Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.

AIM: Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. METHODS: Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). RESULTS: After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. CONCLUSION: Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

A randomized trial of Korodin Herz-Kreislauf-Tropfen as add-on treatment in older patients with orthostatic hypotension.

In a randomized, double-blind, placebo-controlled, parallel group, phase III clinical trial efficacy and safety of Korodin, a combination of natural D-camphor and an extract from fresh crataegus berries, was investigated in patients 50 years and older with orthostatic hypotension. At visit 1 eligibility of patients was checked and a placebo medication was given to all patients. At visit 2 orthostatic hypotension had to be reconfirmed, then the patient was randomized either to Korodin or placebo, study medication (25 drops) was applied once and then outcome was measured. After 7 days of home treatment with daily 3 x 25 drops outcome was measured at visit 3. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were documented 10, 5, 2 and 0 min before as well as 1, 3, 5, 8, and 10 min after getting in the upright position at visit 1, at visit 2 before and after application of study medication and at visit 3. Primary outcome was the change of mean arterial blood pressure (MAP) from just before standing up to the nadir within the first 3 min after standing up. Secondary outcome variables were SBP, DBP, HR, quality of life (SF-12) and seven typical signs and symptoms of orthostatic hypotension. The study was performed in a rehabilitation clinic and in two doctor's practices in Germany from November 2002 to May 2003. During this time, 57 patients were admitted to the study, 39 patients were eligible and randomized, 38 patients were treated according to protocol and evaluated, 21 patients with Korodin and 17 patients with placebo. After a single application the median decrease of MAP was 11.4 mmHg for Korodin and 14.0 mmHg for placebo. Compared to baseline, the median MAP improved 4.3 mmHg for Korodin and 0.3 mmHg for placebo. After 1 week of treatment the decrease of median MAP after standing up was 9.3 mmHg for Korodin and 13.3 mmHg for placebo. Compared to baseline, the improvement was 5.9 mmHg for Korodin and 1.6 mmHg for placebo. Efficacy of 1 week treatment was significant. For the single application a superiority of Korodin over placebo was seen; however, it was not significant. All secondary outcome variables confirmed these findings, except for the physical summary score in the quality of life evaluation (SF-12 questionnaire). Only one adverse event occurred, but this was not serious and without relationship to the study medication. The other safety variables (SBP, DBP, HR, ECG, physical examination) did not show any problems. This study demonstrates that Korodin is efficacious for orthostatic hypotension in patients over 50 years.

Identification of adverse drug reactions by evaluation of a prescription database, demonstrated for "risk of bleeding".

OBJECTIVE: Information about adverse drug reactions plays an important role when assessing the benefit/risk profile of a drug. Identifying rare adverse drug reactions, however, is a difficult task. This paper illustrates the advantages of using a prescription database for this purpose. METHODS: The mediplus database used in our analysis covered data from 320,644 outpatients observed between July 1999 and June 2002. The example of bleeding complications during intake of antidementia drugs is used to illustrate this approach. The comparison of cohorts and subgroups is nearly always a problem in surveys. For our analyses we considered a set of patients who had taken a selected medication for a certain period of time and compared the frequency of adverse events with those occurring when the same patients did not take this medication. Hence, the comparison with versus without a certain medication is based on the same set of patients as in a cross-over study. RESULTS: Our evaluations indicate that the rate of bleeding complications is low when taking any of the widely used antidementia drugs, glutamate modulators, cholinesterase inhibitors, calcium antagonists or the phytomedicine Ginkgo biloba. CONCLUSION: Basing the comparison of the rates of complications during periods with and without intake of a certain drug on the same set of patients may be a useful tool for assessing adverse drug reactions from data reported in prescription databases.

Randomised trials versus observational studies: is the comparative observational study a poor compromise or a perfect synthesis?

Overview of some fundamental designs for clinical trials and studies. Some tentative definitions are given in order to stimulate questions and perspectives for further research.

Guidelines for reporting non-randomised studies.

Non-randomised studies (NRSs) are useful because they allow interventions to be evaluated that are difficult to investigate by randomised controlled trials (RCTs). However, NRSs are more susceptible to bias. The Consolidated Standards of Reporting Trials (CONSORT) statement was established to ensure that researchers report features of RCTs that must be considered when appraising their quality. CONSORT has improved the reporting of key information, highlighting missing key information for users. Researchers have a responsibility to report essential information that allows users to assess the susceptibility of NRS to selection, performance, detection and attrition bias. This paper considers criteria for reporting cohort studies: the rationale behind the CONSORT criteria for reporting of RCTs will be applied to cohort studies. Many of the criteria need no modification but application of others raise difficult issues for cohort studies, e.g.: description and standardisation of control and intervention treatments; description of the method of allocation; choice of prognostic factors to be collected; distinguishing between intended and provided treatments; collection of data on adverse and longterm outcomes; establishing a priori plans for analysis.

Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer's disease.

This study was designed to confirm or negate findings from earlier trials demonstrating that Colostrinin, a novel compound derived from ewes' colostrum, has potential in the treatment of mild or moderate Alzheimer's Disease (AD). 105 patients were recruited from six psychiatric centres in Poland. The trial consisted of a 15 week double-blind phase comparing Colostrinin with placebo, followed by a second 15 week open labelled phase when all patients received Colostrinin. The dosage of Colostrinin was 100 microg on alternate days for three weeks followed by two weeks drug-free. This cycle was repeated three times for each phase. The primary outcome measures used were Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-cog) and Clinical Global Impression of Change (CGIC). Secondary outcome measures were Instrumental Activities of Daily Living (IADL); Mini-Mental State Examination (MMSE); ADAS-non cognitive test (ADAS-non cog); and overall Patient Response. The main outcome measures were assessed at week 15 when active was compared with placebo but all parameters were evaluated at baseline, week 15 and week 30. Two separate statistical analyses were undertaken, a Full Sample Analysis (FSA) in which all missing values were replaced with the worst result observed and a Valid for Efficacy (VFE) analysis in which those patients who had serious protocol violations were excluded. This resulted in 14 patients being excluded from the VFE-analysis. The FSA analysis at week 15 showed a stabilizing effect of Colostrinin on cognitive function in ADAS-cog (p = 0.02) and on daily function in IADL (p = 0.02). The overall patient response was also in favour of the active (p = 0.03). Patients graded as mild on entry also showed a superior response of ADAS-cog compared with more advanced cases (p = 0.01). Evidence from this study indicates an early beneficial effect on cognitive symptoms and daily function. Colostrinin has potential value in the treatment AD.

Kava extracts: safety and risks including rare hepatotoxicity.

Kava is a perennial shrub native to some islands of the South Pacific and has been cultivated for centuries to prepare a psychoactive beverage from its rhizoma by means of extraction. Subsequently, kava extracts are commonly used as herbal anxiolytic drugs also in many other countries all over the world including European ones and the USA. Toxicological and clinical studies have shown that kava extracts are virtually devoid of toxic effects with the exception of rare hepatotoxic side effects reported in few patients. When assessed primarily by the British regulatory authority MCA but also by us, a critical analysis of the suspected cases (n = 19) in Germany reveals that only in 1 single patient a very probable causal relationship could be established between kava treatment and the development of toxic liver disease due to a positive result of an unscheduled reexposure test, whereas in another patient there might be a possible association. Out of the remaining 17 cases 12 patients were not yet assessable due to insufficient data and in 5 other cases a causal relationship was unlikely or could be excluded. The German regulatory authority might therefore well be advised to provide now additional information for those 12 patients with so far unsatisfactory data, facilitating a more appropriate assessment of causality. Nevertheless, in the meantime physicians and patients should continue to keep an eye on possible hepatotoxic side effects in the course of kava treatment, to stop the treatment alredy at first suspicion and to start with a careful diagnostic work up ruling out all other causes.

Camphor-Crataegus berry extract combination dose-dependently reduces tilt induced fall in blood pressure in orthostatic hypotension.

In order to test the efficacy of a combination of natural D-camphor and an extract of fresh crataegus berries (Korodin Herz-Kreislauf-Tropfen) on orthostatic hypotension, two similar, controlled, randomized studies were carried out in a balanced crossover design in 24 patients each with orthostatic dysregulation. The camphor-crataegus berry combination (CCC) was orally administered as a single regimen in 3 different dosages of 5 drops, 20 drops and 80 drops; a placebo with 20 drops of a 60% alcoholic solution served as control. Orthostatic hypotension was assessed with the tilt table test before and after medication. Source data of both studies were pooled and meta-analytically evaluated for all 48 patients. CCC drops decreased the orthostatic fall in blood pressure versus placebo, as almost uniformly established at all times by mean arterial pressure and diastolic blood pressure. Mean arterial pressure demonstrated the very fast onset of action by a clearly dose-dependent statistically significant effect even after 1-minute orthostasis. Increase of mean arterial pressure as compared to the orthostasis test before medication was on average 4.5 mmHg. CCC affected diastolic blood pressure after 1 minute of orthostasis in all dosages as compared to placebo. A statistically significant effect of the highest dose of 80 drops on diastolic blood pressure could be demonstrated after 1-, 3-, and 5-minute orthostasis. The hemodynamic findings of a stabilizing effect on arterial pressure in orthostasis corroborate the long-term medical experience with CCC and justify the indication orthostatic hypotension.

[The use of randomisation in clinical studies in rehabilitation medicine: basics and practical aspects]. / Randomisierung in klinischen Studien in der Rehabilitationsforschung: Grundlagen und praktische Aspekte.

New therapies in rehabilitation medicine have to be evaluated with clinical trials. For drug approval the methodology of clinical trials is standardized world wide and the results of these studies are widely accepted. This standard should be achieved in clinical trials in rehabilitation research, too. One of the standards is the existence of a control group, comparing the effect of the new intervention against controls. In addition, the investigational and control groups must be equal in terms of the structure of possible confounders. Randomisation is the best possibility to distribute the patients to the therapy-groups, confounders will be equally distributed by chance. Other procedures for assignment to the study groups can result in confounding and lead into biased results. In spite of these advantages, randomisation is not generally accepted in rehabilitation research up to now. There are some reservations, mostly ethical, organisational and methodological ones. However, randomised clinical trials should be conducted in rehabilitation research in order to obtain more convincing results. Our intention is to bring some input in this debate and to present basics and practical aspects of randomisation.

Efficacy of oral ofloxacin for single-dose perioperative prophylaxis in general surgery--a controlled randomized clinical study.

BACKGROUND: Perioperative antibiotic prophylaxis surely reduces surgical infection rate. Pharmacokinetic data of oral ofloxacin in combination with its antibacterial spectrum suggest effective protection against perioperative infection. In addition, costs, adverse effects, and induction of microbial resistance are low. Therefore we performed a controlled randomized study comparing oral and intravenous single dose prophylaxis. METHODS: A total of 61 patients undergoing colonic or pancreatic resection randomly received either a single dose standard intravenous prophylaxis or ofloxacin 400 mg and metronidazole 500 mg orally 2 h before surgery. Postoperative infections were recorded for 3 weeks. RESULTS: Groups were very well comparable regarding age, overweight, concomitant disease, type and duration of surgery, blood loss, and volume support. Infectious complications occurred in 14.8% after parenteral and 3.3% after enteral antibiotic prophylaxis. There was no difference in post-operative hospital stay. CONCLUSION: The data demonstrate that single-dose oral ofloxacin is at least as effective as a standard intravenous prophylaxis in patients with colonic or pancreatic resection. It offers significant advantages regarding costs and ease of administration.

Results of applying ADCON-L gel after lumbar discectomy: the German ADCON-L study.

OBJECT: Failed-back syndrome is still an unsolved problem. Use of ADCON-L gel, already commercially available, has been proven to reduce postoperative scarring in animal experiments. The authors of two controlled clinical studies have also shown positive results when applying the gel. They did not, however, establish patient-oriented endpoints. The authors report a study of ADCON-L in which they focus on patient-oriented endpoints. METHODS: Patients with lumbar disc herniation were randomized to an ADCON-L-treated or control group. Therapeutic success was evaluated using the validated Hannover Questionnaire on Activities of Daily Living (FFbH) 6 months after surgery. The study took place between November 14. 1996, and April 20, 1998, in eight neurosurgical centers in Germany. A total of 398 patients was recruited; 41 patients dropped out during follow up. The mean functional FFbH score (100 points = all activities are possible without problem; 0 points = no activity is possible) was 78.5 points in the ADCON-L-treated group compared with 80 points in the control group. Furthermore, in terms of secondary outcome variables, the ADCON-L group did not have an advantage over the control group. Only the mean magnetic resonance imaging score showed a slight advantage of ADCON-L over the control group. CONCLUSIONS: The authors found no positive effect of treatment with ADCON-L gel in patients in whom one-level lumbar microdiscectomy was performed. Because of its rather large sample size and its homogeneity, the study had sufficient power to detect even small differences between the two groups.

Randomized, multicenter trial of two different formulas for very early enteral feeding advancement in extremely-low-birth-weight infants.

BACKGROUND: In extremely-low-birth-weight (ELBW) infants, formula feeding is required if human milk is not available. The tolerance of a new 'high' lactose (55 g/L), low protein, low phosphate, hydrolyzed protein formula (HLF) for early enteral feeding advancement of ELBW infants was compared with that of a low lactose (1 g/L) hydrolyzed protein formula (LLF). METHODS: In a randomized multicenter trial, 99 ELBW infants were fed according to a standardized protocol beginning at 48 hours of age with 12 ml/kg daily increments. Primary outcome was the cumulative milk feeding volume (CFV) from days 3 to 14. The authors hypothesized that feeding HLF as a supplement to human milk would increase the CFV at least by 20% in at least 60% of matched pairs compared with LLF. A secondary issue was to investigate whether human milk would increase the CFV compared with formula. RESULTS: The CFV was 720 mL/kg (range, 0-962 mL/kg) with HLF and 613 mL/kg (range, 3-1,283 mL/kg) with LLF feeding. There was no 20% difference. On day 14, the median feeding volume was 103 mL/kg. The CFV was 533 mL/kg (range, 0-962 mL/kg) in infants who received less than 10% of human milk and 832 mL/kg (range, 74-1,283 mL/kg) in infants who received more than 10%. Necrotizing enterocolitis (Bell stage > or =2) occurred only with LLF feeding (n = 5; P < 0.05). CONCLUSIONS: The study failed to find the hypothesized 20% advantage of the new HLF. The observed advantage of human milk supports the hypothesis that it should be the first diet in ELBW infants; however, this hypothesis still must be confirmed in a controlled, randomized trial.

Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE)--rationale, study design and study protocol.

UNLABELLED: SPICE is the first, international, randomized, placebo-controlled, double-blind study to investigate the influence of the herbal drug Crataegus Special Extract WS 1442 (hawthorn leaves with flowers) on mortality of patients suffering from congestive heart failure. BACKGROUND: In vitro and experimental animal studies have suggested the following pharmacological modes of action of standardized Crataegus extracts: (1) cAMP-independent positive inotropy; (2) peripheral and coronary vasodilation; (3) protection against ischemia-induced ventricular arrhythmias; (4) antioxidative properties; and (5) anti-inflammatory effects. STUDY DESIGN: In this randomized, placebo-controlled, double-blind, international trial (approximately 120 investigational centers in seven European countries), up to 2300 patients with congestive heart failure, New York Heart Association class II and III and markedly impaired left ventricular function, will be enrolled and treated over a period of 24 months. During this time patients receive either two film-coated tablets of 450 mg of the Special Extract WS 1442 standardized to 84.3 mg of oligomeric procyanidines or matched placebo per day in addition to standard therapy for congestive heart failure, such as diuretics, digoxin or digitoxin, beta-adrenoceptor blockers and angiotensin-converting-enzyme inhibitors. The primary outcome variable is the combined endpoint of cardiac death, non-lethal myocardial infarction, and hospitalization due to progression of heart failure. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, quality of life as well as pharmacoeconomic parameters. The first patient was included in October 1998. The trial is expected to be completed at the end of 2002.

[Development and validation of a prognosis model for predicting work capacity after rehabilitation based on routinely collected parameters]. / Entwicklung und Validierung eines Prognosemodells zur Vorhersage der Arbeitsfähigkeit nach Rehabilitation anhand routinemässig erhobener Parameter.

For efficient rehabilitation it is important to identify, as early as possible, the patients likely to be successfully returned to work after rehabilitation. The aim of this pilot study was to develop a statistical model for predicting this return as reliably as possible. The model uses only information readily available at the beginning of rehabilitation. A multiple regression analysis with backward elimination was used from a routine data base and identified 8 variables of prognostic value. The model offers a comfortable possibility to predict the probability of return to work of a patient on the basis of routinely registered data. The prognosis was found correct in 68% of those returning to work after rehabilitation (sensitivity) and in 80% of those who did not (specificity). Further work to improve the model for prognosis in rehabilitation research is considered reasonable.

[Clinical studies in rehabilitation research--problems and solutions from biometrical perspective]. / Klinische Studien in der Reha-Forschung--Probleme und Möglichkeiten aus biometrischer Sicht.

Methodology of clinical studies is highly sophisticated in drug research. But clinical trials are also necessary to demonstrate efficacy and safety of rehabilitation treatment. The call for evidence based medicine has also reached rehabilitation. However, in rehabilitation medicine it is much more difficult to design and conduct clinical trials with a high methodological standard. Among the reasons are: A comparable control group is necessary because spontaneous healing and unspecific measures contribute to therapeutic success, too. But what could "placebo rehabilitation" look like? The masking of therapies (blinded studies) will hardly ever be possible. Therefore, it is more difficult to achieve the same treatment and observation for the treatment and control group. Treatments in rehabilitation take longer to become effective than a drug and maybe the success will disappear after some time. Therefore, long-term trials and follow-ups are necessary. Such studies are expensive, need a strong organisation, and drop-outs are unavoidable. An appropriate outcome variable does not always exist. "Return to work" is an important, reliable and valid variable, but it delivers only one bit of information per patient. As a consequence, smaller progress in rehabilitation can only be demonstrated with large sample sizes. Outcome variables based on time enable studies with reasonable sample sizes. Sometimes it is more difficult to obtain acceptance of randomisation in rehabilitation patients than in acute patients. Some rehabilitation hospitals have only recently begun to take an interest in controlled clinical trials, hence are not so experienced. Nevertheless, controlled clinical trials delivering convincing results are possible in rehabilitation medicine as well. But biometrical consultation is necessary e.g. for study design, study conduction and evaluation. Most important points are the methodology of the study design and its practicability. Especially in these topics rehabilitation physicians and biometrician have to cooperate.

Hemoglobin A1c and body mass index in children and adolescents with IDDM. An observational study from 1976-1995.

In adult patients with type 1 diabetes good metabolic control was associated with an undesired weight gain. In the present report the possible association of HbA1c and body mass index (BMI) in children and adolescents with type 1 diabetes (IDDM) was investigated in a long-term retrospective study from 1976 to 1995. Further, the relationship between BMI on one hand and age, gender, duration of IDDM, the number of units of insulin used and the number of injections per day on the other hand were considered. Statistical analysis was performed using repeated measurements analyses of variance. The 208 girls and 201 boys were 5-17 years old and had diabetes for beyond one year. For analysis 2512 data sets, in part measurements on the same patient in the course of the disease, were available. In various statistical models, the results show that age, gender, the daily amount of insulin, and the HbA1c level (p<0.001-0.005) were associated with the BMI. Extremely high HbA1c levels coincided with a remarkably low BMI. Hence, in children and adolescents with IDDM it may be difficult to achieve a constantly good metabolic control accompanied by a normal body weight.

The procedure of new drug application and the philosophy of critical rationalism or the limits of quality assurance with good clinical practice.

K.R. Popper's philosophy of critical rationalism is concerned with the detection and removal of error. Fundamental contradictions exist between Popper's theory of knowledge and the present-day practice of the clinical investigation of new drugs. Currently, the public authorities concerned with the licensing of drugs pass judgment on trials, which are closely linked by the one-sponsor problem: the assertions made by the sponsor are not independently confirmed. This lack leads to excessive documentation and to costly monitoring and auditing, which are intended to ensure the credibility of results. In Popper's view, confirmatory trials, independent of the sponsor and supervised by the regulatory bodies, would be a better way to achieve reliable knowledge. The consequence would, among other things, be a reorganization of phase III of the clinical investigation of new drugs by dividing it into independent parts, one under the control of the sponsor and one under the control of the public authority. The implementation of this suggestion would lead to a more scientific manner of dealing with new drugs and to savings in terms of unproductive measures during the application process.

An epidemiologic survey of human alveolar echinococcosis in southwestern Germany. Römerstein Study Group.

The inhabitants of a rural community in southwestern Germany were examined for alveolar echinococcosis (AE). The study was prompted by the recent increase of the prevalence of the parasite in foxes and the increase of fox populations: in the study area, 75% of the foxes carried Echinococcus multilocularis. The human population was screened using hepatic ultrasound and serology. All participants were interviewed for demographic and potential risk factors. Of 2,560 participants, one was identified with active AE, while 3 others had suspicious liver lesions. Another 9 participants were seropositive for specific antibodies without detectable lesions. Demographic and behavioral factors were not correlated with active or suspected cases nor with seropositivity. If the prevalence of 40/100,000 (95% confidence interval = 15-295/100,000) for active cases would be representative for the rural population in high endemicity areas, the current number of AE cases in southwestern Germany is considerably higher than previously suspected.

Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure: a prospective randomised multicentre trial. International Multicentre Study Group.

BACKGROUND: There is controversy as to whether haemodialysis-membrane biocompatibility (ie, the potential to activate complement and neutrophils) influences mortality of patients with acute renal failure. We did a prospective randomised multicentre trial in patients with dialysis-dependent acute renal failure treated with two different types of low-flux membrane. METHODS: 180 patients with acute renal failure were randomly assigned bioincompatible Cuprophan (n=90) or polymethyl-methacrylate (n=90) membranes. The main outcome was survival 14 days after the end of therapy (treatment success). Odds ratios for survival were calculated and the two groups were compared by Fisher's exact test. Analyses were based on patients treated according to protocol (76 Cuprophan, 84 polymethyl methacrylate). FINDINGS: At the start of dialysis, the groups did not differ significantly in age, sex, severity of illness (as calculated by APACHE II scores), prevalence of oliguria, or biochemical measures of acute renal failure. 44 patients (58% [95% CI 46-69]) assigned Cuprophan membranes and 50 patients (60% [48-70]) assigned polymethyl-methacrylate membranes survived. The odds ratio for treatment failure on Cuprophan compared with polymethyl-methacrylate membranes was 1.07 (0.54-2.11; p=0.87). No difference between Cuprophan and polymethyl-methacrylate membranes was detected when the analysis was adjusted for age and APACHE II score. 18 patients in the Cuprophan group and 20 in the polymethyl-methacrylate group had clinical complications of therapy (mainly hypotension). INTERPRETATION: There were no differences in outcome for patients with dialysis-dependent acute renal failure between those treated with Cuprophan membranes and those treated with polymethyl-methacrylate membranes.