As discussed elsewhere, 6 AChEIs have shown promise of benefit in a variety of other disorders in addition to AD, such as traumatic brain injury and Parkinson disease. There is some evidence that even healthy individuals may benefit from donepezil. It is also possible that the benefit of donepezil in MS is more modest than initially estimated, and therefore difficult to reliably demonstrate with a sample of the current size.
The power estimation for the present sample was derived from the results of an earlier clinical trial in MS with donepezil, 9 and it is possible that those results represent an unusually large effect for MS. The current sample size of approximately 60 per treatment group is substantially smaller than that used in standard AD clinical trials, with sample sizes ranging from approximately 18 to Another characteristic that might have influenced the present results is the choice of cognitive screening criterion.
The subgroup analysis of subjects with more impaired RAVLT performance below the fifth percentile on the RAVLT did reveal a positive treatment effect on the primary outcome measure and showed a trend on 2 secondary cognitive outcomes.
It is possible that if the entire sample had met this criterion of baseline memory impairment a positive treatment with donepezil might have been observed. Nonetheless, the participants in the current study were as impaired as those in the prior positive trial. The trend favoring donepezil for the clinician's impression of memory change is interesting, but should not be overinterpreted given the multiple secondary outcome measures that were examined.
Nonetheless, the use of a structured interview to guide the clinician's impression of change may have enhanced the sensitivity of clinicians' ability to detect improvement. This type of outcome should be further explored in future clinical trials for cognitive impairment in MS. Cognitive impairment has proven to be very difficult to treat and with the results of this trial there are no medications that have consistently shown efficacy in MS-associated cognitive impairment.
RCTs with symptomatic therapy using a different AChEI rivastigmine 13 or other agents such as pemoline, 34 amantadine, 34 ginkgo biloba, 35 and amphetamine 36 have also failed to show a consistent benefit on primary cognitive outcomes.
Overall, this was a negative study due to the failure of donepezil compared to placebo to improve memory functioning or other cognitive abilities in the overall sample.
Future studies with more effective agents are clearly needed to treat cognitive impairment in MS. The authors thank the individuals who participated in the study and Rockwell Compounding Associates for supplying the active medication and placebo.
Heitjan, PhD. Supplemental data at www. Presented in part at the annual meeting of the American Academy of Neurology. Statistical analysis was conducted by Dr. Muenz and D. Krupp has served on scientific advisory boards for Acorda Therapeutics Inc. Christodoulou has received research support from Cephalon, Inc.
Melville, W. Scherl, and L. Pai report no disclosures. Muenz serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. Goodman has served as a consultant for and received funding for travel from Acorda Therapeutics Inc.
Wishart serves on a scientific advisory board for and has received funding for travel from Bayer Schering Pharma; and receives research support from Teva Pharmaceutical Industries Ltd. National Center for Biotechnology Information , U. Krupp , MD, C. Christodoulou , PhD, P. Melville , NP, W. Scherl , MS, L. Pai , MS, L. Muenz , PhD, D. He , MS, R. Benedict , PhD, A.
Goodman , MD, S. Rizvi , MD, S. Weinstock-Guttman , MD, H. Westervelt , PhD, and H. Wishart , PhD. Author information Article notes Copyright and License information Disclaimer. From the Department of Neurology L. Muenz and Associates L. Corresponding author. Address correspondence and reprint requests to Dr. Currently, supportive therapies are the cornerstone for the management of Covid Development of a novel class of medication would not be practical within a short span during the public emergency event such as Covid In light of the long history of evolution and the proven efficacy in patients with influenza Duan et al.
Several candidates with possible antiviral effects have been explored Wang et al. Moreover, LH capsules could significantly ameliorate the cardinal symptoms i. However, no existing study has been conducted with a sufficient sample size and prospective randomized designs in multicenter settings. We hypothesized that LH capsules could effectively ameliorate symptoms including fever, cough and fatigue and shorten the duration of viral shedding. On the basis of usual treatment, we sought to explore the safety and efficacy of LH capsules in patients with Covid by conducting a multicenter randomized controlled trial in mainland China.
In this prospective, open-label, randomized controlled trial, we recruited patients with Covid from 23 hospitals in nine provinces throughout mainland China. The study protocol has been approved by the ethics committee of each participating site.
All patients signed written informed consent. We recruited patients with Covid between February 2 nd and February 15 th , Figure 1. Eligibility criteria consisted of the following: 1 Laboratory-confirmed cases with Covid according to the Protocol for Diagnosis and Treatment of Novel Coronarvirus Pneumonia 4 th edition which was issued by the National Health Commission General Office Of The National Health And Health Commission, Panel 1 Being symptomatic either having fever, coughing, or fatigue plus radiologic abnormalities consistent with pneumonia; 3 Patients aged 18 years or greater of either sex.
Diagnostic criteria : At least one criterion in the epidemiology category, plus any two criteria of the clinical manifestations, plus any criterion for pathogen detection. Key exclusion criteria included: 1 respiratory tract bacterial infections due to primary or secondary immunodeficiency, congenital respiratory malformation, congenital heart disease, gastroesophageal reflux, and lung malformation; 2 asthma or other chronic airway diseases needing maintenance therapy, acute respiratory tract bacterial infection i.
See the study protocol in Online Supplement for the withdrawal criteria. The major ingredients of LH consisted of Forsythia suspensa, Lonicera japonica, Ephedra sinica, Isatis indigotica, Pogostemon cablin, Rheum palmatum, Glycyrrhiza uralensis, Dryopteris crassirhizoma, Rhodiola crenulata, Houttuynia cordata, Prunus sibirica , gypsum and 1-menthol see Online Supplement text for details.
LH capsules were provided by the manufacturer, supplied to the participating sites, and dispensed by the designated research nurses after randomization.
The routine treatment of the two groups was determined based on the Diagnosis and Treatment Protocol for Coronavirus Pneumonia Trial version 7 Diagnosis and Treatment Protocol for Coronavirus Pneumonia. Routine treatment generally consisted of the supportive treatment such as oxygen therapy, antiviral medications and symptomatic therapies.
An open-label study was conducted because of the urgency of major public health events. A computer-generated block randomization scheme was used to assign patients to either treatment group or control group.
Each consecutively coded patient was randomly enrolled by the sub-site investigators until the total number of cases allocated to the site was reached. Competitive recruitment was adopted for enrollment. Eligible patients were randomized to receive usual treatment alone based on The Protocol for Diagnosis and Treatment of Novel Coronarvirus Pneumonia 4 th edition control group or the combination of LH capsules 4 capsules thrice daily for 14 days.
Adherence to the study medications, clinical outcomes, the use of concomitant medications and adverse events were recorded. Vital signs, laboratory testing, chest computed tomography and nucleic acid assays of SARS-CoV-2 were evaluated at baseline after randomization and on day In our study, symptom recovery denoted a complete remission of at least one major symptom coughing, fever, or fatigue. An experienced radiologist who was blinded to the study allocation reviewed the chest computed tomography CT images from all patients.
An improvement in chest CT images was defined as a decreased area of infiltration, a decreased area of any radiologic abnormality, or decreased density of the ground-glass opacity or nodules. We defined clinical cure as having met all of the following criteria: recovery of body temperature for more than 3 days, symptom recovery, marked improvement in chest CT images, and two consecutive negative SARS-CoV-2 RNA testing at least one day apart.
The primary endpoint was the rate of symptom fever, fatigue, and coughing recovery. Fever denoted the subaxillary temperature being The magnitude of fatigue and coughing was self-reported by the patients.
Recovery of symptoms was defined as the complete resolution of fever, fatigue and coughing. Secondary endpoints consisted of the time to symptom recovery, the rate of and the time to the recovery of individual symptoms, the proportion of patients with improvement on chest computed tomography, the proportion of patients with clinical cure, the timing and rate of conversion of SARS-CoV-2 RNA assay. No major reports of the adverse events of LH capsules have been documented after marketing Cai et al.
In this study, we recorded the timing, severity, duration, measures and consequence of adverse events, and determined the association with the use of study medications. All patients were included in the full-analysis set FAS after randomization, while patients with major protocol deviation PV were removed from per protocol set PPS. Count percentage was adopted for summarizing the categorical variables, and compared with Chi-square tests. The hazards ratio HR of the events i.
Of the patients who were assessed for eligibility, were excluded due to the lack of symptoms not having fever, fatigue or coughing , SARS-CoV-2 assay findings, or radiologic abnormality on chest CT. Therefore, patients were included in the FAS each in treatment and control group.
The treatment group had a good compliance with the study medication, with the average duration being The study flow chart is shown in Fig. At baseline, most patients were aged above 45 years and males accounted for approximately half of the patients.
Both groups were comparable in terms of the demographic characteristics, vital signs, symptoms and concomitant treatment. The rate of symptom recovery at day 14 was significantly higher in treatment group as compared with control group FAS: Comparison of the rate of symptom recovery in treatment and control group in the full analysis set,.
Comparison of the rate of symptom recovery in treatment and control group in the per protocol set,. Comparison of the time to symptom recovery in treatment and control group in the full analysis set,. Comparison of the time to symptom recovery in treatment and control group in the per protocol set,. A significantly shorter median time to symptom recovery was observed in treatment group as compared with control group FAS: 7 days vs.
Moreover, the treatment group yielded a significantly shorter time to the recovery of fever FAS: 2 days vs. Dynamic changes in the recovery rate in the full analysis set,. Dynamic changes in the recovery rate in the per protocol set,. Shown is the Kaplan Meier curve for the rate of recovery of the symptoms including fever, coughing and fatigue.
Methods: This multicenter, randomized controlled trial included patients older than 18 years with acute uncomplicated diverticulitis.
All the patients underwent abdominal computed tomography. There were 2 strategies of management: hospitalization group 1 and outpatient group 2. The liberal strategy without antibiotics and without the strict requirement for hospital admission is anticipated to be more a more cost-effective approach.
Approximately three quarters of patients with diverticulosis remain asymptomatic throughout their lifetime. Asymptomatic disease is often an incidental finding during imaging or endoscopy for suspicion of colonic disorders. The cause of colonic diverticular disease has not yet been conclusively established. Epidemiologic studies have demonstrated associations between diverticulosis and diets that are low in dietary fiber and high in refined carbohydrates.
Low intake of dietary fiber results in less bulky stools retaining less water and altering gastrointestinal transit time. These factors could increase intracolonic pressure development of pressure zones that create diverticula alongside the vasa recta , and make evacuation of colonic contents more difficult [ 4 ]. Other factors that have been associated with an increased risk of diverticular disease include physical inactivity, constipation, obesity, smoking, and treatment with non-steroidal anti-inflammatory drugs [ 5 , 6 ].
Although much has been learned about the development of diverticula, less is known about the pathogenesis of diverticular inflammation. As discussed earlier, a minority of patients with diverticulosis will develop symptomatic disease. Initial theories of diverticulitis focused on ideas about the pathogenesis of appendicitis; a diverticulum lumen becomes obstructed by a faecolith leading to increased intradiverticular pressure and eventually causing inflammation.
Interest has been generated in the role of altered peridiverticular colonic flora and low-grade chronic inflammation leading to periods of symptomatic disease, similar to periods of exacerbation and remission in inflammatory bowel disease [ 7 ]. The classical clinical presentation of diverticulitis in the western world includes left lower quadrant abdominal pain, tenderness, low-grade fever and leucocytosis.
However, clinical features can be quite variable. For a reliable diagnosis additional imaging is usually necessary. Computed tomography CT is recommended as initial radiological examination. Positive findings in ultrasound US are equally accurate in the diagnosis of diverticulitis. However CT has an advantage in excluding alternative diagnoses and visualising complications of acute diverticulitis needing intervention.
The severity of diverticulitis is often graded with the use of modified Hinchey's criteria, based on CT imaging and on preoperative findings [ 10 , 11 ].
The Ambrosetti's criteria is based only on CT imaging, classifying in "mild" and "severe" diverticulitis. This classification system does not take into account the effects of coexisting conditions on disease severity or outcome [ 12 ].
Hinchey classification and modified Hinchey classification of acute diverticulitis [ 10 , 12 ]. Conservative treatment of mild diverticulitis usually includes careful observation, restriction of oral intake, administration of intravenous fluids, and most patients receive antibiotic therapy.
The majority of patients with mild diverticulitis improve with these conservative measures. It is, however, uncertain whether patients with acute diverticulitis benefit from antibiotics, since evidence from prospective studies or randomized trials is lacking. In a recent review antibiotics are considered mandatory in the treatment of mild diverticulitis [ 15 ].
This advice lacks evidence and is based on experts' opinion only. Anaerobes are commonly isolated organisms in acute diverticulitis. Gram-negative aerobes, especially Escherichia coli, and facultative gram-positive bacteria, such as streptococci, are often cultured as well [ 16 ]. Therefore, broad-spectrum antibiotics are advised. Which antibiotic regimen should be used in diverticulitis is unclear [ 17 , 18 ].
There is scarse evidence that oral antibiotics are as effective as intravenous antibiotics [ 19 ]. Only one study has investigated the use of antibiotics in the treatment of acute uncomplicated diverticulitis. In a retrospective study by Hjern et al [ 20 ], there was no significant benefit from antibiotics in the treatment of mild diverticulitis.
However, this study was hampered by selection bias due to its retrospective design and small patient groups. Moreover, there is major discrepancy in the use of antibiotics between countries in Northwest Europe and other countries, including the United States and United Kingdom.
In the Netherlands and Scandinavian countries antibiotic use for this disease is less common compared to these other countries, where antibiotics are considered mandatory. A Dutch survey showed that many gastro-enterologists prescribed antibiotics in the treatment of acute diverticulitis, but only a minority of Dutch surgeons did so [ 21 ].
Six professional organisations have issued formal guidelines concerning the use of antibiotics in uncomplicated diverticulitis. Five of these guidelines advice the use of antibiotics. Patients should start with intravenous antibiotics and after improvement within days, oral antibiotics are continued to complete a days treatment regimen.
In the Netherlands, the Dutch Antibiotic Policy Committee considers antibiotics not primarily indicated in the treatment of uncomplicated diverticulitis [ 28 ]. Adverse effects of antibiotics are well known, such as allergic reactions and development of antibiotic resistance of bacterial species. Therefore, efforts are made to minimize the use of antibiotics in various fields in clinical medicine [ 29 ].
The lack of evidence for its use necessitates a scientific judgement of the role of antibiotics in the treatment of uncomplicated diverticulitis. Therefore, we initiated a randomized multicenter trial to investigate the effect of antibiotics on disease course in patients with mild acute diverticulitis. The main goal of the present study is to establish whether antibiotics are necessary in the primary treatment of acute mild diverticulitis, and whether a more liberal strategy without initial antibiotics is more cost-effective with respect to time-to-full recovery.
In daily practice there is an ongoing discussion about the relative benefits and disadvantages of a more conservative treatment strategy embracing the use of intravenous antibiotics. This strategy needs hospital admission and is, at least at the start, an in-hospital treatment regimen.
A more liberal strategy, without antibiotics and without the strict requirement of hospital admission, may lead to a shorter hospital stay and reduced costs without compromising outcome. Our hypothesis is that in uncomplicated mild acute diverticulitis, a liberal strategy treatment without antibiotics is a more cost-effective approach than conservative treatment strategy with hospital admission and antibiotics, outcome is measured by time-to-full recovery as primary outcome and diverticulitis-associated complication rates and patient well-being as secondary outcome.
Diagnosis of diverticulitis by US and conditional CT. Diverticulitis-positive US findings are sufficiently accurate compared to CT findings [ 9 ]. In diverticulitis-negative US findings in clinically suspected patients, immediate i. In diverticulitis-positive US findings CT has to be performed within 24 hours. Patients will be randomly allocated to one of the following two treatment strategies: Conservative strategy including immediate antibiotic treatment or liberal strategy without antibiotics supportive measures only.
In the conservative strategy, the use of antibiotics will be intravenously for at least 48 hours after which route of administration can be switched to orally if tolerated. Hospital admission in the liberal strategy is needed for patients with nausea and vomiting, in need of intravenous fluids or for patients with excessive pain not properly reacting to oral pain medication. The interval between start of symptoms of the patient and administration of antibiotics will be registered.
Also the period after inclusion and the actual first administration of antibiotics will be registered. In both strategies CT is repeated in case of clinical deterioration. Also another infectious focus e. All outpatients will daily monitor and register their body temperature. Written and oral instructions at discharge are given, and relevant telephone numbers and contact information will be provided.
For the choice and duration of antibiotics the practice guidelines of the Dutch Antibiotic Policy Committee [ 28 ] and the American Society of Colon and Rectal Surgeons [ 30 ] are followed. In both guidelines, a minimum of days of broad-spectrum antibiotics is advised.
In the present study amoxicillin-clavulanic acid is chosen as broad-spectrum antibiotic; duration of antibiotic treatment is 10 days. The dosage scheme for the study drug is mg i. In case of allergy known or newly diagnosed , a switch will be made to the combination of ciprofloxacine and metronidazole; ciprofloxacine 2 times a day mg i.
The primary endpoint is time-to-full recovery within a follow-up period of 6 months. Changes in health status and valuation over time will be measured using generic and disease specific quality of life questionnaires Euro-Qol 5D, Short Form 36 SF and the Gastro-Intestinal Quality of Life Index Giqli on admission and after 3, 6, 12 and 24 months.
A recurrence is defined as ultrasound- or CT-proven acute diverticulitis after complete resolution of symptoms more than 1 month after initial discharge from hospital. If a patient dies during follow-up, the reason for death will be recorded as related or unrelated to diverticular disease. Computerized block randomization for allocation of treatment group, stratified for center and for Hinchey 1a and 1b, will take place after all inclusion and exclusion criteria have been verified and informed consent has been obtained.
A standardized case record from CRF will be used. This CRF is partially web-based via a secured internet module. A non-inferiority design was chosen.
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