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Key Outcomes | PMC10034662 |
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Diagnostic Status | The CIS-R | PMC10034662 |
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Primary Outcome | Depression | Depression symptom severity (PHQ-9) | PMC10034662 |
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Safety | ADVERSE EVENTS | Serious adverse events were recorded in line with Health Research Authority (England) guidelines and judged by an independent monitor as study related or study unrelated. An adapted version of the Lasting Negative Effects Questionnaire was completed at 42 weeks. | PMC10034662 |
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Health Economic Evaluation | Health-related quality of life was assessed at baseline, 16 weeks, and 42 weeks using the recently developed 5-level version EuroQoL (EQ-5D-5L) to maximize sensitivity. | PMC10034662 |
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Secondary Outcomes | anxiety | Generalized anxiety, well-being, functioning, and mindfulness were measured at baseline, 16 weeks and 42 weeks. See the eMethods in | PMC10034662 |
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Procedure | depression | HOLIDAYS | Referrals were from the IAPT program. People experiencing depression were also invited through general practitioners and social media to self-refer to IAPT and, if eligible for self-help treatment in IAPT, were assessed for eligibility. Potential participants had a copy of the participant information sheet and the opportunity to ask questions before giving informed consent.Participants completed measures online (with postal option). Participants completed baseline measures with a research assistant present in person or by phone. At the end of baseline, eligible participants were randomized. Participants were then sent their allocated self-help workbook and asked to guide themselves through with 6 Psychological Well-being Practitioner (PWP) 30-minute to 45-minute support sessions. Up to 16 weeks was given to complete each intervention to allow for breaks and holidays. The PWP support sessions were offered by phone or face-to-face, depending on service practice and, where services offered a choice, participant preference.Participants had the option to complete assessments at 16 weeks and 42 weeks with a research assistant present in person or by phone or on their own. Where 16-week and 42-week assessments were not completed, weekly reminders were sent for up to 1 month. | PMC10034662 |
Randomization and Masking | Participants were randomly assigned using Sealed Envelope | PMC10034662 |
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Supervision and Monitoring | In IAPT, PWPs are graduates (in any discipline) who complete a year-long CBT-SH training. The 69 study PWPs received training to support MBCT-SH for this study. Training in the study involved qualified PWPs completing an MBCT course in person or using the workbook and then attending a 2-day MBCT-SH training. As is standard in MBCT, PWPs were encouraged to cultivate their own mindfulness practice.The same PWPs delivered both interventions to account for therapist effects. | PMC10034662 |
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Lived-Experience Involvement | depression | RECRUITMENT | People with lived experience of depression and of CBT and mindfulness were involved in study development. This included contributing to the project proposal, recruitment materials, and qualitative data collection and analysis. A Lived Experience Advisory Panel of 6 members was led by the lived experience coapplicant who also helped train PWPs. See eAppendix 2 in | PMC10034662 |
Statistical Analysis | The study was powered to detect a between-group standardized effect of 0.36 at 16 weeks on the primary outcome. This was based on the difference between the reported between-group effect of CBT-SH (0.42) | PMC10034662 |
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Clinical Outcomes | depressive | REGRESSION | The primary analysis of clinical outcomes was an intention-to-treat (ITT) between-group comparison of MBCT-SH to CBT-SH at 16 weeks and 42 weeks using a linear mixed model with treatment group, time (16 weeks or 42 weeks), and a treatment group × time interaction as fixed factors and site and baseline PHQ-9 score as covariates. Participants were included as random effects. The ITT sample was composed of all participants and observed data, and individuals were analyzed as per randomization allocation. Secondary outcomes were estimated using linear mixed models and contrasts. Secondary per-protocol analyses were conducted for intervention completers (attending 3 or more PWP sessions). As a sensitivity check, missing data were assumed to be missing at random and dealt with using multiple imputation by chained equations and compared with observed-cases findings. Multilevel logistic regression compared treatment completion between groups controlling for center and baseline PHQ-9 score and are presented as adjusted odds ratios. Mediation analyses tested whether treatment completion mediated depressive symptom severity outcomes. Unplanned subgroup analyses were conducted to estimate PHQ-9 treatment effects at 16 weeks by sex, race and ethnicity, and medication use. Statistical analysis was conducted using Stata version 16 (StataCorp). | PMC10034662 |
Health Economic Analysis | The UK National Health Service or personal social services perspective preferred by the National Institute for Health and Care ExcellenceCost-effectiveness was assessed through the calculation of incremental cost-effectiveness ratios explored in terms of quality-adjusted life-years (QALYs) calculated from the EQ-5D-5L. | PMC10034662 |
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Results | In total, 600 people were assessed for eligibility. Of 410 randomized participants, 255 (62.2%) were female, and the median (IQR) age was 32 (25-45) years. Of the 410 participants, 204 were allocated to MBCT-SH and 206 to CBT-SH between November 24, 2017, and January 31, 2020, with final follow-up on December 15, 2020. A total of 17 participants (4.1%) were Asian or Asian British; 15 (3.7%) were Black, African, Caribbean, or Black British; 20 (4.9%) were mixed/multiple ethnic groups; 351 (85.6%) were White British or White Irish; 5 (1.2%) were other ethnic groups; and 2 (0.5%) preferred not to say. Primary outcome data were available for 155 of 204 MBCT-SH participants (76.0%) and 154 of 206 CBT-SH participants (74.8%). At 42 weeks, 146 MBCT-SH participants (71.6%) and 149 CBT-SH participants (72.3%) provided data. See | PMC10034662 |
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CONSORT Trial Profile | CBT-SH indicates cognitive behavioral therapy self-help; CIS-R, Clinical Interview Schedule–Revised; IAPT, Improving Access to Psychological Therapies; ITT, intention to treat; MBCT-SH, mindfulness-based cognitive therapy self-help; PHQ-9, Patient Health Questionnaire. | PMC10034662 |
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Mean Costs per Participant Between Baseline and 42-Week Follow-up | Abbreviations: NA, not applicable; QALYs, quality-adjusted life years.Adjusted by baseline variable of interest plus baseline utility, baseline PHQ-9, site, and follow-up time.Cost-effectiveness analysis found MBCT-SH dominated CBT-SH—it generated better outcomes for lower cost. | PMC10034662 |
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Cost-Effectiveness Acceptability Curve for Mindfulness-Based Cognitive Therapy Self-help (MBCT-SH) vs Cognitive Behavioral Therapy Self-help at 42 Weeks Postrandomization | QALY indicates quality-adjusted life-year. | PMC10034662 |
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Discussion | depressive, depression, anxiety, CBT-SH | ADVERSE EVENTS, SECONDARY, BLIND | The primary hypothesis was supported: practitioner-supported MBCT-SH was superior to practitioner-supported CBT-SH in reducing depressive symptom severity at postintervention follow-up. In addition, PWP-supported MBCT-SH was found to be cost-effective compared with PWP-supported CBT-SH due to significantly lower total costs alongside similar QALY outcomes.No serious adverse events attributable to the interventions were reported, and lasting negative effects were uncommon and similar in each arm, in line with previous psychological intervention research.This study found that practitioner-supported MBCT-SH is not only more clinically effective than CBT-SH but also more cost-effective. On average, the CBT-SH intervention cost health services £526 ($631) more per participant than the MBCT-SH intervention over the 42-week follow-up. A substantial proportion of this additional cost (approximately 50%) was accounted for by additional face-to-face individual psychological therapy accessed by CBT-SH participants outside of the study intervention. If practitioner-supported MBCT-SH were offered as an alternative, it might be expected that some of the cost savings would fall on health services, potentially supporting increased treatment capacity.Findings corroborate and extend findings from previous RCTs of MBCT-SH.In relation to secondary outcomes, we also found superior effects of supported MBCT-SH over CBT-SH on anxiety symptom severity at postintervention. At 42-week follow-up, between-group effects on depressive and anxiety symptom severity remained in the hypothesized direction but were nonsignificant. This could in part by explained by the greater postintervention psychological therapy accessed by CBT-SH participants. Lack of effects at postintervention and follow-up on all but the nonjudge mindfulness subscale was not expected. This potentially suggests that MBCT-SH relative to CBT-SH is effective at improving the specific mindfulness capacity to be accepting of unpleasant thoughts and emotions but not other aspects of the mindfulness construct. Existing measures of mindfulness may need reevaluating to improve their ability to discriminate the specific effects of MBCT.This trial recruited across multiple services representing a broad range of geographic, rural and urban, and sociodemographic characteristics, suggesting that findings can be generalized to other psychological therapy services. The research team included researchers from a predominantly CBT background, an MBCT background, and from both traditions, reducing allegiance effects. Assessments were conducted blind to treatment allocation, participants were not informed about the hypothesized direction of effects, and data analysis was conducted with treatment arm masked, all reducing risk of bias. This pragmatic trial was conducted in the real-world public mental health setting, training practitioners within services to deliver MBCT-SH. This points to feasibility of implementation of practitioner-supported MBCT-SH for depression.Our findings suggest that offering practitioner-supported MBCT-SH as an intervention for mild to moderate depression would improve outcomes and save money compared with practitioner-supported CBT-SH. Therefore, practitioner-supported MBCT-SH should be routinely offered as an intervention for mild to moderate depression alongside practitioner-supported CBT-SH. This would increase patient choice, as currently only CBT-SH is typically recommended in treatment guidelines for depression.Future research should aim to corroborate and extend findings, for example by including more frequent assessments to allow trajectory and mechanisms of change to be more fully explored. Implementing research findings in routine clinical practice is notoriously challenging. Future research should examine factors enabling successful implementation of practitioner-supported MBCT-SH to expedite the pathway to patient benefit and to ensure fidelity to the approach. Future research should include evaluating the relative effectiveness and acceptability of different formats of MBCT-SH for depression, including book-based (as in the current study) and online | PMC10034662 |
Limitations | This study has limitations. Confidence in findings is limited by study dropout. However, this concern is partially mitigated by similar rates of study dropout across arms (eResults and eTables 1 and 2 in | PMC10034662 |
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Conclusions | depressive, depression | In conclusion, this study found that a novel intervention, practitioner-supported MBCT-SH, was clinically superior in targeting depressive symptom severity at postintervention and cost-effective compared with the criterion standard of practitioner-supported CBT-SH for adults experiencing mild to moderate depression. This has important implications for the more than 100 000 people currently offered CBT-SH for depression in the IAPT program each year | PMC10034662 |
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Background | We compared Fakhravac and BBIBP-Corv2 vaccines in a phase III trial. | PMC10355035 |
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Method | DISEASE, RECRUITMENT | 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. | PMC10355035 |
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Result | ADVERSE REACTIONS, ADVERSE EVENT, EVENTS | 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%). | PMC10355035 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12985-023-02121-z. | PMC10355035 |
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Keywords | PMC10355035 |
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Background | VIRUS | Fakhravac is an inactivated SARS-CoV-2 vaccine based on the SARS-CoV-2 IR-sb2-01 strain cultured in a Vero cell line. The IR-sb2-01 strain was isolated from hospitalized patients who had severe clinical illnesses. The virus was inactivated by formaldehyde and emulsified with aluminum hydroxide adjuvant to formulate the final vaccine product [The inactivated vaccines are the oldest and have been used for almost a century. They are safe and can be easily stored and shipped at 2–8 °C, making them suitable for many low-income countries and places with limited cold-storage capacity [The phase I and II trial of Fakhravac compared to the placebo was conducted in early 2021. The studies showed that it is generally safe and induces strong specific antibody responses against SARS-CoV-2 spike antigens in adults 18 years and older. Given the availability of a licensed vaccine, the use of a placebo was no longer justified [ | PMC10355035 |
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Method | PMC10355035 |
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Study design | RECRUITMENT | We conducted a multicenter, parallel-group, active-control, non-inferiority clinical trial with pragmatic considerations comparing the safety and efficacy of Fakhravac and BBIBP-Corv2 vaccines. It started with two randomized and double-blind arms. We added two additional non-randomized and open-label arms of Fakhravac and BBIBP-Corv2 because of slow recruitment (Comprehensive cohort study design). Participants who declared unwillingness to randomization were retained in the study, but their vaccine choice was based on their preference [This study was conducted in collaboration with the Iran University of Medical Science (IUMS) clinical trial center as the academic contract research organization (CRO). The National Research Ethics Committee approved the study protocol (IR. NREC.1400.006, 24th August 2021). | PMC10355035 |
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Participants | alcohol abuse, angioedema, allergic diseases | ACUTE FEBRILE ILLNESS, ANGIOEDEMA, ANAPHYLACTIC REACTION, CHRONIC DISEASES | Volunteer enrollment was managed via the study web-based software. They could read the informed consent and go through an initial self-administered screening questionnaire. Those who passed this stage were invited to attend the clinical trial centers for face-to-face screening by the study officers and signing the written informed consent form. People aged 18 or older were included. Major exclusion criteria were as follows: pregnancy and lactation; History of receiving Covid-19 vaccine; Close contact with a definite case of Covid-19 up to two weeks before the day of receiving the first dose; Acute febrile illness; Current acute or chronic symptomatic illness that requires ongoing medical or surgical care; History of allergic diseases such as angioedema or anaphylactic reactions following the use of drugs, vaccines or food; History of long-term use (14 successive days) of immunosuppressive drugs or systemic corticosteroids in the last four months leading up to the study; History of diagnosis or treatment for HIV; Current drug or alcohol abuse (addiction); Chronic diseases that are not listed as exclusion criteria but are considered unstable within the last four weeks. Detailed inclusion and exclusion criteria are provided in the protocol (for more details please see the protocol). | PMC10355035 |
Randomization and masking | The study epidemiologist created the random allocation sequence to assign the participants to the BBIBP-CorV or Fakhravac vaccine groups (in a 1:1 ratio) in the randomized arms using a variable-sized (4 and 6) block randomization method. Stata software was used for this purpose. We concealed the random allocation sequence using nine-character unique codes and embedded them into the study software. The software allocated the codes to the participants once their eligibility was confirmed. The person responsible for blinding delivered the assigned vaccine for administration by the vaccinator, who was unaware of the type of vaccine used. Participants and the rest of the research team remained masked to the type of vaccine. All vaccine doses had the same volume and color and were prepared in identical syringes. | PMC10355035 |
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Procedures | redness, myalgia, Accidents, diarrhea, swelling, fatigue, pain, headache, tenderness | ADVERSE REACTIONS, ADVERSE EVENT, EMERGENCY | We monitored immediate reactions and vital signs following vaccine injections for half an hour at the clinical trial centers. All collected information was recorded in the web-based study software.We asked the participants to report their daily local (pain, tenderness, swelling, and redness) and systemic (nausea/vomiting, diarrhea, headache, fatigue, and myalgia) adverse reactions in a mobile application during the week after each injection. In the same session, the mobile application was installed and activated on the participants' mobile phones and was an integral part of the web-based study software. Participants were also asked to report weekly any visits to local surgery or hospital A&E (Accidents and Emergency) on their mobile application during the four months of active follow-up. Missing two successive weekly reports triggered a notification for the follow-up team to contact the participant. They could also phone at any time (24/7) study follow-up center where they could consult a resident physician or report their illness or any other matter of concern. Any report of illness or seeking medical advice in the mobile application or direct contact with the follow-up center opened an electronic adverse event file that was followed up until complete resolution. | PMC10355035 |
Outcomes | sore throat, anaphylaxis, myalgia, death, fever, diarrhea, shock, respiratory failure, neurologic dysfunction, cough, anosmia, hyposmia, headache, chills, shortness of breath | SORE THROAT, ADVERSE REACTIONS, ANAPHYLAXIS, ADVERSE EVENT, SARS-COV-2 INFECTION, SHOCK, RESPIRATORY FAILURE, DISEASE, SECONDARY, ADVERSE REACTION, ACUTE RESPIRATORY DISTRESS SYNDROME | The primary outcome was the occurrence of PCR-positive symptomatic Covid-19 disease 14 days or more after the second injection. A SARS-CoV-2 RT-PCR test was requested for all participants with clinical symptoms suspicious of SARS-CoV-2 infection, including fever (temperature ≥ 38 °C), chills, cough, shortness of breath, myalgia, headache, sore throat, diarrhea, anosmia, or hyposmia. All suspected or confirmed cases were followed up daily until all symptoms were resolved.The secondary outcomes were severe cases of Covid-19 disease that had been hospitalized or died 14 days or more after the second injection, immediate reactions including anaphylaxis following vaccine injections, local and systemic adverse reactions within the first-week post-vaccination, and any Medically Attended Adverse Events (MAAEs) including Serious Adverse Events/Reactions (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring within the four months active follow-up. Severe Covid-19 cases were defined by one or more of the following criteria: respiratory rate above 30 per minute; heart rate at or exceeding 125 beats per minute; oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg; respiratory failure; acute respiratory distress syndrome; evidence of shock (systolic blood pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg, or a need for vasopressors); clinically significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death. | PMC10355035 |
Statistical analysis | infectious disease | EVENTS, DISEASE, INFECTIOUS DISEASE | We needed 365 events of the primary outcome to demonstrate the non-inferiority of Fakhravac based on a 10% non-inferiority margin of the reported 72.8% efficacy of BBIBP-Corv-2 [We used frequencies (percentages) for categorical variables and mean (SD) for continuous variables to compare baseline values in the study groups and report adverse events/reactions. All those who received the standard first dose made the safety and the intention-to-treat (ITT) efficacy populations. The ITT population was used for sensitivity analysis. The modified ITT efficacy population included participants who received both vaccine doses.We used Kaplan Meier survival analysis and log-rank test to compare the occurrence of the outcomes in the study groups. Cox proportional hazard modeling was used to estimate hazard ratios and their 95% confidence intervals. Model assumptions were checked using proportional hazard graphs, Schoenfeld residuals against time plots, and formal proportional hazard tests. We used the Stata 11 and R 4.3.2 software.An eight-member data and safety monitoring board (DSMB) oversaw the conduct of the study and received periodic safety reports. The DSMB consisted of one person from each of the following specialties: clinical pharmacotherapist, epidemiologist, cardiologist, infectious disease specialist, oncologist, and representatives from the regularity authorities (FDO), the National Ethics Committee, and the Ministry of Health’s Center for Disease Control.This study was registered with the Iranian Registry of Clinical Trials ( | PMC10355035 |
Role of the funding source | The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10355035 |
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Discussion | SAEs, cardiovascular deaths | ADVERSE REACTIONS, EVENTS, RECRUITMENT, RECRUITMENT | We found that the Fakhravac inactivated SARS-CoV-2 vaccine is similar in safety and efficacy to the BBIBP-Corv2 vaccine. All observed local and systemic adverse reactions were generally self-limited and resolved completely. We observed a slightly higher occurrence of solicited local and systemic adverse reactions and a slightly lower rate of MAAEs and SAEs in the Fakhravac compared to BBIBP-Corv2 vaccine groups in the randomized arm. With 81.5% estimated efficacy, the Fakhravac vaccine was non-inferior to the reported 72.8% vaccine efficacy of BBIBP-Corv2 within the 10% non-inferiority margin after taking into account the 35% information fraction achieved during the study. In the non-randomized arm, the results were inconclusive. Overall, non-inferiority of the efficacy of the Fakhravac vaccine was demonstrated after adjusting for all possible confounding.The non-randomized arm is prone to confounding and bias. Recruitment for this trial started in September 2021, when the BBIBP-Corv2 vaccine became available to the general Iranian population as part of the national Covid-19 vaccination program. This seriously impacted the willingness of the people to participate in the study, undergo randomization and remain unaware of the type of vaccine received. To overcome the slow recruitment, a change in design to allow the participants to choose the type of vaccine they receive became inevitable. Non-randomized and unblinded participants had less incentive to fill out the mobile application and inform the follow-up center about any change in the state of their health. The considerably lower incidence of symptomatic PCR + Covid-19 in both groups in the non-randomized arm reflects this less cooperative population, particularly in those receiving the BBIBP-Corv2 vaccine.A changing pattern of the pandemic curve further complicated the recruitment and follow-up in the non-randomized arm [We can draw a non-inferiority efficacy conclusion for the Fakhravac vaccine just from our randomized arm. The number of events of the primary outcome in the calculated sample size was 365. Based on our conservative estimates of Covid-19 incidence in Iran, we needed to recruit 40,000 and follow them for six months to reach this number. However, the actual occurrence rates of Covid-19 were much higher than predicted, and we observed 855 cases, 129 (35% of 365 required by target sample size) of which occurred in the randomized arm. After adjusting the α error to 0.002 and confidence intervals (one-way) to 99.9% for 35% information fraction using the conservative O’Brien Fleming method, we were able to demonstrate the non-inferiority of the Fakhravac vaccine within the 10% margin from the reported 72.8% efficacy of the BBIBP-Corv2 vaccine (Table We found that those who received the Fakhravac vaccine are four times less likely to be hospitalized due to Covid-19 than the BBIBP-Corv2 vaccine, which agrees with our findings about symptomatic PCR + Covid-19 in the randomized arm. Given the telephone follow-up of those who had missed two successive weekly self-reports on their mobile application, we believe that the ascertainment of hospitalization due to Covid-19 is not affected by the degree of cooperation of the study participants and is likely to be valid.We observed higher rates of grade I and II local and systemic adverse reactions in the Fakhravac compared to the BBIBP-Corv2 vaccine groups; however, they were all self-limited and were of little clinical value. The higher rates of solicited local and systemic reactions in the Fakhravac vaccine group could be partly attributed to the underreporting of these reactions in the unblinded, non-random BBIBP-Corv2 vaccine recipients. Furthermore, the figures in our study were generally lower than those reported for the BBIBP-Corv2 vaccine [We observed a slightly lower rate of MAAEs and SAEs in the Fakhravac compared to the BBIBP-Corv2 vaccine groups. The standardized Mortality Ratio (SMR) for cardiovascular deaths was not significantly different from the general Iranian population. The details of all SAEs are included in the Additional file In summary, our study shows that the efficacy of the Fakhravac vaccine is non-inferior to the BBIBP-Corv2 vaccine, and the safety profile of both vaccines is similar. Therefore, Fakhravac is a reliable and safe addition to our global arsenal of vaccines against Covid-19. | PMC10355035 |
Limitation | CHRONIC DISEASES, BLINDNESS | First of all, the study was initially designed as an RCT, but due to the dissatisfaction of the volunteers with the blindness and randomness of the study, the study design was changed to a comprehensive cohort study. Second, the study did not include pregnant women or those younger than 18 years; thus, the efficacy and safety of the inactivated vaccines in these groups remain unknown. Third, the trial was mainly conducted on generally healthy Iranian people. There was insufficient power to test the efficacy among those with chronic diseases, older adults, and those in other geographic populations. Fourth, there were only two severe cases of Covid-19, so we cannot make conclusions about preventing severe cases. | PMC10355035 |
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Conclusion | Covid19 | DISEASE | Fakhravac vaccine is safe and effective as the Sinopharm vaccine in preventing symptomatic PCR-positive covid-19 disease. In another way, we could prove the non-inferiority of Fakhravac to the BBIBP-Corv2 vaccine. However, the Fakhravac vaccine is significantly more effective than the Sinopharm vaccine in preventing hospitalization due to Covid19 symptomatic disease. | PMC10355035 |
Acknowledgements | This work was supported by the Milad Daro Noor Pharmaceutical (MDNP) Company. The immunology lab and all other research staff involved in collecting and examining blood samples taken for immunogenicity assessment were masked to the identity of the participants and the allocated interventions. The study was overseen by an independent data and safety monitoring board | PMC10355035 |
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Author contributions | MP, FGN | Conceptualization: PB, MSD, and MF. Data Curation: AS, and KG. Formal Analysis: AS, and KG. Investigation: MSD, PB, MM, MA, AS, KG, SG, AS, MP, AM, MH, SK, FG, ZR, FGN. Methodology: MSD, RHF, and MF. Project Administration: MSD, AKR, and KN. Validation: MSD, AA, AS, KG, MA, FG, and ZR. Visualization: MSD, AS, and KG. Writing—Original Draft Preparation: PB, MSD, KG, MA, AS. | PMC10355035 |
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Funding | Milad Daro Noor Pharmaceutical (MDNP) Company provided the funding for this study and the logistics for study conduct but had no role in data management, analysis, interpretation, or writing the report. The Grant number of this study is Not Applicable. | PMC10355035 |
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Availability of data and materials | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10355035 |
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Declarations | PMC10355035 |
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Ethics approval and consent to participate | The clinical trial protocol was approved by the Iranian National Ethics Committee for research (approval number IR. NREC.1400.006, 31st August 2021). | PMC10355035 |
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Consent for publication | Not applicable. | PMC10355035 |
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Competing interests | MH | ASH | AKR, SG, AS, AM, MH, and SK are employees of Milad Daro Noor Pharmaceutical (MDNP). MSD is an Iran University of Medical Science (IUMS) employee. MSD, PB, AA, MA, ASH, ZR, FGH, and KG are members of the clinical trial center of the Iran University of Medical Science that acted as academic CRO. All other authors declare no other competing interests. | PMC10355035 |
References | PMC10355035 |
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Background | Ketamine is administered in the perioperative period for its benefits in analgesia, anti-agitation and anti-depression when administered at a small dose. However, it is not clear whether the intra-operative administration of ketamine would affect emergence under sevoflurane anesthesia. To investigate this effect, we designed this trial. | PMC10288804 |
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Methods | delirium, postoperative agitation | In this randomized, double-blind, placebo-controlled study, we enrolled 44 female patients aged 18–60 who were scheduled to elective laparoscopic gynecological surgeries. All patients were randomly assigned to saline or s-ketamine group. In s-ketamine group, patients received 0.125 mg/kg s-ketamine 30 min after the start of surgery. In saline group, patients were administered the same volume of saline. Sevoflurane and remifentanil were used to maintain general anesthesia. The primary outcome was emergence time. We also assessed postoperative agitation, cognitive function, and delirium. In addition, we collected and analyzed prefrontal electroencephalogram (EEG) during and after general anesthesia. | PMC10288804 |
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Results | There were no significant differences in emergence time between s-ketamine group and saline group (10.80 ± 3.77 min vs. 10.00 ± 2.78 min, | PMC10288804 |
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Conclusion | Ketamine administered during sevoflurane anesthesia had no apparent influence on emergence time in young and middle-aged female patients undergoing laparoscopic surgery. Subanesthetic s-ketamine induced an active prefrontal EEG pattern during sevoflurane anesthesia but did not raise neurological side effects after surgery. | PMC10288804 |
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Trial registration | Chinese Clinical Trial Registry, ChiCTR2100046479 (date: 16/05/2021). | PMC10288804 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12871-023-02170-5. | PMC10288804 |
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Keywords | PMC10288804 |
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Background | Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, was initiated to be used clinically for anesthetic induction and maintenance in the 1970s [Theoretically, the co-administration of subanesthetic ketamine during general anesthesia could deepen the anesthetic depth. A series of studies have confirmed that low-dose ketamine reduces the consumption of propofol [S-ketamine (induction dose 0.5–1 mg/kg i.v.), the pure dextrorotatory enantiomer of ketamine, has an approximately two-fold higher sedative potency compared with ketamine, associated with a stronger effect at the NMDA receptor [ | PMC10288804 |
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Methods | MAY | This prospective, randomized, controlled, double-blind trial was registered in the Chinese Clinical Trial Registry (chictr.org.cn) (ChiCTR2100046479, date: 16/05/2021). Ethical approval for this study (NO. KY20202065-X-1, date: 07/04/2021) was provided by the Medical Ethics Committee of the First Affiliated Hospital of the Fourth Military Medical University. This trial was conducted from May 2021 to September 2021 in the Department of Anesthesiology and Perioperative Medicine of the First Affiliated Hospital of the Fourth Military Medical University. Written informed consent was obtained from all patients before enrollment. The principles of Declaration of Helsinki were followed for this study. This manuscript adheres to the applicable CONSORT guidelines. | PMC10288804 |
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Study population | abnormal cognitive function, psychiatric disorders | NEUROLOGICAL DISEASE | Han Chinese patients aged 18–60 years old with an American Society of Anesthesiologists (ASA) physical status of I–II who were scheduled for elective laparoscopic gynecological surgery and signed the informed consent voluntarily were eligible for inclusion in this study. Patients with a history of psychiatric disorders or neurological diseases, alcohol or drug abuse, operation within one month before surgery, use of sedative medicine or antidepressant within one week before surgery, abnormal cognitive function, inability to communicate fluently, body mass index (BMI) ≥ 28 or ≤ 18, contraindications to s-ketamine, and who participated in other trials or who once were recruited were excluded from this study. The withdrawal criteria included: operation time of < 1 h or > 3 h, unexpected intraoperative conversion to laparotomy, incomplete cases data, patients admitting to Intensive Care Unit (ICU) after surgery. | PMC10288804 |
Randomization and blinding | The simple randomization was chosen in our trial which was performed using an online randomization list to ensure that each group contained 22 subjects. The subjects were randomly assigned 1:1 to either the saline group or the s-ketamine group. The randomization envelopes contained grouping information. The nurses who preserved and opened the envelops and prepared the s-ketamine or 0.9% saline were not involved in patient care. S-ketamine was diluted in saline to a total volume of 10 ml. The same volume of saline was used in the control group. Syringes of saline and ketamine were identical. The other investigators and all subjects were blinded to randomization. | PMC10288804 |
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Anesthesia and monitoring | Dexmedetomidine, midazolam, and anticholinergic drugs were not permitted before surgery. Vital signs such as pulse oximetry, blood pressure (BP), and electrocardiography were monitored as soon as the patients arrived in the operating room. A Chinese brand of anesthesia depth monitor based on EEG, ConView system (ConView YY-105, Pearlcare Medical Technology Company Limited, Zhejiang, China), was used. Anesthesia index (Ai) is a digital indicator for anesthesia depth derived from the ConView [ | PMC10288804 |
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Outcome measures | delirium, agitation, Delirium, Confusion | The primary outcome was emergence time, which was defined as the interval between the cessation of sevoflurane and the point at which the patient opened their eyes. During this recovery period, we aroused the subjects by calling their names every 30 s until they responded by opening their eyes.Secondary outcomes included the characteristics of prefrontal EEG spectra across the administration of s-ketamine, Ai (generated by the ConView YY-105), gamma power, gamma peak frequency and agitation score during the recovery period, and cognitive function and delirium assessments one day after the surgery. The agitation level was assessed using the Sedation-Agitation Score (SAS). Delirium and cognitive function were evaluated using the Confusion Assessment Method for the ICU (CAM-ICU) and Mini-Mental State Examination (MMSE), respectively. These scales of assessment used in our trial are all in Chinese, which have been widely used for Chinese in both clinic practice and clinical trials [ | PMC10288804 |
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Spectral processing | EEG data were obtained at a sampling rate of 500 Hz by using ConView. The ConView system is designed by Pearlcare Medical Technology Company Limited (Zhejiang, China), based on three different parameters of EEG: sample entropy (SampEn), 95% spectral edge frequency (SEF) and burst suppression ratio (BSR). The new anesthetic index named Ai is calculated with the algorithm based on decision tree and least square. Ai ranges from awake (80–99), to light sedation (60–80), general anesthesia during surgery (40–60), deep hypnotic state (< 40) and an isoelectric EEG (0). A multicenter clinical study has confirmed that the performance of Ai as a depth of anesthesia monitor was similar to that of BIS [We analyzed the EEG and Ai value across the period of the administration of s-ketamine and the 2-min EEG epochs that were selected 10 min before and 2–8 min after the administration of s-ketamine or saline in detail. We also analyzed the EEG during recovery period.The power spectra quantifying the energy in the EEG at each frequency were calculated using the multi-window spectrum algorithm in MATLAB R2018b (MathWorks, Natick, MA). The parameters used for statistical inference were as follows: time-bandwidth product = 3, number of tapers = 5, window size = 2 s, and window overlap rate = 99.5%. Group-level spectrograms were obtained by computing the median power across all subjects at each time point and at each frequency. We also computed the power and peak frequency at the time and frequency bands of interest, respectively. The peak frequency is the frequency with the highest power within a certain frequency band. We obtained the Ai value from ConView YY-105 directly.The mean power and peak frequency of the EEG signal were calculated for the following frequency bands: slow wave (0.3–1 Hz), delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–25 Hz), gamma (25–50 Hz), and beta-gamma (12–50 Hz). | PMC10288804 |
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Statistical analysis | SD | SECONDARY | The sample size was calculated based on the time of emergence. According to the results of our previous study, the emergence time was 7.7 min with a standard deviation (SD) of 1.2. In our pilot trial, we found that the administration of subanesthetic s-ketamine could reduce the emergence time by 10.6%. Then, we hypothesized that the s-ketamine could decrease the emergence time by 15%. Considering 80% power, 20% dropout, and adopting a ratio of 1:1, 22 participants were required in each group.Statistical analyses were performed using SPSS Statistics 23 (IBM, Armonk, NY) and GraphPad Prism 8.0.1 (GraphPad Software, San Diego, CA). Per-Protocol (PP) analysis was used to analyze all outcomes. According to withdrawal criteria, 5 patients were excluded at the data analysis even though they have received the interventions. The remaining patients will be categorized and analyzed according to their allocation and they have strictly followed the trial procedure. The results are expressed as mean ± SD, median, or n (%). The primary endpoint was compared between the two groups using a two-tailed t-test. For the secondary outcomes, ordinal and continuous data were computed using two-tailed t test or two-way ANOVA corrected with the Bonferroni test, while non-normally distributed data and rates were analyzed with the Mann–Whitney U test and the chi-squared test, respectively. The relationship between Ai values and EEG features was explored by using Pearson’s Correlation. If | PMC10288804 |
Primary outcome | The time from the cessation of sevoflurane administration to the emergence of patients in the s-ketamine group was not significantly different from that in the saline group (saline: 10.80 ± 3.77 min vs. s-ketamine: 10.00 ± 2.78 min, | PMC10288804 |
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Secondary outcomes | PMC10288804 |
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Prefrontal EEG spectra | To evaluate the intra-operative effect of subanesthetic s-ketamine, we exhibited the full-range EEG median spectrograms of saline and s-ketamine groups (Fig. Spectral analysis of EEG signals before and after the administration of s-ketamine. During the recovery period after the cessation of sevoflurane, the power and peak frequency showed no differences between two groups. The power of gamma oscillations gradually increased and then declined after recovery of consciousness (Fig. The characteristics of prefrontal EEG signals across anesthesia recovery states. The dynamic changes of gamma power ( | PMC10288804 |
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Discussion | delirium, agitation | In this randomized controlled study, we observed the effects of a bolus of subanesthetic s-ketamine administered during elective laparoscopic gynecological surgery on emergence time in the female patients. We did not find a difference in the time duration from cessation of anesthetics to eye opening between the s-ketamine and saline groups. The agitation level, cognitive function and incidences of delirium, in the s-ketamine group were similar to those in the saline group. However, the administration of subanesthetic s-ketamine induced active EEG spectra with decreased power of slow wave, delta, and alpha bandwidths, and increased power of beta-gamma waves during sevoflurane anesthesia. The alpha peak frequency significantly increased.A synergistic interaction tends to occur when two or more drugs produce similar effects by different mechanisms [We did not find these differences in high-frequency and Ai values between the two groups during recovery period because of the fast metabolic rate of s-ketamine [However, these increases in indices of depth of anesthesia do not indicate the lightened hypnosis [The administration of ketamine (≤ 1 mg/kg i.v.) during general anesthesia has beneficial effects on cognition in elderly patients undergoing major surgery [Our study has some limitations. First, only young and middle-aged female patients were recruited, which may have avoided the bias of gender and age on anesthesia emergence [ | PMC10288804 |
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Conclusion | In conclusion, intra-operative administration of subanesthetic s-ketamine did not change the emergence time of young and middle-aged women undergoing elective laparoscopic gynecological surgery. The administration of s-ketamine can induce active EEG during sevoflurane anesthesia but did not have negative effects on neurological symptoms. Further multicenter studies with larger sample sizes are necessary to investigate whether ketamine affects the emergence time during sevoflurane anesthesia. | PMC10288804 |
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Acknowledgements | Not applicable. | PMC10288804 |
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Authors’ contributions | Study design and supervision: Qianzi Yang and Hailong Dong. Project administration and randomization: Ao Li, Tingting Liu, Xue Yang. Generating the random allocation sequence: Ao Li. Preparing s-ketamine or saline: Huanhuan Zhang. Data collection: Tiantian Liu. Anesthesiologist: Yanling Lei. Data analysis: Tiantian Liu, Xinxin Zhang and Ao Li. Figures | PMC10288804 |
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Funding | This study was supported by the National Natural Science Foundation of China (Grant No. 82071554 to Qianzi Yang and No. 82030038 to Hailong Dong). | PMC10288804 |
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Availability of data and materials | The datasets generated during the current study are not publicly available due ethical concerns but are available from the corresponding author on reasonable request. | PMC10288804 |
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Declarations | PMC10288804 |
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Ethics approval and consent to participate | Ethical approval for this clinical study (NO. KY20202065-X-1) was provided by the Medical Ethics Committee of the First Affiliated Hospital of the Fourth Military Medical University on 7 April 2021. All participants or their legal representatives provided written informed consent before enrollment. The trial was registered before patient enrolment at Chinese Clinical Trial Registry with registration number ChiCTR2100046479 (date: 16/05/2021), and adhered to the Consolidated Standards of Reporting Trials guidelines and the Declaration of Helsinki. | PMC10288804 |
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Consent for publication | Not applicable. | PMC10288804 |
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Competing interests | The authors declare no competing interests. | PMC10288804 |
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References | PMC10288804 |
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Background | intradialytic exercise, kidney failure | KIDNEY FAILURE | Patients with kidney failure experience derangements of circulating markers of mineral metabolism and dysregulation of skeletal and cardiovascular physiology which results in high mortality rate in these patients. This study aimed to evaluate the effect of intradialytic exercise on regulation of these abnormalities in patients receiving chronic hemodialysis (HD). | PMC10512624 |
Methods | In this randomized controlled trial conducted in an HD center in Iran, adult patients receiving chronic HD were randomized to intradialytic exercise (60 min) in the second hour of thrice weekly dialysis for 6 months (intervention) or no intradialytic exercise (control). The primary outcomes were serum calcium, serum phosphorous and parathyroid hormone levels. Secondary outcomes were serum alkaline phosphatase and calcium-phosphorous product. | PMC10512624 |
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Results | The study included 44 participants randomized to intervention ( | PMC10512624 |
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Conclusion | Intradialytic, bone mineral disorders, HD | Intradialytic exercise performed for at least 60 min during thrice weekly dialysis sessions improves bone mineral metabolism in adult patients receiving HD. Further studies should focus on observing and comparing the effect of different types of exercise on bone mineral disorders and all-cause mortality in HD patients. | PMC10512624 |
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Trial registration | Intradialytic | PARATHYROID | ClinicalTrials.gov Identifier: NCT04916743, Registered on 08/06/2021. Registered trial name: The Effect of Intradialytic Exercise on Calcium, Phosphorous and Parathyroid Hormone: A Randomized Controlled Trial. | PMC10512624 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12882-023-03327-7. | PMC10512624 |
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Keywords | PMC10512624 |
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Background | muscle atrophy, disordered muscle protein, ESKD, CVD, anemia, PD, hyperphosphatemia, malnutrition, hypocalcemia | MUSCLE ATROPHY, CVD, KIDNEY REPLACEMENT, HYPERPARATHYROIDISM, ANEMIA, HYPERPHOSPHATEMIA, SECONDARY HYPERPARATHYROIDISM, MALNUTRITION, END STAGE KIDNEY DISEASE, HYPOCALCEMIA, CARDIOVASCULAR DISORDERS | In recent years, there has been a rapid increase in the prevalence of patients with end stage kidney disease (ESKD) that require kidney replacement therapy, including hemodialysis (HD), peritoneal dialysis (PD) or kidney transplant [The primary etiological factors responsible for these outcomes include cardiovascular disorders (CVD), muscle atrophy and malnutrition [Hyperparathyroidism is one of the aggravating causes of anemia in hemodialysis patients, in addition to resistance to erythropoietin treatment. Defects in calcitriol synthesis, which along with PTH stimulates calcium reabsorption, causes hypocalcemia and hyperphosphatemia in dialysis patients. In this condition, there is an increase in PTH synthesis to regulate calcium and phosphorus homeostasis, leading to secondary hyperparathyroidism [Abnormal levels of PTH are associated with disordered muscle protein metabolism, which has been linked to increased mortality in these patients [The regulation of PTH is critical for bone metabolism in healthy individuals as well as HD patients [ | PMC10512624 |
Methods | PMC10512624 |
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Trial design | RECRUITMENT | This study is an open-label, parallel arm, randomized controlled trial with blinded end-points, which was conducted in a medical center in Iran. Recruitment occurred between July 25, 2021 and 10 August 2021. | PMC10512624 |
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Participants | cardiac instability, myocardial infarction, angina, decompensated congestive heart failure, arteriovenous stenosis, musculoskeletal pain, hyperglycemia, infection, arrhythmias, lower extremity amputation, shortness of breath | MYOCARDIAL INFARCTION, HEMODYNAMIC INSTABILITY, HYPERGLYCEMIA, INFECTION, HYPOGLYCEMIA, ARRHYTHMIAS | Individuals were eligible to participate in the study after meeting all of the following inclusion criteria: 1) age ≥ 18 years; 2) receiving regular HD 3 times a week; 3) on HD for at least 1 year, 4) absence of a history of myocardial infarction within the past 3 months; 5) permission from their physician to participate; and, 6) had capacity to provide informed consent to participate in the study. Individuals were excluded if they met any of the following exclusion criteria: 1) cardiac instability (angina, decompensated congestive heart failure, severe arteriovenous stenosis, uncontrolled arrhythmias, etc.); 2) active infection or acute medical illness; 3) hemodynamic instability (systolic blood pressure < 90 mmHg or mean arterial pressure < 60 mmHg); 4) labile glycemic control (extreme swings in blood glucose levels, causing hyperglycemia or hypoglycemia); 5) inability to exercise (e.g. lower extremity amputation with no prosthesis); 6) severe musculoskeletal pain at rest or with minimal activity; 7) inability to sit, stand or walk unassisted (walking device such as cane or walker allowed); or, 8) shortness of breath at rest or with activities of daily living (NYHA Class IV). | PMC10512624 |
Trial procedures | comorbidity, cardiac diseases, cancer, diabetes, dysrhythmia, intradialytic, cerebrovascular accident/transient | CARDIAC DISEASES, ATHEROSCLEROTIC HEART DISEASE, CANCER, GASTROINTESTINAL BLEEDING, LIVER DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ISCHEMIC ATTACK, DYSRHYTHMIA, CONGESTIVE HEART FAILURE, KIDNEY FAILURE, PERIPHERAL VASCULAR DISEASE, DIABETES | Before starting the study, some educational and motivational posters were installed in the dialysis center so that all patients became familiar with the benefits of exercise and especially intradialytic exercise. Then, the principal investigator described the side-effects of inactivity and sedentary lifestyle to all interested patients. Specifically, the PI encouraged all patients to be active and provided information regarding potential benefits of intradialytic exercise. After providing written informed consent, eligible patients received a baseline assessment. Data were collected on demographic characteristics (age, sex, and time on hemodialysis), primary cause of kidney failure, and comorbidities (atherosclerotic heart disease, congestive heart failure, cerebrovascular accident/transient ischemic attack, peripheral vascular disease, dysrhythmia, and other cardiac diseases, chronic obstructive pulmonary disease, gastrointestinal bleeding, liver disease, cancer, and diabetes). Comorbidities were quantified using Charlson comorbidity index (CCI) established for dialysis patients, which included the underlying cause of kidney failure, as well as 11 comorbidities [Participants were then randomized in a 1:1 ratio to either the intervention group or control group. The randomization sequence was generated by a study biostatistician who was not otherwise involved in the study using a computer-generated random schedule (using Stata 16, Stata Crop, College Station, Tx). Allocation concealment was safeguarded through the use of sequentially numbered, sealed, opaque envelopes by a specified staff member who was not involved in the study. | PMC10512624 |
Intervention | AV fistula, fistula, shoulder horizontal abduction | Subjects in the intervention group performed concurrent intradialytic exercise during the 2nd hour of dialysis (60-min exercise sessions three times a week) for 6 months. The intervention was a combination of aerobic and resistance exercises. Workout time at the beginning was 30 min and gradually increased to 60 min. Each workout session included 5 min of warm-up, aerobic exercises, resistance exercises and finally 10 min of stretching exercises to cool down. The fistula arm was kept stationary thoroughly the exercise session, with necessary precautions taken into consideration. Also, the exercise protocol was not performed on the arm with AV fistula.Exercises were individualized in a way that matched the level of physical fitness of participants (See Additional File The rhythm of continuous movements was adjusted by the beats per minute of the music. This meant that participants had to coordinate the movements of their arms and legs with the beats per minute of the song being played to them. In this way, the speed and intensity of aerobic exercise was controlled by the rhythm. Resistance training was performed in a semi-recumbent position and included exercises for the upper and lower limbs as well as core strength exercises using body weight, weight cuffs, dumbbells, and elastic bands of varying intensity. Chest press, shoulder press, triceps extension, straight arm shoulder flexion, shoulder horizontal abduction, seated row, supine grip, prone grip, neutral grip, bicep curl, leg abduction, plantarflexion, dorsiflexion, straight-leg/bent knee raises, knee extension, and knee flexion were all part of the resistance training program.All of the exercises were prescribed by an exercise physiologist who also monitored the exercise sessions and helped patients with any questions they had. At the end of each session, the exercise physiologist reviewed the adherence checklists. If a person did not attend an exercise session, a counseling session was held in the presence of a nephrologist and the exercise physiologist. The reason for the individual's non-participation was investigated and the positive effects of exercise were explained through motivational statements. When possible, patients were reminded of previous benefits of exercise they had experienced as an incentive for them to increase adherence with the training.Participants in the control group did not undertake any specific physical activity during dialysis.All other pharmacological, dialysis, dietary and management protocols were identical for participants in both groups and remained unchanged during the study. Despite differences in some hematological parameters at baseline, different medications were not used for intervention group. Major medications related to abnormalities in Ca, P and PTH included phosphate binders like lanthanum carbonate calcium and sevelamer hydrochloride, calcitriol, calcimimetic, and Ca supplement. All participants received normal bicarbonate hemodialysis, which was carried out three times a week for an average of 4 h. Volumetric ultrafiltration control was available on all machines. The standard dialysate flow rate was 500 mL/min and blood flow rates were prescribed according to the participant’s needs. Automated methods were applied to perform dialyzer reuse uniformly. | PMC10512624 |
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Blood sampling | Baseline blood samples were collected one day before the start of the exercise session. Exercise began at the mid-week dialysis session. After the end of the 36th session (end of the third month) and after the end of the 72nd session (end of the sixth month), subsequent blood samples were collected the day before the midweek dialysis session. The control group was assessed at the same time points. On a nondialysis day, blood samples were taken from the scalp vein after at least an 8-h fast. Approximately 30 ml of blood were collected and centrifuged for 15 min at 20 °C and 2500 g. Plasma was next pipetted into cryotubes and stored at -80 °C in a freezer that was electronically monitored. All samples were measured in duplicate, in line with the manufacturers' suggested protocol, and within the manufacturer's specified range of acceptable variation and sensitivity. | PMC10512624 |
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Outcomes | ADVERSE EVENTS | The primary outcome measures included changes in serum calcium (mg/dL), serum phosphorous (mEq/L) and parathyroid hormone (pg/mL) over time. Rate of changes of alkaline phosphatase (ALP) (U/L) and calcium-phosphorous product (mgSafety outcomes included all serious adverse events and adverse events. | PMC10512624 |
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Adherence | Intervention adherence was defined as the number of sessions performed divided by the number of sessions offered, multiplied by 100. | PMC10512624 |
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Blinding | BLIND | Due to the nature of the intervention, it was not feasible to blind participants or study staff.However, outcome assessors and data analysts were blinded to participants’ treatment allocations. | PMC10512624 |
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Sample size | The sample size was calculated in accordance with a previous study [Assuming an effect size of 0.45 for reduction of PTH and a drop-out rate of 20%, 44 participants (22 per group) were required to provide 80% power. | PMC10512624 |
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Statistical analysis | SECONDARY | Data are presented as frequency (percentage) or mean ± standard deviation, depending on data type and distribution. A detailed statistical analysis plan was prepared and completed prior to database lock. Primary and secondary outcomes were evaluated using Repeated Measure ANOVA and the Friedman test. Statistical analyses were performed using IBM SPSS software 25. | PMC10512624 |
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Results | Overall, 58 patients were assessed for eligibility, of whom 44 were consented and randomized. The corresponding flowchart is presented in Fig. Participant flow during the studyDuring the 6-month intervention period, 2 participants in the intervention group and 3 participants in the control group dropped out of the study. | PMC10512624 |
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Safety | muscle cramps | ADVERSE EFFECTS | No treatment-related serious adverse effects were observed during the period of the study. During the intervention period, one patient had muscle cramps after the first exercise session, but this was not serious or harmful. | PMC10512624 |
Discussion | CKD, chronic kidney disease, CKD-MBD, bone loss, HD, fracture, bone mineral disorders, bone disorder, intradialytic, renal insufficiency, intradialytic exercise | HIGH TURNOVER BONE DISEASE, BONE LOSS, METABOLIC BONE DISEASE, LIVER DISEASE, COMPLICATION, BONE DISORDER, SECONDARY, RENAL HYPERPARATHYROIDISM, RENAL INSUFFICIENCY | The purpose of this study was to examine the effects of intradialytic exercise on calcium, phosphorous and parathyroid hormone. Our primary findings showed that the 6-month intradialytic concurrent exercise program was effective in improving PTH levels, reducing serum phosphorous and improving serum calcium and calcium-phosphorous product as well. However, contradictory results have been reported by some other studies.Previous work showed that exercise decreased plasma PTH levels in CKD patients [In the present study, phosphorus levels in the intervention group were significantly reduced to lower than the baseline. The effect of exercise on phosphorus level was in line with findings of the several previous studies [Reviewing the limited available research on the effects of exercise in reducing phosphorus levels showed that although exercise often decreases the level of phosphorus, longer-term exercise and perhaps more intense exercise might be required to see reductions in some studies [This study revealed that serum calcium levels showed significant change in the intervention group, but some other researchers failed to show any influence of exercise on serum calcium [Renal hyperparathyroidism is a common complication of chronic kidney disease characterized by elevated PTH levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D [Abnormalities in calcium, phosphorous, and PTH, hallmarks of the condition known as chronic kidney disease – mineral and bone disorder (CKD-MBD) [Cardoso et al. in their systemic review found evidence supporting a positive relation between physical activity and bone outcomes in patients with CKD [The present study demonstrated that ALP levels significantly decreased in exercise group, but controls showed no similar change.Previous observational studies on dialysis patients revealed a relationship between physical activity and serum levels of ALP due to the fact that energy expenditure has a strong relationship to the total BMD [The study by Gomes et al. and the other one by Elshinnawy et al. showed there was significant increase in ALP levels following exercise in patients with CKD [One of the reasons for the contradiction in ALP changes with the previous studies is that in those studies, the ALP level of the patients was within the normal range before the intervention, and the intervention has somehow improved the condition. However, in the current study, the ALP level of the patients was much higher than normal, and exercise has been able to have a significant positive effect on improving the patients' condition by reducing the ALP level.ALP is an enzyme measurable in most body fluids and usually originates from the liver or bone. In CKD patients without liver disease, ALP is a surrogate of high turnover bone disease and is used to monitor the metabolic bone disease associated with renal insufficiency [Bones are subjected to two sources of loading, including ground reaction force and muscular force [High proinflammatory cytokine levels may contribute to bone loss and fracture in patients with CKD [A major strength of the present study was the fact that all exercises were tailored according to each individual's functional status within a pre-specified structure. There was also a high participation rate, despite including HD patients that exhibit considerable diversity with respect to demographic characteristics and associated comorbidities. It is also important to recognize that by the end of the study, levels of calcium, phosphorus and parathyroid hormone in the intervention group reached the level recommended by KDOQI guidelines [This discrepancy between the results of the present study and the findings of the above-mentioned studies may be attributed to differences in participants’ age and sex or duration, intensity, and type of exercise program. In particular, the duration of our intervention was longer than much of what is in the intradialytic exercise literature. Moreover, the intradialytic intervention included both endurance and resistance training components, as opposed to most other studies was performed as concurrent exercise which was different from other studies that include only resistance or aerobic exercise.Balanced against these strengths, the study also had a number of limitations. Not measuring the effect of exercise on bone mass and cardiovascular indexes are limitations of this study. Indeed, not measuring bone mineral density in this work is a limitation as bone strength depends on bone quality and quantity. Future work should focus on observing and comparing the effect of different types of exercise on bone mineral disorders and all-cause mortality in HD patients. | PMC10512624 |
Conclusion | Intradialytic, bone mineral disorders, HD | Intradialytic exercise performed for at least 60 min during thrice weekly dialysis sessions improves bone mineral metabolism in adult patients receiving HD and perhaps decrease all-cause mortality in these patients. Further studies should focus on observing the effect of different types of exercise on bone mineral disorders and all-cause mortality in HD patients. | PMC10512624 |
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Acknowledgements | RENAL | The authors would like to express their heart-felt gratitude to all the investigators for their contribution to the trial, especially Dr. Hugo Corrêa1 and Dr. João Viana and all the staff of the dialysis center for their efforts and patience in helping to maintain the standards of the research, as well as all patients involved in this study. Also, the authors would like to thank Pardis Specialized Wellness Institute and all the personnel of the institute for their support throughout the study. The authors would also like to thank the opportunity that medRxiv offered them to deposit the preprint version.This study is endorsed by the Global Renal Exercise (GREX) network. The interpretation and conclusions contained herein are those of the researchers and do not represent the views of GREX. | PMC10512624 |
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Authors’ contributions | MAT: conceptualizing the study, project leader of the study, conducting the study, writing of the manuscript, supervising of the analysis, interpreting the results, approval of the manuscript, KW: conceptualizing of the study, interpreting the results, co-writing of the manuscript, supervising of the manuscript, approval of the manuscript, NS: project leader of the study, analyzing the data, interpreting the results, co-writing of the manuscript, approval of the manuscript, SN: conceptualizing the study, conducting the study, co-writing of the manuscript, supervising of the manuscript, approval of the manuscript, MS: conceptualizing the study, conducting the study, co-writing of the manuscript, supervising of the manuscript, approval of the manuscript, ZR: conceptualizing the study, conducting the study, co-writing of the manuscript, supervising of the manuscript, approval of the manuscript, FA: conceptualizing the study, conducting the study, co-writing of the manuscript, supervising of the manuscript, approval of the manuscript, SA: conceptualizing the study, conducting the study, co-writing of the manuscript, approval of the manuscript. Each author contributed with important intellectual content during the manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors read and approved the final manuscript. | PMC10512624 |
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