The Early Treatment for Retinopathy of Prematurity (ETROP) study was a randomized, prospective multicenter trial comparing the safety and efficacy of earlier vs. conventionally timed ablation of the peripheral retina for the management of moderate to severe retinopathy of prematurity (ROP). Approximately 7000 infants with birth weights <1251 g were screened at 26 centers over a 2-year period to achieve the sample size of 401 consented infants for the randomized trial. In order to minimize treatment of eyes with ROP that were likely to undergo spontaneous regression of the disease, a risk analysis model, RM-ROP2, was used to select for inclusion in the randomized trial only prethreshold eyes that had a high risk of an adverse outcome. The primary outcome measure was grating visual acuity measured by Teller acuity card testing conducted by masked testers in eyes randomized to earlier treatment vs. eyes randomized to conventional management when infants were 9 months post-term. Results were categorized into favorable (>or=1.85 cycles/degree) vs. unfavorable (<1.85 cycles/degree). The secondary outcome measure was retinal structure, assessed by ophthalmological examinations conducted at 6 and 9 months post-term. Here we describe a unique approach used in the ETROP study to select high-risk prethreshold ROP eyes for randomization and details about design of the study. Study results indicated that earlier intervention in selected high-risk prethreshold eyes results in improved vision in premature infants with ROP.
In large clinical trials where outcome assessment is possible using questionnaires, it may be more cost-effective to mail them to patients than to conduct interviews in-person. However, nonresponse to mailed questionnaires reduces the effective sample size and can introduce bias. We conducted a systematic review and meta-analysis of randomized controlled trials evaluating the effect of questionnaire length on response rates. We searched 14 electronic bibliographic databases, the reference lists of relevant trials, and we contacted the authors of eligible trials to ask about unpublished data. For each trial identified, we used logistic regression to estimate the odds ratio for response per one page increase in the number of pages included in the questionnaire. We pooled the regression coefficients in a random effects meta-analysis. Heterogeneity among the coefficients was assessed using a chi-square test at a 5% significance level. We specified a priori that the reduction in the odds of response per one page increase would be greatest among trials comparing relatively short questionnaires. We used meta regression to examine the relationships between the regression coefficients, the length of the questionnaires used in each trial, and other study characteristics. A total of 38 randomized controlled trials were identified where participants were allocated to questionnaires of differing lengths and where the number of pages used was known. There was significant heterogeneity between the regression coefficients estimated from each trial. In meta regression, most of the heterogeneity was explained by variation in the length of the questionnaires used in each trial. Among trials in which the shortest questionnaire was a postcard, the odds of response were more than halved for each additional page used (0.39; 95% CI 0.34 to 0.45). In the remaining trials, pooled effect sizes were much smaller. In trials of one page compared with either two or three pages, the odds of response per one page increase was 1.01 (95% CI 0.82 to 1.24). For one page compared with four or more pages, and for two or more pages compared with longer alternatives, the odds ratios per one page increase were 0.90 (95% CI 0.83 to 0.98) and 0.98 (95% CI 0.96 to 0.99), respectively. There were no statistically significant associations between trial results and other study characteristics. It appears that response can be increased by using a shorter questionnaire. Moderate changes to the length of shorter questionnaires will be more effective than moderate changes to the length of longer questionnaires. If a choice of follow-up questionnaire exists for a clinical trial, the shorter one should be used. If a new follow-up questionnaire is to be designed, it should be made as short as possible without compromising the data collection requirements of the trial.
Background: Patients may be asked to register a symptom daily in clinical trials. A problem associated with this kind of registration is that patients do not always fill in the diary at the appropriate time. As there is evidence showing that memory is unreliable, this undermines the entire purpose of collecting daily data on paper diaries. We aimed to compare accuracy, autocorrelations of consecutive entries. and responsiveness in paper diaries (P-Diaries) with electronic diaries (E-Diaries) and telephone diaries (T-Diaries).Methods: In a multi-centre, open, and parallel trial, 177 patients were allocated at random to P-Diaries, E-Diaries, or T-Diaries for the registration of symptoms through 4 weeks of treatment of gastro-oesophageal reflux disease (GORD). The primary outcome measure was the diaries.Findings: The proportion of patients completing all morning and all evening entries on time was low for both E-Diary and T-Diary groups. By accepting entries that were done half a day late, the proportion was increased to 19/57 (33%) for the E-Diary group, and to 9/61 (15%) for the T-Diary group. For P-Diary, where no control for time registration and entries was adapted, 37/59 (63%) of the patients completed all morning and all evening entries. A significant higher autocorrelation in P-Diaries was also found. Responsiveness was similar regardless of method of data capture.Interpretation: The results are consistent with the suggestion that data in the P-Diaries are not filled in at the appropriate time. Use of E-Diaries or T-Diaries improves quality and is recommended in future clinical trials. (C) 2004 Elsevier Inc. All rights reserved.
Success of blinding is a fundamental issue in many clinical trials. The validity of a trial may be questioned if this important assumption is violated. Although thousands of ostensibly double-blind trials are conducted annually and investigators acknowledge the importance of blinding, attempts to measure the effectiveness of blinding are rarely discussed. Several published papers proposed ways to evaluate the success of blinding, but none of the methods are commonly used or regarded as standard. This paper investigates a new approach to assess the success of blinding in clinical trials. The blinding index proposed is scaled to an interval of -1 to 1, 1 being complete lack of blinding, 0 being consistent with perfect blinding and -1 indicating opposite guessing which may be related to unblinding. It has the ability to detect a relatively low degree of blinding, response bias and different behaviors in two arms. The proposed method is applied to a clinical trial of cholesterol-lowering medication in a group of elderly people.
The optimum site and investigator selection process remains a closely guarded confidential matter and an essential part of development expertise of big pharmaceutical companies and CROs. The right and careful selection and evaluation of investigators and site is critical for successful completion of the trial within budget, timelines and generation of high quality data. The criteria for site and investigator selection in India for Good Clinical Practices (GCP) clinical trials are described for a start up company/CRO and can be applied to any country in Asia and Africa. Foreign sponsors doing clinical studies in India should pay close attention to site and investigator selection. The first GCP study in India was done only in 1995. At the dawn of 21st century, India is at the take off stage in clinical trials now. GCP studies can be done in India, as the quality of data is good, costs are lower and patient enrolment is much faster resulting in early completion of studies.
The difference between two proportions is often the focus of interest in prospective comparative studies such as randomized controlled trials that have a binary outcome. Consequently, interval estimation for this parameter has received considerable attention in the literature. A hybrid procedure resulting from combining two sets of confidence limits for a single proportion as proposed by Newcombe has been previously recommended for this purpose because of its superior properties and relative simplicity. In this paper, we propose a simple alternative approach based on Fisher's z transformation. The results of an exact evaluation study show that this new procedure performs as well as Newcombe's procedure in terms of percent coverage and expected confidence interval width. Several examples are presented.
Hysterectomy may be overused as treatment for abnormal uterine bleeding due to benign causes in reproductive women. Medical therapies are an alternative, and there is a need for randomized trials comparing the outcomes of these approaches. Women of reproductive age who continued to have bothersome abnormal uterine bleeding after cyclic hormonal treatment with medroxyprogesterone acetate (MPA; 10–20 mg for 10–14 days/month) for 3–5 months were invited to participate in a randomized trial of hysterectomy versus other medical therapies. Participating gynecologists were free to choose the particular surgical (transabdominal or transvaginal) or medical (generally oral contraceptives and/or a prostaglandin synthetase inhibitor) approaches. Outcomes during 2 years of follow-up include quality of life (primary), sexual function, clinical effectiveness and cost. We screened 1557 women to find 413 who began 3–5 months of MPA; 215 completed this treatment, of whom 102 still had bothersome symptoms, and of these 38 consented to be randomized. Another 25 women with bothersome symptoms after a documented history of 3 months of cyclic MPA were also randomized, for a total of 63. The average age of randomized women was 41; 54% were African-American, and they reported uterine bleeding 12 days/month on average, heavy bleeding 6 days/month. Anemia (hematocrit<32) was present in 38% of African-Americans and 15% of Caucasians (p=0.05). Two thirds of the women had fibroids and 80% reported pelvic pain. Obesity was common (45% had a body mass index (BMI)>30), and associated with a longer duration of symptoms (12 vs. 4 years for BMI<25; p=0.02) and a greater prevalence of incontinence (44% vs. 16%; p=0.046). Although recruitment was difficult, we have completed enrollment in a randomized clinical trial comparing surgical and medical treatments for abnormal uterine bleeding.
The selection of a trial design is an important issue in the planning of clinical trials. One of the most important considerations in trial design is the method of treatment allocation and appropriate analysis plan corresponding to the design. In this article, we conducted computer simulations using the actual data from 2158 rectal cancer patients enrolled in the surgery-alone group from seven randomized controlled trials in Japan to compare the performance of allocation methods, simple randomization, stratified randomization and minimization in relatively small-scale trials (total number of two groups are 50, 100, 150 or 200 patients). The degree of imbalance in prognostic factors between groups was evaluated by changing the allocation probability of minimization from 1.00 to 0.70 by 0.05. The simulation demonstrated that minimization provides the best performance to ensure balance in the number of patients between groups and prognostic factors. Moreover, to achieve the 1 percentile for the p-value of chi-square test around 0.50 with respect to balance in prognostic factors, the allocation probability of minimization was required to be set to 0.95 for 50, 0.80 for 100, 0.75 for 150 and 0.70 for 200 patients. When the sample size was larger, sufficient balance could be achieved even if reducing allocation probability. The simulation using actual data demonstrated that unadjusted tests for the allocation factors resulted in conservative type I errors when dynamic allocation, such as minimization, was used. In contrast, adjusted tests for allocation factors as covariates improved type I errors closer to the nominal significance level and they provided slightly higher power. In conclusion, both the statistical and clinical validity of minimization was demonstrated in our study.
When estimating the treatment effect in a randomized controlled trial, it is common to have a continuous outcome which is also observed at baseline. These observations are often prone to measurement error, for example due to within-patient variability. Controversy exists in the literature about whether baseline measurement error should be adjusted for in this context. Computer simulations were used to compare the biases in the estimated treatment effect, with and without adjusting for measurement error, and for different levels of observed baseline imbalance. The impacts of sample size (30 per group and 300 per group) and reliability coefficient (0.6, 0.8 and 1) were also assessed. The results show that in randomized controlled trials, the ordinary least squares (OLS) estimator without adjusting for measurement error is unbiased. On the contrary, adjusting for measurement error leads to bias, especially when sample sizes are small and/or measurement error is large. The treatment effect adjusting for measurement error is on average overestimated when the baseline mean of the control group is larger than that of the treated group. It is underestimated when the control group has a smaller baseline mean.
While randomised controlled trials remain the accepted ‘gold standard’ in medical research, participant recruitment is often problematic, particularly with primary care trials or those requiring healthy volunteers. Such difficulties can jeopardise the trial, leading to early abandonment, reduced statistical power or timetable and budget overruns. Substantial changes in recruitment plans may reduce the generalisability of the research. In order to overcome some of the more common recruitment difficulties, it is important that researchers share their recruitment strategy successes and failures. We report our experience of recruiting healthy volunteers to a condom trial, based within primary care and community populations. This was an RCT of the effect that using an additional spermicidal lubricant has on condom failure. We originally aimed to recruit entirely from Family Planning Clinics, but eventually required a wide variety of strategies. Targeted mailings, newspaper coverage and electronic ‘posters’ were among the most successful we used to bolster clinic recruitment. Concerned at our slow recruitment rates, we conducted a questionnaire survey investigating the reasons for participation and non-participation in the research completed by 101 trial participants, 112 decliners and 90 controls (total 303). The most important reasons given for taking part included ‘considering the research to be important’ (85%), ‘wanting to help the researchers’ (70%), ‘having time to help’ (62%) and ‘getting free condoms and lubricant’ (56%). The most popular reasons for declining were ‘not wanting to use condoms’ (38%), ‘partner's unwillingness to take part’ (29%), ‘not wanting to alter usual contraceptive practice’ (27%), ‘not having time’ (21%). Contrary to expectations, embarrassment and fears about confidentiality were relatively unimportant factors in this decision. In conclusion, the key to attaining recruitment targets was the core research team taking an active part, working closely with clinic staff and maintaining tight control of the process. Altruism remains a powerful motivation for participants, supported by incentives and procedural details to minimise personal inconvenience. Even for intimate research topics, these general factors outweigh specific issues.
Repeated measures are exploited to study reliability in the context of psychiatric health sciences. It is shown how test-retest reliability can be derived using linear mixed models when the scale is continuous or quasi-continuous. The advantage of this approach is that the full modeling power of mixed models can be used. Repeated measures with a different mean structure can be used to usefully study reliability, correction for covariate effects is possible, and a complicated variance-covariance structure between measurements is allowed. In case the variance structure reduces to a random intercept (compound symmetry), classical methods are recovered. With more complex variance structures (e.g., including random slopes of time and/or serial correlation), time-dependent reliability functions are obtained. The methodology is motivated by and applied to data from five double-blind randomized clinical trials comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia. Model assumptions are investigated through residual plots and by investigating the effect of influential observations.
The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.
This paper discusses some of the processes for establishing a large cluster-randomized trial of a community and primary care intervention in 16 local government areas in Victoria, Australia. The development of the trial in terms of design factors such as sample size estimates and the selection and randomization of communities to intervention or comparison is described. The intervention program to be implemented in Program of Resources, Information and Support for Mothers (PRISM) was conceived as a whole community approach to improving support for all mothers in the first 12 months after birth. A cluster-randomized trial was thus the design of choice from the outset. With a limited number of communities available, a matched-pair design with eight pairs was chosen. Sample size estimates, adjusting for the cluster randomization and the pair-matched design, showed that with eight pairs, on average, 800 women from each community would need to respond to provide sufficient power to determine a 3% reduction in the prevalence of maternal depression 6 months after birth—a reduction deemed to be a worthwhile impact of the intervention to be reliably detected at 80% power. The process of selecting suitable communities and matching them into pairs required careful collection of data on numbers of births, size of the local government areas (LGAs), and an assessment of the capacity of communities to implement the intervention. Ways of dealing with boundary issues associated with potential contamination are discussed. Methods for the selection of feasible configurations of sets of pairs and the ultimate allocation to intervention or comparison are provided in detail. Ultimately, all such studies are a balancing act between selecting the minimum number of communities to detect a meaningful outcome effect of an intervention and the maximum size budget and other resources allow.
Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 μg or placebo via metered-dose inhaler and Aerochamber® for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.
This study was performed to evaluate randomized cancer trials resulting negative regarding inadequate accrual, unsupported assumptions of equivalence and factors implied in such assumptions. A search in PubMed electronic data base was done for a sample of 800 most recently entered studies by March 2003 indexed with MESH term "neoplasms" and categorized according to design, intervention, outcome and conclusion. Minimal detectable differences with optimized power were calculated in each comparison according to number of patients accrued. Factors related with inadequate claim for equivalence in negative comparisons were also searched. Among the papers located, 194 met requirements and 188 were analyzed leading to 392 valid comparisons addressing survival, anti cancer effect or major toxicity, 235 of which resulted "negative". According to accrual, only 15.2% (ci95%, 9.9% to 20.3%) of negative comparisons would detect a 10% absolute difference between arms with 80% of chance. 53.6% (ci95%, 47.0% to 60.1%) of negative comparisons inadequately claimed equivalence. However, equivalence was supported by data in only 20.5% (ci95%, 12.6% to 28.4%) of negative comparisons that claimed for it. Negative comparisons based on new drugs had higher likelihood to be inadequately presented as supporting equivalence than those based in older drugs (66.7% vs. 43.5%, chi-square p=0.024). We concluded that most cancer clinical comparisons resulting negative are affected by poor accrual. They often inadequately claim for equivalence without supporting data. Comparisons involving new drugs are specially affected by this problem. Authors, editors and readers must be more rigorous regarding adequate assumptions of equivalence.
Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood–brain barrier with new compounds. This article reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.
From a methodological point of view, an enormous flexibility has been achieved with respect to the timing of interim analyses and the type I error α to be spend. Actual plans to spend α, however, are too often guided by the consideration of preserving as much α as possible for the final analysis. Practical consequences of spending tiny portions of α in many interim analyses are too often not appropriately acknowledged.
Purpose: To report the protocol for surveillance of the eye and vision in a clinical trial of MART1-transduced dendritic cells for metastatic melanoma. Methods: In a phase I/II clinical trial of dendritic cell-based genetic immunotherapy for metastatic cutaneous melanoma, ophthalmic evaluation is performed prior to immunization (Baseline Evaluation), 56±7 days after first vaccination (mid-study evaluation), when dendritic cell injections are complete 112±7 days after first vaccination (end-study evaluation) and 168±7 days after first vaccination (post-study evaluation). Results: The protocol for baseline, mid-study and end-study evaluations of the eye and vision includes ophthalmic history, comprehensive ophthalmic examination, psychophysical and electrophysiological visual function assessment, fundus photography and fluorescein angiography. Post-study evaluation consists of the 25-item visual functioning questionnaire augmented to elicit autoimmune manifestation with complete ophthalmic evaluation if vision-related symptoms or abnormalities are noted during or after the vaccination. Conclusion: Limited adverse effects on the eye and vision have been reported in melanoma immunotherapy trials, although this novel mode of therapy has the potential to induce melanoma paraneoplastic syndromes known to severely impair vision. Therefore, surveillance of the eye and vision should be considered in melanoma immunotherapy trials.
Methods: The prevalence of asthma in adults in the United States is approximately 7%, and 9% of asthma patients will require hospitalization each year. Many patients do not seek care, as they do not recognize overuse of beta-agonists as a risk factor for poorly controlled asthma. However, pharmacists are able to identify these patients through refill information on reliever medication prescriptions and potentially initiate community-management opportunities for these patients.Design: The study is a randomized, controlled trial. Patients are randomized to intervention or usual care.Study population: Patients are high-risk asthma patients (defined as having an ER visit or hospitalization in the previous year, or using >2 canisters of short-acting beta-agonist in the previous 6 months). They are identified through community pharmacies.Objectives: The primary objective is to determine the effect of an education and referral intervention program initiated by community pharmacists, working with high-risk asthma patients, family physicians and respiratory therapists, on asthma control, as measured by the Asthma Control Questionnaire (ACQ). Secondary objectives include determining the effect of this program on ER visits/hospitalizations, inhaled corticosteroid use, courses of oral steroids and FEV1.Intervention: The intervention includes patient education, assessment and optimization of drug therapy, and physician referral as needed. Patients are referred to a respiratory therapist within 1 week of randomization for measurement of FEV1 and reinforcement of education. Patients assigned to usual care receive written asthma information, referral to a respiratory therapist and usual pharmacy and physician care. Unique aspects: The design of the Better Respiratory Education and Asthma Treatment in Hinton and Edson (BREATHE) study is unique, given the multidisciplinary involvement, rural and community based, pharmacist initiated and targets specifically high risk patients. We believe that this study will show that management of asthma patients, involving the major role-players in their asthma care, will improve their asthma control. (C) 2004 Elsevier Inc. All rights reserved.
