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Discussion | death, pneumonia, stroke, hypoperfusion, infections, ischemic stroke, Pneumonia, neurological deterioration, artery atherosclerosis, infarct | PNEUMONIA, STROKE, HYPOPERFUSION, INFECTIONS, ISCHEMIC STROKE, SECONDARY, PNEUMONIA, EVENTS, ACUTE STROKE, INFARCT | In this investigator-initiated, randomized, multicenter trial, we investigated the effect of HDP (−20°) on functional outcomes in acute moderate ischemic stroke patients with probable LAA. We found that treatment with HDP for 2 weeks, applied as an adjunct to guideline-based medical management, was safe and did not improve the primary outcome (mRS 0–2 at 90 days), when compared with guideline-based medical management alone. However, HDP may have an improved effect on major secondary outcomes, including excellent functional outcome (mRS 0–1), ordinal shift distribution of mRS at 90 days, END, and change in NIHSS.Many studies have investigated the effect of head position on cerebral blood flow and cerebral perfusionThere are several differences between the current study and prior studies. First, the head position at −20° was adopted in the current study, while a horizontal supine versus sitting position was utilized in prior studiesThird, we implemented different head position interventions over time: 15 h duration within 24 h of presentation, followed by three times daily for 2 weeks in the current study, while only the first 24 h after randomization were implemented in the HeadPoST study. We postulate that longer-term HDP intervention may result in more benefits of improved cerebral perfusion, given that there may be the presence of long-lasting penumbra in this populationFor secondary outcomes, we found a significant mRS improvement at 90 days in the HDP group vs the control group, as well as improvement in NIHSS from baseline to day 12. We also observed a significant improvement in the proportion of mRS scores 0–1 at 90 days in the HDP group. For safety outcomes, there was no difference in mortality between the two groups, and no END in the HDP group. Collectively, these results support the safety and potentially improved neurological outcomes with HDP in patients with acute moderate ischemic stroke with LAA in a Chinese population.In our study, other safety endpoints, including pneumonia and cardiovascular events, were similar between the two groups. Pneumonia is a major risk factor for death after acute stroke. Preventive administration of antibiotics is superior in reducing infections after severe ischemic strokeThe strength of this study is the randomized multicenter design to determine the safety and possible efficacy of HDP in acute moderate ischemic stroke patients with probable LAA etiology. These promising results may promote further trials to investigate the effect of HDP in a broader array of AIS patients, for example, patients who develop early neurological deterioration due to hypoperfusion mechanisms, in addition to the current patients. We acknowledge several limitations to our study. The main limitation is the relatively small sample due to the pilot nature, which makes the conclusion exploratory and subgroup analysis, such as the effect of site on primary outcome, impossible. Second, the open-label design may have resulted in bias, although we used blinded evaluation at 90 days to mitigate this potential bias. Third, the highly selected population, for example, excluding patients who received thrombolysis or thrombectomy, limited to anterior circulation stroke, introduce selection bias and may limit the generalizability of our results. Fourth, the neuroimaging infarct or penumbra size was not determined in detail in the pilot study. Finally, there was no limit of head position in the control group in this trial, but we did not record the actual head position in the control group during the trial, especially within 24 h after randomization. This detailed information would be important to understand the effect of different head positions on stroke outcomes.In conclusion, this randomized clinical trial suggests that in patients with acute moderate ischemic stroke with large artery atherosclerosis, the head-down position seems safe and feasible, but does not improve 90-day favorable functional outcome as a primary outcome, although a direction of benefit was present with the potential to improve secondary outcomes. A prospective, large-sample, multicenter trial is warranted to confirm these findings. | PMC10163013 |
Methods | PMC10163013 | |||
Study design | artery atherosclerosis, Stroke | STROKE | HOPES2 (Head-dOwn Position for acutE moderate ischemic Stroke with large artery atherosclerosis) was an investigator-initiated, prospective, randomized, open-label, blinded-endpoint (PROBE), multicenter and phase-2 trial to assess the feasibility, safety and possible efficacy of two weeks of HDP in moderate AIS-LAA patients within 24 h from symptom onset. Due to the small sample size and no involving genetic information and materials, this trial was waived approval from China’s Ministry of Science and Technology related to the export of genetic information and materials. The trial was conducted at 10 medical sites (Supplementary Note | PMC10163013 |
Participants | death, TOAST, Stroke, stroke, Head and neck CTA, ischemic stroke, AIS | STROKE, ACUTE STROKE, STROKE, ISCHEMIC STROKE | Eligible patients were adults aged 18 years or older with acute moderate ischemic stroke (defined as baseline National Institutes of Health Stroke Scale [NIHSS] scores 6 to 16) with probable LAA etiology at the time of randomization who had been functioning independently in the community (modified Rankin Scale [mRS] scores 0 to 1; range 0 [no symptoms] to 6 [death]) before the stroke, and were enrolled up to 24 hours after onset of stroke symptoms (defined as the time the patient was last seen well). Head and neck CTA or MRA imaging were done on admission to identify AIS patients with probable LAA etiology based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria | PMC10163013 |
Randomization and masking | In this trial, eligible patients were randomly assigned (1:1) using a computer-generated randomization sequence with a block size of four and sealed envelopes, prepared by an independent statistician, into either HDP group receiving Trendelenburg as an adjunct to guideline-based medical management, or a control group only receiving guideline-based medical management. The final 90-day mRS was evaluated by one qualified personnel who was blinded to treatment allocation according to a standardized procedure manual in each study center. Central adjudication of clinical and safety outcomes was also conducted by assessors unaware of treatment allocation or clinical details. | PMC10163013 | ||
Procedures | stroke, ischemic stroke | STROKE, ISCHEMIC STROKE | In the HDP group, patients were positioned to −20° Trendelenburg position from 8:00 a.m. to 10:00 p.m. within the first 24 h after randomization. During this period, the patients were continuously monitored by ECG and blood oxygen saturation, and asked to report any discomfort. If the patients could not tolerate this position, they were then adjusted slowly to a horizontal position for 10 to 30 min, and then returned to −20°. The repositioning could be repeated during HDP treatment. After 24 h, patients were placed in a −20° Trendelenburg position with 1 to 1.5 h duration three times a day, from 9:00–11:00, 15:00–17:00, and 20:00–22:00, respectively. The treatment procedure lasted for 10 to 14 days. During the treatments, the side-lying position with −20° Trendelenburg was allowed if there was a high risk of aspiration suspected by local providers. In the control group, patients were treated according to the AHA/ASA 2018 guidelines for the early management of ischemic stroke without any intervention of head position (supine or sitting position determined by local investigator).Neurological status, measured with the NIHSS, was assessed at baseline, 7 days, and 12 days after randomization. Demographic and clinical details were obtained at randomization. Follow-up data were collected at 7 days, 12 days (or at hospital discharge if earlier), and 90 days after randomization. Remote and on-site quality control monitoring and data verification were performed throughout the study. All patients received standard medical management according to national stroke guidelines | PMC10163013 |
Outcomes | pneumonia, headache, anxiety | PNEUMONIA, ADVERSE EVENTS, INTRACRANIAL HEMORRHAGE, ADVERSE EVENT, EVENTS | In the original design, the primary endpoint was the proportion of excellent functional outcome, defined as an mRS score of 0–1 at 90 days (Supplementary Note Prespecified safety outcomes included any adverse events and serious adverse events during HDP, such as patient fear, headache, anxiety, intracranial hemorrhage, cardiopulmonary events, and pneumonia, which were not present at the beginning of the study. Adverse events with HDP were adjudicated by the chairman of the data safety monitoring board (YLW). | PMC10163013 |
Statistical analysis | No formal sample size calculation was performed due to no relevant data available from previous trials. For this exploratory trial, the sample size (50 patients per group) was based on the recommendation of the Steering Committee. Statistical analyses were performed on a modified intention-to-treat (mITT) principle, which comprised of patients who are randomized, regardless of whether they prematurely discontinue treatment or are otherwise protocol violators/deviators. Participants who lost to follow-up or withdrew will not be included in the mITT population. Baseline characteristics and procedural details were compared with Student’s This trial of HOPES2 was registered with ClinicalTrials.gov with the number NCT03744533 on November 16, 2018, and is now closed at all participating sites. | PMC10163013 | ||
Reporting summary | Further information on research design is available in the | PMC10163013 | ||
Supplementary information |
Supplementary InformationPeer Review FileReporting Summary | PMC10163013 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-38313-y. | PMC10163013 | ||
Acknowledgements | We thank the investigators and research staff of the HOPES2 trial (Supplementary Note | PMC10163013 | ||
Author contributions | N.-N.Z. and H.-S.C. wrote the first draft of the manuscript. H.-S.C. designed the study and critically revised the manuscript. N.-N.Z., Y.C., X.-Q.L., C.-S.Z., Y.-T.M., H.Z., C.-H.J., R.-H.L., L.-S.W., Z.J., H.-B.X., Z.L., and T.-G.Y. participated in data collection. N.-N.Z., Y.C., and D.-L.W. analyzed the data. T.N.N. critically revised the manuscript. All authors vouch for the data and analysis and contributed to writing the paper. | PMC10163013 | ||
Peer review | PMC10163013 | |||
Data availability | De-identified data collected for the study, including age, sex, baseline NIHSS score, treatment allocation, and functional outcome, will be shared beginning 3 months and ending 5 years following publication by requesting the corresponding author (Hui-Sheng Chen, email: chszh@aliyun.com) for academic purposes. The corresponding author will reply to the request within 2 months, subject to the approval of the ethics committees of the General Hospital of Northern Theater Command. | PMC10163013 | ||
Competing interests | The authors declare no competing interests. | PMC10163013 | ||
References | PMC10163013 | |||
Background: | mild-to-moderate coronavirus disease 2019 | CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME | Limited treatment options exist for patients with mild-to-moderate coronavirus disease 2019 (COVID-19), irrespective of vaccination history or risk status. Ensitrelvir is a novel oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like (3CL) protease inhibitor. While phase 2 studies of ensitrelvir have demonstrated promising results in treating mild-to-moderate COVID-19, evaluation of its clinical efficacy due to shifting vaccination status and emergence of the Omicron variant represents significant challenges. Here, we describe the protocol for a phase 3 study designed to evaluate the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19, regardless of risk status or vaccination history. | PMC9949372 |
Methods: | sore throat, tiredness, cough | SORE THROAT, SECONDARY, ADVERSE EVENTS | This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. Patients with mild-to-moderate COVID-19 within 120 hours from onset will be randomized in a 1:1:1 ratio into 3 treatment arms–ensitrelvir 125 mg (375 mg loading dose on Day 1), ensitrelvir 250 mg (750 mg loading dose on Day 1), and placebo. The study interventions will be administered orally, once-daily, for 5 days. The primary endpoint will be the time to resolution of 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and the key secondary endpoints will include the change from baseline on Day 4 in the amount of SARS-CoV-2 viral ribonucleic acid (RNA) and the time to first negative SARS-CoV-2 viral titer. The primary population for the primary and key secondary endpoints will be patients with <72 hours from COVID-19 onset to randomization and, subsequently, patients in entire patient population (<120 hours) in the ensitrelvir 125 mg group. Closed testing procedure will be used for the primary and key secondary endpoints in both the primary and entire patient populations. All safety assessments and adverse events (AE) will be reported. | PMC9949372 |
Discussion: | In a post hoc analysis of the phase 2b study, compared with placebo, ensitrelvir demonstrated a reduced time to resolution of 5 symptoms in patients with mild-to-moderate COVID-19. Through this study, we intend to validate and establish the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. | PMC9949372 | ||
1. Introduction | SARS-CoV-2 infection, illness, infectious respiratory illness | CORONAVIRUS, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME, SARS-COV-2 INFECTION | Coronavirus disease 2019 (COVID-19) is an infectious respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)The SARS-CoV-2 Omicron is a variant of concern designated by WHO.As of April 2022, several therapeutic antiviral drugs against SARS-CoV-2 infection are available worldwide.Ensitrelvir fumaric acid (S-217622, hereafter ensitrelvir) is a novel oral SARS-CoV-2 3CL protease inhibitor that originated through collaborative research efforts between Shionogi & Co., Ltd., and Hokkaido University.In this manuscript, we describe the protocol for a phase 3 study, with emphasis on the study rationale and key endpoints designed to assess the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19, irrespective of their risk status of developing severe illness and vaccination history. | PMC9949372 |
2. Materials and methods | PMC9949372 | |||
2.1. Study design | This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study to test the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. The study will be conducted across several sites in Japan, Korea, Singapore, and Vietnam beginning in February 2022 and has been registered in the Japan Registry of Clinical Trials: jRCT2031210350. Patients will be randomized into 3 arms—ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo. The intervention period will span 5 days (Days 1–5), during which patients will be administered ensitrelvir or placebo, followed by a follow-up period of 23 days (Days 6–28; Fig. Study design. | PMC9949372 | ||
2.2. Study ethics | MINOR | This study will be conducted in accordance with the protocol and consensus ethical principles derived from the Declaration of Helsinki, the Council for International Organizations of Medical Sciences international ethical guidelines, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guidelines, and Good Clinical Practice guidelines. The protocol, protocol amendments, and other relevant documents will be submitted to the institutional review boards of the participating sites for approval. All patients will be required to provide written informed consent/assent to participate in the study before undergoing any evaluations or procedures. For minor patients, written informed consent will be obtained from a parent/legal guardian. All patients will be informed about the use of their personal, study-related data in accordance with data protection laws. The information and results of this study will be disclosed at the clinical study registration site and other sites. The results of this study may be published or presented at scientific meetings. | PMC9949372 | |
2.3. Randomization and blinding | EVENT, ADVERSE EVENT | Eligible patients will be randomly assigned to the 3 treatment arms in a 1:1:1 ratio using an interactive response technology, and a study intervention allocation table will be created. Randomization will be stratified by the time from the onset of COVID-19 to randomization (<72 hours vs ≥72 hours) and by SARS-CoV-2 vaccination history (vaccinated [first dose completed] vs unvaccinated). Placebo drugs will be indistinguishable in appearance, labeling, and packaging from treatment drugs. All relevant personnel, including the sponsor, patients, investigator, and subinvestigator, will remain blinded to the treatments. Unblinding at the request of the investigator may be permitted only in the event of an emergency or adverse event (AE) when knowledge of the intervention may be needed for an appropriate course of therapy. | PMC9949372 | |
2.4. Eligibility criteria | PMC9949372 | |||
2.4.1. Inclusion criteria. | sore throat, diarrhea, cough, tiredness, headache, nausea,, shivering, chills, aches, shortness of breath | SORE THROAT, TASTE DISORDER, SMELL DISORDER | Patients must be capable of providing signed informed consent/assent and must be ≥12 years and <70 years of age at the time of providing informed consent/assent. All patients must have been diagnosed as SARS-CoV-2–positive within 120 hours before randomization via either a nucleic acid detection test using a nasopharyngeal swab, nasal swab, or saliva (qualitative/quantitative reverse transcription-polymerase chain reaction [RT-PCR] test or an isothermal nucleic acid amplification method [e.g., the loop-mediated isothermal amplification method or the transcription-mediated amplification method]), a quantitative antigen test using a nasopharyngeal swab, nasal swab, or saliva, or a qualitative antigen test using a nasopharyngeal or nasal swab; have a time from COVID-19 onset to randomization of ≤120 hours (when at least 1 of the 14 symptoms occurs: low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, stuffy or runny nose, sore throat, cough, shortness of breath, nausea, vomiting, diarrhea, smell disorder, and taste disorder); and have at least 1 moderate symptom (COVID-19 symptom score 2; Supplemental Table 1, | PMC9949372 |
2.4.2. Exclusion criteria. | gallstones, SARS-CoV-2 infection, kidney disease, liver disease, hepatic or biliary abnormalities, Gilbert syndrome | GALLSTONES, ADVERSE EVENT, SARS-COV-2 INFECTION, KIDNEY DISEASE, LIVER DISEASE, SYSTEMIC INFECTION, GILBERT SYNDROME | Patients will be excluded if they have ≤ 93% (room air) saturation of percutaneous oxygen during wakefulness; require oxygen administration or respirators; are strongly suspected or expected to have worsening of symptoms associated with SARS-CoV-2 infection within 48 hours after randomization in the opinion of the investigator or subinvestigator; have suspected active and systemic infections (excluding SARS-CoV-2 infection) requiring treatment at the time of randomization; currently have or have a chronic history of moderate or severe liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert syndrome or asymptomatic gallstones), or moderate or severe kidney disease (Grade 2 or higher based on Common Terminology Criteria for Adverse Events version 5.0Patients satisfying inclusion criteria 1 to 3 and not satisfying exclusion criteria 1 to 4 listed above are considered to have mild-to-moderate COVID-19. | PMC9949372 |
2.5. Interventions | PMC9949372 | |||
2.5.1. Drug dose and administration. | Based on the results of the phase 2a | PMC9949372 | ||
2.5.2. Criteria for discontinuation. | SARS-COV-2 INFECTION | The study intervention will be discontinued for patients who experience worsening of SARS-CoV-2 infection, experience serious or intolerable AEs, are found to be ineligible for the study by the investigator or subinvestigator, request to discontinue the study interventions, are lost to follow-up, become pregnant, or for any other reason per the judgment of the investigator or subinvestigator. | PMC9949372 | |
2.5.3. Prohibited concomitant therapy. | APPENDIX | Because ensitrelvir has an inhibitory effect on CYP3A, patients must refrain from consuming any foods and beverages containing grapefruit or Seville oranges and also avoid consuming products containing St. John wort during the study intervention period. Details of prohibited concomitant drugs are provided in the Supplemental Appendix 1, | PMC9949372 | |
2.6. Outcome measures and endpoints | sore throat, smell or taste disorder, tiredness, cough | SORE THROAT, SECONDARY, RECURRENCE, SARS-COV-2 INFECTION | The primary endpoint for this study will be the time to resolution of the 5 COVID-19 symptoms, defined as the time from the start of the study intervention until the resolution of the 5 symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness) of SARS-CoV-2 infection. Patients will assess their symptoms using a partially modified index prescribed by the Food and Drug Administration (FDA)The 2 key secondary endpoints for this study will be change from baseline on Day 4 in the amount of SARS-CoV-2 viral RNA (key secondary endpoint 1) and the time to first negative SARS-CoV-2 viral titer, defined as the time from the first administration of the study intervention until the first confirmation of SARS-CoV-2 viral titer below a predetermined detection limit (key secondary endpoint 2). To evaluate the antiviral and clinical efficacy more clearly, for the primary and key secondary endpoints, the primary analysis population was defined as patients randomized <72 hours from the onset of COVID-19.Other secondary endpoints will include the time to resolution of the 5 COVID-19 symptoms without symptom recurrence, defined as no increase of any symptom scores to moderate or severe at least for 48 hours after achieving resolution; the time to resolution of the 12 and 14 COVID-19 symptoms; the proportion of patients with smell or taste disorder at each time point; the proportion of patients without resolution of COVID-19 symptoms 3 weeks after the study intervention; change from baseline in SARS-CoV-2 viral titer and viral RNA at each time point; and scores on the 8-point ordinal scale at each time point (Supplemental Table 3, | PMC9949372 |
2.7. Rationale for the primary endpoint | CORONAVIRUS DISEASE 2019, PROLIFERATION, PATHOPHYSIOLOGY, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME | The phase 2aIn the phase 2a and 2b studies,Patient demographics and clinical characteristics (ITTThis population comprises all patients randomly assigned to the study intervention with SARS-CoV-2 viral titer detected at baseline. The detection of SARS-CoV-2 viral titer was confirmed by viral titer assessment based on nasopharyngeal swab samples. Patients were analyzed according to the assigned study intervention.This table was presented as a poster at OPTIONS-XI(26-29 Sep 2022): Post-Hoc Analyses of Ensitrelvir Phase 2b part in Phase 2/3 Study (SCORPIO-SR): Exploratory Clinical Endpoints in Patients with Mild to Moderate COVID-19 Symptoms (P-535).Hiroshi Yotsuyanagi, Norio Ohmagari, Yohei Doi, Hiroki Sakaguchi, Takuhiro Sonoyama, Genki Ichihashi, Yuko Tsuge, Takeki Uehara, Hiroshi Mukae.ITT = intention-to-treat, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.The main pathophysiology of COVID-19 is due to viral proliferation for several days after onset followed by inflammatory reaction by the host immune system starting around 7 days after onset,In the post hoc analysis of the phase 2b study, the median time to resolution of the 5 COVID-19 symptoms in patients randomized to the study intervention <72 hours from the COVID-19 onset was shorter both in ensitrelvir 125 mg and 250 mg arms compared with the placebo arm (placebo, 10.4 days; ensitrelvir 125 mg, 6.9 days; ensitrelvir 250 mg, 6.3 days; Fig. Kaplan–Meier plot of the time to resolution of the 5 COVID-19 symptoms in the patient group with <72 h from the onset to randomization in the phase 2b study (ITT* population). *This population comprises all patients randomly assigned to the study intervention with SARS-CoV-2 viral titer detected at baseline. The detection of SARS-CoV-2 viral titer was confirmed by viral titer assessment based on nasopharyngeal swab samples. Patients were analyzed according to the assigned study intervention. COVID-19 = coronavirus disease 2019, ITT = intention-to-treat, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.The primary endpoint was finalized after consultations with experts and regulatory authorities. | PMC9949372 | |
2.8. Patient timelines | The schedule of activities for each patient will include efficacy and safety assessments (Table Schedule of activities. | PMC9949372 | ||
2.9. Statistical analysis | PMC9949372 | |||
2.9.1. Analysis populations. | SARS-CoV-2 infection | SECONDARY, SARS-COV-2 INFECTION | Primary and secondary endpoints and other efficacy endpoints, except for endpoints related to the viral titer, will be assessed in the intention-to-treat (ITT) population, comprising all patients randomized to a study intervention and having SARS-CoV-2 infection confirmed by an RT-PCR test based on the nasopharyngeal swab sample from Visit 1 (preintervention). Secondary endpoints and other efficacy endpoints related to the SARS-CoV-2 viral titer will be assessed in the modified ITT (mITT) population, comprising all patients randomized to a study intervention with positive RT-PCR test results on Visit 1 and a SARS-CoV-2 viral titer detected at baseline. All safety assessments will be conducted in the safety analysis population comprising patients who were randomized to a study intervention and who received at least 1 dose of the study intervention.The population whose time from onset of COVID-19 to randomization in the ITT (or mITT for viral titer-based endpoints) population is <72 hours will be the primary analysis population for both the primary and key secondary endpoints. If a significant difference is found in the populations, the same analysis as the primary endpoint and key secondary endpoints will be performed on the entire ITT (or mITT) population.Pharmacokinetic/pharmacodynamic analysis of the phase 2b study showed no clear difference in the antiviral efficacy between ensitrelvir 125 mg and 250 mg. | PMC9949372 |
2.9.2. Statistical tests. | SECONDARY, RECURRENCE | For discrete variables, summary statistics such as the number and proportion of patients in each group will be calculated. For continuous variables, summary statistics such as the number of patients, arithmetic mean (mean), standard deviation, minimum, median, and maximum values will be calculated for each group. The 95% confidence intervals (CIs) will be calculated using the Clopper-Pearson methodAs primary analysis for the primary endpoint, a comparison of the time to resolution of the 5 COVID-19 symptoms will be performed between the ensitrelvir 125 mg group and placebo group using a Peto-Prentice generalized Wilcoxon testThe primary analyses for each of the 2 key secondary endpoints are as follows: for the key secondary endpoint 1, a comparison of the change from baseline on Day 4 in the amount of SARS-CoV-2 viral RNA will be performed between the ensitrelvir 125 mg group and the placebo group using an analysis of covarianceOther analyses for the primary and key secondary endpoints in the population with <72 hours from COVID-19 onset to randomization from the ITT or mITT population are as follows: a comparison of the time to resolution of the 5 COVID-19 symptoms and the time to the first negative SARS-CoV-2 viral titer will be performed between the ensitrelvir 125 mg group and the placebo group using a log-rank testAnalysis of the time to sustained resolution of the 5 COVID-19 symptoms for 48 hours or longer without any recurrence of the 5 COVID-19 symptoms for 2 days (48 hours) or longer after the resolution of the 5 COVID-19 symptoms will be performed using the same analysis as that for the primary endpoint (except for multiplicity adjustment).For the analysis of the time to resolution of the 12 COVID-19 symptoms that persist for ≥24 hours between the ensitrelvir 125 mg and the placebo group, the same analyses as for the primary endpoint will be performed (except for multiplicity adjustment).For analyzing the change from baseline in SARS-CoV-2 viral titer and the amount of viral RNA at each time point, least squares means and difference between the ensitrelvir 125 mg group and the placebo group based on the analysis of covariance model | PMC9949372 | |
2.9.3. Sample size estimation. | coronavirus disease | Referring to the Kaplan–Meier curve of the time to resolution of the 5 COVID-19 symptoms in a patient group with <72 hours from the onset of COVID-19 to randomization in the phase 2b study, we assumed a Weibull distribution as shown in Figure Weibull distribution (A) and corresponding hazard ratio curve (B) assumed when calculating the required number of patients for the phase 3 study for the time to resolution of the 5 symptoms of COVID-19. COVID-19 = coronavirus disease 2019.As described above, phase 3 consisted of 3 arms: the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo arms. The analysis population and the primary endpoint were changed based on the phase 2b outcomes as well as the sample size estimation. The original sample size estimation was as follows: in the phase 2b study, the median time to resolution for each ensitrelvir arm was conservatively assumed to be 8 days, while that for the placebo arm was assumed to be 10 days. The original primary comparisons were pairwise comparisons between each ensitrelvir group and the placebo group, which required multiplicity adjustment. Using the Bonferroni method | PMC9949372 | |
2.9.4. Imputation of missing data. | Missing data will not be imputed; all statistical analyses will be based on observed cases, unless otherwise specified. Missing assessments in a patient diary after the initial administration of the study intervention will be imputed: morning times will be imputed as 11:59:59 and evening times will be imputed as 23:59:59 (only evening times apply for Days 10–21). | PMC9949372 | ||
2.9.5. Data management and monitoring. | ADVERSE EVENT | No interim analyses will be performed for this phase 3 study. An Independent Data Monitoring Committee will not be established. A Data and Safety Monitoring Board will be established for the purpose of third-party evaluation of safety throughout the study period. All patient data relating to the study will be recorded on electronic case report forms (eCRFs) unless electronically transferred to the sponsor or designee (e.g., laboratory data, electronic patient-reported outcomes). After the follow-up period is complete, all data in the eCRFs for each patient will be locked. Source data verification will be performed to confirm that the data entered into the eCRFs by authorized site personnel are accurate, complete, and verifiable from source documents, that the safety and rights of patients are being protected, and that the study is being conducted in accordance with the currently approved protocol and any other study agreements and applicable regulatory requirements.All AEs and serious adverse event (SAEs) will be monitored from the time of providing informed consent/assent until the end of the follow-up period, as per the schedule of activities (Table | PMC9949372 | |
3. Discussion | infection, taste disorder, smell disorder, illness | TASTE DISORDER, SARS-COV-2 INFECTION, DISEASE, RECRUITMENT, SEVERE ACUTE RESPIRATORY SYNDROME, INFECTIONS, INFECTION, OF SMELL DISORDERS, CORONAVIRUS, SMELL DISORDER | We described the protocol for a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial to assess the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3CL protease inhibitor, in expediting the resolution of symptoms in patients with mild-to-moderate COVID-19. We aimed to test the hypothesis that COVID-19 symptoms resolve sooner when patients are treated with ensitrelvir compared with placebo. Through this study, we sought to validate the potential antiviral efficacy of ensitrelvir observed in previous studies and to further establish its clinical efficacy and safety.Approximately 81% to 85% of patients with COVID-19 experience mild-to-moderate symptoms.To maximize patient recruitment during the SARS-CoV-2 epidemic, the phase 3 study aims for a seamless study design with continuous patient enrollment after the phase 2b study.Both the ensitrelvir 125 mg and 250 mg regimens demonstrated a potent antiviral efficacy against SARS-CoV-2 in the phase 2aTo evaluate the clinical efficacy of ensitrelvir against the SARS-CoV-2 infection, we will apply the primary endpoint focusing on the 5 major symptoms of the SARS-CoV-2 infection. In the post hoc analyses of the phase 2b study data, a trend toward a difference in the time to resolution of symptoms was observed between the ensitrelvir groups and placebo group; the time to resolution of symptoms was shorter in the ensitrelvir groups than in the placebo group. Additional analysis of the phase 2b study on smell and taste disorder revealed that compared with placebo, ensitrelvir reduced the number of patients experiencing both smell disorder (ensitrelvir 125 mg, Proportion of patients showing occurrence of smell disorder (A) and taste disorder (B) in the phase 2b study (ITT* population). *This population comprises all patients randomly assigned to the study intervention with SARS-CoV-2 viral titer detected at baseline. The detection of SARS-CoV-2 viral titer will be confirmed by viral titer assessment based on nasopharyngeal swab sample. Patients will be analyzed according to the assigned study intervention. ITT = intention-to-treat, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.Irrespective of risk factors and the severity of infection, symptoms of COVID-19 may persist for a prolonged duration. Therefore, a stringent endpoint such as the time to resolution of symptoms may be suitable for evaluating the clinical efficacy of ensitrelvir in mild-to-moderate infections. Moreover, this endpoint is also appropriate in light of disease modification due to vaccination and the emergence of new variants. Since there is no information on how symptoms in mild-to-moderate COVID-19 progress over time, the endpoint of time to resolution of COVID-19 symptoms will provide clarity on how symptoms resolve with or without an antiviral treatment.One of the strengths of this study is that it includes patients with COVID-19, irrespective of whether they are at a high-risk of developing severe illness, which broadens its relevance to the general adolescent and adult populations. Additionally, this study will enroll both vaccinated and unvaccinated individuals, unlike other studies assessing oral antivirals that mainly recruited unvaccinated patients. Since vaccination has a large impact on how the infection manifests in individuals, including vaccinated patients in the study will provide a comprehensive understanding of the antiviral treatment that reflects the current status of the SARS-CoV-2 pandemic.It is hoped that this phase 3 study will be able to confirm the clinical efficacy and safety of ensitrelvir in the treatment of mild-to-moderate COVID-19, and that the results will help provide evidence on symptom progression or improvement. | PMC9949372 |
Acknowledgments | We thank Shintaro Tanaka, Masahiro Kinoshita, Satoshi Kojima, and Manami Yoshida for their contributions toward the development and review of this manuscript. Medical writing and editorial support were provided by Varsha Sreenivasan, PhD, of Cactus Life Sciences (part of Cactus Communications Pvt. Ltd.) and funded by Shionogi & Co., Ltd. | PMC9949372 | ||
Corrections | Table 2 was formatted incorrectly in the original article. This has been updated in the current version of the article. The publication years of references 34 and 35 have been updated from 2017 to 2022. | PMC9949372 | ||
Supplementary Material | PMC9949372 | |||
Abbreviations: | SARS-CoV-2 infection, respiratory syndrome, Sonoyama T | CORONAVIRUS, INFECTIOUS DISEASES, SARS-COV-2 INFECTION | 3C-likeadverse eventconfidence intervalcoronavirus disease 2019cytochrome P450 3Afood and drug administrationelectronic case report formintention-to-treatmodified intention-to-treatribonucleic acidreverse transcription-polymerase chain reactionserious adverse eventsevere acute respiratory syndrome coronavirus 2World Health OrganizationProtocol version: Version 10, Amendment 9, Issued 20 September 2022. Publication history: This manuscript was previously posted to Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.This study was funded by Shionogi & Co., Ltd., and financially supported by the Organization of the Ministry of Health, Labor and Welfare. Employees of Shionogi & Co., Ltd., participated in and approved the design and conduct of the study, wrote the protocol, and were involved in the collection, management, analysis, and interpretation of data. Institutional authors reviewed and approved the protocol and collected and interpreted the data.Supplemental Digital Content is available for this article.HY reports consulting fees from Shionogi, lecture fees from Shionogi and ViiV Healthcare, and travel support from Shionogi outside the submitted work. He serves as an advisory board member for Shionogi and President of the Japanese Society of Infectious Diseases. NO declares no conflict of interest. YD reports grants from Shionogi and Entasis; consulting fees from Shionogi, Meiji Seika Pharma, Gilead Sciences, GSK, MSD, Chugai, and bioMerieux; and lecture fees from MSD, AstraZeneca, Shionogi, and Teijin Healthcare outside the submitted work and serves as an advisory board member for FujiFilm. TI, T Sonoyama, GI, T Sanaki, YT, and TU are full-time employees of Shionogi & Co., Ltd., and may own stocks or stock options. HM has received funding relevant to the submitted work from Shionogi and grants from Taisho Pharma; lecture fees from Pfizer, MSD, Shionogi, and Taisho Pharma; and advisory fees from Pfizer, MSD, and Shionogi outside the submitted work.Trial sponsor: Shionogi & Co., Ltd.Trial registration: Japan Registry of Clinical Trials (How to cite this article: Yotsuyanagi H, Ohmagari N, Doi Y, Imamura T, Sonoyama T, Ichihashi G, Sanaki T, Tsuge Y, Uehara T, Mukae H. A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part). Medicine 2023;102:8(e33024). | PMC9949372 |
References | PMC9949372 | |||
Key Points | PMC10163390 | |||
Question | TBI, traumatic brain injury | Does a home-based intervention that is individually tailored and goal oriented improve health-related quality of life (HRQOL) and participation and ameliorate symptoms in the chronic phase of traumatic brain injury (TBI)? | PMC10163390 | |
Findings | TBI | In this randomized clinical trial including 120 adult participants in the chronic phase of TBI, no significant results were seen in disease-specific HRQOL or social participation. However, generic HRQOL and TBI- and anxiety-related symptom levels improved significantly in the intervention group compared with the control group. | PMC10163390 | |
Meaning | TBI | These findings suggest that an individually tailored and goal-oriented rehabilitation program might be effective in improving generic HRQOL and symptom burden in the chronic phase of TBI. | PMC10163390 | |
Importance | heterogeneous difficulties, TBI, Traumatic brain injury | Traumatic brain injury (TBI) can cause long-lasting and heterogeneous difficulties that require an individually tailored approach to rehabilitation. However, high-quality studies of treatment options in the chronic phase of TBI are lacking. | PMC10163390 | |
Objective | TBI | To evaluate the effect of a home-based, individualized, and goal-oriented rehabilitation intervention in the chronic phase of TBI. | PMC10163390 | |
Design, Setting, and Participants | TBI, TBI-related difficulties | This study was an intention-to-treat parallel-group assessor-blinded randomized clinical trial with 1:1 randomization to an intervention or control group. Participants included adults in southeastern Norway who had sustained a TBI more than 2 years earlier, lived at home, and had ongoing TBI-related difficulties. A population-based sample of 555 individuals were invited, and 120 were included. Participants were assessed at baseline, 4 months, and 12 months after inclusion. Specialized rehabilitation therapists provided the intervention in patients’ homes or via video conference and telephone. Data collection was conducted between June 5, 2018, and December 14, 2021. | PMC10163390 | |
Interventions | The intervention group received an 8-session individually tailored and goal-oriented rehabilitation program over 4 months. The control group received usual care in their municipality. | PMC10163390 | ||
Main Outcomes and Measures | Anxiety, Preestablished, anxiety, Brain Injury, TBI, psychological distress, depression | DISORDER, SECONDARY, POST CONCUSSION SYMPTOMS | Preestablished primary outcomes were disease-specific health-related quality of life (HRQOL; measured by the Quality of Life After Brain Injury [QOLIBRI] overall scale) and social participation (measured by the Participation Assessment With Recombined Tools–Objective [PART-O] social subscale). Preestablished secondary outcomes included generic HRQOL (measured by the EuroQol 5-dimension 5-level [EQ-5D-5L] questionnaire), difficulty with TBI-related problem management (target outcomes; mean severity calculated across 3 main self-identified problem areas that were individually measured using a 4-point Likert scale), TBI symptoms (measured by the Rivermead Post Concussion Symptoms Questionnaire [RPQ]), psychological distress (depression and anxiety; measured by the Patient Health Questionnaire 9-item scale and the Generalized Anxiety Disorder 7-item scale [GAD-7], respectively), and functional competency (measured by the Patient Competency Rating Scale). | PMC10163390 |
Results | TBI | Among 120 participants in the chronic phase of TBI, the median (IQR) age was 47.5 (31.0-55.8) years, and the median (IQR) time since injury was 4 (3-6) years; 85 (70.8%) were male. A total of 60 participants were randomized to the intervention group, and 60 were randomized to the control group. Between baseline and 12 months, no significant between-group effects were found for the primary outcomes of disease-specific HRQOL (QOLIBRI overall scale score: 2.82; 97.5% CI, −3.23 to 8.88; | PMC10163390 | |
Conclusions and Relevance | TBI, anxiety | SECONDARY | In this study, no significant results were observed for the primary outcomes of disease-specific HRQOL or social participation. However, the intervention group reported improvements in secondary outcomes (generic HRQOL and symptoms of TBI and anxiety) that were maintained at 12-month follow-up. These findings suggest that rehabilitation interventions could help patients even in the chronic phase of TBI. | PMC10163390 |
Trial Registration | chronic traumatic brain injury | ClinicalTrials.gov Identifier: This randomized clinical trial assesses the effect of a home-based, individualized, and goal-oriented rehabilitation intervention among adult patients with chronic traumatic brain injury. | PMC10163390 | |
Introduction | chronic disease process, TBI, Traumatic brain injury | Traumatic brain injury (TBI) is a chronic disease process with potential lifelong impact on health and well-being.There are few methodologically rigorous studies that document treatment options in the chronic phase of TBI. The World Health Organization Rehabilitation 2030 InitiativeA challenge when investigating interventions among patients with TBI is the highly heterogeneous consequences of the injury. Interventions should further be aimed not only at symptom reduction, but also at improving HRQOL and participation. To better meet the challenges of individual patients, TBI interventions should be tailored to the specific problem profiles reported by the patient rather than being prespecified by researchers.A randomized clinical trial (RCT) of a home-based goal-oriented intervention has been conducted in the US by Winter et al. | PMC10163390 | |
Methods | This study followed the Consolidated Standards of Reporting Trials ( | PMC10163390 | ||
Trial Design | This trial was a parallel 2-group RCT with 1:1 randomization to either an intervention or control group. Participants were assessed at baseline before randomization. Outcome assessments were performed at 4 months after inclusion (after the end of intervention, some assessments were performed between 4 and 5 months) and again at 12 months after inclusion. Full details are provided in the trial protocol in | PMC10163390 | ||
Participants | TBI | The principal investigator (C.R.) identified potentially eligible participants by screening patients in southeastern Norway who were included in previous studies and outpatient registries, who then were invited by letter. Patients were thereafter contacted by telephone and screened for eligibility. Inclusion criteria included a diagnosis of TBI (based on | PMC10163390 | |
Eligibility Criteria | PMC10163390 | |||
Inclusion Criteria | yLives, TBI | TBI diagnosis (based on Age 18-72 y; age ≥16 y at time of injuryTime since injury ≥2 yLives at homeOngoing TBI-related cognitive, emotional, and/or physical problems and/or reduced physical and mental health and/or difficulties with participation in activities with family, friends, and/or in the communityAble to use computer or tablet computer; internet access (added criterion because of the COVID-19 pandemic) | PMC10163390 | |
Exclusion Criteria | violent tendencies, death, psychiatric | DISORDER | Unable to provide informed consentSevere progressive neurological condition or severe ongoing psychiatric disorder that may confound outcomesUnable to collaborate in goal-setting processInsufficient command of Norwegian language (cannot communicate with rehabilitation therapists or respond to questionnaires)Active substance misuse and/or violent tendencies that may put rehabilitation therapists at risk
Abbreviations: Demographic and injury-related data were collected; data on race and ethnicity were not collected because it is not conventional in Norwegian research practice. All participants were evaluated using the Glasgow Outcome Scale–Extended version (score range, 1-8, with 1 indicating death and 7-8 indicating good recovery). | PMC10163390 |
Intervention Group | The intervention group received an 8-session rehabilitation program over 4 months. In-home and video conference sessions typically lasted 2 hours, while telephone sessions typically lasted 1 hour. Four experienced rehabilitation therapists (psychologist [I.M.H.B.], neuropsychologist [S.L.H.], physician [M.V.F.], and physiotherapist [I.K.]) delivered the intervention, and 1 rehabilitation therapist (I.M.H.B., S.L.H., M.V.F., or I.K.) followed up with each participant throughout the intervention. If available and relevant, family members or local health care personnel participated in sessions.An overview of intervention content is available in the eFigure in | PMC10163390 | ||
Control Group | epilepsy, TBI, psychiatric disorders | EPILEPSY | All control group participants received feedback on their baseline assessment, and a brief report was sent to their general practitioner. Because an active control group was not feasible, the control group continued to receive any concomitant care (registered at each time point) they were already receiving, with no additional treatment. In Norway, municipal health care services are mainly responsible for treatment in the chronic phase of TBI. There are no specialized TBI services in the communities, but specialized health care services at hospitals are provided when needed (eg, in cases of moderate to severe psychiatric disorders or epilepsy). | PMC10163390 |
Outcomes | TBI | Two primary outcomes, disease-specific HRQOL and participation, were defined based on experiences from the feasibility study.Secondary outcomes included target outcomes, generic HRQOL, TBI symptoms, depression- and anxiety-related symptoms, and functional competency. Outcome measures consisted of 1 interview-based assessment and 5 questionnaires. For the target outcomes, an interview-based measure was adapted from the study by Winter et al. | PMC10163390 | |
Sample Size | Sample size calculations were conducted before the trial and were based on between-group differences in the change in primary outcomes. The significance level was Bonferroni corrected for a clinically meaningful between-group mean difference of 12% on the QOLIBRI overall scale (with an estimated SD of 20%) and a between-group mean difference of 1.8 on the PART-O (with an estimated SD of 3.0). Thus, with equal randomization to treatment groups, power of 80%, and a significance level of α = .025 (correcting for 2 primary outcomes), the sample size was calculated as 55 patients in each group for both primary outcomes. Allowing for an attrition rate of 10%, 60 participants were included in each treatment group. Sample size calculations were performed using G*Power software, version 3 (Faul et al | PMC10163390 | ||
Randomization | Participants were randomized 1:1 by web-based block allocation (variable sizes of 4 and 6) generated in Stata software, version 15 (StataCorp LLC), by an independent statistician, and the randomization list was provided in a fixed sequential order. The allocation sequence could only be accessed by the principal investigator (C.R.), who was not involved in inclusion procedures. Rehabilitation therapists were responsible for the inclusion of participants and sent a sham number to the principal investigator via email to receive information on group allocation. | PMC10163390 | ||
Blinding | Outcome assessors were blinded. Statistical analyses were conducted by an independent statistician. The first author (I.M.H.B.) wrote the Results section of this article while blinded to group allocation. | PMC10163390 | ||
Statistical Analysis | SECONDARY | Linear mixed-effects models were fitted to primary and secondary outcome variables with time and time-by-treatment interaction as categorical fixed effects. The main effect of treatment was removed from the model to adjust for potential baseline differences in the outcome. The models included a random intercept and a random effect for time. Three variables (PART-O social subscale score, QOLIBRI overall scale score, and GAD-7 score) could not be modeled with the random effect for time; thus, only a random intercept was used. Based on the linear mixed-effects models, mean values for primary outcomes were estimated with 97.5% CIs for all time points (baseline, 4 months, and 12 months) for each group. We also estimated mean within-group and between-group differences in change from baseline to 4 months and from baseline to 12 months. Analyses were performed using the intention-to-treat approach. To accommodate for having 2 independent primary outcomes, a conservative significance level of 2-tailed | PMC10163390 | |
Results | Among 120 participants included in the intention-to-treat analysis, the median (IQR) age was 47.5 (31.0-55.8) years, and the median (IQR) time since injury was 4 (3-6) years; 85 participants (70.8%) were male and 35 (29.2%) were female. A total of 60 participants were randomized to the intervention group (median [IQR] age, 45.5 [29.5-54.0] years; 44 men [73.1%]) and 60 to the control group (median [IQR] age, 49.0 [33.0-60.5] years; 41 men [68.3%]). Overall, 4 participants withdrew from the study or could not be reached at 12 months. The study flowchart is shown in | PMC10163390 | ||
Study Flowchart | Baseline demographic and clinical characteristics were generally similar between groups ( | PMC10163390 | ||
Demographic and Clinical Characteristics of the Intervention and Control Groups | death, TBI, Coma, traumatic brain injury | COMA | Abbreviations: GCS, Glasgow Coma Scale; GOS-E, Glasgow Outcome Scale–Extended; NPCS-Gets, Needs and Provisions Complexity Scale–Gets subscale (measuring levels of service provided); TBI, traumatic brain injury.Among 56 patients.Among 57 patients.Severity was measured using the GCS, with scores of 13 to 15 indicating mild TBI, 9 to 12 indicating moderate TBI, and 3 to 8 indicating severe TBI.Score range, 1 to 8, with 1 indicating death and 7 to 8 indicating good recovery.From baseline to 12 months, no statistically significant between-group differences were found for the primary outcome measures of HRQOL (QOLIBRI overall scale score: 2.82; 97.5% CI, −3.23 to 8.88; | PMC10163390 |
Linear Mixed-Effects Model Results for Primary and Secondary Outcomes | Anxiety, anxiety, traumatic brain injury, Brain Injury, depression | DISORDER, SECONDARY, POST CONCUSSION SYMPTOMS | Abbreviations: EQ-5D-5L, EuroQol 5-dimension 5-level; GAD-7, Generalized Anxiety Disorder 7-item scale; PART-O, Participation and Recombined Tools–Objective; PCRS, Patient Competency Rating Scale; PHQ-9, Patient Health Questionnaire 9-item scale; NA, not applicable; QOLIBRI, Quality of Life After Brain Injury; RPQ, Rivermead Post Concussion Symptoms Questionnaire.97.5% CI was used for primary outcomes and 95% CI for secondary outcomes.Score range, 0 to 100, with higher scores indicating better health-related quality of life.Score range, 0 to 5, with higher scores indicating higher levels of social participation.Mean severity score of 3 main self-identified problems related to traumatic brain injury, which were individually assessed using a 4-point Likert scale, with 0 indicating not difficult at all and 4 indicating extremely difficult.Score range, 0 to 1, with higher scores indicating better health-related quality of life.Score range, 0 to 64, with higher scores indicating greater severity of symptoms.Score range, 0 to 27, with higher scores indicating greater severity of depression.Score range, 0 to 21, with higher scores indicating greater severity of anxiety.Score range, 30 to 150, with higher scores indicating greater functional competency. | PMC10163390 |
Linear Mixed Model Results for Primary and Secondary Outcomes | Brain Injury, Anxiety | DISORDER, SECONDARY, POST CONCUSSION SYMPTOMS | EQ-5D-5L indicates EuroQol 5-dimension 5-level; GAD-7, Generalized Anxiety Disorder 7-item scale; PART-O, Participation and Recombined Tools–Objective social participation subscale; PCRS, Patient Competency Rating Scale; PHQ-9, Patient Health Questionnaire 9-item scale; QOLIBRI, Quality of Life After Brain Injury; and RPQ, Rivermead Post Concussion Symptoms Questionnaire.Within-group results indicated different trajectories in the groups. For the intervention group, statistically significant improvements were seen in all secondary outcomes (eg, target outcomes mean severity score at 12 months: −0.77; 95% CI, −1.01 to −0.53; | PMC10163390 |
Discussion | TBI, TBI-related difficulties, anxiety | SECONDARY | This RCT aimed to evaluate the effect of a home-based, individually tailored, and goal-oriented intervention in improving HRQOL and participation, TBI-related difficulties, and symptoms. Although the 2 primary outcomes, disease-specific HRQOL (as measured by QOLIBRI overall scale scores) and social participation (as measured by PART-O social subscale scores), did not reveal between-group differences, we did see group effects in favor of the intervention group for the secondary outcomes of generic HRQOL, target outcomes severity, TBI-related symptoms, and anxiety.The lack of significant between-group differences in the 2 primary outcomes warrants discussion. It is, however, noteworthy that a significant effect on HRQOL was found in the generic HRQOL measure. Some researchers argue that studies should include both generic and disease-specific measures of QOL.This RCT was modeled after a study by Winter et al,Reductions in TBI- and anxiety-related symptoms were seen. Reduced anxiety may signify less worry and stress as participants experienced less difficulty managing TBI-related problems. The fact that the intervention group showed within-group improvements over time on all outcome measures except the PART-O social subscale supports this interpretation. High goal attainment has been previously documented in this trial,This intervention aimed to address common health care needs among patients in the chronic phase of TBI. Although efforts were made to standardize intervention design and intensity, treatment content was individualized. There is an inherent challenge in measuring mean group effects of an intervention addressing individual needs, despite the fact that symptom heterogeneity requires individual tailoring of rehabilitation.The fact that this intervention resulted in positive changes many years after injury confirms that rehabilitation in the chronic phase of TBI may be effective. | PMC10163390 |
Limitations | TBI sequelae, intracranial injury, TBI, intracranial damage | This study has several limitations. It is important to emphasize that only participants with a radiologically verified intracranial injury were included. The eligibility criteria only allowed inclusion of patients with the capacity to contribute to goal setting and with self-reported TBI-related symptoms. Hence, results might not be applicable to patients with mild TBI without intracranial damage or patients with severe difficulties in awareness and cooperation in goal-setting procedures. Both primary outcomes may have been affected by the COVID-19 pandemic, but other findings nonetheless indicate effectiveness. Although this is one of the larger trials of individualized home-based rehabilitation in chronic TBI sequelae to date, the sample size is nonetheless limited. Both the sample size and the multiple outcomes applied in this trial entail a risk of both type 1 and type 2 errors. Lack of an active control group and exposure to follow-up in the control group (baseline interviews and reports to the participant’s general practitioner) could potentially bias results. | PMC10163390 | |
Conclusions | TBI | In this RCT of a home-based, individually tailored, and goal-oriented intervention in the chronic phase of TBI, participants in the intervention group reported significantly improved generic HRQOL and fewer TBI- and anxiety-related symptoms, which were maintained at 12-month follow-up. These findings suggest that rehabilitation interventions could help patients in the chronic phase of TBI improve their HRQOL and symptom burden. | PMC10163390 | |
Objective | Alzheimer’s disease, AD | Edited by: Hailiang Wang, Hong Kong Polytechnic University, Hong Kong SAR, ChinaReviewed by: Jiaxin Zhang, Southern University of Science and Technology, China; Daniel Young, Hong Kong Baptist University, Hong Kong SAR, ChinaWe aimed to investigate the effect of internet-based and in-person cognitive interventions on cognition, mood, and activities of daily living (ADL) on patients with mild to moderate Alzheimer’s disease (AD) and examine whether internet-based intervention is as effective as the in-person intervention. | PMC10361252 | |
Methods | AD | We recruited 52 patients with probable mild AD, of whom 42 completed the trial. We randomly divided participants into intervention and control groups at a 1:1 ratio and statistically compared the neuropsychological test results of the two groups. In addition, patients in the intervention group were randomly assigned to a 4 weeks internet-based or in-person intervention, with subsequent crossover to the other group for 4 weeks. We statistically analyzed and compared the neuropsychological test scores between internet-based and in-person interventions. | PMC10361252 | |
Results | Compared with the control group, the intervention group (internet-based and in-person) showed significantly improved profile in cognition ( | PMC10361252 | ||
Conclusion | anxiety | This study suggests that both types of cognitive intervention (in-person and internet-based) may be viable supplementary treatments along with approved pharmacological therapy. In terms of anxiety and ADL, the effect of the in-person interventions may be more effective than the-internet based interventions. | PMC10361252 | |
Introduction | Alzheimer’s disease, AD, dementia, coronavirus disease 2019 | CORONAVIRUS DISEASE 2019 | Alzheimer’s disease (AD), a prevalent form of dementia, represent a growing burden in an aging society (The coronavirus disease 2019 (COVID-19) pandemic has challenged the in-person delivery of cognitive interventions to dementia patients ( | PMC10361252 |
Method | PMC10361252 | |||
Participants | Disorders and Stroke-Alzheimer Disease, psychotic or mood disorders, alcoholism, seizure, stroke, metabolic diseases, depressive disorder, schizophrenia, diabetes | FOLIC ACID DEFICIENCY, DISORDERS, CHRONIC RENAL FAILURE, STROKE, HEPATIC FAILURE, METABOLIC DISEASES, HYPERTHYROIDISM, DIABETES | We registered the data of 52 patients at Myongji Hospital in Goyang, Republic of Korea, and Cheongpungho Geriatric Hospital from September to December 2021. All patients underwent a detailed medical history taking, neurological examinations, neuroimaging (brain computed tomography or magnetic resonance imaging), and blood and neuropsychological tests, and met the criteria of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) (The exclusion criteria were the presence of metabolic diseases that could affect cognitive function (hyperthyroidism, vitamin B12 or folic acid deficiency, chronic renal failure, uncontrolled diabetes, and hepatic failure), chronic alcoholism, and a history of stroke, seizure, and brain surgery. Furthermore, patients who met the Diagnostic and Statistical Manual of Mental Disorders (Fifth edition) for psychotic or mood disorders such as schizophrenia or major depressive disorder were also excluded ( | PMC10361252 |
Study design | Fifty-two eligible participants were randomized and allocated into the control (only pharmacological treatment, Study design. We randomly divided participants into intervention and control groups at a 1:1 ratio. In addition, patients in the intervention group were randomly assigned to a 4 weeks internet-based or in-person intervention, with subsequent crossover to the other group for 4 weeks. | PMC10361252 | ||
Randomization | Using covariate-constrained randomization in the cvcrand package, the participants were randomized and allocated to the intervention and control groups. In addition, the participants in the case groups were randomized and allocated to intervention A and intervention B groups. When randomized, age, sex, and baseline CDR were controlled for. | PMC10361252 | ||
In-person and internet-based cognitive intervention programs | A nonpharmacological treatment program was established, incorporating elements of cognitive, music, and art therapies. This consisted of a 1 hour session (30 min each for 32 sessions), split evenly between cognitive training, and either music therapy or art therapy. Cognitive training was provided twice a week, while music and art therapies were conducted once a week. Cognitive training was provided twice a week, and music and art therapy were provided once a week. An internet-based multimodal intervention was delivered over Zoom.Cognitive training comprised 16 sessions of 30 min each conducted over 8 weeks (twice a week). Out of these 16 sessions, eight were conducted via the internet and the other eight in person. Each session consisted of four stages: introductory activity, brain health lifestyle education, main activity, and finishing the activity. The primary activities included five domains: memory, attention, visuospatial function, frontal-executive function, and language and related functions.Music therapy included eight 30 min sessions over 8 weeks (once a week), with half of these sessions conducted over Zoom and the rest in person. Each session was structured into three stages: introductory activity (5 min), main activity (20 min), and finishing activity (5 min). In the therapeutic song singing activity, the participants had time to listen to or sing all the prepared songs together, share feelings, and discuss the meaning of the lyrics. Afterward, each section was divided into groups and solos, and each group member sang in solo and proceeded in a solo-tutti structure performed in the chorus. In addition, therapeutic singing included the writing of song lyrics by group members. In the instrumental activity, participants were expected to improvise their rhythm. After presenting a variety of rhythmic instruments, participants selected their favorite instrument, added their interpretation of the music, and improvised the rhythm presented to them on the therapist’s piano. As participants grew comfortable with their instruments, they began to recognize their roles in the solo-chorus structure, preparing themselves for expression when performing with the rest of the group. The activity involved participants trying to play melody instruments like colored handbells by reading color scores.Art therapy consisted of eight 30 min sessions over 8 weeks (once a week), evenly split between the internet-based and in-person sessions. The content of the internet based art therapy sessions were interconnected with the in-person sessions, involving the four specific sessions: “self-introduction,” (to make name tags), “Henri Matisse” (after appreciating a painting by Henri Matisse, to put the prepared color pieces together, and to make a single picture), “my hometown” (color the letters mandala and complete it), and “memory box” (to make a panorama that expresses the journey of life). The in-person art therapy sessions included the following activities: “self-introduction,” (to make name tags), “Henri Matisse” (after appreciating a painting by Henri Matisse, to carve them, and color each piece by individuals, and to take a picture and share the work by the therapist online), “my home town” (quizzes on my hometown online), and “memory box” [to make trees symbolize old age (present stage) by decorating it with pictures of one’s face and wishes, and share it online]. | PMC10361252 | ||
Neuropsychological tests | The Seoul Neuropsychological Screening Battery ( | PMC10361252 | ||
Assessment of the level of satisfaction | dementia | The level of satisfaction was assessed using the following questions: (1) Was the Centenarian’s Good Memory Program satisfactory? (2) Was the schedule of the Centenarian’s Good Memory Program satisfactory? (3) Were the space and facilities of the Centenarian’s Good Memory Program satisfactory? (4) Was the Centenarian’s Good Memory Program helpful in the prevention of dementia in daily life? (5) Would you recommend participating in the Centenarian’s Good-Memory Program to your acquaintances? (6) Do you want to participate in the Centenarian’s Good Memory Program? Responses to each question were graded from 1 ( | PMC10361252 | |
Statistical analysis | Demographic characteristics between the control and intervention groups were compared using a two-sample | PMC10361252 | ||
Results | PMC10361252 | |||
Participants’ flow, adherence to interventions, and baseline characteristics | depression, dementia, anxiety | Fifty-six patients were included in this study. Fifty-two participants were randomized and assigned in a 1:1 ratio to the intervention and control groups The intervention group was also divided into two subgroups, intervention A and intervention B, through random allocation: (i) intervention A group underwent an internet-based intervention for 4 weeks, followed by in-person therapy for 4 weeks; (ii) intervention B group received the opposite sequence of intervention. In the control group, five participants were excluded according to approved protocols and guidelines of institutional review board because the patients withdrew the consents. Three participants in intervention A group and two in intervention B group discontinued the intervention and were excluded (Demographic and clinical characteristics.NMDA, N-methyl-D-aspartate receptor; SSRI, selective serotonin reuptake inhibitor; MMSE, mini-mental state examination; GdepS, geriatric depression scale; BAI, Beck anxiety inventory; SIADL, Seoul instrumental activity of daily living; CDR, clinical dementia rating. | PMC10361252 | |
Comparison of the score of neuropsychological tests between control and intervention groups | depression, dementia, anxiety | When comparing the effect of non-pharmacological interventions [internet-based intervention (4 weeks) and in-person interventions (4 weeks)] with the control group (pharmacological treatment only for 8 weeks) after controlling for CDR-SOB and education year using ANCOVA, the K-MMSE (Comparison of the neuropsychological test results before and after intervention.MMSE, mini-mental status examination; KDSQ, Korean dementia screening questionnaire; GdepS, geriatric depression scale; BAI, Beck anxiety inventory; SIADL, Seoul instrumental activities of daily living. Post-intervention scores were compared using analysis of covariance (ANCOVA) after adjusting for the baseline education year and clinical dementia rating-sum of boxes (CDR-SOB).Comparison of the neuropsychological test results of the control and intervention groups. The scores of K-MMSE, KDSQ, GdepS, BAI and SIADL after 8 weeks was compared with baseline scores. | PMC10361252 | |
Comparison of neuropsychological profiles and the level of satisfaction between the internet-based and in-person intervention periods | depression, dementia, anxiety | For the same participants, we compared the difference in scores during the internet-based and in-person intervention period. The score difference on the internet-based intervention period was not significantly different from that of the in-person intervention period in the MMSE (Comparison of the neuropsychological test results according to the type of cognitive intervention (MMSE, mini-mental status examination; KDSQ, Korean dementia screening questionnaire; GdepS, geriatric depression scale; BAI, Beck anxiety inventory; SIADL, Seoul instrumental activities of daily living. Post-intervention scores were compared using analysis of covariance (ANCOVA) after adjusting for the baseline education year and clinical dementia rating-sum of boxes (CDR-SOB).Comparison of the score of neuropsychological tests of the Zoom and in-person intervention periods. The scores difference of K-MMSE, KDSQ, GdepS, BAI, SIADL and level of satisfaction during the Zoom intervention period were compared with the score difference during the in-person intervention period.In addition, no significant difference was observed in the level of satisfaction between the internet-based and in-person interventions (24.7 vs. 24.5, | PMC10361252 | |
Discussion | depression, AD, anxiety | The present study was a randomized controlled trial (RCT) that investigated the effect of the internet-based and in-person interventions on cognitive function, mood, and ADL of 42 patients with probable AD according to the NINCDS-ADRDA criteria. This study suggests that the multimodal intervention, in conjunction with pharmacological treatment, was more effective in improving cognitive function, mood, and ADL than pharmacological treatment alone which is compatible with previous studies (Previous studies have shown that non-pharmacological interventions, including cognitive training, affect cognition in older adults (First, cognitive intervention was more effective in improving the K-MMSE, S-IADL, GdepS, and BAI scores in the case group than in the control group with only pharmacological treatment. In terms of cognition, because of the practice effect of repeated tests, we double-checked the subjective change in the cognitive function to be identified to caregivers using the KDSQ-C. The KDSQ-C score of the intervention group significantly improved compared to that of the control group. Considering that existing pharmacological treatment has only a limited effect on ADL, it is noteworthy that it added evidence of the effect of cognitive intervention on ADL (Second, when the effect of the internet-based intervention was compared with that of the in-person intervention among the same patients, the effects on cognition and depression were not significantly different between the two interventions. However, the internet-based intervention may be as effective as in-person intervention for improving anxiety and ADL. Regarding depression, the internet-based intervention might be as effective as in-person interventions, which is consistent with a previous study that found that group intervention relieves loneliness and depression among older people during the COVID-19 pandemic (This RCT demonstrated that non-pharmacological multimodal interventions (internet-based and in-person interventions) improve cognitive function, ADL, and mood in patients with AD compared to the control group (pharmacological treatment only). In addition, the effect of the internet-based intervention on cognition and depression was not significantly different from that of the in-person intervention. Therefore, the internet-based intervention may be effective enough to be applied to patients with mild to moderate AD. However, our study has some limitations. First, it’s difficult to say that this study perfectly controlled the effects of the medication. There was no significant difference in the proportion of drug use between the two groups and we maintained the type and dosage of medication from the original drug treatment during the research period, although we could not completely stop medication and purely observe the effects of the intervention due to ethical considerations. Second, the washout period was not allocated between the two intervention periods, considering that each intervention period was only 4 weeks long, and the intervention may not be residual in the body, unlike pharmacologic treatment. Third, we did not use an amyloid biomarker to diagnose AD; therefore, diagnostic uncertainty remains unclear. Fourth, the sample size was relatively small, and the study period was not long. Particularly, due to the limited sample size in both intervention A and B group, it’s still uncertain whether the internet-based interventions is effective as the in-person interventions.In conclusion, this study demonstrated that the intervention (in-person and internet-based) group showed improved cognition, ADL, and mood more than the control group in patients with mild to moderate AD. In terms of anxiety and ADL, the effect of the in-person interventions might be more effective than the-internet based interventions. Furthermore, this study suggested that both types of non-pharmacological interventions (in-person and internet-based interventions) may be viable supplementary treatments to be administered along with an approved pharmacological therapy. | PMC10361252 | |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10361252 |
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