Efficacy and safety of Chinese herbal medicine versus Lopinavir-Ritonavir in adult patients with coronavirus disease 2019: A non-randomized controlled trial

BackgroundTreatments for coronavirus disease 2019 (COVID-19) are limited by suboptimal efficacy.MethodsFrom January 30, 2020 to March 23, 2020, we conducted a non-randomised controlled trial, in which all adult patients with laboratory-confirmed COVID-19 were assigned to three groups non-randomly and given supportive treatments: Group A, Lopinavir-Ritonavir; Group B, Huashi Baidu Formula (a Chinese medicineformula made by the China Academy of Chinese Medical Sciences to treat COVID-19, which is now in the clinical trial period) and Lopinavir-Ritonavir; and Group C, Huashi Baidu Formula. The use of antibiotics, antiviruses, and corticosteroids was permitted in Group A and B. Traditional Chinese medicine injections were permitted in Group C. The primary outcomes were clinical remission time (interval from admission to the first time the patient tested negatively for novel coronavirus or an obvious improvement was observed from chest CT) and clinical remission rate (number of patients whose clinical time was within 16 days/total number of patients).ResultsA total of 60 adult patients with COVID-19 were enrolled at sites in Wuhan, China, and the sample size of each group was 20. In Groups A, B and C, the clinical remission rates were 95.0%%(19/20), 100.0%%(20/20) and 100.0%%(20/20), respectively. Compared with Groups A and B, the clinical remission time of Group C was significantly shorter (5.9 days vs. 10.8 days, p < 0.05; 5.9 days vs. 9.7 days, p < 0.05). There was no significant difference among Groups A, B, and C in terms of the time taken to be released from quarantine. The clinical biochemical indicators and safety indexes showed no significant differences among the three groups.ConclusionsOur findings suggest that Lopinavir-Ritonavir has some efficacy in the treatment of COVID-19, and the Huashi Baidu Formula might enhance this effect to an extent. In addition, superiority was displayed in the treatment of COVID-19 through a combination of the Huashi Baidu Formula and traditional Chinese medicine injection. In future, well-designed prospective double-blinded randomised control trials are required to confirm our findings.     

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p+0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p+0.013; remission: 32.6 vs. 14.6%, p+0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.     

Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial

ObjectivesTo assess the effects of rivastigmine on the core domains of Alzheimer’s disease.DesignProspective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks.Setting45 centres in Europe and North America.Participants725 patients with mild to moderately severe probable Alzheimer’s disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association.ResultsAt the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer’s disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events.ConclusionsRivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer’s disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population.

Key messages

• In a 6 month trial rivastigmine was effective in treating the core cognitive and functional symptoms of patients with mild to moderate Alzheimer’s disease
• Rivastigmine at doses of 6-12 mg/day produces clinically relevant and statistically significant improvements in cognitive and global assessments, and in activities of daily living
• The effects of rivastigmine are dose dependent
• Rivastigmine was well tolerated in this population of elderly patients

     

Efficacy and safety of Abelmoschus manihot for IgA nephropathy: A multicenter randomized clinical trial

Rationale and ObjectiveIgA nephropathy (IgAN) is an important cause for end-stage renal disease worldwide. The treatment for IgAN remains challenging, and few randomized and controlled clinical trials have been conducted to evaluate new therapies. The present study assesses the efficacy and safety of Abelmoschus manihot (AM) in IgAN patients.Study DesignRandomized, non-inferiority, double-blind, double-dummy multicenter trial.Setting and ParticipantsThis trial was designed to recruit 1,600 biopsy-proven IgAN patients (proteinuria between 0.5-3.0 g/d and estimated glomerular filtration rate [eGFR] of ≥ 45 ml/min/1.73 m²) across China.InterventionsThe participants were randomized at 1:1 to AM (2.5 g for three times per day) or losartan potassium (100 mg per day) for 48 weeks.OutcomesThe primary outcome was the change in 24-hour proteinuria from baseline to week 48. The secondary outcomes were the change in eGFR from baseline to week 48, and the incidents of endpoint events (proteinuria ≥ 3.5 g/24 h, doubling of serum creatinine, or receiving renal replacement treatment).ResultsAmong 1,470 randomized patients (mean age, 37.4 [SD, 10.6] years old; 777 [52.9%] were female; mean eGFR, 95.0 [SD, 24.3] mL/min/1.73 m²; mean 24-hour proteinuria, 1.2 [SD, 0.7] g/d), the mean decline in 24-h proteinuria at week 48 was 230 mg and 253 mg in the AM and losartan potassium groups, respectively (P = 0.676). The mean difference in the change in 24-h proteinuria between these two groups was -23.32 mg (95% confident interval: -123.2 to 76.6, p = 0.647). The mean decline in eGFR was 0.41 ml/min/1.73 m² and 0.76 ml/min/1.73 m² in the AM and losartan potassium groups, respectively (p = 0.661). The mean difference in the change in eGFR between these two groups was -0.43 ml/min/1.73 m² (95% confident interval: -1.99 to 1.13, p = 0.589). The incidence of endpoint events was 8.6% in the AM group and 8.2% in the losartan group (p = 0.851).LimitationsThe results of the trial may not be generalized to IgAN patients with a proteinuria of > 3.0 g/d and an eGFR of < 45 ml/min/1.73 m². The long-term benefits of AM in reducing the risk of progressive renal dysfunction remains unclear, based on this 48-week observation.ConclusionAM can be recommended as a promising treatment for IgAN patients.     

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter,randomized, controlled,non-inferiority clinical trial

Despite the current guideline’s recommendation of a timely stepwise intensification therapy, the “clinical inertia”, termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.     

Traditional Chinese medicine shenhuang granule in patients with severe/critical COVID-19: A randomized controlled multicenter trial

BackgroundCoronavirus disease 2019 (COVID-19) is still a pandemic, with a high mortality rate in severe/critical cases. Therapies based on the Shenghuang Granule have proved helpful in viral infection and septic shock.Hypothesis/PurposeThe objective of the current study was to compare the efficacy and safety of the traditional Chinese medicine, Shenhuang Granule, with standard care in hospitalized patients with severe/critical COVID-19.Study Design and MethodsThis was an open-label, multicenter, randomized, controlled clinical trial. At 4 medical centers, a total of 111 severe/critical patients were randomly assigned to receive Shenhuang Granule (SHG group) twice a day for 14 days, in addition to standard care, or to receive standard care alone (Control group). The maximal follow up time was 75 days. The clinical endpoint was clinical improvement and mortality.Results54 patients were assigned to the control group and 57 to the SHG group. The overall mortality was 75.9% (41/54) in the control group, and 38.6% (22/57) in the SHG group (p < 0.01 vs. control). The post hoc analysis showed that in the severe category, the mortality of the control group vs. the SHG group was 58.8% (10/17) vs. 5.3% (1/19) (p < 0.01); while in the critical category, it was 83.8% (31/37) vs. 55.3% (21/38) (p < 0.05). In the severe category, the mortality of patients who eventually received an invasive ventilator in the control vs. the SHG group was 58.8% (10/17) vs. 0 (0/19) (p < 0.01). Administration of SHG was associated with increased lymphocytes and decreased adverse events.ConclusionShenhuang Granule is a promising integrative therapy for severe and critical COVID-19.     

Clinical effectiveness and safety of salvia miltiorrhiza depside salt combined with aspirin in patients with stable angina pectoris: A multicenter,pragmatic, randomized controlled trial

BackgroundSalvia Miltiorrhiza Depside Salt (SMDS) was extracted from Salvia miltiorrhiza with high-quality control of active principles. In 2005, China's FDA approved the use of SMDS for stable angina pectoris (SAP), but the evidence of SMDS combined with aspirin remains unclear.PurposeThe aim of this study was to assess the clinical effectiveness and safety of SMDS combined with aspirin in patients with SAP.MethodsA multicenter, pragmatic, three-armed parallel group and an individually randomized controlled superiority trial was designed. Participants aged 35 to 75 years old with SAP were recruited from four "Class Ⅲ Grade A" hospitals in China. Participants who were randomized into the SMDS group were treated with SMDS by intravenous drip. Participants in the control group received aspirin enteric-coated tablets (aspirin). Participants who were randomly assigned to the combination group received SMDS combined with aspirin. All participants received standard care from clinicians, without any restrictions. The primary outcome measure was thromboelastography (TEG). Secondary outcome measures included symptom score of the Seattle Angina Questionnaire (SAQ), visual analogue scale (VAS) score of traditional Chinese medicine (TCM) symptoms, platelet aggregation measured by light transmittance aggregometry (LTA), and fasting blood glucose. Effectiveness evaluation data were collected at baseline and ten days after treatment. Researchers followed up with participants for one month after treatment to determine whether adverse events (AEs) or adverse drug reactions (ADRs) such as bleeding tendency occurred. All statistical calculations were carried out with R 3.5.3 statistical analysis software.ResultsA total of 135 participants completed follow-up data on the primary outcome after ten days of treatment. Participants in the SMDS combined aspirin group had the highest improvement rate of sensitivity in AA% [p < 0.001, 95% CI (0.00–0.00)], from 30.6% before treatment to 81.6% after treatment. Participants with drug resistance (AA% < 20%) in the SMDS combined with aspirin group also had the highest sensitivity rate [p < 0.001, 95% CI (0.00–0.00)] after treatment (accounting for 81.0% of the combination group and 60.7% of the sensitive participants). The improvement of TCM symptoms in participants treated with SMDS combined with aspirin was significantly better than that of the aspirin group [MD = 1.71, 95% CI (0.15–3.27), p = 0.032]. There were no significant differences in other indexes (R, TPI, MA, K, CI, α value) of TEG, SAQ, platelet aggregation and fasting blood glucose among the three groups. No bleeding tendency or ADRs occurred in all participants.ConclusionSMDS combined with aspirin is a clinically effective and safe intervention to treat adults aged 35 and older with SAP. This trial shows that SMDS combined with aspirin can significantly improve the sensitivity rate of AA% in TEG and the VAS score of TCM symptoms. Further large samples and high-quality research are needed to determine if certain participants might benefit more from SMDS combined with aspirin. The study protocol was registered in the Clinical Trials USA registry (registration No. NCT02694848).     

Treatment of COVID-19 patients with quercetin: a prospective,single center,randomized, controlled trial

Scientific research continues on new preventive and therapeutic strategies against severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). So far, there is no proven curative treatment, and a valid alternative therapeutic approach needs to be developed. This study is designed to evaluate the effect of quercetin in COVID-19 treatment. This was a single-centre, prospective randomized controlled cohort study. Routine care versus QCB (quercetin, vitamin C, bromelain) supplementation was compared between 429 patients with at least one chronic disease and moderate-to-severe respiratory symptoms. Demographic features, signs, laboratory results and drug administration data of patients were recorded. The endpoint was that QCB supplementation was continued throughout the follow-up period from study baseline to discharge, intubation, or death. The most common complaints at the time of hospital admission were fatigue (62.4%), cough (61.1%), anorexia (57%), thirst (53.7%), respiratory distress (51%) and chills (48.3%). The decrease in CRP and ferritin levels was higher in the QCB group (all Ps were < 0.05). In the QCB group, the increase in platelet and lymphocyte counts was higher (all Ps were < 0.05). QCB did not reduce the risk of events during follow-up. Adjustments for statistically significant parameters, including the lung stage, use of favipiravir and presence of comorbidity did not change the results. While there was no difference between the groups in terms of event frequency, the QCB group had more advanced pulmonary findings. QCB supplement is shown to have a positive effect on laboratory recovery. While there was no difference between the groups in terms of event frequency, QCB supplement group had more advanced pulmonar findings, and QCB supplement is shown to have a positive effect on laboratory recovery/results. Therefore, we conclude that further studies involving different doses and plasma level measurements are required to reveal the dose/response relationship and bioavailability of QCB for a better understanding of the role of QCB in the treatment of SARS CoV-2.     

Efficacy of a Carrageenan nasal spray in patients with common cold: a randomized controlled trial

Background

The common cold is the most widespread viral infection in humans. Iota-carrageenan has previously shown antiviral effectiveness against cold viruses in clinical trials. This study investigated the efficacy of a carrageenan-containing nasal spray on the duration of the common cold and nasal fluid viral load in adult patients.

Methods

In a randomized, double-blind, placebo-controlled trial, 211 patients suffering from early symptoms of the common cold were treated for seven days. Application was performed three times daily with either a carrageenan-supplemented nasal spray or saline solution as placebo with an overall observation period of 21 days. The primary endpoint was the duration of disease defined as the time until the last day with symptoms followed by all other days in the study period without symptoms. During the study, but prior unblinding, the definition of disease duration was adapted from the original protocol that defines disease duration as the time period of symptoms followed by 48 hours without symptoms.

Results

In patients showing a laboratory-confirmed cold virus infection and adherence to the protocol, alleviation of symptoms was 2.1 days faster in the carrageenan group in comparison to placebo (p = 0.037). The primary endpoint that had been prespecified but was changed before unblinding was not met. Viral titers in nasal fluids showed a significantly greater decrease in carrageenan patients in the intention-to-treat population (p = 0.024) and in the per protocol population (p = 0.018) between days 1 and 3/4.

Conclusions

In adults with common cold virus infections, direct local administration of carrageenan with nasal sprays reduced the duration of cold symptoms. A significant reduction of viral load in the nasal wash fluids of patients confirmed similar findings from earlier trials in children and adults.

Trial registration

Current Controlled Trials ISRCTN80148028     

Efficacy and safety of nitazoxanide, albendazole, and nitazoxanide-albendazole against Trichuris trichiura infection: a randomized controlled trial

Background

The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate.

Methodology

The efficacy and safety of a single oral dose of nitazoxanide (1,000 mg), or albendazole (400 mg), and a nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug administered separately on two consecutive days, were assessed in a double-blind, randomized, placebo-controlled trial in two schools on Pemba, Tanzania. Cure and egg reduction rates were calculated by per-protocol analysis and by available case analysis. Adverse events were assessed and graded before treatment and four times after treatment.

Principal Findings

Complete data for the per-protocol analysis were available from 533 T. trichiura-positive children. Cure rates against T. trichiura were low regardless of the treatment (nitazoxanide-albendazole, 16.0%; albendazole, 14.5%; and nitazoxanide, 6.6%). Egg reduction rates were 54.9% for the nitazoxanide-albendazole combination, 45.6% for single albendazole, and 13.4% for single nitazoxanide. Similar cure and egg reduction rates were calculated using the available case analysis. Children receiving nitazoxanide had significantly more adverse events compared to placebo recipients. Most of the adverse events were mild and had resolved within 24 hours posttreatment.

Conclusions/Significance

Nitazoxanide shows no effect on T. trichiura infection. The low efficacy of albendazole against T. trichiura in the current setting characterized by high anthelmintic drug pressure is confirmed. There is a pressing need to develop new anthelmintics against trichuriasis.

Trial Registration

Controlled-Trials.com ISRCTN08336605     

Efficacy and safety of 2-hour urokinase regime in acute pulmonary embolism: a randomized controlled trial

Backgrounds

Urokinase (UK) 2 200 U/kg·h for 12 hours infusion(UK-12 h)is an ACCP recommended regimen in treating acute pulmonary embolism (PE). It is unclear whether this dose and time can be reduced further. We compared the efficacy and safety of 20, 000 U/kg for 2 hours (UK-2 h) with the UK-12 h regime in selected PE patients.

Methods

A randomized trial involving 129 patients was conducted. Patients with acute PE were randomly assigned to receive either UK-12 h (n = 70), or UK-2 h (n = 59). The efficacy was determined by the improvement of right heart dysfunction and perfusion defect at 24 h and 14 d post UK treatment. The bleeding incidence, death rate and PE recurrence were also evaluated.

Results

Similarly significant improvements in right heart dysfunction and lung perfusion defects were observed in both groups. Overall bleeding incidents were low in both groups. Major bleeding directly associated with UK infusion occurred in one patient in the UK-2 h group and one in the UK-12 h group. Mortality rates were low, with one reported fatal recurrent in the UK-12 h group and none in the UK-2 h group. When the rate of bleeding, death and PE recurrence were compared separately in the hemodynamic instability and the massive anatomic obstruction subgroups, no significant difference was found.

Conclusions

The UK-2 h regimen exhibits similar efficacy and safety as the UK-12 h regimen for acute PE.

Trial Registration

Clinical trial registered with http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00799968","term_id":"NCT00799968"}}NCT00799968 (Identifier: {"type":"clinical-trial","attrs":{"text":"NCT 00799968","term_id":"NCT00799968"}}NCT 00799968)     

Effect and safety of Chinese herbal medicine granules in patients with severe coronavirus disease 2019 in Wuhan,China: a retrospective,single-center study with propensity score matching

BackgroundChinese herbal medicine (CHM) has been used for severe illness caused by coronavirus disease 2019 (COVID-19), but its treatment effects and safety are unclear.PurposeThis study reviews the effect and safety of CHM granules in the treatment of patients with severe COVID-19.MethodsWe conducteda single-center, retrospective study on patients with severe COVID-19 in a designated hospital in Wuhan from January 15, 2020 to March 30, 2020. The propensity score matching (PSM) was used to assess the effect and safety of the treatment using CHM granules. The ratio of patients who received treatment with CHM granules combined with usual care and those who received usual care alone was 1:1. The primary outcome was the time to clinical improvement within 28 days, defined as the time taken for the patients’ health to show improvement by decline of two categories (from the baseline) on a modified six-category ordinal scale, or to be dischargedfrom the hospital before Day 28.ResultsUsing PSM, 43 patients (45% male) aged 65.6 (57–70) yearsfrom each group were exactly matched. No significant difference was observed in clinical improvement of patients treated with CHM granules compared with those who received usual (p = 0.851). However, the use of CHM granules reduced the 28-day mortality (p = 0.049) and shortened the duration of fever (4 days vs. 7 days, p = 0.002). The differences in the duration of cough and dyspnea and the difference in lung lesion ratio on computerized tomography scans were not significant.Commonly,patients in the CHM group had an increased D-dimer level (p = 0.036).ConclusionForpatients with severe COVID-19, CHM granules, combined with usual care, showed no improvement beyond usual care alone. However, the use of CHM granules reduced the 28-day mortality rate and the time to fever alleviation. Nevertheless, CHM granules may be associated with high risk of fibrinolysis.