Clinical trials blinding

Acetyl-i-carnitine (4) is marketed in Italy for dementia as of this writing it is also in Phase III clinical trials in the United States and Europe. In a double-blind, placebo-controUed clinical trial over a one-year period involving 130 patients with clinically diagnosed AD, a slower rate of deterioration in 13 of the 14 outcome measures was observed in the dmg-treated group (28). Earfler smaller scale pilot studies in demented patients had also shown some improvement of various behavioral and cognitive functions (29). 

A clinical trial to evaluate misoprostol as a protector of normal tissue during a course of XRT in cancer patients suggests a reduction in acute normal tissue injury (215). A randomized, prospective, double-blind study indicates that topical misoprostol, administered as an oral rinse 15-20 min before irradiation using conventional 2-Gy (200 rad) fractions, five days a week over 6—7 weeks, significantly protects the oral mucosa from radiomucositis, a frequently observed normal tissue complication during XRT for head and neck cancer (215). 

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. 

It has been proposed that the development of the complications of diabetes mellitus may be linked to oxidative stress and therefore might be attenuated by antioxidants such as vitamin E. Furthermore, it is discussed that glucose-induced vascular dysfunction in diabetes can be reduced by vitamin E treatment due to the inactivation of PKC. Cardiovascular complications are among the leading causes of death in diabetics. In addition, a postulated protective effect of vitamin E (antioxidants) on fasting plasma glucose in type 2 diabetic patients is also mentioned but could not be confirmed in a recently published triple-blind, placebo-controlled clinical trial [3]. To our knowledge, up to now no clinical intervention trials have tested directly whether vitamin E can ameliorate the complication of diabetes. 

Clinical trials should be designed so as to mirtimise potential sources of bias. It is known that patients can demonstrate a positive response to treatments that they believe will benefit them, even if no pharmaceutical agent has been admrrtistered (the placebo effect ). Similarly, investigators may be biased in their observations by an expectation of particular results. To avoid such bias, blinded trial designs are used. 

The regulatory authorities must be informed of any planned recall actions (see Chapter 12). Procedures are also required for emergency un-blinding of materials undergoing clinical trial. The responsibility for complaints and the initiation of product recalls should be assigned to designated individuals. 

Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, Lee JH, Fox TL, Alomar A (2004) Imiquimod 5% cream for the treatment of actinic keratosis results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 51 547-555... 

Breneman DL, Stewart D, Hevia O, Hino PD, Drake LA (1998) A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1% cream to vehicle in patients with rosacea. Cutis 61 44-47... 

Tollefson GD, Sanger TM (1997). Negative symptoms a path analytic approach to a double blind, placebo controlled clinical trial with olanzapine. Am J Psychiatry 154,... 

Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H. Ebselen in acute ischemic stroke a placebo-controlled, double-blind clinical trial. Ebselen study group. Stroke 1998 29 12-17. 

The mean dietary intake of soy isoflavones in Asian populations consuming soy-based diets ranges from 20-40 mg isoflavones/day, with upper percentile consumer intakes of 70 mg/day (corresponding to around 1 mg/kg body weight). In the six month intervention studies in Western postmenopausal women, the effective dose for improved BMD was around 80-90 mg/day, while in the one year, randomized, double-blind, placebo controlled clinical trial, the effective dose was 54 mg/day. Overall, the dietary recommendation is to consume 50 mg isoflavones/day in combination with standard nutritional requirements for calcium and vitamin D. 

KLIPPEL K F, HiLTL D M, scHipp B (1997) A multicentric placebo controlled double-blind clinical trial of beta-sitosterol for the treatment of benign prostate hyperplacia. British J Urology, 80(3) 427-32. 

Clemens, J.A., Bulkley, G.B., Cameron, J.L., Milligan, F.L., Hutcheon, L., Horn, S.D. and MacGowan, S.W. (1991). Effect of xanthine oxidase inhibition with allopurinol on the incidence and severity of post-ERCP pancreatitis and hyper-amylasaemia in a prospective, randomized, double-blind, placebo-controlled clinical trial of 168 patients. Gastroenterology 100, A270. 

The randomization of a patient in a given therapy is the cornerstone of a randomized clinical trial. You may find these data in more than one place. They are often found within some form of Interactive Voice Response System (IVRS), but they may also be found in an electronic file containing the treatment assignments or on the CRF itself. If randomization data are found on the CRF, they usually consist only of the date of randomization for treatment-blinded trials. IVRS data are often found outside the confines of the clinical data management system and usually consist of the following three types of data tables. 

Jiang, R. H., Shu, L., Zhang, H. Y. et al. (2006). A phase II randomized double blind multi-centers and parallel control clinical trial for bupropion SR in the treatment of depressive disorders. Chinese Journal of New Drugs, 15(2), 128-31. 

Unfortunately, not all products that are used in clinical trials are available in the United States. In a randomized, double-blind, multicenter European study, 1069 men with moderate benign prostatic hyperplasia were randomized to receive saw palmetto (Permixon" )1 160 mg twice daily (90% free and 7% esterified fatty acids) or finasteride 5 mg once daily for 6 months [32]. As determined by patients and physicians, Permixon offered similar improvement in symptoms related to benign prostatic hyperplasia compared to finasteride. Since Permixon is not available in the United States, it should be recommended to patients to use a product that is similar to Permixon that contains a standardized extract of saw palmetto containing 85-95% sterols and fatty acids [18]. 

Why are side effects important Imagine that you have been recruited for a clinical trial of an antidepressant medication. As part of the required informed-consent procedure, you are told that you may be given a placebo instead of the active medication, but because this is a double-blind trial, you will not be told which you are getting until the study is over. You are told that... 

But do the clinical-trial data submitted to the FDA even establish proof of principle Recall that the rather small differences found between drug and placebo in the trials submitted to the FDA could have been due to the breaking of blind on the basis of perceived side effects. It may simply be evidence of an enhanced placebo effect, rather than a true drug effect. As I noted in Chapter i, once side effects are taken into account, the difference between SSRI and placebo is not even statistically significant.30... 

Feigin VL, Doronin BM, Popova TF, Gribatcheva EV and Tchervov DV (2001). Vinpocetine treatment in acute ischaemic stroke A pilot single-blind randomized clinical trial. 

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