Long term trials

There have been a number of long-term trials with various P-adrenoceptor blockers in patients surviving acute MI (37—39) that demonstrated a reduction in mortaUty, sudden death, and nonfatal re-infarctions. The term cardioprotective has been used to describe this effect for the dmgs studied. The... 

Inhaled steroids (commonly used are beclomethasone, budesonide, triamcinolone, fluticasone, flunisolide) appear to attenuate the inflammatory response, to reduce bronchial hyperreactivity, to decrease exacerbations and to improve health status they may also reduce the risk of myocar dial infar ction, but they do not modify the longterm decline in lung function. Whether- steroids affect mortality remains unclear. Many patients appear to be resistant to steroids and large, long-term trials have shown only limited effectiveness of inhaled corticosteroid ther apy. Certainly, the benefit from steroids is smaller in COPD than in asthma. Topical side-effects of inhaled steroids are oropharyngeal candidiasis and hoarse voice. At the normal doses systemic side-effects of inhaled steroids have not been firmly established. The current recommendation is that the addition of inhaled gluco-coiticosteroids to bronchodilator treatment is appropriate for patients with severe to veiy sever e COPD. 

The two meta-analyses of long-term efficacy trials were limited to data that had been previously published, as are most metaanalyses. Nevertheless, the differences between drug and placebo were clinically insignificant. We can only wonder whether there are also some unpublished long-term trials that the pharmaceutical industry has sponsored, and if so, what the results were. There is one thing of which we can be fairly certain. Unpublished trials, where they exist, do not show any better results than the published trials. We can be certain of this because drug companies publish their successful studies, often many times over. It is the unsuccessful trials that remain unpublished. 

Several long-term trials comparing organic farming to conventional farming have been carried out in various European countries. A summary of relevant results on soil carbon content and its dynamic is presented in Table 4-4. 

Results from relevant long-term trials seem somewhat contradictory in connection with nitrate leaching potential. This is due to the fact that most trials are conducted with Nt-equality of the compared systems or even equal organic manure application rates. While no differences between organic and conventional systems were observed in the Swiss DOC trial (Alfoldi et al. 

It is not a requirement that a trial must have an interim analysis, either for efficacy or for futility. In most long-term trials, however, where there is the opportunity for an interim evaluation then it may be something worth putting in place. The interim can involve only efficacy, only futility, or both and may indeed involve some other things as well, such as a re-evaluation of sample size (see Section 8.5.3). 

In addition to considerations of efficacy and futility, it will usually be appropriate in most long-term trials to consider safety in an ongoing way. This is not new and we have always, for example, looked at accumulating data on individual serious adverse events and considered stopping (or modifying) trials if these are indicative of problems with the trial or with the treatments. 

A DMC is usually needed in long-term trials in life-threatening diseases and sometimes in non-life-threatening diseases where there are potential safety concerns. It may also be necessary to have DMCs in studies in specific and vulnerable or fragile populations such as children, pregnant women or the very elderly, but DMCs are not usually necessary in phase I and early phase II trials or in short-term studies where the goal is relief of symptoms. 

There has been only one double-blind, placebo-controlled long-term trial of lithium as a treatment for bipolar disorder in adults with MR (Naylor et ah, 1974). In this study, 14 adults with borderline to severe MR and bipolar disorder were treated with lithium (with levels between 0.6 and 1.0 mEq/F) for 1 year. The number of weeks of illness was significantly lower in the treatment group. A year-long, single-blind, placebo-controlled trial of lithium in five persons with bipolar mood disorder and MR treatment resulted in re-... 

Raupp, J. 2001. Manure fertilization for soil organic matter maintenance and its effects upon crops and the environment, evaluated in a long-term trial. In Rees, R.M., Ball, B.C., Campbell, C.D. and Watson, C.A. (eds) Sustainable Management of Soil Organic Matter. CAB International, Wallingford, pp. 301-308. 

In a series of seven cases of neuropathy, all were axonal peripheral neuropathies and both thick and thin nerve fibers were affected (10). No cause of peripheral neuropathy other than statin treatment could be identified. In this series at least four of the cases were irreversible, probably due to long exposure to statins (4—7 years versus 1-2 years in previous reports). Besides an effect on ubiquinone, interference with cholesterol synthesis may alter nerve membrane function, since cholesterol is a ubiquitous component of human cell membranes. Neuropathy has not been observed in extensive long-term trials of lipid-lowering drugs. It could be due to patient selection, a low frequency of the adverse effect, or lack of attention to symptoms of peripheral neuropathy. The observed association may also not be causal. 

Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roth D, Kupin W, Nicolas M, Ruiz P, Rosen A, Miller J. A randomized long-term trial of tacrolimus/sirolimus versus tacro-limus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 2004 77(2) 252-8. 

Przuntek H, Conrad B, Dichgans J, Kraus PH, Krauseneck P, Pergande G, Rinne U, Schimrigk K, Schnitker J, Vogel HP. SHELDO A 5-year long -term trial on the... 

The percent increase in yield is often related to weather conditions. In dry years (1976) a relatively small number of fungicide cereal trials showed an increase in yield, but during wet years (1978) 60% of the tests showed yield increases. In long-term trials (4) in the Western region of Germany, seed treatments and foliar applications of triazole fungicides reduced crop losses from powdery mildew up to 25% (Table VI). ... 

In case LDL oxidation is considered as an important risk factor, the dosage of vitamin E may be important to determine a clinical effect. However, with respect to inhibition of protein kinase-C and the release of proinflammatory cytokines the intracellular transfer of RRRT (natural vitamin E) by the tocopherol-associated protein may be a crucial point. Consequently, natural vitamin E is considered more effective than the synthetic one. Since the activity on LDL oxidation was pointed out as important for the prevention of cardiovascular disease, most of the long-term trials with vitamin E were conducted at dosages >200 mg/day (about 200 lU/d). In a recent meta-analysis the association of plasma levels and mortality was studied in 1168 elderly European men and women (25). No association was found between the plasma concentration and all-cause or cause-specific mortality. 

A very different type of results came out from randomized long-term trials [The a-Tocopherol /3-Carotene Cancer Prevention (ATBC), (41) in which /3-carotene was given at very high dosages and ended up with an increase of first-ever non-fatal Ml. 

Vitamin C results from long-term trials are also conflicting. However, high intake was never found to increase mortality, and moderate intake between 100 and 200 mg/day essentially shows some benefit either taken as a supplement or with a diet plus supplements, particularly in elderly. However, there is no benefit in using dosages higher than 400 mg/day. 

Hoffbrand AY Al-Refaie F Davis B, et al. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood I 998 91 295-300. 

Harvey, P. D., Rabinowitz, J., Eerdekens, M., Davidson, M. 2005, Treatment of cognitive impairment in early psychosis a comparison of risperidone and haloperidol in a large long-term trial, Am.J.Psychiatry, vol. 162, no. 10, pp. 1888-1895. 

These should be presented for the entire drug-exposed population and for logical groups of studies, such as all controlled studies, short-term trials, long-term trials, etc. It is preferable that the same groupings be used in displaying adverse events. 

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