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P11 Evaluation of a two-phase enrollment design: Experience of the age-related eye disease study (AREDS)
116s
Abstracts PlO THE DELICATE BALANCE OF FILTER-COAGULATION AND PATIENT HEMORRHAGE WITH RENAL REPLACEMENT PXOCEDURES: MULTIVARIATE FAILURE TIME DATA ANALYSIS. Aeilko II. Zwinderman Leiden University Leiden. The Netherlands
In a retrospective investigation filtercoagulation free periods and hemorrhage free periods were observed repeatedly in 78 critically ill patients treated for renal failure with continuous renal replacement techniques. In total 241 periods were analyzed (1 to 12 per patient) with 141 filter- coagulations (0 to 8 per patient), and 49 major hemorrhages (0 to 3 per patient). Heparin can be used to reduce the risk of filter coagulation, but as a consequence the risk of hemorrhage will increase. To investigate this delicate balance it is necessary to estimate the within patient correlations between periods, both for filter-coagulation and hemorrhage, and the correlation between the two events. The former were assumed to be positive, and the latter to be negative. For filter coagulation we therefore assumed the hazard in period i for patient v to be Z~UJ,(tJ, whereas for hemorrhage Z l!J h (i & with p an unknown parameter. U, and U, were random gamma distributed variables with variances 6, and b2, Z a random lognormal distributed variables with variance 2, and X, and X, the hazard functions of two Weibull distributions. These assumptions were chosen for convenience sake, but the model appeared to fit the data excellently. The within patient correlation of filter-coagulation was estimated as 0.30 @
AREDS is a 10 year study of the clinical course and effect of pharmacologic doses of antioxidants and zinc on the development and progression of age-related macular degeneration (AMD) and cataract. Eleven Clinical Centers (CCs) were certified two years prior to availability of the study drug. During this two-year screening phase (SP), each CC identified and registered potential study participants. Persons registered in the SP were analyzed to assess both reasons for failure to enroll in the study and possible associations between time to randomization and compliance during follow-up (adherence to study medications and missed visits). Of the 5,086 participants enrolled in the SP, 2,385 (47%) were subsequently randomized. Failure to randomize was primarily due to the following: refusal to stop supplements containing the AREDS study drug ingredients (1 1 %), development of an excluding medical condition (15X), and general refusal (33 %). Older age and more severe AMD were associated with an increased probability of exclusion (p < .Ol). The 25 % of persons with the longest wait time (longer than 32 months) were more likely to refuse randomization than the 25% of persons with the shortest waiting tiie (less than 24 months) (p < .Ol). Among the 11 CCs, 4 of the 5 CCs with the largest number of participants identified in the SP randomized the largest number of participants both in the first year of the RP and overall.
Abstracts
117s Two year follow-up information is available for 1,290 of the 2,338 participants who were identified and randomized after the SP. Compliance with the study protocol for this cohort was compared with that of the 1, 975participant cohort identified in the SP and randomized after an 18 month wait. Prior to randomization, all participants were required to complete a one month trial of medications and demonstrate adherence of >75%. Delay of randomization was not associated with missed followup visits or post-randomization adherence to study medication. In conclusion, the implementation of a screening phase prior to randomization in this clinical trial provided the benefit of having persons ready to enroll once the clinical trial was underway. However, less than half of those so identified were eventually randomized. Older age, longer waiting times prior to randomization, and susceptibility to the clinical endpoint decreased the probability of eventual study enrollment. P12 THE CHANGING FACE OF TAMOXIFEN TREATMENT AND ITS INFLUENCE ON ATI’OM L. Padmore, K. Milligan, R. Gray, J. Dunn and M.J.R. Lee University of Birmingham Birmingham, United Kingdom aTTom is a large, uniquely simple, randomized study designed to recruit 20,000 women in order to determine the optimal duration of tamoxifen in the treatment of early breast cancer. There is considerable variability in the length of time that women are prescribed tamoxifen and clinical practice largely depends on the individual patient being treated. Moreover, as new evidence emerges clinical practice changes. The most recent results concerning the optimal duration of tamoxifen suggest that 5 years tamoxifen is better than 2 years but uncertainty still remains as to whether longer than 5 years treatment will provide any extra benefit. A study published by the NSABP group’ looking at 5 years or longer tamoxifen favored 5 years over 10 years with the ECOG study’ suggesting the opposite. Because of the heterogeneity in clinical opinion aTTom has adopted an extremely pragmatic approach. A patient is eligible after she has been on tamoxifen for at least two years. Randomization can take place at any point at which the clinician or the patient becomes uncertain as to whether to stop or continue tamoxifen treatment. Prior to the release and publication of the recent trial results 77% of aTTom participants randomized their patients after 2 years tamoxifen treatment with only 17% giving 5 years treatment before they reached a point of clinical uncertainty. 94% of UK clinicians questioned consider aTTom to be an important study and this is reflected in increasing Due to the flexible design of the trial aTTom will undoubtedly reach its recruitment. recruitment target. We are currently repeating a survey of UK breast cancer specialists first conducted in 1993 to assess if and how opinion has changed in the light of these results. From these data we will be able to demonstrate that recruitment has not been jeopardized by external influences but the point at which clinical uncertainty is reached may have shifted. References: 1. NSABP Project B-14, 1996 J. Natl. Cancer Inst. 88 1529-42. 2. ECOG Group, 1996 J. Natl. Cancer Inst. 88 1828-32.
Abstracts PlO THE DELICATE BALANCE OF FILTER-COAGULATION AND PATIENT HEMORRHAGE WITH RENAL REPLACEMENT PXOCEDURES: MULTIVARIATE FAILURE TIME DATA ANALYSIS. Aeilko II. Zwinderman Leiden University Leiden. The Netherlands
In a retrospective investigation filtercoagulation free periods and hemorrhage free periods were observed repeatedly in 78 critically ill patients treated for renal failure with continuous renal replacement techniques. In total 241 periods were analyzed (1 to 12 per patient) with 141 filter- coagulations (0 to 8 per patient), and 49 major hemorrhages (0 to 3 per patient). Heparin can be used to reduce the risk of filter coagulation, but as a consequence the risk of hemorrhage will increase. To investigate this delicate balance it is necessary to estimate the within patient correlations between periods, both for filter-coagulation and hemorrhage, and the correlation between the two events. The former were assumed to be positive, and the latter to be negative. For filter coagulation we therefore assumed the hazard in period i for patient v to be Z~UJ,(tJ, whereas for hemorrhage Z l!J h (i & with p an unknown parameter. U, and U, were random gamma distributed variables with variances 6, and b2, Z a random lognormal distributed variables with variance 2, and X, and X, the hazard functions of two Weibull distributions. These assumptions were chosen for convenience sake, but the model appeared to fit the data excellently. The within patient correlation of filter-coagulation was estimated as 0.30 @
AREDS is a 10 year study of the clinical course and effect of pharmacologic doses of antioxidants and zinc on the development and progression of age-related macular degeneration (AMD) and cataract. Eleven Clinical Centers (CCs) were certified two years prior to availability of the study drug. During this two-year screening phase (SP), each CC identified and registered potential study participants. Persons registered in the SP were analyzed to assess both reasons for failure to enroll in the study and possible associations between time to randomization and compliance during follow-up (adherence to study medications and missed visits). Of the 5,086 participants enrolled in the SP, 2,385 (47%) were subsequently randomized. Failure to randomize was primarily due to the following: refusal to stop supplements containing the AREDS study drug ingredients (1 1 %), development of an excluding medical condition (15X), and general refusal (33 %). Older age and more severe AMD were associated with an increased probability of exclusion (p < .Ol). The 25 % of persons with the longest wait time (longer than 32 months) were more likely to refuse randomization than the 25% of persons with the shortest waiting tiie (less than 24 months) (p < .Ol). Among the 11 CCs, 4 of the 5 CCs with the largest number of participants identified in the SP randomized the largest number of participants both in the first year of the RP and overall.
Abstracts
117s Two year follow-up information is available for 1,290 of the 2,338 participants who were identified and randomized after the SP. Compliance with the study protocol for this cohort was compared with that of the 1, 975participant cohort identified in the SP and randomized after an 18 month wait. Prior to randomization, all participants were required to complete a one month trial of medications and demonstrate adherence of >75%. Delay of randomization was not associated with missed followup visits or post-randomization adherence to study medication. In conclusion, the implementation of a screening phase prior to randomization in this clinical trial provided the benefit of having persons ready to enroll once the clinical trial was underway. However, less than half of those so identified were eventually randomized. Older age, longer waiting times prior to randomization, and susceptibility to the clinical endpoint decreased the probability of eventual study enrollment. P12 THE CHANGING FACE OF TAMOXIFEN TREATMENT AND ITS INFLUENCE ON ATI’OM L. Padmore, K. Milligan, R. Gray, J. Dunn and M.J.R. Lee University of Birmingham Birmingham, United Kingdom aTTom is a large, uniquely simple, randomized study designed to recruit 20,000 women in order to determine the optimal duration of tamoxifen in the treatment of early breast cancer. There is considerable variability in the length of time that women are prescribed tamoxifen and clinical practice largely depends on the individual patient being treated. Moreover, as new evidence emerges clinical practice changes. The most recent results concerning the optimal duration of tamoxifen suggest that 5 years tamoxifen is better than 2 years but uncertainty still remains as to whether longer than 5 years treatment will provide any extra benefit. A study published by the NSABP group’ looking at 5 years or longer tamoxifen favored 5 years over 10 years with the ECOG study’ suggesting the opposite. Because of the heterogeneity in clinical opinion aTTom has adopted an extremely pragmatic approach. A patient is eligible after she has been on tamoxifen for at least two years. Randomization can take place at any point at which the clinician or the patient becomes uncertain as to whether to stop or continue tamoxifen treatment. Prior to the release and publication of the recent trial results 77% of aTTom participants randomized their patients after 2 years tamoxifen treatment with only 17% giving 5 years treatment before they reached a point of clinical uncertainty. 94% of UK clinicians questioned consider aTTom to be an important study and this is reflected in increasing Due to the flexible design of the trial aTTom will undoubtedly reach its recruitment. recruitment target. We are currently repeating a survey of UK breast cancer specialists first conducted in 1993 to assess if and how opinion has changed in the light of these results. From these data we will be able to demonstrate that recruitment has not been jeopardized by external influences but the point at which clinical uncertainty is reached may have shifted. References: 1. NSABP Project B-14, 1996 J. Natl. Cancer Inst. 88 1529-42. 2. ECOG Group, 1996 J. Natl. Cancer Inst. 88 1828-32.