Immunogenicity and safety of RAZI recombinant spike protein vaccine (RCP) as a booster dose after priming with BBIBP-CorV: a parallel two groups, randomized, double blind trial.

BACKGROUND: The immunity induced by primary vaccination is effective against COVID-19; however, booster vaccines are needed to maintain vaccine-induced immunity and improve protection against emerging variants. Heterologous boosting is believed to result in more robust immune responses. This study investigated the safety and immunogenicity of the Razi Cov Pars vaccine (RCP) as a heterologous booster dose in people primed with Beijing Bio-Institute of Biological Products Coronavirus Vaccine (BBIBP-CorV). METHODS: We conducted a randomized, double-blind, active-controlled trial in adults aged 18 and over primarily vaccinated with BBIBP-CorV, an inactivated SARS-CoV-2 vaccine. Eligible participants were randomly assigned (1:1) to receive a booster dose of RCP or BBIBP-CorV vaccines. The primary outcome was neutralizing antibody activity measured by a conventional virus neutralization test (cVNT). The secondary efficacy outcomes included specific IgG antibodies against SARS-CoV-2 spike (S1 and receptor-binding domain, RBD) antigens and cell-mediated immunity. We measured humoral antibody responses at 2 weeks (in all participants) and 3 and 6 months (a subgroup of 101 participants) after the booster dose injection. The secondary safety outcomes were solicited and unsolicited immediate, local, and systemic adverse reactions. RESULTS: We recruited 483 eligible participants between December 7, 2021, and January 13, 2022. The mean age was 51.9 years, and 68.1% were men. Neutralizing antibody titers increased about 3 (geometric mean fold increase, GMFI = 2.77, 95% CI 2.26-3.39) and 21 (GMFI = 21.51, 95% CI 16.35-28.32) times compared to the baseline in the BBIBP-CorV and the RCP vaccine groups. Geometric mean ratios (GMR) and 95% CI for serum neutralizing antibody titers for RCP compared with BBIBP-CorV on days 14, 90, and 180 were 6.81 (5.32-8.72), 1.77 (1.15-2.72), and 2.37 (1.62-3.47) respectively. We observed a similar pattern for specific antibody responses against S1 and RBD. We detected a rise in gamma interferon (IFN-γ), tumor necrosis factor (TNF-α), and interleukin 2 (IL-2) following stimulation with S antigen, particularly in the RCP group, and the flow cytometry examination showed an increase in the percentage of CD3 + /CD8 + lymphocytes. RCP and BBIBP-CorV had similar safety profiles; we identified no vaccine-related or unrelated deaths. CONCLUSIONS: BBIBP-CorV and RCP vaccines as booster doses are safe and provide a strong immune response that is more robust when the RCP vaccine is used. Heterologous vaccines are preferred as booster doses. TRIAL REGISTRATION: This study was registered with the Iranian Registry of Clinical Trial at www.irct.ir , IRCT20201214049709N4. Registered 29 November 2021.

Mortality and re-fracture rates in low trauma hip fracture.

OBJECTIVES: This study aimed to estimate the incidence rate of re-fracture and all-cause mortality rate in patients with hip fractures caused by minor trauma in the first year following the event. MATERIALS AND METHODS: This is a retrospective cohort study of patients over 50 years of age conducted in a referral hospital located in Tehran (Shafa-Yahyaian). Using the hospital information system (HIS), all patients hospitalized due to hip fractures caused by minor trauma during 2013-2019 were included in the study. We investigated the occurrence of death and re-fracture in all patients one year after the primary hip fracture. RESULTS: A total of 945 patients with hip fractures during a 307,595 person-days of follow-up, were included. The mean age of the participants was 71 years (SD = 11.19), and 533 (59%) of them were women. One hundred forty-nine deaths were identified during the first year after hip fracture, resulting in a one-year mortality rate of 17.69% (95% CI: 15.06-20.77). The one-year mortality rate was 20.06% in men and 15.88% in women. Out of all the participants, 667 answered the phone call, of which 29 cases had experienced a re-fracture in the first year (incidence rate = 5.03%, 95% CI: 3.50-7.24). The incidence rates in women and men were 6.07% and 3.65%, respectively. CONCLUSION: Patients with low-trauma hip fractures have shown a high rate of mortality in the first year. Considering the increase in the incidence of hip fractures with age, comprehensive strategies are needed to prevent fractures caused by minor trauma in the elderly population.

Safety and efficacy of the FAKHRAVAC compared with BBIBP-Corv2 against SARS-CoV-2 in adults: a non-inferiority multi-center trial.

BACKGROUND: We compared Fakhravac and BBIBP-Corv2 vaccines in a phase III trial. METHOD: We conducted a multicenter, parallel-group, active-control, non-inferiority clinical trial with pragmatic considerations assessing the safety and efficacy of Fakhravac and BBIBP-Corv2 vaccines. We started with two randomized double-blind arms and added two non-randomized open-label arms (based on participant preference) because of slow recruitment. The adult population received 0.5 ml (10 µg per dose) intramuscular injections of Fakhravac or BBIBP-Corv-2 vaccines 21 days apart. The primary outcome was the occurrence of PCR-positive symptomatic Covid-19 disease 14 days or more after the second injection. A 10% non-inferiority margin to the reported 72.8% efficacy of BBIBP-Corv2 was assumed. Cox proportional hazard modeling was used to estimate hazard ratios and their 95% confidence intervals. RESULT: We enrolled 24,056 adults in four groups (randomized-Fakhravac: 824, randomized-BBIBP-Corv2: 832; Non-randomized-Fakhravac: 19,429, Non-randomized-BBIBP-Corv2: 2971). All observed local and systemic adverse reactions were generally self-limited and resolved completely. We observed similar Serious Adverse Event (SAE) rates in the BBIBP-Corv2 (2.57, 95% CI 1.33-4.49) and Fakhravac (2.25, 95% CI 1.72-2.89) groups; none of which were related to the vaccines received. We recorded 9815 Medically Attendant Adverse Events (MAAE), 736 of which were categorized as somehow related. The rate of related MAAE in the Fakhravac was similar to the BBIBP-Corv2 groups (0.31 and 0.26 per 1000 person-day) in the randomized and considerably higher (0.24 and 0.07 per 1000 person-day) in the non-randomized arms. We observed 129 (35% of the 365 required by target sample size) events of PCR + symptomatic Covid-19 during four months of active follow-up in the randomized arm, demonstrating that those receiving the Fakhravac vaccine were significantly less likely (HR = 0.69; 95% CI 0.49-0.98) to be diagnosed with PCR + symptomatic Covid-19 compared with those receiving BBIBP-Corv2 vaccine. After adjusting for type I error using the O'Brien Fleming method, the Fakhravac vaccine was non-inferior to the BBIBP-Corv2 (assuming a 10% non-inferiority margin to the reported 72.8% BBIBP-Corv2 vaccine efficacy; HR < 1.35) (One-way test: HR = 0.66; 99.8% CI 0.38-1.15). In the non-randomized arm, the results were inconclusive (HR = 1.23; 95% CI 0.96-1.61). We observed 5 cases of hospitalized Covid-19 in the randomized arm, none of which occurred in the Fakhravac vaccine group. Those receiving the Fakhravac vaccine were four times less likely to go to the hospital because of a Covid-19 diagnosis (HR = 0.24; 95% CI 0.10-0.60). The vaccine efficacy of the Fakhravac vaccine is estimated to be 81.5% (95% CI 81-82.4%). CONCLUSION: Fakhravac inactivated SARS-CoV-2 vaccine has comparable safety and efficacy to the BBIBP-Corv2 vaccine. Trial registration This study was registered with the Iranian Registry of Clinical Trials ( www.irct.ir : IRCT20210206050259N3).

Phase II randomized, double blind, placebo controlled, clinical trial of safety and immunogenicity of an inactivated SARS-CoV-2 vaccine FAKHRAVAC in adults aged 18-70 years.

BACKGROUND: The FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity in a phase II trial. METHODS: We did a phase II, single-centered, randomized, double-blind, placebo-controlled clinical trial of the FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The two parallel groups received two intramuscular injections of either a 10-µg vaccine or a placebo at 2-week intervals. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were compared over the study period of up to 6 months. Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels. RESULTS: Five hundred eligible participants were randomly (1:1) assigned to vaccine or placebo groups. The median age of the participants was 36 years, and 75% were male. The most frequent local adverse reaction was tenderness (21.29% after the first dose and 8.52% after the second dose), and the most frequent systemic adverse reaction was headache (11.24% after the first dose and 8.94% after the second dose). Neutralizing antibody titers two and four weeks after the second injection in the vaccine group showed about 3 and 6 times increase compared to the placebo group (GMR = 2.69, 95% CI 2.32-3.12, N:309) and (GMR = 5.51, 95% CI 3.94-8.35, N:285). A four-fold increase in the neutralizing antibody titer was seen in 69.6% and 73.4% of the participants in the vaccine group two and four weeks after the second dose, respectively. Specific ELIZA antibody response against a combination of S1 and RBD antigens 4 weeks after the second injection increased more than three times in the vaccine compared to the placebo group (GMR = 3.34, 95% CI 2.5-4.47, N:142). CONCLUSIONS: FAKHRAVAC® is safe and induces a significant humoral immune response to the SARS-CoV-2 virus at 10-µg antigen dose in adults aged 18-70. A phase III trial is needed to assess the clinical efficacy. TRIAL REGISTRATION: Trial Registry Number: Ref., IRCT20210206050259N2 ( http://irct.ir ; registered on 08/06/2021).

Data management system for diabetes clinical trials: a pre-post evaluation study.

BACKGROUND: Data management system for diabetes clinical trials is used to support clinical data management processes. The purpose of this study was to evaluate the quality and usability of this system from the users' perspectives. METHODS: This study was conducted in 2020, and the pre-post evaluation method was used to examine the quality and usability of the designed system. Initially, a questionnaire was designed and distributed among the researchers who were involved in the diabetes clinical trials (n = 30) to investigate their expectations. Then, the researchers were asked to use the system and explain their perspectives about it by completing two questionnaires. RESULTS: There was no statistically significant differences between the users' perspectives about the information quality, service quality, achievements, and communication before and after using the system. However, in terms of the system quality (P = 0.042) and users' autonomy (P = 0.026), the users' expectations were greater than the system performance. The system usability was at a good level based on the users' opinions. CONCLUSION: It seems that the designed system largely met the users' expectations in most areas. However, the system quality and users' autonomy need further attentions. In addition, the system should be used in multicenter trials and re-evaluated by a larger group of users.

The efficacy of corticosteroids therapy in patients with moderate to severe SARS-CoV-2 infection: a multicenter, randomized, open-label trial.

BACKGROUND: We performed a multicenter, randomized open-label trial in patients with moderate to severe Covid-19 treated with a range of possible treatment regimens. METHODS: Patients were randomly assigned to one of three regimen groups at a ratio of 1:1:1. The primary outcome of this study was admission to the intensive care unit. Secondary outcomes were intubation, in-hospital mortality, time to clinical recovery, and length of hospital stay (LOS). Between April 13 and August 9, 2020, a total of 336 patients were randomly assigned to receive one of the 3 treatment regimens including group I (hydroxychloroquine stat, prednisolone, azithromycin and naproxen; 120 patients), group II (hydroxychloroquine stat, azithromycin and naproxen; 116 patients), and group III (hydroxychloroquine and lopinavir/ritonavir (116 patients). The mean LOS in patients receiving prednisolone was 5.5 in the modified intention-to-treat (mITT) population and 4.4 days in the per-protocol (PP) population compared with 6.4 days (mITT population) and 5.8 days (PP population) in patients treated with Lopinavir/Ritonavir. RESULTS: The mean LOS was significantly lower in the mITT and PP populations who received prednisolone compared with populations treated with Lopinavir/Ritonavir (p = 0.028; p = 0.0007). We observed no significant differences in the number of deaths, ICU admission, and need for mechanical ventilation between the Modified ITT and per-protocol populations treated with prednisolone and Lopinavir/Ritonavir, although these outcomes were better in the arm treated with prednisolone. The time to clinical recovery was similar in the modified ITT and per-protocol populations treated with prednisolone, lopinavir/ritonavir, and azithromycin (P = 0.335; P = 0.055; p = 0.291; p = 0.098). CONCLUSION: The results of the present study show that therapeutic regimen (regimen I) with low dose prednisolone was superior to other regimens in shortening the length of hospital stay in patients with moderate to severe COVID-19. The steroid sparing effect may be utilized to increase the effectiveness of corticosteroids in the management of diabetic patients by decreasing the dosage.

The effect of Cornus mas extract consumption on bone biomarkers and inflammation in postmenopausal women: A randomized clinical trial.

The drastic decrease in estrogen levels in menopausal women can elevate bone resorption and osteoporosis. Cornus mas extract (C. mas extract) is a potential candidate for treating menopausal-related bone complications because of its phytoestrogen and anti-inflammatory contents. It was an interventional double-blind placebo-controlled randomized study. Eighty-four women aged 45-60 years old were randomly allocated to either the extract group receiving 3 capsules of 300 mg C. mas extract or the placebo group receiving 3 capsules of 300 mg of starch powder per day for 8 weeks. Then, venous blood was used to measure bone-specific alkaline phosphatase (BAP), osteocalcin (OC), C-terminal telopeptide (TC) as well as serum levels of PTH and hsCRP. Our results indicated the decrease in alkaline phosphatase, PTH, and as an inflammation biomarker, hsCRP, between two groups at the end of the study. No statistically significant difference was observed in telopeptide C, osteocalcin, and calcium between the placebo and extract groups after 8 weeks of intervention. In conclusion, the results indicate that the C. mas extract supplement of 900 mg/day may decrease levels of BAP, PTH, and hsCRP. However, this intervention had no beneficial effect on OC and TC in healthy postmenopausal women.

Scientometric measures of prospectively registered clinical trials over time: A comparison of IRCT and ClinicalTrials.gov.

Background: Iranian Registry of Clinical Trials (IRCT) started as a primary registry in 2008. We examined the characteristics and scientometric measures of prospectively registered clinical trials in IRCT over time and compared them with that of ClinicalTrials.gov. Methods: We selected eligible trial records between 2008 and 2016 from the IRCT database. We assessed their characteristics and the journal metrics of ensuing outputs over the study period and compared our findings with the corresponding information from ClinicalTrials.gov reported by Magdalena Zwierzyna et al. and a random sample of trials registered with this registry. We used the chi-square test for comparison of proportions and Mann-Whitney U test for comparison of medians. P-value <0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics V.22. Results: 1751 prospectively registered clinical trials were eligible for analysis, of which 1526 (87%) had parallel-group design, 1541 (88%) reported to be randomized, 753 (43%) used double-blinding design, 485 (%27.7) had sample size more than 100, 1313 (75%) completed within a year, 1539 (87.9%) were single centered and 1529 (87.3%) exclusively used public money. Comparison with ClinicalTrials.gov showed that they are less likely to have multiple centers, funded by private sectors, continue beyond one year; and more likely to be randomized, double-blind and get published as a paper. The sample sizes were similar. Journal scientometric measures remained constant over the study period for both databases but were higher in ClinicalTrials.gov (median SJR=1.67, IQR=1.1-3.23) compared with IRCT (median SJR=0.58, IQR=0.34-0.91). Conclusion: Our findings suggest that clinical trials registered in IRCT are predominantly investigator-initiated studies with acceptable methodological features and high publication rate albeit in journals with substantially lower scientometric measures compared with that of ClinicalTrials.gov. Journal metric indices remained constant despite an increase in the number of registrations in IRCT.

Challenges in the design, conduct, analysis, and reporting in randomized clinical trial studies: A systematic review.

Background: Randomized clinical trials have been considered as the gold standard for evaluating the effectiveness and safety of medical interventions; however, there are major barriers to their design, conduct, analysis, and reporting. They are multidisciplinary and involve different steps and face a variety of challenges that may vary from one country to another. The aim of this study was to provide a comprehensive presentation of the challenges of clinical trial studies in different steps including design, conducting, analysis, and reporting. Methods: In this study, all original articles conducted during 1991-2017 that reviewed the barriers to clinical trial studies at one of the steps of design, conducing, analysis, and reporting of the results in Medline (through PubMed), Embase, Web of Sciences, Scopus, and Google Scholar were considered. The searched keywords were as follow: challenges, barriers, and randomized clinical trial. Results: The following barriers in different steps of randomized clinical trials were identified: general barriers include insufficient knowledge and understanding of clinical research and research methodology, barriers to ethical and regulatory systems, and lack of funding. The investigator-initiated trials may face similar problems to those of sponsor-initiated trials, such as handling regulatory systems, administrative and financial issues, multiple languages, and different patient compensation approaches. The challenge related to design was poor planning. Other challenges were lack of manpower and financial resources, inappropriate statistical methods for analysis (analysis challenges), and challenges related to reporting which include selective reporting. Conclusion: Based on the results of this systematic review, the most important challenges were barriers related to handling ethical and regulatory systems, patient recruitment, and lack of budget and skilled staff for conducting clinical trials. Training to improve the quality of randomized clinical trial studies in different steps and levels was the most important recommendation in these studies.

Determination of effective factors on geographic distribution of the incidence of colorectal cancer in Tehran using geographically weighted Poisson regression model.

Background: This study aimed to determine effective factors on geographic distribution of the Incidence of Colorectal Cancer (CRC) in Tehran, Iran using Geographically Weighted Poisson Regression Model. Methods: This ecological study was carried out at neighborhood level of Tehran in 2017-2018. Data for CRC incidence was extracted from the population-based cancer registry data of Iran. The socioeconomic variables, risk factors and health costs were extracted from the Urban HEART Study in Tehran. Geographically weighted Poisson regression model was used for determination of the association between these variables with CRC incidence. GWR 4, Stata 14 and ArcGIS 10.3 software systems were used for statistical analysis. Results: The total number of incident CRC cases were 2815 in Tehran from 2008 to 2011, of whom, 2491 cases were successfully geocoded to the neighborhood. The median IRR for local variables were : unemployed people over 15 year old (median IRR: 1.17), women aged 17 years or older with university education (median IRR: 1.17), women head of household (median IRR: 1.06), people without insurance coverage (median IRR: 1.10), households without daily consumption of milk (median IRR: 0.85), smoking households (median IRR: 1.07), household's health expenditure (median IRR: 1.39), disease diagnosis costs (median IRR: 1.03), medicines costs of households (median IRR: 1.05), cost of the hospital (median IRR: 1.09), cost of medical visits (median IRR: 1.27). Conclusion: The spatial variability was observed for most socioeconomic variables, risk factors and health costs that had effects on CRC incidence in Tehran. Spatial variability is necessary when interpreting the results and utterly helpful for implementation of prevention programs.