Subject randomization

The telephone is also utilized in the development of interactive voice response (IVR) systems that support touch-tone or speech recognition responses. IVR systems have been developed for subject randomization, drug assignment, and survey data collection. 

Palmar M, Broekhoven M, Garrah A, Tu D. CTASSIST a computer program for subjects randomization and tracking of drug distribution. Clin Trials 2000 21 2S 110S. 

Campbell K, Radcliffe C, Thomas RG, Grundman M, Thai L. Online subject randomization and drug ordering system using the web linked to central data base. Controlled Clin Trials 1999 20 2S 91S. 

The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) has recently been developed in order to provide patient-specific estimates of the probability of a more favorable outcome with rt-PA, and has been proposed as a decision-making aid to patient selection for rt-PA." The estimates from this tool should, however, be treated with caution. The prediction rule is dependent on post hoc mathematical modeling, uses clinical trial data from subjects randomized beyond 3 hours who are not rt-PA-eligible according to FDA labeling and current best practice, and has not been externally validated. It is, therefore, not appropriate to exclude patients from rt-PA treatment based solely on Stroke-TPI predictions. 

Several European investigations have compared the effects of boiled vs. filtered coffee on serum cholesterol. In a study with 101 Dutch men and women17who typically consumed an average of 5.6 cups/day of filtered coffee, investigators assigned subjects randomly to drink 4 to 6 cups/day... 

Phase II—Safety and efficacy studies, 50-500 subjects, randomized, double-blinded... 

In a prospective placebo-controlled discontinuation trial, we recently demonstrated the efficacy of nortriptyline in doses of up to 2 mg/kg daily in 35 school-aged youth with ADHD (Prince et al., 2000). In that study, 80% of youth responded by week 6 in the open phase. During the discontinuation phase, subjects randomized to placebo lost the anti-ADHD effect. There... 

Therapeutic Efficacy. The efficacy and safety of quetiapine were tested in 109 schizophrenic patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (128). Subjects randomized to quetiapine initially received 25 mg three times a day for 1 to 2 days. Thereafter, the dose was titrated upward, using a combination of 25, 50, 100, and 200-mg tablets, until an adequate therapeutic effect could be achieved. The maximal daily dose was 750 mg, but daily doses greater than 500 mg were limited to 14 days. Patients given placebo treatment received matching tablets administered in the same manner as quetiapine. 

In 55 subjects randomized to olanzapinelO mg/day, risperidone 4 mg/day, or placebo for 2 weeks, there were significant increases in weight with olanzapine (2.25 kg) and risperidone (1.05 kg) (891). 

Figure 4 PVT performance responses to varying doses of daily sleep. Mean PVT lapses per day (07 30-23 30), measured at 2-hr intervals, expressed relative to baseline (BL), in subjects randomized to an 8-hr (n = 9 open diamond), 6-hr (n = 13 open square), or 4-hr (n = 13 open circle) sleep opportunity per day for 14 consecutive days or 0-hr (n = 13 closed square) sleep condition across 3 days. The curves represent statistical nonlinear model-based best-fitting profiles of the PVT performance response to sleep loss. The mean ( s.e.m.) ranges of neurobehavioral functions for 1 and 2 days of total sleep deprivation (0 hr sleep) are illustrated by the light and dark bands, respectively, allowing comparison of the 3-day total sleep deprivation condition and the 14-day chronic sleep restriction conditions. (From Ref. 35.)...

Moreover, daily PVT lapse rates increased at a more rapid rate in the reduced sleep conditions. Figure 4 displays the results from the first of these studies, in which subjects were restricted to 4, 6, or 8-hr time in bed for sleep for 14 consecutive days (35). The results were compared to 88 hr of total sleep deprivation. Figure 4 illustrates the dose-response relationship between sleep opportunity and the degree of impairment in PVT performance. Interestingly, this cumulative impairment was found to be almost linear for lapse rates. Further, subjects randomized to the 4- and 6-hr sleep restriction conditions reached levels of impairment equivalent to those of subjects undergoing 1-2 nights of total sleep deprivation. 

After 180 days of treatment there was a significant improvement of 73 9% (mean SE) in maximal walking distance in PAD patients treated with propionyl-L-carnitine compared to placebo (80). Propionyl-L-camitine has been shown to improve treadmill performance and quality of life in patients with claudication. After six months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 222 seconds (a 54% increase) as compared with an improvement of 75 191 seconds (a 25% increase) for those on placebo (p < 0.001) (81). 

Lithium is also effective in individuals with co-morbid pathological gambling and a mood disturbance. In a randomized, 10-week, placebo-controlled study in 40 subjects randomly assigned to modified-release lithium or placebo, 83% of those who took lithium responded compared with only 29% of those who took placebo (100). 

Selecting experimental subjects randomly to cancel out systematic variation arising from biased selection. 

In 77 HIV-positive subjects randomized to switch from protease inhibitors to nevirapine or efavirenz or to continue taking protease inhibitors, quality of life significantly improved among those who switched (6). In those who took efavirenz there was an increase in... 

We assume a block-diagonal matrix of subject random effects such that rij uuc and %iv are correlated, but independent of Here are the resulting estimates ... 

The LME model of Section 4.2.1 and the NLME model of Section 4.2.2 both involved two random components measurement error and subject random effects. In this section we explore a two-level random effect hierarchy by introducing lO variability in the PK parameters Ka, Ke, and V), so that the subject s parameters may vary from period to period. Note that this is not a period effect, but rather an uncontrollable random variation in the subject s pharmacokinetics. The data frame dp2, incorporating lO random effects, is obtained by calling sim.dp.muit as follows ... 

Although the fixed effects have been well estimated, it is also of interest to examine how closely the estimated standard deviations of the random effects reflect the true variability in the simulated data. The dp2 data frame includes values of the generated subject random effects, interoccasion random effects, and measurement errors, from which sample variances can be obtained and compared to the model estimates. The intersubject sample standard deviations of log(ic ), og AUC), and log(T) are 0.33,0.41, and 0.23, respectively. The corresponding model estimates are 0.36, 0.39, and 0.26. For the lO random effects, the sample SDs are 0.17, 0.22, and 0.17, while the corresponding values obtained in the model fit are 0.20, 0.19, and 0.18, respectively. The sample and model SD for measurement error are both equal to 0.1, indicating a good agreement overall between sample and model estimates. 

The placebo model assumes an endogenous response, influenced by baseline (BL), and two exponential functions. For ai > U2, P(t) increases over time above BL then declines back to BL for sufficiently large t. The drug model is a stimulus model, a function of plasma concentration C(t), maximal effect Pmax, and LCso, the concentration that produces 50% of the maximal effect. In this example, C(t) is generated without measurement error but is influenced by subject random effects in K, K, and V, as discussed in the previous section. Additional subject random effects are considered for BL and Pmax-... 

For example, to fit a model with a single mean parameter and a single subject random effect, one could use... 

In this case subject random effects are set to zero, and... 

Here 0 is a vector of mean population pharmacokinetic parameters and Q is the variance-covariance matrix of between-subject random variability. Np represents a p-dimensional multivariate normal distribution, where p is the number of parameters. It is often more useful to consider the values of the parameters for the individual to be related to the population parameters via a covariate relationship, in which case the expression may be written as... 

The estimate of the between-subject random effect for V (co ) lacked precision. Neither sampling scheme (scheme A versus scheme B) appeared to perform better than the other. When the residual variability was increased, bias in the estimation of V increased and the precision of af and co worsened. For the two-compartment model, an N of 80 resulted in accurate estimates of CL, VI, V2, and and precise estimates of CL, V2, and af. All estimates of intercompartmental clearance (Q) were inaccurate and imprecise regardless of sample size and the precision of VI and co were poor regardless of sample size. 

A proportional error, a constant additive error, and a combination of both error models were evaluated for the residual error model. Between-subject random effects were explored on the clearance of parent drug and metabolite, the volume of distribution of the parent drug, and the absorption rate constant. An exponential model was preferred. Interoccasion random effects were explored on the clearance of the parent drug and of the metabolite, the volume of distribution of the parent drug, and the absorption rate constant. An exponential model was preferred. The joint distribution of the between-subject random effect, the interoccasion random effects, and the residual error were assumed normal with mean 0 and variance-covariance matrices O for the between-subject and interoccasion random effects, and I, for the residual error to be estimated. The FO method was used for the estimation of the parameters. 

Was intention-to-treat analysis performed Intention-to-treat analysis means that the results from all subjects randomized in the study were accounted for and attributed to the group to which they were assigned. This strategy minimizes attrition bias and ensures that the known and unknown prognostic factors are kept equally distributed. For example, exclusion of subjects who withdrew early in treatment may bias the... 

COX-2 inhibitors demonstrate similar analgesic benefits when compared to traditional NSAIDs. For example, 748 subjects randomized to rofecoxib (12.5 or 25 mg daily) or diclofenac (50 mg three times daily) showed similar improvements in pain, stiffness, physical function, and other measures of efficacy. In a 12-week trial of 1003 subjects with knee OA, celecoxib at 100 or 200 mg twice daily was more effective than placebo and comparable to naproxen 500 mg twice daily for relief of pain, stiffness, and limitation of physical function. ... 

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