The results of a multicenter randomized trial on the treatment of acute myeloid leukemia of adults

AIM: Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007. MATERIAL AND METHODS: Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation. RESULTS: A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme. CONCLUSION: The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.     

Vitrum osteomag in prevention of osteoporosis in postmenopausal women: results of the comparative open multicenter trial

AIM: To investigate efficacy, tolerance and safety of the drug vitrum osteomag one tablet of which contains 600 mg calcium (1500 mg calcium carbonate), 200 IU of cholecalcepherol, 40 mg of magnesium, zinc (7.5 mg), copper (1 mg), manganese (1.8 mg) and boron (250 mcg) in women with osteopenia for prevention of osteoporosis. MATERIAL AND METHODS: A multicenter comparative open trial of vitrum osteomag influence on mineral bone density (MBD), change of pain syndrome in bones, index of calcium-phosphorous metabolism covered 334 postmenopausal women with osteopenia. MBD was measured in low-back spine and proximal part of the hip with DEXA method. All the patients were divided into 3 groups: 125 women taking 2 tablets of vitrum osteomag daily for 12 months (group 1); 111 women taking 1500 mg calcium carbonate (group 2); 96 women--control group (only observation). RESULTS: Vitrum osteomag relieved pain in the back and joints, had a positive effect on bone density (+1.5%) and proximal parts of the hip (0.6-0.93%) exceeding the effect of calcium carbonate only which preserves the initial MBD in low back spine but does not prevent bone loss in the hip. MBD dynamics in patients given vitrum osteomag differs essentially from one in the control group (from -1.9 to -2.91%) which demonstrates a reliable preventive anti-osteoporotic effect of this medication. The drug increases the level of general and ionized calcium in blood but does not cause hypercalcemia lowering the level of parathormone in blood. The rate of side effects in group 1 was 14.4% and did not differ much from that in group 2 (16.2%). CONCLUSION: The results of the study allow to recommend vitrum osteomag for prophylaxis of a rapid loss of bone tissue mineral density.     

Monitoring and treatment of severe bronchial ashma in adults: results of national multicenter trial NABAT

AIM: To study quality of monitoring, features of a course and therapy of severe bronchial asthma (BA) in Russia. MATERIALS AND METHODS: The trial recruited 378 patients with severe bronchial asthma (SBA) in 7 cities of Russia. Each center participating in the study filled in individual case sheets recording demographic, clinical, monitoring, pharmacotherapeutic data. A special focus was on factors influencing the disease course. The chi-square and Mann-Witney criteria were used. RESULTS: It was found that current recommendations of BA patients' management are not used in full. Most of the patients do not receive adequate therapy. Phenotypes of uncontrolled course of severe BA are prevalent. The key role of adequate management of severe BA patients in control of the disease is shown. CONCLUSION: Wider use of updated recommendations on therapy and monitoring of BA with special focus on patients with uncontrolled course of the disease is urgent. Fulfilment of all the components of management of a patient with bronchial asthma recommended by GINA including the patient education and control over the disease triggers contribute much to effective treatment and control over BA.     

Donor safety in triple plateletpheresis: results from the German and Austrian Plateletpheresis Study Group multicenter trial

BACKGROUND: The objective was to investigate potential risks for apheresis donors associated with a triple‐plateletpheresis (TP) program. STUDY DESIGN AND METHODS: Eleven hemapheresis centers randomly assigned 411 repeat donors (ratio, 1:1.2) to either double plateletpheresis (DP; 185 donors) or TP (226 donors) with a platelet (PLT) target content of at least 5.0 × 10¹¹ PLTs/DP and at least 7.5 × 10¹¹ PLTs/TP. The primary endpoint was procedure‐related postapheresis PLT count of at least 150 × 10⁹/L (probability, ≥98%). Secondary endpoints were apheresis characteristics and donor adverse reactions. RESULTS: In 6 of 1133 DPs (0.5%) in 4 of 185 donors (2.2%) and in 20 of 1020 TPs (2.0%) in 14 of 226 donors (6.2%), postapheresis PLT counts were below 150 × 10⁹/L. There were marginal but significant differences in collection efficiency (DP, 69.2 ± 9.1%; TP, 70.9 ± 9.0%; p ≤ 0.0001) and collection rate (DP, 10.4 × 10⁹ ± 2.3 × 10⁹ PLTs/min; TP, 10.8 × 10⁹ ± 2.3 × 10⁹ PLTs/min; p ≤ 0.005). The PLT yields were 5.9 × 10¹¹ ± 0.8 × 10¹¹ PLTs for DP and 8.3 × 10¹¹ ± 0.9 × 10¹¹ PLT for TP (p ≤ 0.0001) at processing times of 59 ± 13 minutes (DP) versus 80 ± 16 minutes (TP; p ≤ 0.0001). Significant PLT recruitment (1.10 ± 0.14 vs. 1.20 ± 0.23; p < 0.0001) was seen for both DP and TP. DP and TP did not differ with regard to venous access problems (VAPs) without discontinuation (3.8% for both), but DP induced fewer VAPs with discontinuation (1.1% vs. 3.0%; p < 0.01). Mild citrate toxicity (1.7% vs. 3.9%; p < 0.01) and circulatory reactions (0.4% vs. 2.2%; p < 0.01) were more often noticed in TP, but caused no increase in discontinuations. CONCLUSIONS: TP results in an increase in mild donor reactions but does not significantly impair donor safety or product quality.     

Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial

Sports-related soft tissue injuries, such as sprains, strains, and contusions, are a common painful condition. Current treatment includes oral nonsteroidal anti-inflammatory drugs (NSAIDs), which have a high incidence of intolerable gastrointestinal side effects. Topically applied drugs have the potential to act locally in the soft tissues without systemic effects. This study assessed the efficacy and safety of topical diclofenac (NSAID) patch applied directly to the painful injury site for the treatment of acute minor sports injury pain. Adult subjects (N = 222) were recruited from two communities for a multicenter, randomized, placebo-controlled, parallel design study. All subjects had suffered a painful minor sports injury within the prior 72 hours of study entry. Either a diclofenac epolamine or placebo topical patch was applied directly to the skin overlying the painful injured site twice daily for 2 weeks. Measures of pain intensity were performed in a daily diary and at clinic visits on days 3, 7, and 14. Diclofenac patch was superior to placebo patch in relieving pain. Statistical significance was seen on clinic days 3 (P = 0.036) and 14 (P = 0. 048), as well as the daily diary pain ratings at days 3, 7, and 14 (P < or =0.044). No statistically significant differences were seen in any safety or side-effect measures with the diclofenac patch as compared to the placebo patch. Diclofenac epolamine patch is an effective and safe pain reliever for treatment of minor sports injury pain. The advantages of this novel therapy include its ease of use and lack of systemic side effects.     

A premarketing multicenter trial of lorazepam injection

Before the introduction of lorazepam injection to the Canadian market, its usefulness and acceptability were assessed in an open multicenter study. Anesthesiologists in teaching hospitals across the country were asked to substitute lorazepam injection for their usual anxiolytic premedicant in ten patients and to complete a brief case report on each patient. The results from 360 patients showed that suitable preoperative sedation, accompanied by anxiolysis but without undue effects on arousability, was obtained in 88% of the patients prior to surgery. The adverse effect most often reported, accounting for 84% of the drug-related adverse reactions, was postoperative drowsiness, which highlighted the need to administer the drug at least two hours before surgery. The anesthesiologists found lorazepam injection to be a satisfactory premedicant, rating it excellent to good in 73% of the patients treated.     

Efficacy of naftidrofuryl in patients with vascular or mixed dementia: results of a multicenter, double-blind trial

BACKGROUND: Dementia is a cerebral disorder resulting in a progressive deterioration of intellectual function that compromises the patient's ability to function. The diagnostic criteria for dementia are primarily clinical and are based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The Hachinski score and computed tomography of the brain help distinguish between degenerative and vascular dementias. OBJECTIVE: This study examined the efficacy of naftidrofuryl in patients with vascular or mixed dementia. METHODS: This multicenter, randomized, double-blind study compared naftidrofuryl 600 mg/d with placebo for 1 year in patients with vascular or mixed dementia. A preliminary 2-month washout period allowed selection of patients who were compliant with treatment. The end point was change in the scores on the Alzheimer Disease Assessment Scale cognitive subscale and the Mini-Mental State Examination. RESULTS: Eighty-four patients were assessable on an intent-to-treat basis, and 74 were assessable for the per-protocol analysis (on-treatment). Statistically significant improvements in cognitive and global function were observed in patients receiving naftidrofuryl. Naftidrofuryl was well tolerated, and produced no clinically significant abnormalities in laboratory test results. CONCLUSION: The results of this study suggest that naftidrofuryl is effective and well tolerated in treating the symptoms of vascular and mixed dementia.     

Implementing the EGASIS trial, an international multicenter acute intervention trial in stroke

This paper describes some of the problems that were encountered during implementation of the Early GABA-ergic Activation Study In Stroke (EGASIS), a large international multicenter clinical trial evaluating the neuroprotective effect of diazepam in acute stroke. The focus is on obtaining funding for such a large international nonprofit trial, getting approval from all national and local ethics committees, shipping trial medication, and trial insurance. For each topic the specific problems and ways in which they were solved are described. Several recommendations for facilitating the running of a large international multicenter clinical trial such as EGASIS are made.     

A multicenter trial of sulindac in osteoarthritis of the hip.

Sulindac (cis-5-fluoro-2-methyl-l-[(p-methyl sulfinyl)-benzylidene]-indene-3-acetic acid) is a new nonsteroidal antirheumatic drug recently evaluated in a double-blind trial of 91 patients with hip osteoarthritis. Consecutive patients with documented flare following previous drug withdrawal were randomly assigned to one of 3 treatment groups: (1) sulindac given twice daily, (2) sulindac given 4 times daily, and (3) placebo. The dosage of sulindac, 100 to 300 mg daily, was adjusted according to patient global response and tolerance at 3- to 7-day intervals over 3 wk. Of 15 efficacy measurements evalulated, there was no difference between sulindac given 2 or 4 times daily, but differences were disclosed between one or both sulindac treatment groups and placebo in 11 of the 15 efficacy measurements (p less than 0.05, less than 0.01). The frequency of adverse reactions was of the same order for each treatment group. These included gastrointestinal upset, rash, and dizziness, usually transient and mild to moderate in severity. Serial laboratory studies revealed no evidence of renal, hepatic, or hematopoietic toxicity.     

A multicenter trial of enalapril in the treatment of essential hypertension

The therapeutic profile of enalapril in mild to moderate uncomplicated essential hypertension was assessed in 265 patients who participated in a multicenter, open-label, prospective study lasting eight weeks. There were 54 younger (aged 39 years or less), 136 middle-aged (40 to 59 years), and 75 older patients (60 years or over). Monotherapy with enalapril in a single daily dosage regimen ranging between 5 and 40 mg resulted in normotension (in the sitting position) in 73% of the younger, 50% of the middle-aged, and 56% of the older patients. Normotension was achieved with 5 mg/day of enalapril in 41%, 18%, and 37% of the subgroups, respectively. Both systolic and diastolic pressures at the end of eight weeks of treatment were significantly lower (P less than 0.01) in the younger patients than in the other two age groups. White patients had significantly greater (P less than 0.001) response of both systolic and diastolic blood pressures than did black patients and required significantly smaller (P less than 0.01) average daily dosages of enalapril (14 mg versus 22 mg, respectively). The overall incidence of side effects was 14% among all 276 patients enrolled in the study. Most were mild and transient, but six patients discontinued enalapril during the first week of therapy because of side effects. There were no cases of rash, dysgeusia, hematological disorders, or deterioration in renal function, but there were two cases of pruritus, one of glossitis associated with an upper respiratory infection, and three of dry cough or wheezing. Angioedema was not observed. Monotherapy with enalapril, usually in a single daily dose of 10 to 20 mg, was effective in inducing normotension in approximately half of the middle-aged and older hypertensive individuals and in nearly three fourths of those below age 40. In this study it was generally well tolerated, with a relatively small incidence of side effects.     

Impact of the humidification device on intubation rate during noninvasive ventilation with ICU ventilators: results of a multicenter randomized controlled trial

Purpose

The use of heat and moisture exchangers (HME) during noninvasive ventilation (NIV) can increase the work of breathing, decrease alveolar ventilation, and deliver less humidity in comparison with heated humidifiers (HH). We tested the hypothesis that the use of HH during NIV with ICU ventilators for patients with acute respiratory failure would decrease the rate of intubation (primary endpoint) as compared with HME.

Methods

We conducted a multicenter randomized controlled study in 15 centers. After stratification by center and type of respiratory failure (hypoxemic or hypercapnic), eligible patients were randomized to receive NIV with HH or HME.

Results

Of the 247 patients included, 128 patients were allocated to the HME group and 119 to the HH group. Patients were comparable at baseline. The intubation rate was not significantly different: 29.7 % in the HME group and 36.9 % in the HH group (p = 0.28). PaCO₂ did not significantly differ between the two arms, even in the subgroup of hypercapnic patients. No significant difference was observed for NIV duration, ICU and hospital LOS, or ICU mortality (HME 14.1 vs. HH 21.5 %, p = 0.18).

Conclusions

In this study, the short-term physiological benefits of HH in comparison with HME during NIV with ICU ventilators were not observed, and no difference in intubation rate was found. The physiologic effects may have been obscured by leaks or other important factors in the clinical settings. This study does not support the recent recommendation favoring the use of HH during NIV with ICU ventilators.     

Results of an open, longitudinal multicenter LDL-apheresis trial

The German Multicenter LDL-Apheresis Trial showed that a partial regression of tendon xanthomas could be obtained applying LDL-apheresis without cholesterol lowering drug therapy over a period of 3 years, whereas secondary prevention of coronary heart disease was generally observed in the mainly heterozygous patients. As there were considerably fewer homozygous patients and the average age of the heterozygous patients in this study was higher compared to the phase I trial regression may well occur with this therapy although it appears to be restricted to young patients only. If the additional information obtained from continuation of the treatment these patients and from other patients under going regular LDL-apheresis for up to 16 years is also taken into consideration the assumption appears to be well supported that interventions such as a second PTCA or a second coronary bypass operation can be avoided. LDL-apheresis increases the quality of live by decreasing the frequency of angina pectoris and also--at least in homozygous patients--is able to prolong life expectancy to a considerable extent. However, additional risk factors may play a role and have to be taken into consideration.     

Asian multicenter trial of cefoperazone in respiratory tract infection

The safety and clinical efficacy of cefoperazone were evaluated in a multicenter trial conducted at institutions in Japan, Korea, and Taiwan. Cefoperazone was given as the sole antibiotic for 481 respiratory tract infections in 476 patients. An overall satisfactory clinical response was achieved in 73.7% of patients. Cefoperazone was effective in 78.9% of cases of pneumonia, 81.1% of acute exacerbations of chronic bronchitis, and 69.4% of bronchiectasis with infection. A satisfactory bacteriological effect was obtained in 93.2% of cases in which Haemophilus influenzae was isolated, 70.2% of Klebsiella infections, and 84.6% of infections with Streptococcus pneumoniae. Although the eradication rate was only 38.6% in patients with Pseudomonas aeruginosa, the success rate increases to 59.1% if patients showing a decrease in the number of organisms are included. Cefoperazone was effective in 63.5% of the 148 cases that had failed to respond to treatment with other antibiotics. Adverse reactions occurred in 8.0% of patients and consisted primarily of rash, diarrhea, and fever. Cefoperazone appears to be an extremely useful injectable antibiotic for the treatment of respiratory tract infections in hospitalized patients.     

Site visits in a multicenter ophthalmic clinical trial

Site visits were conducted to 19 clinical centers in a large multicenter ophthalmologic clinical trial, the Early Treatment Diabetic Retinopathy Study (ETDRS). The purpose of these site visits was to ensure the consistency of study procedures among clinics and to verify that these procedures were being carried out in accordance with the ETDRS Manual of Operations. The five major aspects of this quality control program are as follows: To monitor and review each clinical center's organization and procedures; To promote comparability of participating centers in all important aspects of the clinical trial; To gain more understanding about special problems facing individual clinical centers; To establish good rapport between the site visitor and clinic staff to aid future clinic monitoring; To promote and maintain enthusiasm for the study. The ETDRS clinical center site visits were conducted by using an observational approach. Presite visit preparations included the formation of a site visit agenda and the design of a site visit form, providing a guide for the site visitor, and a list of the topics that were to be reviewed at each center. Important concerns common to all site visits proved beneficial in the ETDRS.