RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial.

Enisamium is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication. We evaluated the clinical efficacy of enisamium treatment combined with standard care in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection were randomly assigned to receive either enisamium (500 mg per dose, four times a day) or a placebo. The primary outcome was an improvement of at least two points on an eight-point severity rating (SR) scale within 29 days of randomization. We initially set out to study the effect of enisamium on patients with a baseline SR of 4 or 5. However, because the study was started early in the COVID-19 pandemic, and COVID-19 had been insufficiently studied at the start of our study, an interim analysis was performed alongside a conditional power analysis in order to ensure patient safety and assess whether the treatment was likely to be beneficial for one or both groups. Following this analysis, a beneficial effect was observed for patients with an SR of 4 only, i.e., patients with moderate COVID-19 requiring supplementary oxygen. The study was continued for these COVID-19 patients. Overall, a total of 592 patients were enrolled and randomized between May 2020 and March 2021. Patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. An analysis of the population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms (n = 33), the median time to improvement was 8 days for the enisamium group and 13 days for the placebo group (p = 0.005). For patients treated within 10 days of the onset of COVID-19 symptoms (n = 154), the median time to improvement was 10 days for the enisamium group and 12 days for the placebo group (p = 0.002). Our findings suggest that enisamium is safe to use with COVID-19 patients, and that the observed clinical benefit of enisamium is worth reporting and studying in detail.

Phytomedicine ELOM-080 in Acute Viral Rhinosinusitis: A Randomized, Placebo-Controlled, Blinded Clinical Trial.

BACKGROUND: ELOM-080 is a phytomedicine approved for the treatment of acute and chronic inflammatory diseases of the respiratory tract, sinusitis, and bronchitis in particular. This prospective, randomized, placebo-controlled, double-blind clinical trial was conducted to assess efficacy and safety of ELOM-080 in the treatment of acute viral rhinosinusitis (AVRS). METHODS: Patients with AVRS received oral treatment (4 × 1 capsule per day) with either ELOM-080 or matching placebo. Primary endpoints were the change in major symptom score (MSS) after 7 and 14 days of treatment assessed by the investigator (MSSINV ). Secondary endpoints were changes in MSS assessed by the patients (MSSPAT ), olfactory function (12-item Sniffin' Sticks), 20-Item Sino-Nasal Outcome Test (SNOT-20 GAV; German adapted version), influence of treatment on viral load, and safety. RESULTS: Four hundred and sixty-three patients were randomized. At day 4, subjective burden of disease (MSS) was significantly ameliorated compared to placebo (p = 0.012). During the first treatment week MSS scores improved about 1 day earlier, and 3 days earlier in the second week. Effect with ELOM-080 on mean MSSINV was statistically significantly superior to placebo at visit 3 (p = 0.016) and visit 4 (p = 0.014). In chemosensory testing identification scores improved comparably in both treatments. The improvement of the SNOT-20 GAV was more pronounced in ELOM-080 patients. Treatment with ELOM-080 indicated a potential for decreasing viral load. Both treatments were well tolerated. CONCLUSION: ELOM-080 improves the burden of AVRS significantly in comparison to placebo, remission of symptoms occurred 3 days earlier. The results confirm the efficacy and safety of ELOM-080 for treatment of AVRS. LEVEL OF EVIDENCE: 1 Laryngoscope, 133:1576-1583, 2023.

Vaginal treatment with lactic acid gel delays relapses in recurrent urinary tract infections: results from an open, multicentre observational study.

PURPOSE: The main objective of this open, prospective, multicentre, observational study is to investigate the relapse rate and tolerability of lactic acid gels in adult female patients with recurrent urinary tract infections during routine practice. METHODS: Data were collected from patients undergoing intermittent short courses of intravaginal treatment with lactic acid gel for prevention of recurrent urinary tract infections. The observation period for individual patients was 4 months, aimed at covering four short courses of intravaginal treatment. Data on UTI relapses, tolerability, handling and satisfaction with the treatment were collected via patient diaries and physician assessments and comprised any adverse events (AEs). RESULTS: In total, 72 patients were treated. During the last 12 months prior to the study, patients had on average 4.0 UTIs. In the 4 months after commencing treatment, 63.5% of patients had no recurrence of UTI symptoms. Overall efficacy was rated by physicians as 'excellent/good' for 96.7% of patients. The patients' overall acceptance of local treatment was high with 94.1% being '(very) satisfied'. Similarly, handling was rated as '(very) easy' by 94.2% of patients. The tolerability was assessed as 'highly tolerable/tolerable' by over 98% of patients and physicians alike. Safety analyses reported six AEs of mild intensity, all of which had resolved by the end of the study. CONCLUSION: Treatment with lactic acid gel may increase resilience against uropathogens, possibly preventing the need for antibiotic prevention of recurrent urinary tract infections. Treatment was positively assessed by the patients. The physician assessments corroborate these findings. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: DRKS00016760, 18.02.2019.

Enisamium Reduces Influenza Virus Shedding and Improves Patient Recovery by Inhibiting Viral RNA Polymerase Activity.

Infections with respiratory viruses constitute a huge burden on our health and economy. Antivirals against some respiratory viruses are available, but further options are urgently needed. Enisamium iodide (laboratory code FAV00A, trade name Amizon) is an antiviral, marketed in countries of the Commonwealth of Independent States for the treatment of viral respiratory infections, but its clinical efficacy and mode of action are not well understood. In this study, we investigated the efficacy of enisamium in patients aged between 18 and 60 years with confirmed influenza virus and other viral respiratory infections. Enisamium treatment resulted in reduced influenza virus shedding (at day 3, 71.2% in the enisamium group tested negative versus 25.0% in placebo group [P < 0.0001]), faster patient recovery (at day 14, 93.9% in the enisamium group had recovered versus 32.5% in placebo group [P < 0.0001]), and reduced disease symptoms (from 9.6 ± 0.7 to 4.6 ± 0.9 score points in enisamium group versus 9.7 ± 1.1 to 5.6 ± 1.1 score points in placebo group [P < 0.0001]) compared to those in the placebo group. Using mass spectrometry, and cell-based and cell-free viral RNA synthesis assays, we identified a hydroxylated metabolite of enisamium, VR17-04. VR17-04 is capable of inhibiting influenza virus RNA synthesis and is present in plasma of patients treated with enisamium. VR17-04 inhibits the activity of the influenza virus RNA polymerase more potently than its parent compound. Overall, these results suggest that enisamium is metabolized in humans to an inhibitor of the influenza virus RNA polymerase that reduces viral shedding and improves patient recovery in influenza patients. (This study has been registered at ClinicalTrials.gov under identifier NCT04682444.).

Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial.

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon®) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamium's antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.

Efficacy and safety of a triple active sore throat lozenge in the treatment of patients with acute pharyngitis: Results of a multi-centre, randomised, placebo-controlled, double-blind, parallel-group trial (DoriPha).

OBJECTIVE: The aim of this multi-centre, randomised, double-blind, placebo-controlled trial was to compare the efficacy and safety of the fixed combination of 0.5 mg tyrothricin, 1.0 mg benzalkonium chloride, and 1.5 mg benzocaine (study drug marketed as Dorithricin® ) in repeat dosing for 3 days to match placebo lozenges in the treatment of acute pharyngitis in adults. METHODS: Patients (pts, aged ≥18 years) with acute pharyngitis, ie, non-streptococcal sore throat and moderate-to-severe pain (intensity NRS ≥ 7; VAS ≥ 50) were assigned to study drug (n = 160) or matching placebo (n = 161). Efficacy was assessed by investigator for 2 hours post initial dose (p.i.d.), and 3 days later (Visit 2). Primary efficacy endpoint was the complete resolution of throat pain and difficulty in swallowing at Visit 2 (3 days p.i.d.). Safety and local tolerability were also assessed. RESULTS: Seventy-two hours (p.i.d.), complete resolution of throat pain and difficulty in swallowing were achieved by 44.6% patients on study drug compared with 27.2% patients on placebo (difference 17.4% (CI [5.8%; 29.7%]; 64% improvement [GEE, P = 0.0022]). Until 2 hours p.i.d., reduction in symptoms was better with study drug (P < 0.005). Treatment satisfaction was higher with study drug (patients'/investigators' assessment (78.9%/78.9% vs 55.0%/55.6% for placebo) and was well tolerated, overall safety profile was comparable to placebo. CONCLUSION: The strength of this randomised controlled trial lies in the endpoint of complete remission after 3 days p.i.d., especially in the light of other trials addressing acute pharyngitis. The results of this study show a significant benefit of the study drug over placebo in the treatment of acute pharyngitis. Local treatment with the fixed combination (0.5 mg tyrothricin, 1.0 mg benzalkonium chloride, and 1.5 mg benzocaine) provides a rapid analgesic effect and is effective in relieving both severe throat pain as well as difficulty in swallowing associated with acute pharyngitis leading to a 64% improved complete remission within 72 hours. The triple active combination is a suitable treatment option for patients in the self-management of acute pharyngitis and sore throat. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03323528.

[Clinical efficacy of a herbal drug combination in acute viral rhinosinusitis]. / Klinische Wirksamkeit eines pflanzlichen Kombinationspräparates in der Behandlung der akuten viralen Rhinosinusitis.

BACKGROUND: Acute rhinosinusitis is a frequent inflammatory disease of the mucosa of the nose and paranasal sinuses, usually associated with substantial morbidity having considerable socioeconomic impact. A new herbal drug based on a dry extract of a combination of 5 medicinal drugs (Sinupret® extract Dragees) was tested in a confirmatory trial in patients with acute viral rhinosinusitis. METHODS: 386 patients with symptomatic acute viral rhinosinusitis have been treated with the herbal drug combination (daily dosage 3 × 160 mg) or placebo in a double-blind, randomised, placebo-controlled clinical trial for 15 days. Primary efficacy endpoint was the investigator assessed symptom score at the end of therapy (Major Symptom Score, MSSINV). RESULTS: Treatment with verum lead to a statistically significant, clinically relevant improvement of the symptom score (2.07 ± 0.18 [SEM] vs. 3.47 ± 0.28 score points, p = 0.0001; PP: N = 300) compared to placebo at visit 5. The Number Needed to Treat (NNT) was 7 (PP). Adverse events occurred in 9.8% of the patients treated with verum and 14.1% of the patients treated with placebo. No serious adverse event was observed. The investigators assessed the tolerability of the herbal drug combination predominantly as good and very good (96.4% verum, 95.3% placebo). CONCLUSION: The results prove the efficacy and tolerability of the herbal drug in the indication acute viral rhinosinusitis. Especially due to the favorable benefit-risk ratio the drug represents a suitable treatment alternative.

Herbal drug BNO 1016 is safe and effective in the treatment of acute viral rhinosinusitis.

CONCLUSION: Daily intake of 480 mg of BNO 1016 for 15 days is an effective treatment in acute viral rhinosinusitis. OBJECTIVES: The pooled efficacy data of two similar randomized placebo-controlled clinical trials were analyzed. Safety was evaluated on the basis of the individual trials. METHODS: The efficacy analysis was based on 589 patients. Treatment was performed orally with either 3 × 160 mg BNO 1016 (n = 294) or 3 × placebo (n = 295) for 15 days. In both trials patients underwent five visits to the investigational sites. Symptoms were evaluated according to the EPOS 2012 guideline. Ultrasonography was used to confirm the diagnosis at onset of treatment and the remission of symptoms at the last visit. Efficacy was evaluated by the investigator as the mean major symptom score (MSS) at the end of treatment (visit 5, day 14). Patients reported symptoms and social/emotional consequences of rhinosinusitis using a quality of life questionnaire (SNOT-20 GAV). RESULTS: MSS improved during the treatment period by a mean of 10.02 ± 1.61 score points to 2.47 ± 2.55 for BNO 1016 and of 9.87 ± 1.52 to 3.63 ± 3.63 for placebo. Differences between treatment groups at end of therapy (1.16 ± 3.14 score points; p < 0.0001) and patient-assessed quality of life (p = 0.0015) were statistically significant in favor of BNO 1016.

Treatment of pruritus with topically applied opiate receptor antagonist.

BACKGROUND: Pruritus is the most common and distressing skin symptom, and treatment of itch is a problem for thousands of people. The currently available therapies are not very effective. Therefore there is an urgent need to find new effective topical drugs against itching. OBJECTIVE: We conducted two separate studies to evaluate the efficacy of topically applied naltrexone, an opioid receptor antagonist, in the treatment of severe pruritus. The objective of the first open study was to correlate the clinical efficacy of topically applied naltrexone in different pruritic skin disorders to a change of epidermal mu-opiate receptor (MOR) expression. The second study was a double-blind, placebo-controlled, crossover study on pruritus in atopic dermatitis. METHODS: Initially we performed an open pilot study on 18 patients with different chronic pruritic disorders using a topical formulation of 1% naltrexone for 2 weeks. A punch biopsy was performed in 11 patients before and after the application of the naltrexone cream and the staining of epidermal MOR was measured. Subsequently, a randomized, placebo-controlled, crossover trial was performed with the same formulation. We included in this trial 40 patients with localized and generalized atopic dermatitis with severe pruritus. RESULTS: In the open study more than 70% of the patients using the 1% naltrexone cream experienced a significant reduction of pruritus. More interestingly, the topical treatment with naltrexone caused an increase of epidermal MOR staining. The regulation of the epidermal opioid receptor correlated with the clinical assessment. The placebo-controlled, crossover trial demonstrated clearly that the cream containing naltrexone had an overall 29.4% better effect compared with placebo. The formulation containing naltrexone required a median of 46 minutes to reduce the itch symptoms to 50%; the placebo, 74 minutes. LIMITATIONS: We could only take biopsy specimens in 11 patients, which means that a satisfactory statistical analysis of the changes of epidermal MOR staining was not possible. In addition, there was an insufficient number of patients with nephrogenic pruritus and pruritic psoriasis to draw definitive conclusions. CONCLUSIONS: The placebo-controlled study showed a significant advantage of topically applied naltrexone over the placebo formulation. This finding is supported by the biopsy results from the open studies, showing a regulation of MOR expression in epidermis after treatment with topical naltrexone, especially in atopic dermatitis. These results clearly show potential for topically applied opioid receptor antagonist in the treatment of pruritus. The placebo formulation also had some antipruritic effects. This underlines the importance of rehydration therapy for dry skin in the treatment of pruritus.

Efficacy and tolerability of a fluid extract combination of thyme herb and ivy leaves and matched placebo in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled clinical trial.

STUDY OBJECTIVE: To assess the efficacy and tolerability of a fixed fluid extract combination of thyme and ivy leaves (thyme-ivy combination) and matched placebo in patients suffering from acute bronchitis with productive cough. METHODS: In a double-blind, placebo-controlled, multicentre Phase IV study 361 outpatients with acute bronchitis and > or =10 coughing fits during the day, onset of bronchial mucus production with impaired ability to cough up at a maximum of 2 days prior to recruitment, and a Bronchitis Severity Score (BSS) > or =5 score points were randomly assigned to an 11-day treatment (5.4 ml three times daily) with either thyme-ivy combination syrup (Bronchipret Saft; N=182) or placebo syrup (N=179). After the baseline examination (Visit 1 = Day 0), 2 control examinations were scheduled (Visit 2 = Day 4; Visit 3 = Day 10/end of treatment). The efficacy of study treatment on acute bronchitis was evaluated by the patient's daily counting of coughing fits during the daytime (manual counter), assessment of acute bronchitis related symptoms and by the investigator's assessment of the most important symptoms of acute bronchitis using the BSS. Evaluation of tolerability was based upon adverse event (AE) monitoring, measurement of vital signs as well as the Primary outcome was the change in frequency of coughing fits during daytime on days 7-9 according to patient's accurate daily recording with a manual counter and documentation in the diary. Treatment effects were analysed by analysis of variance (ANOVA) adjusted for centre effects. Due to significant deviation from the "preconditions" of the ANOVA, the Wilcoxon test (stratified by centre) was carried out additionally. RESULTS: The mean reduction in coughing fits on days 7 to 9 relative to baseline was 68.7% under thyme-ivy combination compared to 47.6 % under placebo (p < 0.0001). In the thyme-ivy combination group, a 50% reduction in coughing fits from baseline was reached 2 days earlier compared to the placebo group. The symptoms of acute bronchitis (BSS) improved rapidly in both groups, but regression of symptoms was faster and the responder rates (p < 0.0001) compared to placebo were higher at Visit 2 (83.0% vs 53.9%) and Visit 3 (96.2% vs. 74.7%) under the treatment of thyme-ivy combination. Treatment was well tolerated with no difference in the frequency or severity of AEs between thyme-ivy combination and placebo groups. Severe or serious AEs were not reported. CONCLUSION: Oral treatment of acute bronchitis with thyme-ivy combination for about 11 days was superior to pla-

Bootstrap confidence intervals for costs-of-illness of type 2 diabetes mellitus in Germany.

OBJECTIVE: The Costs of Diabetes in Europe-Type 2 study (CODE-2, SmithKline Beecham plc) measures costs of managing patients with type 2 diabetes mellitus in Germany. The aim of this analysis was to assess the uncertainty of these estimates. DESIGN AND SETTING: The German study arm was based on a sample of 809 patients with type 2 diabetes registered in general practices. Information on socioeconomic data, medical resource use, and clinical data was collected retrospectively for 1998. PATIENTS AND PARTICIPANTS: Patients were grouped in five strata based on their complication status, because of the high impact of complications on costs. To obtain higher credibility of resulting estimates, rare complication groups were overrepresented. To be representative, results were weighted using real prevalence data on complications from a prestudy. MAIN OUTCOME MEASURES AND RESULTS: Within each stratum, results were calculated as arithmetic mean except for demographic data, where the median was applied as input for weighted averages. Because the degree of precision of calculated estimates was not accessible analytically, 95% confidence intervals (CIs) were computed via bootstrapping of 10,000 independent bootstrap samples for each of the calculated estimates. All costs are given for the payers' perspective in German Deutsche Mark (DM). Costs per patient and year for ambulatory care were DM 775 with 95% CI (721-835), for hospitalizations DM 2771 (2242-3342), for drug treatment DM 1496 (1399-1598), and for rehabilitation DM 120 (70-177). The indirect cost was DM 372 (144-645). From the perspective of the sickness funds, cost per patient and year was DM 5539 (5184-5894). Mean HbA1c status was 7.51% (7.37-7.66) with the majority of patients not achieving glycemic control below 6.5%. CONCLUSION: Bootstrap CIs are remarkably narrow. Combining a weighted stratification with bootstrap estimation is an appropriate method for analyzing the weighted average of highly variable and skewed parameters such as costs of diabetes.