The effects of organic nitrates on osteoporosis: a randomized controlled trial [ISRCTN94484747]

Background

Osteoporotic fractures are common and are associated with increased morbidity, mortality and health care costs. The most effective way to moderate increases in health care costs and the sickness and premature death associated with osteoporotic fractures, is to prevent osteoporosis. Several lines of evidence suggest that nitrates, drugs typically prescribed for the treatment of angina, may be effective in preventing postmenopausal osteoporosis.

Methods

We have designed a multicentre randomized controlled trial to determine the effects of nitrates on bone. The trial consists of two studies. The objective of the first study is to determine whether isosorbide mononitrate at 20 mg/day or nitroglycerin ointment at 15 mg/day leads to fewer headaches. The nitrate that is best tolerated will be used in a second study with one main objective: To determine if postmenopausal women with a T-score at the lumbar spine (L1 to L4) between 0 and -2.0 randomized to two years of treatment with intermittent nitrates have a greater increase in spine bone mineral density as compared to women randomized to placebo. We hypothesize that: 1. Women will report fewer headaches when they are randomized to intermittent nitroglycerin ointment at 15 mg/day compared to intermittent oral isosorbide mononitrate at 20 mg/day, and, 2. After two years, women randomized to intermittent nitrates will have a greater percent increase in lumbar spine bone mineral density compared with women randomized to placebo.

Discussion

We have completed our pilot study and found that transdermal nitroglycerin was associated with fewer headaches than oral isosorbide mononitrate. We are currently recruiting patients for our second main study.     

Transient and Persistent Pain Induced Connectivity Alterations in Pediatric Complex Regional Pain Syndrome

Evaluation of pain-induced changes in functional connectivity was performed in pediatric complex regional pain syndrome (CRPS) patients. High field functional magnetic resonance imaging was done in the symptomatic painful state and at follow up in the asymptomatic pain free/recovered state. Two types of connectivity alterations were defined: (1) Transient increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb vs. unaffected limb in the CRPS state, but with normalized connectivity patterns in the recovered state; and (2) Persistent increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb as compared to the unaffected limb that persisted also in the recovered state (recovered affected limb versus recovered unaffected limb). The data support the notion that even after symptomatic recovery, alterations in brain systems persist, particularly in amygdala and basal ganglia systems. Connectivity analysis may provide a measure of temporal normalization of different circuits/regions when evaluating therapeutic interventions for this condition. The results add emphasis to the importance of early recognition and management in improving outcome of pediatric CRPS.     

Randomised prospective study for the effect of therapy on residual beta cell function in type-1 diabetes mellitus [ISRCTN70703138]

BACKGROUND: Newly diagnosed insulin-dependent diabetes mellitus is characterised by a temporary recovery of endogeneous insulin ("remission") after the beginning of medical treatment with subcutaneous insulin injections. Although most diabetologists think, that insulin reserve is related to reduced occurrence of diabetic long-term complications, such as eye, nerve and kidney disease, there is only one prospective controlled clinical study (the DCCT) addressing this question, however as secondary hypothesis. METHODS/DESIGN: Therefore, we composed a trial consisting of two cohorts with two therapeutic options within each cohort (conventional versus intensive therapy) and a three-year follow-up. In one group the patients are randomly assigned to the treatment regimes to test the statistical alternative hypothesis if variable insulin dosage is superior to fixed insulin injection in preserving insulin reserve measured by C-peptide in serum. Another group includes patients who prefer one of the two therapies, decline randomisation, but consent to follow-up. Apart from the determination of insulin reserve as a biological parameter a second primary endpoint was defined as 'therapeutic failure' according to the criteria of the European Association for the Study of Diabetes. Patients pass a training program to help them self-manage diabetes. A standardised protocol is being set up to minimize centre effects and bias of health care providers. Potential patient dependent bias will be investigated by questionnaires measuring psychic coping processes of people with diabetes. Management of visit dates is directly navigated by the database. Automated visit-reminders are mailed to patients and caregivers to optimise the number of visits on schedule. Data quality is regularly monitored and centres are informed on the results of continuous data management.     

Randomised controlled trial of structured personal care of type 2 diabetes mellitus

ObjectiveTo assess the effect of a multifaceted intervention directed at general practitioners on six year mortality, morbidity, and risk factors of patients with newly diagnosed type 2 diabetes.DesignPragmatic, open, controlled trial with randomisation of practices to structured personal care or routine care; analysis after 6 years.Setting311 Danish practices with 474 general practitioners (243 in intervention group and 231 in comparison group).Participants874 (90.1%) of 970 patients aged ⩾40 years who had diabetes diagnosed in 1989-91 and survived until six year follow up.InterventionRegular follow up and individualised goal setting supported by prompting of doctors, clinical guidelines, feedback, and continuing medical education.ResultsPredefined non-fatal outcomes and mortality were the same in both groups. The following risk factor levels were lower for intervention patients than for comparison patients (median values): fasting plasma glucose concentration (7.9 v 8.7 mmol/l, P=0.0007), glycated haemoglobin (8.5% v 9.0%, P<0.0001; reference range 5.4-7.4%), systolic blood pressure (145 v 150 mm Hg, P=0.0004), and cholesterol concentration (6.0 v 6.1 mmol/l, P=0.029, adjusted for baseline concentration). Both groups had lost weight since diagnosis (2.6 v 2.0 kg). Metformin was the only drug used more frequently in the intervention group (24% (110/459) v 15% (61/415)).Intervention doctors arranged more follow up consultations, referred fewer patients to diabetes clinics, and set more optimistic goals.ConclusionsIn primary care, individualised goals with educational and surveillance support may for at least six years bring risk factors of patients with type 2 diabetes to a level that has been shown to reduce diabetic complications but without weight gain.

What is already known on this topic

Evidence is increasing that control of hyperglycaemia, hypertension, and dyslipidaemia may postpone the development of diabetic complications in patients with type 2 diabetesMaintaining good control over a long period can be difficult

What this study adds

Structured individualised personal care with educational and surveillance support for general practitioners reduced levels of risk factors in type 2 diabetic patients after six yearsRisk factors were reduced to a level that has been shown to have a beneficial effect on diabetic complicationsParticipants also showed modest weight loss     

A cluster randomized controlled trial comparing three methods of disseminating practice guidelines for children with croup [ISRCTN73394937]

Background

The optimal management of croup – a common respiratory illness in young children – is well established. In particular, treatment with corticosteroids has been shown to significantly reduce the rate and duration of intubation, hospitalization, and return to care for on-going croup symptoms. Furthermore treatment with a single dose of corticosteroids does not appear to result in any significant adverse outcomes, and yields overall cost-savings for both families and the health care system. However, as has been shown with many other diseases, there is a significant gap between what we know and what we do. The overall aim of this study is to identify, from a societal perspective, the costs and associated benefits of three strategies for implementing a practice guideline that addresses the management of croup.

Methods/designs

We propose to use a matched pair cluster trial in 24 Alberta hospitals randomized into three intervention groups. We will use mixed methods to assess outcomes including linkage and analysis of administrative databases obtained from Alberta Health and Wellness, retrospective medical chart audit, and prospective telephone surveys of the parents of children diagnosed to have croup. The intervention strategies to be compared will be mailing of printed educational materials (low intensity intervention), mailing plus a combination of interactive educational meetings, educational outreach visits, and reminders (intermediate intensity intervention), and a combination of mailing, interactive sessions, outreach visits, reminders plus identification of local opinion leaders and establishment of local consensus processes (high intensity intervention). The primary objective is to determine which of the three intervention strategies are most effective at lowering the rate of hospital days per 1,000 disease episodes. Secondary objectives are to determine which of the three dissemination strategies are most effective at increasing the use of therapies of known benefit. An economic analysis will be conducted to determine which of the three intervention strategies will most effectively reduce total societal costs including all health care costs, costs borne by the family, and costs stemming from the strategies for disseminating guidelines.     

A randomized, controlled trial of spinal endoscopic adhesiolysis in chronic refractory low back and lower extremity pain [ISRCTN 16558617]

Background

Postoperative epidural fibrosis may contribute to between 5% to 60% of the poor surgical outcomes following decompressive surgery. Correlations have been reported between epidural scarring and radicular pain, poor surgical outcomes, and a lack of any form of surgical treatment. The use of spinal endoscopic adhesiolysis in recent years in the management of chronic refractory low back and lower extremity pain has been described.

Methods

A prospective, randomized, double-blind trial was conducted to determine the outcome of spinal endoscopic adhesiolysis to reduce pain and improve function and psychological status in patients with chronic refractory low back and lower extremity pain. A total of 83 patients were evaluated, with 33 patients in Group I and 50 patients in Group II. Group I served as the control, with endoscopy into the sacral level without adhesiolysis, followed by injection of local anesthetic and steroid. Group II received spinal endoscopic adhesiolysis, followed by injection of local anesthetic and steroid.

Results

Among the 50 patients in the treatment group receiving spinal endoscopic adhesiolysis, significant improvement without adverse effects was shown in 80% at 3 months, 56% at 6 months, and 48% at 12 months. The control group showed improvement in 33% of the patients at one month and none thereafter. Based on the definition that less than 6 months of relief is considered short-term and longer than 6 months of relief is considered long-term, a significant number of patients obtained long-term relief with improvement in pain, functional status, and psychological status.

Conclusion

Spinal endoscopic adhesiolysis with targeted delivery of local anesthetic and steroid is an effective treatment in a significant number of patients with chronic low back and lower extremity pain without major adverse effects.     

Randomised controlled trial of nicotine chewing-gum.

The effectiveness of 2 mg nicotine chewing-gum as an aid to stopping smoking was compared with a placebo containing 1 mg nicotine, but unbuffered, in a double-blind randomised trial. Of 58 subjects given the active gum, 27 (47%) were not smoking at one-year follow-up compared with 12 (21%) of the 58 subjects treated with placebo (p less than 0.025). By the most stringent criterion of outcome, 18 (31%) subjects in the active treatment group and eight (14%) in the placebo group had not smoked at all from the start of treatment to follow-up at one year (p less than 0.05). Subjects receiving the active gum experienced less severe withdrawal symptoms and rated their gum as more helpful than did the placebo group. Minor side effects were common but only gastric symptoms were more frequent with the active gum. Subjects receiving active gum used it for longer than those receiving placebo but most stopped using it within six months and only four (7%) developed longer-term dependence. The number of gums used daily correlated significantly with pretreatment blood nicotine concentrations in the active treatment group and with pretreatment cigarette consumption in the placebo group. A lower pretreatment blood nicotine value was the best predictor of success at one year (p less than 0.001) but there was no significant relation to cigarette consumption, sex, and social class. The results clearly confirm the usefulness of nicotine chewing-gum as an aid to stopping smoking and imply a definite role for nicotine in cigarette dependence and withdrawal. Successful use of the gum requires careful attention to subjects'' expectations and clear instructions on how to use it.     

The safety of over-the-counter niacin. A randomized placebo-controlled trial [ISRCTN18054903]

Background  

Niacin is widely available over the counter (OTC). We sought to determine the safety of 500 mg immediate release niacin, when healthy individuals use them as directed.     

Design of the Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial [ISRCTN19943732]

The Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial is a multicentre,randomised, placebo-controlled trial of magnesium sulphate (MgSO₄) funded by the UK Medical Research Council. When complete, it will be the largest single neuroprotective study undertaken to date. Conscious patients presenting within 12 h of acute stroke with limb weakness are eligible. The primary outcome measure is combined death and disability as measured using the Barthel Index at 90-day follow up. By randomizing 2700 patients, the study will have 84% power to detect a 5.5% absolute reduction in the primary end-point. By April 2000, 86 centres were participating, with representation in Canada, USA, Europe, South America, Singapore and Australia. So far, 1206 patients have been randomised, of whom 37% were treated within 6 h. Overall 3-month mortality was 20% and the primary outcome event rate was 43%. The study is ongoing and centres worldwide are encouraged to participate.     

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background  

Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback.     

Complex Regional Pain Syndrome Type I Affects Brain Structure in Prefrontal and Motor Cortex

The complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder that mostly occurs after injuries to the upper limb. A number of studies indicated altered brain function in CRPS, whereas possible influences on brain structure remain poorly investigated.We acquired structural magnetic resonance imaging data from CRPS type I patients and applied voxel-by-voxel statistics to compare white and gray matter brain segments of CRPS patients with matched controls. Patients and controls were statistically compared in two different ways: First, we applied a 2-sample ttest to compare whole brain white and gray matter structure between patients and controls. Second, we aimed to assess structural alterations specifically of the primary somatosensory (S1) and motor cortex (M1) contralateral to the CRPS affected side. To this end, MRI scans of patients with left-sided CRPS (and matched controls) were horizontally flipped before preprocessing and region-of-interest-based group comparison. The unpaired ttest of the “non-flipped” data revealed that CRPS patients presented increased gray matter density in the dorsomedial prefrontal cortex. The same test applied to the “flipped” data showed further increases in gray matter density, not in the S1, but in the M1 contralateral to the CRPS-affected limb which were inversely related to decreased white matter density of the internal capsule within the ipsilateral brain hemisphere. The gray-white matter interaction between motor cortex and internal capsule suggests compensatory mechanisms within the central motor system possibly due to motor dysfunction. Altered gray matter structure in dorsomedial prefrontal cortex may occur in response to emotional processes such as pain-related suffering or elevated analgesic top-down control.     

Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized,controlled trial [ISRCTN01928173]

To determine the efficacy and safety of risedronate in patients with knee osteoarthritis (OA), the British study of risedronate in structure and symptoms of knee OA (BRISK), a 1-year prospective, double-blind, placebo-controlled study, enrolled patients (40–80 years of age) with mild to moderate OA of the medial compartment of the knee. The primary aims were to detect differences in symptoms and function. Patients were randomized to once-daily risedronate (5 mg or 15 mg) or placebo. Radiographs were taken at baseline and 1 year for assessment of joint-space width using a standardized radiographic method with fluoroscopic positioning of the joint. Pain, function, and stiffness were assessed using the Western Ontario and McMaster Universities (WOMAC) OA index. The patient global assessment and use of walking aids were measured and bone and cartilage markers were assessed. The intention-to-treat population consisted of 284 patients. Those receiving risedronate at 15 mg showed improvement of the WOMAC index, particularly of physical function, significant improvement of the patient global assessment (P < 0.001), and decreased use of walking aids relative to patients receiving the placebo (P = 0.009). A trend towards attenuation of joint-space narrowing was observed in the group receiving 15 mg risedronate. Eight percent (n = 7) of patients receiving placebo and 4% (n = 4) of patients receiving 5 mg risedronate exhibited detectable progression of disease (joint-space width ≥ 25% or ≥ 0.75 mm) versus 1% (n = 1) of patients receiving 15 mg risedronate (P = 0.067). Risedronate (15 mg) significantly reduced markers of cartilage degradation and bone resorption. Both doses of risedronate were well tolerated. In this study, clear trends towards improvement were observed in both joint structure and symptoms in patients with primary knee OA treated with risedronate.     

Multifactorial day hospital intervention to reduce falls in high risk older people in primary care: a multi-centre randomised controlled trial [ISRCTN46584556]

Background

There are many barriers to patient participation in randomised controlled trials of cancer treatments. To increase participation in trials, strategies need to be identified to overcome these barriers. Our aim was to assess the effectiveness of interventions to overcome barriers to patient participation in randomised controlled trials (RCTs) of cancer treatments.

Methods

A systematic review was conducted. Published and unpublished studies in any language were searched for in fifteen electronic databases, including MEDLINE, EMBASE, CINAHL and PsycINFO, from inception to the end of 2004. Studies of any interventions to improve cancer patient participation in RCTs, which reported the change in recruitment rates, were eligible for inclusion. RCTs and non-randomised controlled trials as well as before and after studies reporting baseline rates specific to the population being investigated were included. Data were extracted by one reviewer into structured summary tables and checked for accuracy by a second reviewer. Each included study was assessed against a checklist for methodological quality by one reviewer and checked by a second reviewer. A narrative synthesis was conducted.

Results

Eight studies were identified that met the inclusion criteria: three RCTs, two non-randomised controlled trials and three observational studies. Six of the studies had an intervention that had some relevance to the UK. There was no robust evidence that any of the interventions investigated led to an increase in cancer patient participation in RCTs, though one good quality RCT found that urologists and nurses were equally effective at recruiting participants to a treatment trial for prostate cancer. Although there was no evidence of an effect in any of the studies, the evidence was not of sufficient quality to be able to conclude that these interventions therefore do not work.

Conclusion

There is not a strong evidence-base for interventions that increase cancer patient participation in randomised trials. Further research is required to evaluate the effectiveness of strategies to increase participation in cancer treatment trials.     

Residual sleepiness after N2O sedation: a randomized control trial [ISRCTN88442975]

Background

Nitrous oxide (N₂O) provides sedation for procedures that result in constant low-intensity pain. How long do individuals remain sleepy after receiving N₂O? We hypothesized that drug effects would be apparent for an hour or more.

Methods

This was a randomized, double blind controlled study. On three separate occasions, volunteers (N = 12) received 100% oxygen or 20% or 40% N₂O for 30 min. Dependent measures included the multiple sleep latency test (MSLT), a Drug Effects/Liking questionnaire, visual analogue scales, and five psychomotor tests. Repeated measures analysis of variance was performed with drug and time as factors.

Results

During inhalation, drug effects were apparent based on the questionnaire, visual analogue scales, and psychomotor tests. Three hours after inhaling 100% oxygen or 20% N₂O, subjects were sleepier than if they breathed 40% N₂O. No other drug effects were apparent 1 hour after inhalation ceased. Patients did not demonstrate increased sleepiness after N₂O inhalation.

Conclusion

We found no evidence for increased sleepiness greater than 1 hour after N₂O inhalation. Our study suggests that long-term effects of N₂O are not significant.     

Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.

OBJECTIVE--To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN--One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING--Outpatient clinics of five hospitals. SUBJECTS--79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE--Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS--For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS--Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine.     

Randomised controlled trial of computer-held medical records in hypertensive patients.

A total of 278 hypertensive patients in three clinics were randomly allocated to have their medical records held in a computer system (136) or on standard hospital notes (142). For the computer system the doctor completed a structured input form, and the information on symptoms, physical findings, and diagnoses was more complete than that in the standard notes. This resulted in certain symptoms and risk factors being recognised more often when the computer system was used. The hypertension clinics'' routines were not disrupted by the introduction of a computer-held system, and follow-up consultation times were not affected by the type of records kept, although the first consultation took eight minutes longer when computer documents were completed. The patients remained in the trial for one year and clinical management was assessed from blood pressure control, drop-out rates, and the frequency of performing investigations. These estimates of management showed no significant difference between the two groups, but the attempt to tailor the computer system to help management made the system acceptable to the doctors using it. The computer system continues to be used and is providing data for research into hypertension.