Multicenter studies

The definition of the minimally clinically relevant difference of interest involves clinical, medical, and regulatory experience and judgments. The appropriate sample size formula depends on the test of interest and should take into account the need for multiple comparisons (either among treatments or with respect to multiple examinations of the data). The project statistician provides critical guidance in this area. 

In summary, sample size estimation requires the input of a number of disciplines involved in the design of clinical trials. 

A certain number of participants need to be recruited for any given trial. In Section 12.2 we discussed sample size estimation, which takes into account a number of considerations that are important not only to the statistician but also to the clinical scientist and the regulator. Once determined, the value produced by this process of estimation is incorporated into the study protocol. 

We have seen that relatively small numbers of participants are recruited for early phase trials (perhaps 20-80 in FTIH studies and 200-300 in early Phase II studies), and relatively larger numbers are recruited for therapeutic confirmatory trials (perhaps 3000-5000). It is relatively easy to recruit between 20 and 80 participants at 

Chapter 1 2 Additional statistical considerations in clinical trials 

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GaetaGB, Stroffolini T, Chiaramonte M, Asdone T, Stomaiuolo G, LobeUo S, Sagnelli E, Brunetto MR, Rizzetto M (2000) Chronic hepatitis D a vanishing disease An Italian multicenter study. Hepatology 32 824-827... 

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Numerous positive delayed skin tests in patients with contrast medium-induced non-immediate skin reactions have been reported when the patients were tested with the culprit contrast medium [summarized in 1]. In a large European multicenter study, 37% of patients with non-immediate reactions were positive in delayed IDEs and/or patch tests [13]. The majority of the patients also reacted to the culprit contrast medium and also to other, structurally similar RCM. Notably, in more than 30% of those skin test-positive patients a RCM had been administered for the first time. Thus, there is a lack of a sensitization phase. Again it may be hypothesized that these previously non-exposed patients may have already been sensitized. Different patterns of RCM cross-reactivity indicate that several chemical entities could be involved. No positive skin tests have been obtained with other contrast medium excipients, such as ethylenediaminetetraacetic acid (EDTA), and only rarely patients have been found to react to inorganic iodide. 

Brockow K, Romano A, Aberer W et al Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European multicenter study. Allergy 2009 64 234-241. 

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Clark WM, Albers GW, Madden KR Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part a (a0276g) results of a double-bhnd, placebo-controlled, multicenter study. Thrombolytic Therapy in Acute Ischemic Stroke Study Investigators. Stroke. 2000 31 811-816. 

In a multicenter study, Jauss et al. °° evaluated the clinical features of 84 cerebellar infarction patients, and found that poor outcome was associated with a decreasing level of consciousness after clinical deterioration. Half of the patients in this study who deteriorated to coma had a meaningful recovery after undergoing ventricular drainage or suboccipital decompression, but unfortunately the trial was not randomized or controlled. 

Shen, Y. F., Li, H. F., Ma, C. et al. (2005). Comparison of reboxetine with fluoxetine in treatment of depressions randomized double-blind multicenter study. Chinese Journal of New Drugs and Clinical Remedies, 24(8), 619-23. 

Wang, G., Cai, Z. J., Wang, L. F. ex al. (2004). A multicenter study of risperidone treatment for acute agitation in patients with schizophrenia. Journal of Chinese Psychiatry, 37(2), 88-91. 

Zhang, H. Y., Shu, L., Li, H. F. et al. (2006). Risperidone versus haloperidol in treatment of acute manic episodes of bipolar 1 disorder a randomized double-blind controlled multicenter study. Journal of Chinese Psychiatry, 39(1), 33-7. 

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Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [see comments). 

Interestingly, in a small study on patients with AIDS, rifaximin was found to be effective against infectious diarrhea with stool cultures positive for protozoal pathogens, such as Cryptosporidium parvum and Blastocystis hominis [34], The favorable effects of rifaximin on protozoal diarrhea have been also reported in a recent multicenter study on patients with travelers diarrhea [33], In fact, patients with pretreatment stools positive for Cryptosporidium infections obtained a clinical improvement with rifaximin significantly superior to the placebo-treated subjects. 

Negendank, W. G., Sauter, R., Brown, T. R. et al. Proton magnetic resonance spectroscopy in patients with glial tumors a multicenter study. /. Neurosurg. 84 449-458, 1996. 

Compiled from US. Modafinil in Narcolepsy Multicenter Study Group and Standard of Practice Committee of the American Sleep Disorders Association. Pradice parameters for the use of stimulants in the treatment of narcolepsy. Seep 1994 17 348-351. 

Gillen water, J.Y. et al. 1995. Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension A double-blind, placebo-controlled, dose-response multicenter study. J Urol. 154 110. 

In a placebo controlled, double-blind, multicenter study with 47 chronic stable angina pectoris patients Pirsidomine showed significant hypotensive, anti-ischemic and antianginal effects [126]. 

Phase III Multicenter studies in populations of perhaps 100-3000 subjects (or more) for whom the medicine is eventually intended. 

Meyer B. (1986b). [A multicenter study of tinnitus. Epidemiology and therapy]. Ann Otolaryngol Chir Cervicofac. 103(3) 185-88. 

Hagen NA, Souich P, Lapointe B, Ong-Lam M, Dubuc B, Walde D, Love R, Ngoc AH. (2008) Tetrodotoxin for moderate to severe cancer pain A randomized, double blind, parallel design multicenter study. J Pain Symptom Manage 35 420 29. 

Hauschild, A. (2006) A phase II multicenter study on the HDACi MS-275, comparing two dosage schedules in metastatic melanoma. Abs. 8044, Annual Meeting of the American Society of Clinical Oncology, Atlanta, Ga. 

Whittaker, S., Scarisbrick, J., Kim, Y.H., Reddy, S., Kim, E.J., Rook, A.H. et al. (2008) Romidepsin activity and clinical benefit in refractory CTCL results fiom an international multicenter study. Abstract 444, 5th Joint Meeting ofthe JSID, SID and ESDR, Kyoto. 

No precise formula can be given to convert to fluphenazine decanoate use. However, in a controlled multicenter study, oral 20 mg/day fluphenazine hydrochloride was equivalent to 25 mg fluphenazine... 

Kaye SB, Lubinski J, Matulonis U et al (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCAI or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30 372-379... 

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