not recommended because of the potential for an increased risk of infections. Flowever, barely three months after its approval, natalizumab was voluntarily withdrawn from the MS market by its manufacturer and all ongoing clinical trials were suspended due to the occurrence of a rare neurological disease, progressive multifocal leukoencephalopathy (PML), in 3 out of approximately 3,000 patients enrolled in clinical trials (2 in MS and 1 in CD).107 108 109... 

Pre-clinical trials (as well as phase I and II clinical trials) utilizing CNTF yielded promising results, but the neurotrophic factor then failed phase III clinical trials on the basis of insufficient efficacy. However, myotrophin (IGF-1, produced by Cephalon Inc.) has proved more successful. A 266 patient phase III clinical study found that IGF-1 administration to ALS sufferers resulted in reduced severity of symptoms, and slower disease progression, although this or no related product has yet been approved for medical use. The potential world market for an ALS therapeutic agent approaches 1 billion. 

In projecting results of short-term trials over patients lifetimes, it is typical to present at least two of the many potential projections of lifetime treatment benefit. A one-time effect model assumes that the clinical benefit observed in the trial is the only clinical benefit received by patients. Under this model, after the trial has ended, the conditional probability of disease progression for patients is the same in both arms of the trial. Given that it is unlikely that a therapy will lose all benefits as soon as one stops measuring them, this projection method generally is pessimistic compared to the actual outcome. A continuous-benefit effect model assumes that the clinical benefit observed in the trial is continued throughout the patients lifetimes. Under this model, the conditional probability of disease progression for treatment and control patients continues at the same rate as that measured in the clinical trial. In contrast to the one-time model, this projection of treatment benefit most likely is optimistic compared to the treatment outcome. 

B. Matthews, E.R. Siemers, P.D. Mozley, Image-based measures of disease progression in clinical trials of disease-modifying drugs for Alzheimer disease, Am. J. Geriatr. Psychiatry 11 (2003) 146-159. 

This was an open-label, parallel group, randomised trial in patients with chronic HIV-1 infection reported by van Leth et al. (2004). The primary endpoint was treatment failure, a composite endpoint based on virology, disease progression or therapy change. Initially patients were randomised equally to one of the following three groups ... 

In patients with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of treatment with a COMT inhibitor or rasagiline may be helpful. Regulation of dietary protein intake may also improve response fluctuations. Deep brain stimulation is often helpful in patients who fail to respond adequately to these measures. Treating patients who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration. 

As opposed to the development of vaccines that produce antibodies, the development of T-cell vaccines is a novel concept. These vaccines are designed to induce primarily T-cell responses that will control the viral proliferation and viral levels during the early stages of infection and will delay the disease progression. These vaccines will not prevent infection but will inhibit HIV levels and protect uninfected memory CD4+ T cells. It is expected that HIV-infected patients receiving this vaccine may remain disease-free for a prolonged period of time. A number of current HIV vaccine trials have focused on CD8+ cell-mediated products that... 

A meta-analysis was performed on randomized trials assessing lipid-lowering therapy in 698 patients with PAD who were treated with a variety of therapies, including diet, cholestyramine, probucol, and nicotinic acid, for four months to three years (8). There was a significant difference in total mortality [0.7% in the treated patients, as compared with 2.9% in the patients given placebo (p = NS)], with an additional reduction in disease progression, as measured by angiography and the severity of claudication. 

The rationale to initiate treatment with an HIV-1 protease inhibitor plus combination nucleosides for patients with HIV-1 infection and CD4 cells above 200 relies on interpretation of large randomized studies as-well as on investigations with small numbers of patients in trials with elegant laboratory-based evaluations (Table IV). This line of reasoning begins with the observation that ART delays disease progression... 

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