Placebo-controlled Randomized Clinical Trial Research Articles

Does application of honey improve surgical outcome in pilonidal cyst excision with secondary intention healing? A prospective randomized placebo-controlled clinical trial

BackgroundPilonidal sinus disease (PSD) is a common chronic inflammatory debilitating illness caused by ingrowth of hair into the skin. Excision and healing by secondary intention is one of the acceptable managements. The post-operative wound care needs frequent and time-consuming follow-ups. Honey is considered to be a traditional remedy for wound healing. The current study aimed at finding if application of honey could improve surgical outcome in pilonidal cyst excision with secondary intention healing.MethodsThis study was designed as a randomized placebo-controlled parallel assignment interventional (clinical trial) study conducted at the surgical ward of Shahid Beheshti Hospital affiliated to the Yasuj University of Medical sciences, Yasuj, Iran, and was consisted of the 48 patients who underwent surgical resection for PSD with secondary intention healing (24 patients in intervention and placebo-controlled groups). The main element of honey medicinal gel was the unheated natural honey of Dena Biosphere Reserve within the Zagros Mountains. Patients' wounds were visited by a surgeon and a nurse on the days 7, 15, 30, 45, 60, and 90 post-operation. The surgical outcomes including the time to complete wound healing, pain intensity, odor, discharge at the site of surgery, use of analgesics, the time of to return to the daily activities, and occurring of any side effects including infection, erythema, and bleeding were all recorded.ResultsIn intervention group, there was significantly lower wound healing time, the lower time to return to the daily activities, lower mean wound volume at the days of 30, 45, 60, and 90 of the follow-up, higher mean post-operative pain level at the days of 15, 30, 45, 60, and 90 of the follow-up, and more usage of analgesics at the days of 15, 30, 45, and 60 of the follow-up. There was no significant difference between intervention and placebo-controlled groups according to the foul smell and fluid discharge at the site of the operation. There were no side effects and complications in both groups of the study.ConclusionsApplication of honey after resection surgery with secondary wound healing is associated with a better surgical outcome and could eventually decrease healing time and reduce duration of return to normal activities, but could increase post-operation pain and analgesic consumption, and no effect on foul smell and discharge.Trial registrationThe project was found to be in accordance to the ethical principles and the national norms and standards for conducting research in Iran with the approval ID and date of IR.YUMS.REC.1399.088 and 2020.05.30 respectively, and is the result of a residency dissertation to get the specialty in general surgery, which has been registered with the research project number 960508 in the Vice Chancellor for Research and Technology Development of Yasuj University of Medical Sciences, Yasuj, Iran, URL: https://ethics.research.ac.ir/EthicsProposalViewEn.php?id=144742

Double-blind placebo-controlled randomized clinical trial to assess the efficacy of montelukast in mild to moderate respiratory symptoms of patients with long COVID: E-SPERANZA COVID Project study protocol

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic continues to affect the globe. After 18 months of the SARS-CoV-2 emergence, clinicians have clearly defined a subgroup of patients with lasting, disabling symptoms. While big strides have been made in understanding the acute phase of SARS-CoV-2 infection, the pathophysiology of long COVID is still largely unknown, and evidence-based, effective treatments for this condition remain unavailable.ObjectivesTo evaluate the efficacy of 10 mg oral montelukast every 24 h versus placebo in improving quality of life associated with mild to moderate respiratory symptoms in patients with long COVID as measured with the COPD Assessment Test (CAT) questionnaire. The secondary objectives will evaluate the effect of montelukast versus placebo on improving exercise capacity, COVID-19 symptoms (asthenia, headache, mental confusion or brain fog, ageusia, and anosmia), oxygen desaturation during exertion, functional status, and mortality.Methods and analysisPhase III, randomized, double-blind clinical trial. We will include 18- to 80-year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow-up will finish 56 days after the start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting the treatment. The following are the secondary outcomes: (a) exercise capacity and oxygen saturation (1-min sit-to-stand test); (b) Post-COVID-19 Functional Status Scale; (c) other symptoms: asthenia, headache, mental confusion (brain fog), ageusia, and anosmia (Likert scale); (d) use of healthcare resources; (e) mortality; (f) sick leave duration in days; and (g) side effects of montelukast.Ethics and disseminationThis study has been approved by the Clinical Research Ethics Committee of the IDIAPJGol (reference number 21/091-C). The trial results will be published in open access, peer-reviewed journals and explained in webinars to increase awareness and understanding about long COVID among primary health professionals.Trial registrationClinicalTrials.govNCT04695704. Registered on January 5, 2021. EudraCT number 2021-000605-24. Prospectively registered.

Cardiovascular and Osteoporosis Protection at Menopause with Lycopene: A Placebo-Controlled Double-Blind Randomized Clinical Trial.

Objective:The effect of lycopene (LycoRed) supplementation was evaluated in healthy postmenopausal women by biochemical markers for cardiovascular protection and osteoporosis protection.Study Settings and Design:This was a multi-centric placebo-controlled double-blind randomized clinical trial that screened 198 postmenopausal women at 21 centers across 12 cities in India. Levels of lycopene, lipid profile, high-risk C-reactive protein, and bone turnover markers: amino-terminal propeptide of Type I collagen (P1NP) and C-terminal telopeptide of Type I collagen (β-CTx) were measured at baseline and 6 months postsupplementation with LycoRed or placebo.Interventions:The study was completed with 57 of the 100 women on LycoRed 8 mg (antioxidant potency is equivalent to 24 mg of lycopene) and 43 placebos for 6 months by randomization.Main Outcome Measures:Rise in serum lycopene and effect of serum lycopene on surrogate markers of cardiovascular health and bone health.Results:LycoRed supplementation increases lycopene levels and P1NP and nonsignificant fall in β-CTx levels in healthy postmenopausal women.Conclusions:Lycopene supplementation in Indian menopausal women may confer protection from osteoporosis as shown by the directional change in the surrogate biochemical markers. This study can form a basis for larger studies with different doses to understand the effect of lycopene to prevent and act as adjuvant treatment on clinical endpoints for cardiovascular disease (CVD) and bone health.

Hyaluronidase following buccal infiltrations of articaine with epinephrine for anesthesia of mandibular first molars: A split-mouth, double-blind, placebo-controlled randomized clinical trial.

Adjunctive hyaluronidase has been widely used for ophthalmic anesthesia; however, in Dentistry, very few studies are available so far. Thus, the present study aimed to evaluate anesthetic outcomes of adjunctive hyaluronidase administration following buccal infiltration of articaine with epinephrine for anesthesia of mandibular first molars. Twenty-eight patients received a buccal supraperiosteal infiltration of 4% articaine with 1:100,000 epinephrine for anesthesia of the mandibular first molars, in a split-mouth approach. Afterward, randomly and using the same technique, they received either 1.0 mL of hyaluronidase (150 UTR/mL) or a placebo solution. Considering patients' pain perceptions provoked by electric and mechanical stimulations, as well as using a pain scale, success rate, action onset time, duration of both pulpal and soft tissue anesthesia, and pain immediately after both punctures and on the 2nd day were assessed. The pulpal anesthetic success rate was 85.7% for hyaluronidase and placebo groups. Soft tissue anesthesia showed a shorter action onset time and a longer duration when hyaluronidase was used; however, there was no difference between the groups regarding action onset time and duration of pulpal anesthesia. Pain at the puncture sites did not differ between the groups, regardless of the time point evaluated. Adjunctive hyaluronidase following buccal infiltration of articaine with epinephrine for mandibular first molars seems not to provide any advantage in anesthetic outcomes in which the nerve fibers are intraosseous (i.e., pulpal anesthesia). On the other hand, soft tissue anesthesia may be improved substantially by using this pharmacological strategy. Key words:Hyaluronidase, local anesthesia, dentistry.

Efficacy and safety of acetylcysteine for the prevention of liver injury in COVID-19 intensive care unit patients under treatment with remdesivir.

Aim:The present double-blinded placebo-controlled randomized clinical trial evaluated prophylactic use of acetylcysteine for the prevention of liver injury in patients with severe COVID-19 pneumonia under treatment with remdesivir.Background:Liver injury is reportedly common in patients with severe COVID-19 pneumonia and can occur not only as a result of disease progression, but as an iatrogenic reaction to remdesivir.Methods:A total of 83 adult patients with severe COVID-19 pneumonia were randomly assigned in parallel groups to receive either acetylcysteine or placebo. All the patients received standard care according to institutional protocols, including remdesivir for a total of five days. One gram acetylcysteine was administered intravenously every 12 hours for 42 patients, and 41 patients received the same volume of 0.9% sodium chloride as placebo (Trial Registration: www.irct.ir identifier, IRCT20210726051995N1). Results:After 5 days, median aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in the acetylcysteine than in the placebo group. Of those who received the placebo, 30 (73.2%), 4 (9.7%), and 3 (7.3%) patients had serum AST levels elevated between 1-2.5, 2.5-5, and over 5 times the upper limit of normal (ULN), respectively; while in the acetylcysteine group, 33 (78.6%) and 0 patients had AST levels between 1-2.5 and over 2.5 times ULN, respectively (p-value=0.037). In the acetylcysteine group, 23 (54.8%), 1 (2.4%), and 1 (2.4%) patient had serum ALT levels elevated between 1-2.5, 2.5-5, and over 5 times ULN, respectively; in the placebo group, however, 24 (58.5%), 7 (17.1%), and 1 (2.4%) patient had serum ALT levels between 1-2.5, 2.5-5, and over 5 times ULN, respectively (p-value=0.073). Conclusion:Intravenous administration of acetylcysteine significantly prevents liver transaminases elevation and liver injury in seriously ill COVID-19 patients treated with remdesivir.

Effect of 0.5% povidone-iodine on the nasopharyngeal and oropharyngeal viral loads in patients with COVID-19: A double-blind placebo-controlled randomized clinical trial.

The povidone-iodine (PvP-I) nasal antiseptic has been shown to completely inactivate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro at variable concentrations. This study was performed to investigate the effect of 0.5% PvP-I nasal drops and oral gargles on the nasopharyngeal and oropharyngeal viral loads in SARS-CoV-2-positive patients. This was a double-blind, placebo-controlled, randomized clinical trial among patients aged ≥18 years with reverse-transcriptase polymerase chain reaction confirmed in the mild to moderate category of SARS-CoV-2 infection. A total of 32 patients were randomly assigned to receive either freshly prepared 0.5% PvP-I solution or distilled water in the form of supervised self-administered 4-5 nasal drops, followed by 20 ml for gargling for at least 30 seconds. The main outcome measure was the mean change in viral titer and Ct values in the nasopharyngeal and oropharyngeal samples at baseline, 5 minutes, and 3 hours post intervention. The mean change in viral titers across the time duration for the test group when compared with the control group was not statistically significant (P = 0.109). However, the mean change in Ct value was found to be borderline statistically significant (P = 0.042). Noticeable differences were noted among the mean viral titers and Ct values in the intervention group when plotted against the time of testing as compared to the control group. PvP-I solution at 0.5% dilution was well tolerated, and no evident side effects were reported. This study shows that 0.5% PvP-I has an effect on reducing nasopharyngeal and oropharyngeal viral loads in COVID-19 patients. This can be of substantial aid for the primary care physicians, especially for the practitioners in remote and resource poor areas.

Probiotic milk drink as adjuvant therapy for the treatment of periodontitis: a randomized clinical trial with 180 days follow-up

The effect of probiotic milk drinks associated with non-surgical periodontal therapy (NSPT) in treating periodontitis was evaluated. A double-blind placebo-controlled randomized clinical trial with patients with periodontitis was conducted. Two groups were used: TG (n=15, test group, probiotic milk drink, Lacticaseibacillus casei 01, 8-9 log CFU/mL) and CG (n=15, control group, conventional milk drink). The milk drinks (100 mL) were consumed once a day at breakfast for 15 days. Both groups also received NSPT, supra and subgingival scaling and root planning per quadrant, and oral hygiene instruction. All patients were clinically evaluated after 30, 90, and 180 days of the last NSPT session. Reductions in clinical attachment loss and probing pocket depth were observed at 30 days in both groups, maintained throughout the follow-up. Decreases in visible plaque index (VPI) and bleeding on probing were observed after probiotic milk drink consumption for 30 days, suggesting an effect provided by probiotics in the control of biofilm and inflammation. However, the impact on VPI was not persistent for more than 30 days, demonstrating the need for regular consumption of the probiotic milk drink. In conclusion, probiotic milk drinks may be used as adjuvant therapy to treat periodontitis.

Comparing the Effect of Aromatherapy With Geranium and Lemon Essential Oil on Situational Anxiety and Physiological Indices of Patients After Coronary Angioplasty

Objective: Postoperative anxiety, such as coronary artery bypass graft surgery, is one of the most common stressors in this group of patients, which can endanger their physical and mental health. This study aimed to compare the effect of aromatherapy with geranium and lemon essential oil on situational anxiety and physiological indices of patients after coronary angioplasty. Methods: In this placebo-controlled randomized clinical trial study, 150 patients undergoing coronary angioplasty were selected by convenience sampling method and obtained their informed written consent. They were randomly divided into three groups: geranium essential oil, lemon essential oil, and the control group. The patients’ anxiety was measured using a situational anxiety questionnaire before and after the intervention. Also, the physiological indices of patients were measured before and after the intervention. Data analysis was performed at descriptive and inferential levels (analysis of covariance and the Kruskal-Wallis test) in SPSS version 22. Results: The effect of aromatherapy with geranium essential oil on reducing anxiety (35.94±8.64) in patients was significantly greater than aromatherapy with lemon essential oil (44.16±8.72) and almond oil (41.14±5.08) (P<0.001). There was no significant difference between the effect of aromatherapy with almond oil (41.14±5.08) and lemon essential oil (44.16±8.72) in reducing patients’ anxiety (P = 0.241). Also, the effect of aromatherapy with geranium essential oil on reducing pulse rate and systolic blood pressure was significantly greater than aromatherapy with lemon essential oil (P <0.001). Conclusion: According to the results of the present study on the effect of aromatherapy on anxiety in patients after angioplasty, it is recommended to use aromatherapy as a complementary and low-risk treatment to reduce anxiety in this group of patients.

Glycated hemoglobin as a surrogate for evaluating the effectiveness of drugs in diabetes mellitus trials: a systematic review and trial-level meta-analysis.

The objective of this study was to investigate whether glycated hemoglobin (HbA1c) is a valid surrogate for evaluating the effectiveness of antihyperglycemic drugs in diabetes mellitus (DM) trials. We conducted a systematic review of placebo-controlled randomized clinical trials (RCTs) evaluating the effect of a treatment on HbA1c (mean difference between groups) and clinical outcomes (relative risk of mortality, myocardial infarction, stroke, heart failure, and/or kidney injury) in patients with DM. Then, we investigated the association between treatment effects on HbA1c and clinical outcomes using regression analysis at the trial level. Lastly, we interpreted the correlation coefficients (R) using the cut-off points suggested by the Institute for Quality and Efficiency in Healthcare (IQWiG). HbA1c was considered a valid surrogate if it demonstrated a strong association: lower limit of the 95 percent confidence interval (95 percent CI) of R greater than or equal to .85. Nineteen RCTs were identified. All studies included adults with type 2 DM. None of the associations evaluated was strong enough to validate HbA1c as a surrogate for any clinical outcome: mortality (R = .34; 95 percent CI -.14 to .69), myocardial infarction (R = .20; -.30 to .61), heart failure (R = .08; -.40 to .53), kidney injury (R = -.04; -.52 to .47), and stroke (R = .81; .54 to .93). The evidence from multiple placebo-controlled RCTs does not support the use of HbA1c as a surrogate to measure the effectiveness of antihyperglycemic drugs in DM studies.

Assessment of Erenumab Safety and Efficacy in Patients With Migraine With and Without Aura

Migraine with aura may respond differently to therapies than migraine without aura. Individuals with migraine with aura have an elevated vascular risk, necessitating a safety assessment of migraine preventive treatments in this patient subgroup. To assess the efficacy and safety profiles of erenumab in patients with migraine with aura. This post hoc secondary analysis evaluated 4 double-blind, placebo-controlled randomized clinical trials that were conducted in treatment centers in North America, Europe, Russia, and Turkey between August 6, 2013, and November 12, 2019. Participants were adults aged 18 to 65 years with episodic migraine or chronic migraine and were randomized to receive either erenumab or placebo. One or more dose of erenumab (70 mg or 140 mg once per month) or placebo was administered by subcutaneous injection in the double-blind treatment phase and open-label or dose-blinded active treatment, and erenumab, 70 mg or 140 mg, was administered once per month by subcutaneous injection during extension phases. Efficacy assessments included change from baseline monthly migraine days (MMDs) and monthly acute migraine-specific medication (AMSM) days. Safety end points included patient incidences of adverse events. Subgroups of patients were categorized according to their history of aura. Of the 2682 patients who were randomized in the 4 trials, 1400 (52.2%) received 1 or more dose of erenumab, 70 mg or 140 mg, and 1043 (38.9%) received placebo. Patients had a mean (SD) age of 41.7 (11.2) years and were predominantly women (n = 2055 [84.1%]). Reductions from baseline MMDs and AMSM days were greater in the erenumab than placebo groups in patients with and without a history of aura during the double-blind treatment phase, and these reductions were maintained throughout the extension phases. In patients with episodic migraine and a history of aura, least-squares mean differences in change from baseline MMDs at week 12 were -1.1 (95% CI, -1.7 to -0.6) in those who received erenumab, 70 mg, and -0.9 (95% CI, -1.6 to -0.2) in those who received erenumab, 140 mg, compared with placebo. In patients with chronic migraine with a history of aura, the least-squares mean differences from placebo treatment were -2.1 (95% CI, -3.8 to -0.5) in those who received erenumab, 70 mg, and -3.1 (95% CI, -4.8 to -1.4) in those who received erenumab, 140 mg. Overall safety profiles were similar across treatment groups regardless of aura history and were comparable to that of placebo over 12 weeks, with no increased emergence of adverse events over time. Results of this secondary analysis of 4 randomized clinical trials showed reduced migraine frequency and AMSM days with erenumab treatment in patients with migraine with and without a history of aura. The findings support the efficacy and safety of using erenumab in this patient population. ClinicalTrials.gov Identifiers: NCT01952574, NCT02456740, NCT02483585, NTCT02066415, and NCT02174861.

Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome

In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses. This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. The primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39.

Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study.

(1) Background: Based on its antiviral activity, anti-inflammatory properties, and functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included 15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = 29.5). We compared mortality rates between patients who received hydroxyzine at hospital admission and those who did not, using a multivariable logistic regression model adjusting for patients’ characteristics, medical conditions, and use of other medications. (3) Results: This analysis showed a significant association between hydroxyzine use and reduced mortality (AOR, 0.51; 95%CI, 0.29–0.88, p = 0.016). This association was similar in multiple sensitivity analyses. (4) Conclusions: In this retrospective observational multicenter study, the use of the FIASMA hydroxyzine was associated with reduced mortality in patients hospitalized for COVID-19. Double-blind placebo-controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results, as are studies to examine the potential usefulness of this medication for outpatients and as post-exposure prophylaxis for individuals at high risk for severe COVID-19.

Effects of sodium selenite and selenium-enriched yeast on cardiometabolic indices of patients with atherosclerosis: A double-blind randomized clinical trial study.

Introduction: Atherosclerosis and related cardiovascular diseases (CVDs) are the major causes of mortality worldwide. The available reports regarding the effects of selenium (Se) supplementation in the realm of atherosclerosis have been equivocal. The present investigation is aimed to assess the effects of sodium selenite and Se-enriched yeast supplementation on metabolic parameters among atherosclerotic patients. Methods: In this double-blind placebo-controlled randomized clinical trial, 60 patients diagnosed with atherosclerosis were randomly allocated into either 200 μg/day selenite, yeast, or placebo groups for eight consecutive weeks. Serum levels of lipid profile and glycemic indices were measured at the baseline and end of the intervention. Results: There were no significant within-or between-group changes in levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), fasting blood sugar, insulin, and homeostatic model assessment for IR throughout the study (P ≥0.05). Only the low density lipoprotein cholesterol (LDL-c) levels were significantly lower in the yeast group in comparison with the placebo group (P = 0.015). Conclusion: The administration of Se-enriched yeast is significantly effective in decreasing LDL-c levels in patients with atherosclerosis. Additional clinical trial studies investigating the effect of Se administration on glucose homeostasis parameters and lipid profiles in atherosclerotic patients are suggested for a more definitive conclusion.

Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction

ObjectiveTo evaluate the efficacy and safety of intranasal theophylline saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction (PVOD). MethodsBetween May 2019 and April 2020, we conducted a double-blinded, placebo-controlled randomized clinical trial of adults with 6–36 months of PVOD. Patients were randomized to nasal theophylline saline irrigation or placebo saline irrigation twice a day for 6 weeks. The primary outcome was the Global Rating of Smell Change. Secondary outcomes were changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS). ResultsTwenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients. ConclusionsWhile safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects.

Effect of atorvastatin on serum periostin and blood eosinophils in asthma - a placebo-controlled randomized clinical trial.

ObjectiveTo investigate the effect of atorvastatin on serum periostin level and blood eosinophil count in patients with asthma.MethodsPatients diagnosed with asthma were enrolled and randomised into an intervention or placebo group, to receive 40 mg atorvastatin or similar placebo, daily, for 8 weeks. Spirometry was performed at baseline, and at the end of weeks 4 and 8; patients also provided blood samples and completed an asthma control test (ACT) at baseline and at the end of week 8. Primary study outcomes were blood eosinophil count and serum periostin levels.ResultsEighty patients completed the study (40 per group). Mean ACT scores were similar between the intervention and placebo groups at baseline (17.95 ± 3.75 versus 17.98 ± 3.77, respectively), and improved in the intervention group (19.88 ± 3.28), but remained unchanged in the placebo group (18.6 ± 3.26) during the treatment period. No statistically significant differences in spirometric changes, blood eosinophil count or serum periostin levels were observed between the groups during the treatment period.ConclusionSpirometric parameters and inflammatory markers did not change significantly in response to atorvastatin treatment, and did not differ between the placebo and intervention groups.

Clinical evaluation of antiseptic mouth rinses to reduce salivary load of SARS-CoV-2

Most public health measures to contain the COVID-19 pandemic are based on preventing the pathogen spread, and the use of oral antiseptics has been proposed as a strategy to reduce transmission risk. The aim of this manuscript is to test the efficacy of mouthwashes to reduce salivary viral load in vivo. This is a multi-centre, blinded, parallel-group, placebo-controlled randomised clinical trial that tests the effect of four mouthwashes (cetylpyridinium chloride, chlorhexidine, povidone-iodine and hydrogen peroxide) in SARS-CoV-2 salivary load measured by qPCR at baseline and 30, 60 and 120 min after the mouthrinse. A fifth group of patients used distilled water mouthrinse as a control. Eighty-four participants were recruited and divided into 12–15 per group. There were no statistically significant changes in salivary viral load after the use of the different mouthwashes. Although oral antiseptics have shown virucidal effects in vitro, our data show that salivary viral load in COVID-19 patients was not affected by the tested treatments. This could reflect that those mouthwashes are not effective in vivo, or that viral particles are not infective but viral RNA is still detected by PCR. Viral infectivity studies after the use of mouthwashes are therefore required. (https://clinicaltrials.gov/ct2/show/NCT04707742; Identifier: NCT04707742)

Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest

It is unclear whether administration of calcium has a beneficial effect in patients with cardiac arrest. To determine whether administration of calcium during out-of-hospital cardiac arrest improves return of spontaneous circulation in adults. This double-blind, placebo-controlled randomized clinical trial included 397 adult patients with out-of-hospital cardiac arrest and was conducted in the Central Denmark Region between January 20, 2020, and April 15, 2021. The last 90-day follow-up was on July 15, 2021. The intervention consisted of up to 2 intravenous or intraosseous doses with 5 mmol of calcium chloride (n = 197) or saline (n = 200). The first dose was administered immediately after the first dose of epinephrine. The primary outcome was sustained return of spontaneous circulation. The secondary outcomes included survival and a favorable neurological outcome (modified Rankin Scale score of 0-3) at 30 days and 90 days. Based on a planned interim analysis of 383 patients, the steering committee stopped the trial early due to concerns about harm in the calcium group. Of 397 adult patients randomized, 391 were included in the analyses (193 in the calcium group and 198 in the saline group; mean age, 68 [SD, 14] years; 114 [29%] were female). There was no loss to follow-up. There were 37 patients (19%) in the calcium group who had sustained return of spontaneous circulation compared with 53 patients (27%) in the saline group (risk ratio, 0.72 [95% CI, 0.49 to 1.03]; risk difference, -7.6% [95% CI, -16% to 0.8%]; P = .09). At 30 days, 10 patients (5.2%) in the calcium group and 18 patients (9.1%) in the saline group were alive (risk ratio, 0.57 [95% CI, 0.27 to 1.18]; risk difference, -3.9% [95% CI, -9.4% to 1.3%]; P = .17). A favorable neurological outcome at 30 days was observed in 7 patients (3.6%) in the calcium group and in 15 patients (7.6%) in the saline group (risk ratio, 0.48 [95% CI, 0.20 to 1.12]; risk difference, -4.0% [95% CI, -8.9% to 0.7%]; P = .12). Among the patients with calcium values measured who had return of spontaneous circulation, 26 (74%) in the calcium group and 1 (2%) in the saline group had hypercalcemia. Among adults with out-of-hospital cardiac arrest, treatment with intravenous or intraosseous calcium compared with saline did not significantly improve sustained return of spontaneous circulation. These results do not support the administration of calcium during out-of-hospital cardiac arrest in adults. ClinicalTrials.gov Identifier: NCT04153435.

Lithium and preventing chemotherapy-induced peripheral neuropathy in breast cancer patients: a placebo-controlled randomized clinical trial

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of some chemotherapy regimens. Lithium has been suggested for CIPN in some animal studies. We aimed to study lithium’s preventive effect on CIPN in breast cancer patients treated with taxanes and platinum-based medications.MethodA double-blind placebo-controlled randomized clinical trial (RCT) was implemented on 36 breast cancer patients in two equal-size groups by block randomization. Participants in both groups consumed daily tablets, either placebo or lithium (300 mg), for 5 days in each course of chemotherapy. The tablets were prescribed 1 day before the start of chemotherapy. The electromyography (EMG) and nerve-conduction-velocity (NCV) tests were achieved before the first chemotherapy, 3 and 9 months after the treatment. The changes and signs or symptoms of CIPN, such as numbness, tingling, freezing, sensitivity to touch, muscle weakness, fibrillation, and knee and elbow reflex disorders, were recorded by examination. The trend of outcome changes was compared between two groups during the 9 months of study.ResultsIn both groups, neurologic signs and symptoms were exacerbated during the first 3 months and improved up to the ninth month of study. Results showed significant changes of all EMG-NCV variables during the 9 months of research in each group (P < 0.001), but the interaction of time and group effect was not significant in none of those indices. All symptoms changed significantly over the study time (P < 0.001) without significant statistical difference between the two groups (P=0.352). No side effect was found during the study.ConclusionThe study showed that 300 mg lithium prescription once daily for 5 days might not effectively prevent CIPN in breast cancer patients. Evaluation of lithium effect on CIPN on different cancers in future studies is suggested.Trial registrationIranian Registry of Clinical Trials IRCT20160813029327N10. Registration date: May 16, 2018.

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder

Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. ClinicalTrials.gov Identifier: NCT01928446.

Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a double-blind, placebo-controlled randomized clinical trial

BackgroundPre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period.MethodsWe conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets.Results52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID-19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041).ConclusionsAlthough the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe.Trial registrationClinicalTrials.govNCT04331834. Registered on April 2, 2020.