Randomization and allocation concealment: a practical guide for researchers

Although the randomized controlled trial is the most important tool currently available to objectively assess the impact of new treatments, the act of randomization itself is often poorly conducted and incompletely reported. The primary purpose of randomizing patients into treatment arms is to prevent researchers, clinicians, and patients from predicting, and thus influencing, which patients will receive which treatments. This important source of bias can be eliminated by concealing the upcoming allocation sequence from researchers and participants. Although there are many approaches to randomization that are known to effectively conceal the randomization sequence, the use of sequentially numbered, opaque sealed envelopes (SNOSE) is both cheap and effective. The purpose of this tutorial is to describe a step-by-step process for the preparation of SNOSE. We will outline how to prepare SNOSE to preserve allocation concealment in a trial that (a) uses unrestricted (simple) randomization, (b) stratifies randomization on one factor, (c) uses permuted blocks and, and (d) is conducted at more than 1 study site.     

Understanding high quality research designs for speech language pathology

As innovative methods, strategies, or curriculum are introduced to assist clients with speech and language disorders, many Speech-Language Pathologists (SLPs) may question the effectiveness of the intervention and more specifically whether the results that they are seeing are the result of the intervention (i.e., cause/effect). Several research designs allow researchers to examine causality including the most widely known, the randomized controlled trial (RCT). While not all situations are suited to applying the RCT, other high quality designs may be used that still lend evidence of causality even when randomization is not possible. The purpose of this paper is to provide a brief summary and illustrations of randomized controlled trials (RCT) and quasi-experimental design (QED) that are appropriate for the study of treatment effectiveness in speech-language pathology research, present potential barriers to quality randomization, and provide guidelines to help identify RCTs.     

Short-course Regimen for Subsequent Treatment of Pulmonary Tuberculosis: A Prospective,Randomized, Controlled Multicenter Clinical Trial in China

Purpose

We designed a prospective, multicenter, randomized, controlled study to assess a 5-month regimen compared with the standard regimen on previously treated patients with pulmonary tuberculosis (TB).

Blinding techniques in randomized controlled trials of laser therapy: an overview and possible solution

Low-level laser therapy has evidence accumulating about its effectiveness in a variety of medical conditions. We reviewed 51 double blind randomized controlled trials (RCTs) of laser treatment. Analysis revealed 58% of trials showed benefit of laser over placebo. However, less than 5% of the trials had addressed beam disguise or allocation concealment in the laser machines used. Many of the trials used blinding methods that rely on staff cooperation and are therefore open to interference or bias. This indicates significant deficiencies in laser trial methodology. We report the development and preliminary testing of a novel laser machine that can blind both patient and operator to treatment allocation without staff participation. The new laser machine combines sealed preset and non-bypassable randomization codes, decoy lights and sound, and a conical perspex tip to overcome laser diode glow detection.     

Tolfenamic Acid Rapid Release Versus Sumatriptan in the Acute Treatment of Migraine: Comparable Effect in a Double-Blind, Randomized, Controlled, Parallel-Group Study

The efficacy and safety of tolfenamic acid and oral sumatriptan in the acute treatment of migraine was studied at five neurological centers in Finland. One hundred forty-one patients experiencing 289 migraine attacks, fulfilling the diagnostic criteria for migraine with or without aura as defined by the International Headache Society, were randomized.
For first attacks, 77% of patients receiving tolfenamic acid experienced a reduction of the initial severe or moderate headache to mild or no headache after 2 hours, as compared to 79% in the sumatriptan group and 29% in the placebo group. No significant difference was found between active treatments ( P =0.85, 95% Cl [−22%, 18%]), however, both active treatments were significantly better than placebo; P =0.001, 95% Cl (26%, 69%) for tolfenamic acid and P =0.001, 95% Cl (28%, 71%) for sumatriptan. For second attacks, results were similar with 70% of patients receiving tolfenamic acid experiencing relief, as compared to 64% in the sumatriptan group and 39% in the placebo group.
No significant differences were observed in accompanying symptoms.
Both drugs were well tolerated with the frequency of adverse events; 30% for tolfenamic acid and 41% for sumatriptan, a nonsignificant difference.
In this study, tolfenamic acid and oral sumatriptan are comparably effective in the acute treatment of migraine. When comparably effective, factors like individual effect, tolerance, and cost of treatment should be considered when prescribing migraine medication.     

Planning and managing research into day-surgery for cataract

Between 1995 and 1997, a randomized controlled study, funded by the Department of Health, was carried out into the management of patients with cataract attending a peripheral ophthalmic clinic and who had been assessed as suitable for day-surgery. The research took place in a clinical setting and it was accepted from the outset that, while such studies have the power to give information about the real clinical world, this also means that the research is potentially at the mercy of events within that world. The purpose of this paper is to report how the study was set up and integrated into the clinic. First, a literature review was undertaken in order to focus the aims of the study more clearly. Second, drawing on principles of action research, clinical and research staff worked together to implement the study. This strategy allowed a flexible approach to the research which enabled problems to be handled as they arose.     

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

BACKGROUND: Current anticoagulant development focuses on agents with predictable pharmacokinetic and pharmacodynamic (PD) properties. BIBT 986 is a novel potent anticoagulant with a dual mechanism of action: it competitively inhibits factor (F) Xa and FIIa. AIMS: To determine the safety, tolerability, pharmacokinetics (PK) and PD of BIBT 986 following intravenous infusion in healthy male volunteers. METHODS: In three randomized, double-blind, placebo-controlled trials, subjects were administered by intravenous infusion escalating doses of BIBT 986 for up to 32 h. BIBT 986 concentrations were determined in plasma and urine samples by high pressure liquid chromatography tandem mass spectrometry. Pharmacodynamic response was assessed by measuring the changes in blood coagulation times. Activated partial thromboplastin time, International Normalized Ratio, thrombin time and ecarin clotting time were determined and compared with baseline results. RESULTS: In all three studies, intravenous infusion of BIBT 986 was safe and well tolerated. BIBT 986 exhibited linear PK over the dose range tested. Clearance was about 8 L h(-1) and V(ss) about 50 L. Apparent steady state concentrations were reached within 24 h, indicating a dominant half-life of about 6 h. The terminal half-life of BIBT 986 was approximately 12 h. Renal excretion contributes approximately 50% to total elimination. Overall interindividual variability in pharmacokinetic and PD parameters was < 40%. There was a linear correlation between plasma concentrations and PD responses, suggesting excellent predictability. CONCLUSION: BIBT 986 is the first small molecule of a novel class of anticoagulants that potently and directly inhibits both coagulation FXa and thrombin. It has predictable pharmacokinetic and PD characteristics.     

New developments in the conduct and management of multi-center trials: an international review of clinical trial units

Summary— There is an urgent need for the performance of more, better designed, and better managed randomized clinical trials. After visits to 43 leading organizations and units involved in clinical trials in Europe and North America during 1993, the way of conducting randomized clinical trials was analyzed. By using a structured questionnaire, information on recent improvements in the way randomized clinical trials are performed was identified. These developments encompass human aspects (better information, collaboration, and communication) as well as non-human aspects (press button phone randomization and data management systems). By employing such developments, randomized clinical trials can run much more efficiently. This facilitates faster and better answers to the questions addressed by randomized clinical trials, thereby also making them more ethical.     

Recovery of walking ability using a robotic device in subacute stroke patients: a randomized controlled study

Purpose: This study investigates the effectiveness of Lokomat + conventional therapy in recovering walking ability in non-ambulatory subacute stroke subjects involved in inpatient rehabilitation. Method: Thirty first-ever stroke patients completed 8 weeks of intervention. One group (n?=?16) received Lokomat therapy twice a week, combined with three times 30?min a week of conventional overground therapy. The second group (n?=?14) received conventional assisted overground therapy only, during a similar amount of time (3.5?h a week). The intervention was part of the normal rehabilitation program. Primary outcome measure was walking speed. Secondary outcome measures assessed other walking- and mobility-related tests, lower-limb strength and quality of life measures. All outcome measures were assessed before and after the intervention and at wk 24 and wk 36 after start of the intervention. Results: Patients showed significant (p?Conclusion: These results indicate that substituting Lokomat therapy for some of conventional therapy is as effective in recovering walking ability in non-ambulatory stroke patients as conventional therapy alone.

• Implications for Rehabilitation

• Recovery of walking after stroke is important.

• Robot-assisted therapy is currently receiving much attention in research and rehabilitation practice as devices such as the Lokomat seem to be promising assistive devices.

• Technical developments, sub-optimal study designs in literature and new therapy insights warrant new effectiveness studies.

• Results of a financially and practically feasible study indicate that substituting Lokomat therapy for some of conventional therapy is as effective in recovering walking ability in non-ambulatory stroke patients as compared to conventional overground therapy alone.

     

Efficacy of proprioceptive neuromuscular facilitation compared to other stretching modalities in range of motion gain in young healthy adults: A systematic review

The objective of this study was to evaluate the efficacy of proprioceptive neuromuscular facilitation (PNF) on range of motion (ROM) gain in young healthy adults. We performed a systematic review of randomized controlled trials and quasi-randomized trials, including young healthy adults. The interventions were: PNF compared with different PNF techniques, control, other muscle stretching exercises and musculoskeletal manipulations. The outcome measures were: articular ROM and adverse effects. The final number of included studies was 46, involving 1,864 adults. There was difference on ROM comparing assisted hold-relax (HR) on diagonal plane to control, based on very low-quality evidence. There was also difference on ROM comparing assisted HR to self-HR; self-contract-relax (CR) to control; assisted CR contract to control; and assisted HR contract to control, based on low-quality evidence. Moderate-quality evidence shows that results differ between self HR and control (SMD: 0.95; 95%CI 0.03, 1.86; I²49%; P = 0.16) in terms of ROM gain. When performing the other comparisons, the results were based on low or very low-quality evidence and do not allow to state if PNF is more or less effective than other stretches for improving ROM in healthy young adults. No adverse effects were mentioned.     

Double-blind placebo-controlled trial of lithium in episodic cluster headache

Lithium is widely used in the prophylaxis of episodic cluster headache without formal evidence of efficacy. Placebo-controlled clinical trials are not easy in conditions characterized by frequent severe pain. In this study, it was assumed that lithium would work quickly if at all, and placebo response would be zero. Strict diagnostic criteria excluded uncertain or atypical cases. Patients were male in so-far untreated episodes expected to last for at least 3 weeks more. In a double-blind, placebo-controlled comparison of matched parallel groups, treatment was either slow-release lithium carbonate, 800 mg/day, or placebo. After 7 days, compliance was estimated by tablet count, blood was taken for lithium assay, efficacy was assessed (attacks stopped or substantially improved) and adverse reactions were recorded. The study was stopped after planned sequential analysis of the 27th patient (13 on lithium, 14 on placebo). Estimated compliance was usually but not always good. Plasma lithium levels were mostly in the range 0.5–0.6 mmol/1 on lithium, zero on placebo. Cessation of attacks within 1 week occurred in two patients in each group, substantial improvement in 6/14 (43%) on placebo, 8/13 (62%; NS) on lithium. Only minor adverse events were reported. Lithium treatment was therefore associated with a useful subjective improvement rate but the assumptions made at outset had proved wrong. The trial was stopped because superiority over placebo could not be demonstrated. There were lessons for future trials.     

齐拉西酮与利培酮治疗急性期精神分裂症的随机对照研究

目的 比较齐拉西酮和利培酮对急性期精神分裂症患者的疗效和安全性.方法 对90例精神分裂症急性发作的住院患者,随机设计使用齐拉西酮(80～120 mg/d,分两次服用)、利培酮(4～6 mg/d,分两次服用)治疗8周,疗效评价指标采用阳性症状量表和阴性症状量表(PANSS),安全性指标采用体质量指数、空腹血糖、心电图QT间期以及药物不良反应量表(TESS)来评定.结果 在疗效上,两组有效率分别为86.7%和88.1%,差异无统计学意义.齐拉西酮治疗阳性症状稍差于利培酮,治疗阴性症状比利培酮效果要好,但二者差异均无统计学意义.在安全性方面,齐拉西酮较少引起静坐不能、体质量改变,与利培酮相比差异有统计学意义(P<0.05).结论 齐拉西酮和利培酮的疗效相近,但齐拉西酮比利培酮较少引起静坐不能、体质量改变,具有安全性方面的优势.     

Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial

BACKGROUND: The risk of decreased bone mineral density (BMD) with prophylactic dose long-term low-molecular-weight heparin (LMWH) is unknown. OBJECTIVES: We sought to determine whether long-term prophylactic dalteparin in pregnancy leads to loss of BMD. PATIENTS/METHODS: Patients in a substudy of an ongoing multicenter randomized trial investigating the effect of antepartum dalteparin prophylaxis on pregnancy outcomes in thrombophilic pregnant women were randomized to either dalteparin 5000 U s.c. daily until 20 weeks and then 5,000 U s.c. q12 h until >37 weeks or to the control group. The primary outcome was absolute spine BMD at six weeks postpartum. RESULTS: Of 77 patients eligible for the BMD substudy, 62 were analyzed. 33 patients received a mean of 212 days of dalteparin in the intervention group. 29 patients received a mean of 38 days of postpartum dalteparin in the control group. There was no difference in mean BMD between the intervention (1.11 g cm(-2)) and the control groups (1.14 g cm(-2)). Similarly, there was no difference in T-scores; the difference of -0.34 (95% confidence interval -0.93 to +0.25) in favor of the control group excludes a clinically important increase in fracture risk. CONCLUSIONS: Our results suggest that the use of long-term prophylactic dalteparin in pregnancy is not associated with a significant decrease in BMD. Clinical trial registration: ISRCTN87441504 at http://www.controlled-trials.com.