Study Design for Final Height Determination in Turner Syndrome: Pros and Cons

Abstract

Early studies on the use of human growth hormone (hGH) for the treatment of Turner syndrome are reviewed and attention is drawn to the higher dose used compared with the doses for growth hormone deficiency (GHD). Patients with Turner syndrome responded less consistently than GHD patients to hGH. The prediction of final height in Turner syndrome from bone age is uncertain – long-term trials are essential to resolve final height questions. The pros and cons of randomized placebo-controlled trials, randomized nontreatment-controlled trials and historical controlled trials are compared, and it is concluded that in the USA, a randomized placebo-controlled trial is the most appropriate study design. The ethical considerations of such a long-term trial, in terms of risk vs. benefit, and the need for a placebo-treated group are also discussed.

Ethical issues in the design and conduct of randomised controlled trials.

“…Collective and individual equipoise. Nineteen articles regarded the existence of collective equipoise as sufficient justification for a trial, that is, a trial is ethical if experts in general, rather than the particular clinician (or clinician-patient pair) are equipoised (Alderson, 1996;Chipman, 1993;Collins et al, 1992;de Groot and Kennedy, 1995;Eichler, 1995;Emrich and Sedrank, 1996;Freedman, 1987;Gillett, 1994;Johnson and Lilford, 1991;Kadane, 1986Kadane, , 1996Passamani, 1991;Pfeffer, 1993;Sedrank, 1996;Shimm and Spece, 1983;Weymuller, 1996). This willingness to discredit individual 'hunches' in favour of the collective equipoise is buttressed by evidence which indicates that innovative therapies that are brought to the stage of an RCT are 'successful' only half of the time (Gilbert et al, 1977) and that people who hazard, even educated, 'guesses' are frequently much further off the mark than they expect to be (Albert and Raiffa, 1969).…”

Impact of Growth Hormone Supplementation on Adult Height in Turner Syndrome: Results of the Canadian Randomized Controlled Trial

“…Compared with the height predicted or projected at the beginning of treatment and/or to the height attained by historical control groups of patients with Turner syndrome, GH supplementation was estimated to have no effect on adult height in some studies (4,5), a dramatic effect in others [mean ϩ16.9 cm in a study in The Netherlands (6)], and a moderate effect in most (7,8). Factors contributing to wide variability in estimated effectiveness include methodological difficulties in predicting or projecting adult height (9,10), questionable appropriateness of using historical controls (11), patient selection biases, and differences in treatment protocols (age of initiation of GH therapy, dosing regimen, adjuvant therapies). Specifically, delaying estrogen replacement well beyond the physiological age of thelarche was suggested as a way to maximize any effect of GH on adult height (12).…”

Ethical Issues in the Design and Conduct of Randomised Controlled Trials

“…Collective and individual equipoise. Nineteen articles regarded the existence of collective equipoise as sufficient justification for a trial, that is, a trial is ethical if experts in general, rather than the particular clinician (or clinician-patient pair) are equipoised (Alderson, 1996;Chipman, 1993;Collins et al, 1992;de Groot and Kennedy, 1995;Eichler, 1995;Emrich and Sedrank, 1996;Freedman, 1987;Gillett, 1994;Johnson and Lilford, 1991;Kadane, 1986Kadane, , 1996Passamani, 1991;Pfeffer, 1993;Schaffner, 1996;Sedrank, 1996;Shimm and Spece, 1983;Tannsjo, 1994;Weymuller, 1996). This willingness to discredit individual 'hunches' in favour of the collective equipoise is buttressed by evidence which indicates that innovative therapies that are brought to the stage of an RCT are 'successful' only half of the time (Gilbert et al, 1977) and that people who hazard, even educated, 'guesses' are frequently much further off the mark than they expect to be (Albert and Raiffa, 1969).…”