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PRAGMATISM OF RANDOMIZED CLINICAL TRIALS ON RANIBIZUMAB FOR THE TREATMENT OF DIABETIC MACULAR EDEMA: Impact on Clinical Outcomes.
Stewart, S, Yeong, JL, Virgili, G, Azuara-Blanco, A, Lois, N
Retina (Philadelphia, Pa.). 2020;(5):919-927
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PURPOSE To evaluate the pragmatism and generalizability of randomized clinical trials (RCTs) on ranibizumab for diabetic macular edema and determine whether clinical outcomes would differ based on whether or not patients fulfill the eligibility criteria of these RCTs. METHODS Pragmatism and generalizability of three RCTs on ranibizumab for diabetic macular edema (DRCRnet Protocols I and T, and RESTORE) were rated using the PRECIS-2 tool. A cohort of consecutive patients with diabetic macular edema was assessed to determine whether clinical outcomes differed based on whether or not patients met the RCT eligibility criteria. Univariable and multivariable regression analyses, adjusted for baseline best-corrected visual acuity, central retinal thickness and number of injections received, were used. RESULTS All RCTs were rated as being more pragmatic than explanatory, with DRCRnet trials being the most pragmatic. Of the 216 eyes (176 patients) included in the cohort, 63% would have met eligibility criteria for Protocol T, 61% for Protocol I, and 56% for RESTORE. When adjusted for best-corrected visual acuity, central retinal thickness, and number of ranibizumab injections received, there were no statistically significant differences in best-corrected visual acuity or central retinal thickness found between "eligible" and "ineligible" patients. CONCLUSION Randomized clinical trials evaluating ranibizumab for diabetic macular edema were more pragmatic than explanatory. "Ineligible" patients still benefited from ranibizumab therapy.
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ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY AND RISK OF TRACTION RETINAL DETACHMENT IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY: Pooled Analysis of Five DRCR Retina Network Randomized Clinical Trials.
Bressler, NM, Beaulieu, WT, Bressler, SB, Glassman, AR, Melia, BM, Jampol, LM, Jhaveri, CD, Salehi-Had, H, Velez, G, Sun, JK, et al
Retina (Philadelphia, Pa.). 2020;(6):1021-1028
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PURPOSE To investigate whether anti-vascular endothelial growth factor (anti-VEGF) for diabetic macular edema or proliferative diabetic retinopathy (PDR) increases the risk of traction retinal detachment (TRD) among eyes with PDR. METHODS Pooled analysis of PDR eyes from Protocols I, J, N, S, or T with Early Treatment Diabetic Retinopathy Study level ≥61 (prompt vitrectomy was not planned) randomly assigned to the control group (laser photocoagulation, sham, or intravitreal saline; 396 eyes) or anti-VEGF (487 eyes). The primary outcome was investigator-identified TRD within 1 year of randomization. RESULTS The 1-year cumulative probability of TRD was 6.8% (95% confidence interval: 4.6%-9.9%, 25 events) in control-group eyes and 4.8% (95% confidence interval: 3.2%-7.3%, 22 events) in anti-VEGF group eyes (hazard ratio = 0.95 [95% confidence interval: 0.54-1.66, P = 0.86]). The cumulative probability of vitrectomy for TRD was 4.4% (16 events) in control-group eyes and 2.2% (9 events) in anti-VEGF group eyes (P = 0.19). Percentage with TRD and vitrectomy for TRD were similar within strata of diabetic retinopathy severity. CONCLUSION These findings do not support the hypothesis that anti-VEGF therapy for diabetic macular edema or PDR increases the risk of TRD among eyes with PDR similar to those enrolled in five DRCR Retina Network protocols for which prompt vitrectomy was not planned.
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Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes.
Wang, Q, Ma, A, Bygbjerg, IC, Han, X, Liu, Y, Zhao, S, Cai, J
BMC infectious diseases. 2013;:104
Abstract
BACKGROUND The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas β-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. METHODS/DESIGN This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. DISCUSSION This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. TRIAL REGISTRATION ChiCTR-TRC-12002546.
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Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) screening and recruitment: methods and results.
Stewart, TM, Bhapkar, M, Das, S, Galan, K, Martin, CK, McAdams, L, Pieper, C, Redman, L, Roberts, S, Stein, RI, et al
Contemporary clinical trials. 2013;(1):10-20
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The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study is a systematic investigation of sustained 25% calorie restriction (CR) in non-obese humans. CALERIE is a multicenter (3 clinical sites, one coordinating center), parallel group, randomized controlled trial. Participants were recruited, screened, and randomized to the CR or control group with a 2:1 allocation. Inclusion criteria included ages 21-50 years for men and 21-47 years for women, and a body mass index (BMI) of 22.0 ≤ BMI < 28.0 kg/m(2). Exclusion criteria included abnormal laboratory markers, significant medical conditions, psychiatric/behavioral problems, and an inability to adhere to the rigors of the evaluation/intervention schedule. A multi-stage screening process (telephone screen and 3 in-clinic visits) was applied to identify eligible participants. Recruitment was effective and enrollment targets were met on time. 10,856 individuals contacted the clinical sites, of whom 9787 (90%) failed one or more eligibility criteria. Of the 1069 volunteers who started the in-clinic screening, 831 (78%) were either ineligible or dropped. 238 volunteers were enrolled (i.e., initiated the baseline evaluations), 220 were randomized, and 218 started the assigned intervention (2% from the first screening step). This study offered lessons for future multi-center trials engaging non-disease populations. Recruitment strategies must be tailored to specific sites. A multi-disciplinary screening process should be applied to address medical, physical, and psychological/behavioral suitability of participants. Finally, a multi-step screening process with simple criteria first, followed by more elaborate procedures has the potential to reduce the use of study resources.
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Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature.
Stein, A, Glockzin, G, Wienke, A, Arnold, D, Edelmann, T, Hildebrandt, B, Hollerbach, S, Illerhaus, G, Königsrainer, A, Richter, M, et al
BMC cancer. 2012;:356
Abstract
BACKGROUND More than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis. METHODS/DESIGN In these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/- irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability. DISCUSSION The CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients' characteristics in the CHARTA trial. TRIAL REGISTRATION Clinical trial identifier CHARTA NCT01321957, PERIMAX NCT01540435.
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Simultaneous ring voice-over-Internet phone system enables rapid physician elicitation of explicit informed consent in prehospital stroke treatment trials.
Sanossian, N, Starkman, S, Liebeskind, DS, Ali, LK, Restrepo, L, Hamilton, S, Conwit, R, Saver, JL, ,
Cerebrovascular diseases (Basel, Switzerland). 2009;(6):539-44
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BACKGROUND Cellular phone conversations between on-scene patients or their legally authorized representatives (LARs) and off-scene enrolling physician-investigators require immediate and reliable connection systems to obtain explicit informed research consent in prehospital treatment trials. METHODS The NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Trial implemented a voice-over-internet protocol (VOIP) simultaneous ring system (multiple investigator cell phones called simultaneously and first responder connected to call) to enable physician-investigators to elicit consent immediately from competent patients or LARs encountered by 228 ambulances enrolling patients in a multicenter prehospital stroke trial. For 1 month, the number, origin, duration, and yield of enrolling line calls were monitored prospectively. RESULTS Six investigators were connected to 106 enrolling line calls, with no identified unanswered calls. Thirty-five percent of new patient calls yielded an enrollment. The most common reasons for non-enrollment were last known well >2 h (n = 7) and unconsentable patient without LAR available (n = 7). No non-enrollments were directly attributable to the VOIP system. In enrollments, consent was provided by the patient in 67% and a LAR in 33%. The duration of enrollment calls (mean +/- SD: 8.4 +/- 2.5 min, range 6-14) was longer than non-enrollment calls (5.5 +/- 3.5, range 2-13; p < 0.001). The median interval from last known well to study agent start was 46 min, and 70% were enrolled within 60 min of onset. CONCLUSIONS The simultaneous ring system was reliable and effective, permitting enrollment of a substantial number of patients within the first hour after stroke onset. VOIP cellular networks with simultaneous ring are a preferred means of facilitating consent in prehospital treatment trials.
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Eban health promotion intervention: conceptual basis and procedures.
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Journal of acquired immune deficiency syndromes (1999). 2008;(Suppl 1):S28-34
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OBJECTIVE This article concerns the health promotion intervention that served as the comparison condition in Project Eban, the NIMH Multisite HIV/STD Prevention Trial for African American Couples. Considerable research has documented the high rates of chronic diseases, including heart disease, cancer, stroke, and diabetes, among African Americans. Many of these diseases are tied to behavioral risk factors-the things that people do or do not do, their diet, the amount of exercise they get, and their substance use practices. DESIGN The Eban Health Promotion Intervention was designed to increase healthful behaviors, including physical activity, healthful dietary practices, ceasing cigarette smoking and alcohol abuse, practicing early detection and screening behaviors, and improving medication adherence. As a comparison condition, the Eban Health Promotion Intervention was designed to be structurally similar to the Eban HIV/STD Risk Reduction Intervention. METHODS This article describes the intervention and how it was developed, integrating social cognitive theory with information collected in formative research to ensure that the intervention was appropriate for African Americans affected by HIV. CONCLUSION Project Eban not only tests the efficacy of an HIV/STD risk reduction intervention for African American serodiscordant couples, but also tests the efficacy of an intervention addressing many of the other health problems common in this population.
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Is there really a power shortage in clinical trials testing the "homocysteine hypothesis?".
Hankey, GJ, Eikelboom, JW, Loh, K, Yi, Q, Pizzi, J, Tang, M, Hickling, S, Le, M, Klijn, CJ, Dusitanond, P, et al
Arteriosclerosis, thrombosis, and vascular biology. 2004;(8):e147
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The second progress report on the Hypertension Objective treatment based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study.
Saito, S, Asayama, K, Ohkubo, T, Kikuya, M, Metoki, H, Obara, T, Hashimoto, J, Totsune, K, Miura, Y, Imai, Y, et al
Blood pressure monitoring. 2004;(5):243-7
Abstract
BACKGROUND The Hypertension Objective treatment based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study is a large-scale intervention trial to determine both optimal target blood pressure (BP) on the basis of self-measured BP at home, and optimal initial antihypertensive medication. OBJECTIVE To investigate the quality of randomization at the end of March 2003, and BP-controlled conditions during initial 6 months. METHODS We evaluated the number of patients randomized by the end of March 2003, and BP changes during the initial 6 months based on intention-to-treat analysis. RESULTS By the end of March 2003, a total of 1086 patients (12% of a planned randomization of 9000 patients) had been randomized. Among 653 patients who had been followed for > or =6 months after randomization, mean systolic/diastolic BPs at randomization in the calcium antagonist, angiotensin-converting enzyme and angiotensin II receptor blocker groups were 149/89, 150/89 and 149/88 mmHg, respectively. Blood pressures were reduced after 3 months (137/83, 139/82 and 136/82 mmHg, respectively), and further reduced after 6 months (134/81, 135/80 and 133/80 mmHg, respectively), with no significant differences identified between groups. In more- and less-intensive BP-lowering groups, mean systolic/diastolic BPs at randomization were 149/88 and 150/89 mmHg, respectively. Although BPs were reduced after treatment for 3 months (137/83 and 137/82 mmHg, respectively) and 6 months (134/80 and 135/80 mmHg, respectively) in each target group, significant differences were still not observed between groups. CONCLUSIONS Good quality of randomization was observed at the end of March 2003, but rate of achievement for target BPs was insufficient.
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Dietary quality assurance processes of the DASH-Sodium controlled diet study.
Most, MM, Craddick, S, Crawford, S, Redican, S, Rhodes, D, Rukenbrod, F, Laws, R, ,
Journal of the American Dietetic Association. 2003;(10):1339-46
Abstract
A thorough quality assurance (QA) program upholds the integrity of nutrition research studies by yielding reliable data and results. Continually evaluating the implementation of a procedure against a goal and making adjustments when needed enhance the quality of a study's conduct and outcomes. Controlled diet studies require QA processes at various steps beginning with the screening of study participants, through diet preparation and delivery to data collection. Staff training and observations with monitoring activities, are important so tasks are completed according to protocol. When several clinical sites participate as partners in a controlled diet study, uniform procedures must be followed and a formal standardized QA program will assist. The Dietary Approaches to Stop Hypertension (DASH)-Sodium study employed such a program, described in this article, that included training staff, observing procedures, monitoring data for completeness and accuracy, evaluating processes, giving feedback, and documenting that tasks were done according to protocol. Furthermore, QA processes were used in the areas of participant screening, orientation, diet adherence, food procurement and preparation, and exit interviews. Other researchers may implement similar activities to ensure quality in their nutrition research programs.