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Data Availability | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10150529 |
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Declarations | PMC10150529 |
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Ethics approval and consent to participate | Cancer | CANCER | All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol and informed consent were approved by the City of Hope Comprehensive Cancer Center Institutional Review Board IRB# 20731. Informed consent was obtained from all study participants. | PMC10150529 |
Consent for publication | Not applicable. | PMC10150529 |
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Competing interests | The authors declare that they have no competing interests. | PMC10150529 |
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References | PMC10150529 |
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Background | cancer, Colorectal cancer, skeletal muscle mass, colorectal | CANCER, COLORECTAL CANCER, POSTOPERATIVE COMPLICATIONS | Colorectal cancer survivors often experience decline in physical performance and poor quality of life after surgery and during adjuvant therapies. In these patients, preserving skeletal muscle mass and high-quality nourishment are essential to reduce postoperative complications and improve quality of life and cancer-specific survival. Digital therapeutics have emerged as an encouraging tool for cancer survivors. However, to the best of our knowledge, randomized clinical trials applying personalized mobile application and smart bands as a supportive tool to several colorectal patients remain to be conducted, intervening immediately after the surgical treatment. | PMC10069348 |
Methods | skeletal muscle mass, pain | COLORECTAL CANCER, SECONDARY | This study is a prospective, multi-center, single-blinded, two-armed, randomized controlled trial. The study aims to recruit 324 patients from three hospitals. Patients will be randomly allocated to two groups for one year of rehabilitation, starting immediately after the operation: a digital healthcare system rehabilitation (intervention) group and a conventional education-based rehabilitation (control) group. The primary objective of this protocol is to clarify the effect of digital healthcare system rehabilitation on skeletal muscle mass increment in patients with colorectal cancer. The secondary outcomes would be the improvement in quality of life measured by EORTC QLQ C30 and CR29, enhanced physical fitness level measured by grip strength test, 30-sec chair stand test and 2-min walk test, increased physical activity measured by IPAQ-SF, alleviated pain intensity, decreased severity of the LARS, weight, and fat mass. These measurements will be held on enrollment and at 1, 3, 6 and 12 months thereafter. | PMC10069348 |
Discussion | cancer, colorectal cancer | CANCER, COLORECTAL CANCER | This study will compare the effect of personalized treatment stage-adjusted digital health interventions on immediate postoperative rehabilitation with that of conventional education-based rehabilitation in patients with colorectal cancer. This will be the first randomized clinical trial performing immediate postoperative rehabilitation in a large number of patients with colorectal cancer with a tailored digital health intervention, modified according to the treatment phase and patient condition. The study will add foundations for the application of comprehensive digital healthcare programs focusing on individuality in postoperative rehabilitation of patients with cancer. | PMC10069348 |
Trial registration | MAY | NCT05046756. Registered on 11 May 2021. | PMC10069348 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12885-023-10728-2. | PMC10069348 |
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Keywords | PMC10069348 |
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Background | colorectal cancer, fatigue, cancer, pain, Colorectal cancer | COLORECTAL CANCER, LOW ANTERIOR RESECTION SYNDROME, CANCER, SECONDARY, COLORECTAL CANCER | Colorectal cancer is the third and second most common cancer worldwide in men and women, respectively [Health behaviors, such as physical activity and nutrition, can have positive effects on physical functioning, quality of life, and symptoms related to cancer treatment, such as fatigue among cancer survivors [At present, many cancer survivors rarely use tools to report subjective data such as pain, fatigue, and distress [Mobile health care application has emerged as an encouraging device in managing the clinical course of cancer and improving quality of life and physical performance in cancer survivors. Mobile health is defined as the provision of health services and information through mobile and wireless technologies [To the best of our knowledge, randomized clinical trials that applied a personalized, phase-specific digital health program using mobile application and smart bands to a large number of patients with colorectal cancer have not yet been conducted, especially starting immediately post cancer operation. The primary objective of this protocol is to clarify the effect of mobile application and wearable smart band on skeletal muscle mass increment in patients with colorectal cancer. The secondary outcomes will be improvement in quality of life, enhanced physical fitness level, increased physical activity, diminished pain intensity, decreased severity of the low anterior resection syndrome, weight, and fat mass. | PMC10069348 |
Methods | PMC10069348 |
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Study design | This protocol will be a prospective multi-centered two-armed randomized controlled trial. The study design meets SPIRIT guidelines [ | PMC10069348 |
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Participants | colorectal cancer, neuromusculoskeletal disease, cognitive or visual impairment | DISEASE, COLORECTAL CANCER | In this study, we will enroll 324 participants who were diagnosed with colorectal cancer and have undergone surgery. The inclusion criteria will be as follows: (a) aged 19–85 years, (b) diagnosed with colorectal cancer and undergone colorectal cancer resection surgery, (c) uses an Android- or iOS-based smartphone, (d) able to use mobile application and have regular follow-up assessment as outpatient, (e) voluntary participation. The exclusion criteria will be as follows: (a) unable to perform exercise and diet management because of severe underlying disease, neuromusculoskeletal disease, or cognitive or visual impairment, (b) communication difficulties.All eligible patients will be informed about this study, and after consultation with the department of surgery and the department of rehabilitation medicine they will be invited to participate. All patients will submit a written informed consent if they agree to participate in the study. | PMC10069348 |
Randomization, allocation, and blinding | We used blocked randomization with randomly selected block sizes (block size: 3 and 6). This study is an open study; therefore, the name of the group is not blinded. Owing to the nature of the intervention, the participant and evaluator can recognize which intervention has been assigned to the participant. After randomly allocating patients into two groups with a 1 (control group): 2 (intervention group) ratio, baseline assessment will be performed.
Flow chart of the randomized controlled trial | PMC10069348 |
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Interventions | PMC10069348 |
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Personalized digital therapeutic (intervention) group | cancer, colorectal cancer, Colon Cancer | CANCER, COLORECTAL CANCER, COLON CANCER | For the personalized digital therapeutic group, Colon Cancer by Second Doctor program (Medi Plus Solution, Seoul, Korea) for health management after colorectal cancer surgery and DoFit as a smart band on the wrist (NF-B20, Medi Plus Solution, Seoul, South Korea) will be used. The application and fundamental contents are developed by an expert team consisting of app developers, designers, service programmers, cancer rehabilitation specialists, and researchers as the basis of evidence. It can be used on both Android and iOS platforms. Data collected from smart band can be transferred to application via Bluetooth connection. This smart band is capable of measuring the physical activity (step counts and energy expenditure), heart rate through a built-in 6-axis accelerometer, gyroscope, and photoplethysmography sensor. In addition, information from smart devices such as blood pressure monitors, blood glucose monitors, and weight scales can be linked with the application.The key app functions are indicated in Table Health care professionals can monitor the individual usage of participant using a web-based open architecture management program including all life log data. To manage the adherence to the mHealth-based intervention, we will monitor the application usage rate every 2 weeks for 12 months, and feedback will be provided during initial 3 months. | PMC10069348 |
Control group | pelvic floor muscle, comorbid diseases | The control group will go through conventional education and usual care in hospital for 12 months.
Functions of the mobile application and key characteristics• It offers an aerobic exercise program with target heart rate and exercise time according to the user’s treatment type. In addition, using a weekly step-by step approach, the exercise program with video clips is provided by combination of stretching and muscle strengthening exercises and pelvic floor muscle training.• The contents of exercise are personalized according to the user information (surgery and treatment type); difficulty is adjusted by rating the perceived exertion after the exercise.• If a user inputs their daily diet using speech recognition and text input functions, it provides feedback of the intake, food balance, and protein and fat, with the marking as insufficient, adequate, or excessive.• The weight information entered at the time of membership registration becomes the standard for the initial recommended calorie intake.• It simply recommends foods and its amount for breakfast, lunch, dinner, and snacks. Moreover, it recommends nutritional intake according to comorbid diseases from the 13th week.• It indicates target blood pressure and blood glucose level based on the clinical practice guidelines.• It informs the user whether their weight is within the normal weight range.
Screenshots of the representative function and smart-band: (A) home (today’s to do list), (B) second doctor journal, (C) exercise management, (D) weight management, (E) diet management, (F) exercise video (pelvic floor muscle training), and (G) DoFit. Reproduced with permission of Medi Plus Solution. Co., Ltd | PMC10069348 |
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Primary outcome | colorectal cancer, skeletal muscle mass | COLORECTAL CANCER | The primary objective of this study is to determine the effect of mobile application and wearable smart band in the management of prognostic factors in colorectal cancer patients. Therefore, the primary outcome would be the skeletal muscle mass increment in the intervention group compared to the control group in 12 months from the baseline, measured using the bio impedance analysis. | PMC10069348 |
Secondary outcomes | muscle mass, NRS, pain | LOW ANTERIOR RESECTION SYNDROME, RECTAL CANCER, MINOR, SECONDARY, APPETITE LOSS | The secondary objectives of our study are quality of life, body function and composition, and pain intensity over time.The quality of life will be evaluated using the European Organization for Research and Treatment of Cancer-Quality of life Questionnaire (EORCT-QLQ-C30 and CR29). EORTC QLQ-C30 is composed of functional, symptom, and global quality of life domain. The quality-of-life scale uses a modified 7-point linear analog scale. All other items are scored on a 4-point categorical scale, ranging from 1 “not at all” to 4 “very much” [International physical activity questionnaire-short form (IPAQ-SF) is divided into vigorous activity, moderate activity, walking, and lying down to evaluate the amount of activity in the last seven days. The participants are also asked to define the number of min and days spent performing a specific activity category [Mini nutritional assessment (MNA) defines nutritional status. It is divided into several domains for anthropometric assessment (weight, height, and weight and appetite loss) [Physical fitness is evaluated using the grip strength test, 30-sec chair stand test (CST), and 2-min walk test (2MWT). Grip strength is assessed using a hand-held dynamometer (microFET® Digital HandGRIP Dynamometer, Hoggan Scientific LLC, USA). The patients are asked to use the maximal hand grip power (kg). The patients repeat this three times for three seconds, and the average of the results will be recorded [The abdomen and pelvis will be analyzed using computed tomography (CT). To measure muscle mass and visceral fat, we will analyze the cross-sectional area in a single CT slice at the height of the third lumbar vertebra [Rectal cancer patients without ileostomy or colostomy would be evaluated for defecation function by Low Anterior Resection Syndrome Score (LARS) questionnaire. Patients are categorized into three groups: no LARS (0–20), minor LARS (21–29), and major LARS (30–42) [The pain intensity for the past week will be evaluated by a 11-point Numeric Rating Scale (NRS) [Additionally, the intervention group will undergo a general assessment with e-health literacy at baseline and the self-developed satisfaction questionnaire for mobile application and Internet of Things device after 6 months. The eHealth Literacy Scale (eHEALS) is designed to assess consumer’s perceived skills at using information technology for health and to aid in determining the applicability of eHealth programs for individual consumers. The eHEALS has 10 items, where items 1 and 2 are supplementary. Eight questions assess eHealth literacy on a 5-point Likert scale, in which a higher score indicates higher literacy [ | PMC10069348 |
Sample size calculation | Based on a previous study [ | PMC10069348 |
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Data management | For systematic data management, electronic data capture of Medicallogic Company ( | PMC10069348 |
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Statistical analysis | skeletal muscle mass | REGRESSION, SECONDARY | All data will be analyzed using IBM SPSS Statistics version 28.0.1 (Armonk, New York, USA) and a significance level of 5% will be set with a 95% confidence interval. Patient demographics will be calculated using descriptive statistics. Kolmogorov–Smirnov test will be performed to assess the distribution of data. To compare baselines between the two groups, a student’s t-test and chi-squared test will be conducted. In case the randomization is not balanced, the baseline difference will be corrected through multivariate logistic regression and analyzed. To compare the mean difference, if the primary outcome (skeletal muscle mass) data in both groups are found to be normally distributed, we will perform an independent t-test. Missing data will be handled depending on the distribution of data after study completion. To investigate the effects of the interventions and differences between groups for secondary outcomes, a mixed effects model or generalized estimating equations will be conducted, with one between-subject factor (group) and one within-subject factor (evaluation time). | PMC10069348 |
Discussion | cancer, colorectal cancer | DISEASE, CANCER, COLORECTAL CANCER | Owing to COVID-19 pandemic, home-based exercise is emerging as a promising tool for physical therapy. However, the biggest shortcoming of home-based program is still the poor management of compliance. Contrarily, previous studies on health management service applications had segmental interventions, such as only applying the health program during chemotherapy or dealing mainly with only psychological or nutrition-related issues [To the best of our knowledge, this will be the first randomized clinical trial performing digital therapeutics for personalized postoperative rehabilitation in patients with colorectal cancer. The study has several differentiated strong points. First, it starts immediately after the operation for one year. Second, a large number of colorectal cancer patients will be enrolled. Third, the program will be composed of a tailored digital health intervention, modified according to the treatment phase and patient condition. Another short-term positive consequence of our program includes reduction of financial and time burden on patients as well as on clinicians. In the long term, an integrated medical management of disease and psychological intervention would enable more comprehensive disease controlling systems.In conclusion, this study will clarify the effect of patient-centered mobile and wearable digital health interventions on immediate postoperative rehabilitation of the patients with colorectal cancer. The study will add foundations for the application of comprehensive digital healthcare programs in postoperative rehabilitation for cancer patients in remote areas. | PMC10069348 |
Trial status | MAY, RECRUITMENT | The first participant recruitment began on 11 May 2020. | PMC10069348 |
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Participant safety and withdrawal | cancer metastasis | DISEASE, RECURRENCE | The researcher’s name and phone number for an emergency contact will be provided to ensure the patient’s safety. All participants are informed that they can voluntarily discontinue the study at any time and they could be withdrawn when the significant disease non-related to study is detected, cancer metastasis and recurrence occurs, or if they did not follow the instruction of doctor in charge. | PMC10069348 |
Ethics and dissemination | KC21FNSI0177 | All study procedures were approved by the Institute Review Board of three hospitals (approval numbers: SMC-2021-01-090, 2021AN0104 and KC21FNSI0177). The trial is registered on clinicaltrials.gov (approval ID: NCT05046756). The study protocol was reviewed by the institutional review board of Samsung Medical Center on 1 Feb 2021 and was approved on 23 Feb 2021 as original protocol. In the case of important protocol modifications, principal investigator will share them with coordinating investigators and trial participants, and report to the institutional review board.Personal information about enrolled participants will be collected, shared with clinic (i.e., Korea University Anam Hospital and Seoul St. Mary’s Hospital), and retained only by the research team during study. After the end of the study, all personal information will be retained for 3 years and subsequently destroyed.The trial results will be published in the journal and report of results will be posted on the funding institute’s site for the public, participants, and healthcare professionals.Any publications containing the results of this study have not been already published or submitted to any journal. | PMC10069348 |
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Acknowledgements | We thank Medi Plus Solution for their technical support and all of the hospital members who devoted their effort for the study. | PMC10069348 |
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Author Contribution | JHH and JYL2 conceptualized the project idea and study design, refined the final manuscript, and acquired the funding. IK, JYL1, and SWK drafted the project proposal manuscript in preparation for publication submission. All authors participated in the design of the study and coordination of the study. All authors read and approved the final manuscript. | PMC10069348 |
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Funding | Cancer | CANCER, -20 | This research which was reviewed by external peers during the funding process, is financially supported by the National IT Industry Promotion Agency (NIPA) funded by the Ministry of Science and ICT of Korea (Project number: S2001-20-1006 and S2401-21-1001, Project Healthcare big data showcase utilization service support: Cancer patient treatment and prognosis management service development). The funding body gives financial support to the patient as well as in data collection, data management and designing of the study. | PMC10069348 |
Data Availability | Not applicable. | PMC10069348 |
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Declarations | PMC10069348 |
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Ethics approval and consent to participate | All study procedures were approved by the Institute Review Board of Samsung Medical Center, Korea University Anam Hospital and Seoul St. Mary’s Hospital (approval numbers: SMC-2021-01-090, 2021AN0104 and KC21FNSI0177) respectively. A written informed consent will be obtained from the patient. | PMC10069348 |
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Consent for publication | Not applicable. | PMC10069348 |
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Competing interests | The authors declare that they have no competing interests. | PMC10069348 |
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List of Abbreviations | ANTERIOR | Computed tomographyEuropean Organization for Research and Treatment of Cancer-Quality of life QuestionnaireMini Nutritional AssessmentInternational Physical Activity Questionnaire-Short FormLow Anterior Resection Syndrome30-second chair stand test2-minute walk testNumeric Rating ScaleeHealth Literacy Scale | PMC10069348 |
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References | PMC10069348 |
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Background and Objectives | GENETIC DISORDERS, MITOCHONDRIAL MYOPATHIES | Go to The Article Processing Charge was funded by Stealth Biotherapeutics.Coinvestigators are listed at This Null Hypothesis article is published as part of a collaborative effort between NeurologySubmitted and externally peer reviewed. The handling editor was Associate Editor Anthony Amato, MD, FAAN.Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. | PMC10382259 |
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Methods | fatigue, Fatigue | MITOCHONDRIAL MYOPATHY | After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. | PMC10382259 |
Results | SE, tiredness, fatigue | Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was −3.2 (95% CI −18.7 to 12.3; | PMC10382259 |
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Discussion | Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. | PMC10382259 |
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Trial Registration Information | Trial registered with | PMC10382259 |
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Classification of Evidence | Primary mitochondrial diseases, primary mitochondrial myopathy, fatigue, MMPOWER-1, primary mitochondrial myopathies | MITOCHONDRIAL DISEASES, DISORDERS, METABOLIC DISORDERS | This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.A consensus of experts define primary mitochondrial myopathies (PMMs) as a diverse group of genetically confirmed disorders of the mitochondria, affecting predominantly, but not exclusively, skeletal muscle, thereby adversely affecting physical function and quality of life.Primary mitochondrial diseases (PMDs) caused by both mitochondrial (mtDNA) and nuclear DNA (nDNA) alteration are among the most common inherited metabolic disorders.Currently, available standards of care primarily use dietary supplements that have limited clinical impact.Elamipretide is an investigational mitochondrial-targeting agent in development for treating patients with a variety of mitochondrial diseases.The elamipretide clinical development program included MMPOWER-1 and MMPOWER-2, whereby treatment with elamipretide demonstrated meaningful improvements in patient-reported outcomes (PROs) for patients with confirmed PMM. | PMC10382259 |
Methods | PMC10382259 |
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Study Design and Participants | myopathy, end-organ damage, fatigue, 7–28 | MITOCHONDRIAL DISEASE, MYOPATHY, MUSCLE WEAKNESS | MMPOWER-3 was a 24-week , randomized, double-blind, parallel-group, placebo-controlled clinical trial for adults with PMM conducted at 27 clinical research centers in 7 countries (Canada, Denmark, England, Germany, Hungary, Italy, and the United States).MMPOWER-3 trial participants were primarily identified by the RePOWER registry, a global, prospective, noninterventional registry enrolling 413 ambulatory individuals 16–80 years of age with signs and/or symptoms of PMM.After screening (7–28 days), eligible participants were randomized in a 1:1 ratio to receive either 24-weeks of once-daily SC dosing of 40 mg of elamipretide or placebo. Study drug or placebo was self-administered subcutaneously by trained participants or their caregivers, at rotating sites around 4 quadrants of the abdomen or the thighs. Treatment began at the baseline visit with assessments at weeks 4, 12, and 24.Eligible participants were those between 16 years or older and 80 years or younger (18 years or older in Germany), diagnosed with PMM with a confirmed sequence alteration affecting mitochondrial function, and those with symptoms (i.e., exercise intolerance, fatigue, muscle weakness) and/or physical examination findings consistent with a myopathy as the predominant manifestation of their mitochondrial disease. In addition, participants had to be willing and able to provide consent and adhere to trial requirements for inclusion. An acceptable form of birth control was required of participants of childbearing potential during the study.Participants walking <100 meters or >450 meters during the 6MWT at screening/baseline were also excluded. Participants were not allowed to have had a recent (within 30 days) or planned hospitalization/procedure and were excluded if they had a clinically significant end-organ damage in the opinion of the investigator. | PMC10382259 |
Standard Protocol Approvals, Registrations, and Patient Consents | ICH | MMPOWER-3 was conducted in accordance with international ethics guidelines, including the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, ICH GCP guidelines, and all applicable laws and regulations. The study was approved by institutional review boards, and all participants provided written informed consent ( | PMC10382259 |
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Randomization and Masking | Assignment to treatment groups within each cohort for the randomized portion of the study was determined by a computer-generated random sequence using an Interactive Web-Response System to assign identical glass vials containing either the elamipretide or a placebo, which consisted of the same formulation without elamipretide. Participants were stratified by the subclassification of the specific sequence alteration causing their PMM, as determined by the adjudication committee formed to review and confirm eligibility for study enrollment. | PMC10382259 |
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Study Assessments and Procedures | SECONDARY | MMPOWER-3 was designed to assess the safety and efficacy of elamipretide through primary and secondary clinical study endpoints. | PMC10382259 |
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Efficacy Assessments | tiredness, fatigue | SECONDARY, MITOCHONDRIAL MYOPATHY | Coprimary endpoints evaluated the effect of elamipretide for 24 weeks including the distance walked (in meters) on the 6MWT and the total fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA), previously described in detail.Most bothersome symptom score on the PMMSA and the NeuroQoL Short-Form fatigue scores were secondary endpoints. The Neuro-QoL evaluates and monitors sensations ranging from tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that decreases capacity for physical, functional, social, and mental activities, based on a 5-point scale (1 = never, 2 = rarely, 3 = sometimes, 4 = often, and 5 = always).Other secondary endpoints included the patient global impression (PGI) and clinician global impression (CGI) of PMM symptoms. PGI and CGI assess patient and clinician overall assessment of the severity of patients' symptoms related to PMM on a 5-point scaled question scored 0 to 4 (0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very Severe) and changes to their symptoms on a 7-point scale scored −3 to 3 (−3 = very much worse, −2 = moderately worse, −1 = a little worse, 0 = no change, 1 = a little better, 2 = moderately better, and 3 = very much better).The PMMSA was performed during screening, baseline, and daily throughout the 24-week study period. Other efficacy endpoints were performed at screening, baseline, and at weeks 4, 12, and 24 of randomized treatment. | PMC10382259 |
Safety Assessments | ADVERSE EVENTS, ADVERSE EVENT | Safety and tolerability of elamipretide at a dose of 40 mg/d SC were assessed through recording of adverse events (AEs), ascertained through self-report, vital signs, physical examination, ECGs, and clinical laboratory evaluations. Adverse events were assessed for severity and relationship to study medication throughout the 24-week study. Safety measures were assessed during screening, baseline and weeks 4, 12, and 24. | PMC10382259 |
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Statistical Analysis | SECONDARY, EVENT | A sample size of 202 participants, with 101 participants in each treatment arm, was determined to provide 90% power to detect a 30-meter difference between treatment groups in the 6MWT and a 90% power to detect a 1-unit difference in the PMMSA TFS. This was assuming standard deviations of 60 meters for 6MWT and 2 units for the PMMSA TFS, at an alpha level of 0.025, as established from a previous study of elamipretide in patients with PMM.Efficacy was assessed in the intention-to-treat (ITT) population, defined as all participants who received at least 1 dose of investigational medication, and the per-protocol (PP) population, which included all ITT participants without defined protocol violations/deviations identified per blinded data review before database lock. These protocol violations/deviations included not meeting inclusion/exclusion criteria or having a selected major protocol deviation deemed to potentially affect efficacy findings; not completing the study; not receiving investigational treatment within 2 days before the week 24 visit; having <80% compliance to investigational product; and not completing the study. Safety was assessed in the safety population, defined as all participants who received at least 1 dose of investigational medication.Primary and secondary efficacy outcomes were assessed as the change from baseline to each on-treatment time point with the primary time point being end of treatment (week 24). Analyses of continuous endpoints were conducted using a mixed-model repeated measures approach, with fixed effects for treatment, visit, the treatment-by-visit interaction, and participant as a random effect. The baseline value and a baseline-by-visit interaction for the endpoint were included as covariates. A family-wise alpha level of 0.05 was maintained for the primary endpoints, using Hochberg procedure at the primary time point of 24 weeks. If both primary endpoints were significantly different from placebo at the 0.05 (2-sided ) level of significance in favor of elamipretide, then both endpoints were considered statistically significant. If not, the endpoint with the smaller In the event that both endpoints in the primary endpoint family were significant at the 5% level, then secondary endpoints were to be tested at week 24 with type I error control, achieved by testing sequentially using a 2-sided alpha level of 0.05. The endpoints and hierarchy of comparisons were as follows: (1) change from baseline in Neuro-QoL Fatigue Short-Form (T score); (2) change from baseline in PGI of PMM symptoms; (3) change from baseline in CGI of PMM symptoms; and (4) change from baseline in most bothersome symptom score on the PMMSA. Sequential comparisons to control type I error were only to be completed if previous comparisons were statistically significant. For these analyses, | PMC10382259 |
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Subgroup Analyses by PMM Genotype | Given the extensive genetic heterogeneity of the study population, an exploratory analysis of genetic subgroups by genomic alteration (mtDNA and nDNA) was performed using the same methods as described for the primary efficacy endpoints earlier (ITT population using similar mixed-model repeated measure [MMRM] models).Because of a potential data entry error, which was later identified in post hoc data analysis, 3 participants were misclassified in the clinical study report as having a pathogenic mtDNA variant. Post hoc analyses revealed that these 3 participants instead had nDNA alteration, either in | PMC10382259 |
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Pharmacokinetic Analysis | The PK population included 106 participants randomized and treated with elamipretide, with at least 1 PK sample taken during their participation. PK modeling for elamipretide and its metabolites, M1 and M2, were performed using NONMEM computer software. Covariates, such as age, genotype, weight, height, lean body mass, body mass index, liver function tests, serum creatinine, and renal function (as described by estimated glomerular filtration rate [eGFR]) were analyzed. The exposure-response analysis examined response based on the 6MWT as a function of steady-state exposure to elamipretide and its metabolites. | PMC10382259 |
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Role of the Funding Source | The funding source for this study participated in the development of the study design. All authors participated in data collection, data interpretation, and the clinical study report writing. The manuscript lead author had full access to the totality of the study data. The remaining authors were provided with an aggregate data analysis. All authors had final responsibility for the decision to submit for publication. | PMC10382259 |
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Data Availability | Anonymized data not published within this article will be made available by request from any qualified investigator. | PMC10382259 |
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Protocol and Statistical Analysis Plan | The study protocol and statistical analysis plan were published. | PMC10382259 |
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Results | PMC10382259 |
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Participants | Of the 296 participants screened for eligibility in MMPOWER-3, 218 were enrolled and randomized to treatment (elamipretide n = 109; placebo n = 109) between October 2017 and December 2019 ( | PMC10382259 |
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Participant Disposition | ADVERSE EVENT | Two hundred ninety-six participants were screened, and 218 participants were randomized to treatment. Two participants in the elamipretide group and 1 patient in the placebo group had the treatment withdrawn due to adverse event before study discontinuation. The ITT population included 109 participants in the elamipretide group and 109 participants in the placebo group. The PP population included 102 participants in the elamipretide group and 103 participants in the placebo group. ITT = intention-to-treat; PP = per-protocol.Participant demographics at baseline were similar between treatment groups, and characteristics demonstrated similar impairment in PMM (Baseline Participant DemographicsMost Bothersome Symptom in PMMSA at ScreeningBaseline genetic test results showed most of the participants (74%, n = 162) had mtDNA alteration, with the remainder (26%, n = 56) having nDNA defects (Participants' Genetic Classifications | PMC10382259 |
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Efficacy | PMC10382259 |
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Primary Endpoints of Overall ITT | SE | Analysis of the 6MWT at the end of treatment showed the least squares mean (LS) (SE) of change from baseline in distance walked at week 24 was 14.1 (±5.7) meters for participants receiving elamipretide and 17.3 (±5.7) meters for participants receiving placebo, a −3.2-meter difference between the 2 groups (95% CI −18.7 to 12.3; | PMC10382259 |
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MMPOWER3 Change in Endpoints From Baseline to End of Treatment (Week 24) | SE, Primary Mitochondrial Myopathy, fatigue, Fatigue | MITOCHONDRIAL MYOPATHY | In 6-minute walk test (6MWT) (A), in Primary Mitochondrial Myopathy Symptom Assessment Total Fatigue Score (PMMSA) (B), in patient global impression (PGI) of Primary Mitochondrial Myopathy Symptoms (C), and in clinician global impression (CGI) of Primary Mitochondrial Myopathy Symptoms (D). Elamipretide-treated participants reported more total fatigue at baseline and less total fatigue at end of treatment, as assessed by the PMMSA TFS. The LS mean (SE) of change from baseline to week 24 on the PMMSA TFS was −1.13 (±0.22) for participants receiving elamipretide and −1.05 (±0.22) for participants receiving placebo, a −0.07 difference between the 2 groups (95% CI −0.69 to 0.54; Secondary endpoint results are summarized in eTable 1 ( | PMC10382259 |
Analyses by Genetic Subgroup: mtDNA vs nDNA | SE | mtDNA: Subgroup analysis for participants with mtDNA alteration of the 6MWT at the end of treatment showed the LS mean (SE) of change from baseline in distance walked at week 24 was 14.0 (±6.1) meters for participants receiving elamipretide (n = 74) and 25.0 (±6.1) meters for participants receiving placebo (n = 79), an −11.0-meter between-group difference favoring placebo (95% CI −28.1 to 6.1; | PMC10382259 |
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Change From Baseline to End of Treatment (Week 24) in 6-Minute Walk Test: Subgroup Analysis by Genetic Abnormality | SE, −0.21 | Subgroup analysis by genetic abnormality for change from baseline to end of treatment (week 24) in 6MWT for (A) participants with mtDNA alteration and (B) participants with nDNA alteration.nDNA: For participants with nDNA alteration (post hoc analysis), the LS mean (SE) change from baseline in distance walked at week 24 was 25.5 (±8.0) meters for participants receiving elamipretide (n = 29) and 0.3 (±7.7) meters for participants receiving placebo (n = 29), a 25.2-meter difference between the 2 groups favoring elamipretide (95% CI 3.1–47.3; For participants with mtDNA alteration, the LS mean (SE) of change from baseline at week 24 on the PMMSA TFS was −1.3 (±0.2424) for participants receiving elamipretide and −1.1 (±0.2525) for participants receiving placebo, a −0.21 difference between the 2 groups (95% CI −0.9 to 0.5; | PMC10382259 |
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Safety | ADVERSE EVENT | In total, 109 participants received elamipretide and 109 received placebo. AEs during the treatment period were reported by a higher percentage of elamipretide-treated participants (98.2% [n = 107/109]) than placebo-treated participants (76.1% [n = 83/109]) (Adverse Events for Participants in the Elamipretide and Placebo Groups | PMC10382259 |
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Pharmacokinetics | Population pharmacokinetic models were fit successfully to 3 analytes, elamipretide and 2 metabolites, M1 and M2. For elamipretide, systemic parameters scaled allometrically. No covariates influenced the systemic or absorption parameters. For M1 and M2, apparent clearance decreased with age and increased with renal function. No other covariates influenced the systemic parameters. In the exposure-response analysis, participants with an nDNA alteration had an increase in the change and fractional change at week 24 compared with that at day 1 (i.e., baseline) value for the 6MWT as a function of the elamipretide steady state area under the curve ( | PMC10382259 |
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Discussion | mitochondrial myopathy, PMD, fatigue, Fatigue | SECONDARY, DRUG MECHANISM, MITOCHONDRIAL MYOPATHY | We present the results of the first phase 3 trial in PMM with elamipretide. Overall, participants who received elamipretide did not meet either primary or secondary endpoints. Specifically, there were no statistically significant changes between elamipretide and placebo in the 6MWT or the PMMSA Total Fatigue Score. MMPOWER-3 uncovered several findings, specifically the importance of considering pathogenic genotypes within the PMM population when evaluating the effect of investigational treatments. Among the most interesting findings of the trial, identified in a post hoc analysis, was that participants with PMM with nDNA defects performed significantly better on the 6MWT, whereas participants with mtDNA alteration did not differ from placebo. The insight from these subgroups are novel findings and are expected to contribute substantially to future PMM studies.Patient improvements in 6MWT and PMMSA TFS from this study showed a similar trend as those results obtained from the phase 1/2 (MMPOWER-1) and phase 2 (MMPOWER-2) clinical trials of elamipretide in patients with PMM.While this study did not meet either of its primary endpoints (changes in the 6MWT and PMMSA Total Fatigue Score), participants treated with elamipretide did report slightly less total fatigue (between-group difference was not statistically significant) at the end of treatment, as assessed by the PMMSA Total Fatigue Score. Future studies are needed to elucidate whether the slight change in PMMSA Total fatigue score in treated and untreated participants is within the test variability range or a true measure of fatigue improvement not reaching statistical significance due to the mild-to-moderate impairment of participants at baseline and increased heterogeneity in participant selection.The response in 6MWT in the nDNA cohort, as a function of plasma area under the curve (AUC0-24), demonstrates a statistically significant correlation, which supports this subgroup finding, and suggests that the therapeutic dose may not be optimized. It is possible that the exposure-response relationship may differ by genotype/phenotype. These findings warrant further investigation and clearly underscore the importance of considering genetic subtypes in mitochondrial myopathy and the drug mechanism of action. All the genes responsible for mtDNA maintenance are expressed in the nuclear genome.Although the patient population with PMM included in the MMPOWER-3 study was impaired on the 6MWT at baseline compared with literature-based healthy controls (655 [±91] meters),In this phase-3 study, elamipretide was generally well tolerated. Most AEs were mild to moderate in severity, with the most commonly reported AEs including injection site reactions. This safety was similar to that observed in the MMPOWER-2 studyThere are important lessons to be learned from this clinical trial regarding trial design in PMD. The first is that a better understanding of the natural history of PMM will help in future studies. Although the RePOWER pretrial, noninterventional registryThe second lesson is that there is a clear need to further study meaningful endpoints in this patient population. Fatigue has been identified as the primary issue which this patient population experiences, identifying a definitive focal point to be addressed in future therapeutic trials. Refining the sensitivity of the PMMSA fatigue scores in PMD and PMM further to capture signals is tantamount for future studies to address data gaps.The lack of available biomarkers for PMM also presented challenges. The variability of participant responses to the PMMSA Total Fatigue score, which is susceptible to a placebo effect were all challenges that skewed the objectivity of the study endpoints. Furthermore, the mild-to-moderate fatigue scores observed at baseline point to a lack of sensitivity of this endpoint. The identification of objective endpoints or biomarkers assessing PMM would be beneficial for future trial design because the availability of biomarkers helps to target individuals who are most likely to respond to treatment, providing the ability to verify target engagement, which could allow the use of enrichment strategies and reduce reliance on effort-dependent endpoints. For example, altered plasma acylcarnitine levels have previously been seen in patients with PMM,The third lesson is from the basket design from MMPOWER-3, which pooled both nDNA and mtDNA participants. The placebo effect on 6MWT was prominent in mtDNA participants in the prespecified subgroup analysis, and given the size of this subgroup, this drove the placebo effect observed in the trial. Conversely, there was not a discernible placebo response on 6MWT in nDNA participants (depicted in The MMPOWER clinical development program was the most advanced and complete in PMM and provided significant lessons regarding study design and patient enrollment parameters. MMPOWER-3 was the first trial that progressed into phase 3 to assess a therapy for participants with PMM. Although the primary endpoints were not met for the overall population, the observation of the improvement in the 6MWT in the nDNA subgroup is encouraging and hypothesis generating. Efforts are currently underway to confirm this positive benefit and these findings in a follow-up and targeted phase 3 trial in participants with PMM with pathogenic nDNA variants. | PMC10382259 |
Acknowledgment | David A. | RECRUITMENT, MITOCHONDRIAL DISEASE, BROWN | The authors thank the investigators, healthcare providers, research staff, participants, and caregivers who participated in the MMPOWER-3 study. The authors thank the following staff who have significantly contributed to the study: Erica Lynn Kelly and Michele Guyette, Massachusetts General Hospital, Boston, MA, United States. Statistical analyses were performed by the biostats team at Everest Clinical Research, Everest Clinical Research Corp, Markham, ON. Post hoc analyses were performed by Jeffrey S. Finman, PhD. Jupiter Point Pharma Consulting, LLC. Writing and editing assistance, including preparation of a draft manuscript under the direction and guidance of the authors, incorporating author feedback, was provided by James A. Shiffer, RPh (Write On Time Medical Communications, LLC), David A. Brown, PhD. (Stealth BioTherapeutics), and Gene Kelly, RPh (Stealth BioTherapeutics). The authors thank Jim Carr, PharmD, and Anthony Aiudi, PharmD (Stealth BioTherapeutics) for their support of the clinical study endpoints, statistical analysis, and interpretation of the study results. The authors also thank the Mito Action and United Mitochondrial Disease Foundation for helping with recruitment. They also acknowledge TCRC/Harvard Catalyst (Class of Evidence: Null Hypothesis: | PMC10382259 |
Study Funding | This trial was funded by Stealth BioTherapeutics, Newton, MA. All payments from Stealth BT were directly pertaining to travel for investigator meetings and the conduct of this clinical trial. | PMC10382259 |
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Disclosure | obesity, Neurologic Disorders, NS078059, D. A., Muscular Dystrophy, Pompe Disease, P., Barth Syndrome, Zogenix, MitoAction, mitochondrial disease, mitochondrial dysfunction | OBESITY, HAAS, MUSCULAR DYSTROPHY, MITOCHONDRIAL DISORDERS, MITOCHONDRIAL DISORDERS, BARTH SYNDROME, NEUROMUSCULAR DISEASES, MITOCHONDRIAL DISEASE, TUBEROUS SCLEROSIS COMPLEX, MITOCHONDRIAL DYSFUNCTION, NEUROLOGIC DISORDERS, FOUNDER, MITOCHONDRIAL DNA DEPLETION SYNDROME, POMPE DISEASE, LEIGH SYNDROME, MITOCHONDRIAL DISEASE, BROWN, NEUROMUSCULAR DISORDERS, BRAIN, CONGENITAL DISORDERS OF GLYCOSYLATION | A. Karaa: received research grant, reimbursement for travel, and consulting payments from Stealth BT, Sanofi Genzyme, and Takeda; received research grant and reimbursement for travel from Protalix and REATA; received research grants from Astellas, MitoBridge, Cyclerion, PTC therapeutics, and Idorsia; received consulting payments from MitoBridge, Astellas, Alexion, Lumleian, Homology, MitoBridge, Akros, Neurovive, Reneo, and Zogenix; and is on the medical advisory board of MitoAction and on the scientific and medical advisory board of the United Mitochondrial Disease Foundation; is a founder and board member of the mitochondrial care network, President of the Mitochondrial Medicine Society; and is an investigator in the North American Mitochondrial Disease Consortium. E. Bertini: received funds for consulting and Advisory Board from PTC, Roche, Novartis, Biogen, and Sarepta and is responsible for an HCP that is part of both the European Rare Neurologic Disorders (ERN RND) and the ERN-NMD (neuromuscular disorders) network. V. Carelli: received research grant from Stealth BioTherapeutics; consulting payments for Advisory Board and speaker honoraria from Chiesi Farmaceutici; clinical trial funding from Stealth BioTherapeutics, Santhera Pharmaceuticals, and GenSight Biologics; research grants from the Italian Ministry of Health, Italian Ministry of University and Research, Telethon-Italy, and European Union (Horizon 2020 program); and research funding from patient donations and serves the scientific advisory board of IFOND and MITOCON. G. M. Enns: Consulting—Evvia Therapeutics/cofounder, AllStripes/consultant, Glycomine/consultant, Hemoshear/consultant, Homology Medicines/consultant, Moderna Therapeutics/consultant, M6P Therapeutics/consultant, Ultragenyx/consultant. DMC member—Amicus Therapeutics, Audentes Therapeutics, Biomarin, Modis Therapeutics, Paradigm Biopharmaceuticals, Passage Bio, RegenxBio. Clinical Trials (site PI)—Aeglea Biotherapeutics, Artcurus Therapeutics, Astellas Pharma, Biomarin, LogicBio, Moderna, PTC Therapeutics, Stealth BioTherapeutics, and University of Florida. M.J. Falk: Marni J. Falk, MD, is engaged with several companies involved in mitochondrial disease therapeutic preclinical and/or clinical stage development not directly related to the work, including as an advisory board member with equity interest in RiboNova, Inc., as a scientific board member as a paid consultant with Khondrion and Larimar Therapeutics, as a paid consultant (Astellas [formerly Mitobridge] Pharma Inc., Casma Therapeutics, Cyclerion Therapeutics, Epirium Bio, HealthCap VII Advisor AB, Imel Therapeutics, Minovia Therapeutics, NeuroVive Pharmaceutical AB, Reneo Therapeutics, Stealth BioTherapeutics, and Zogenix Inc.), and/or as a sponsored research collaborator (AADI Bioscience, Astellas Pharma Inc., Cyclerion Therapeutics, Epirium Bio (formerly Cardero Therapeutics), Imel Therapeutics, Khondrion, Minovia Therapeutics Inc., Mission Therapeutics, NeuroVive Pharmaceutical AB, PTC Therapeutics, Raptor Therapeutics, REATA Inc., Reneo Therapeutics, RiboNova Inc., Standigm Inc., and Stealth BioTherapeutics). MJF also receives royalties from Elsevier, speaker fees from Agios Pharmaceuticals, and educational honorarium from PlatformQ. G. Gorman: received research grant, consulting payments for Advisory Board, and clinical trial funding from Stealth BioTherapeutics. R. Haas: received research grant, reimbursement for travel, and consulting payments from Stealth BT; is on the scientific and medical advisory board of the United Mitochondrial Disease Foundation and the advisory board for MitoBridge; received clinical trial funding from Edison Pharmaceuticals, Stealth BioTherapeutics, Horizon Pharma (previously Raptor), Reneo Pharmaceuticals, PTC Therapeutics, Acadia Pharmaceuticals, and Sarepta Therapeutics; and received grant funding through the FDA Orphan Products Clinical Trials Grants Program (previously Orphan Products Grants; #1RO1FD004147) and the NIH (U54 NS078059). M. Hirano: has received research support, honoraria, or both from Stealth BioTherapeutics, Entrada Therapeutics, and Modis Therapeutics (wholly owned subsidiary of Zogenix) and grant support from the NIH (U54 NS078059 and P01 HD32062), Department of Defense (FPA W81XWH2010807), Muscular Dystrophy Association (577392), and J. Willard and Alice S. Marriott Foundation. Columbia University has a patent for deoxynucleoside therapies for mitochondrial DNA depletion syndrome including TK2 deficiency, which is licensed to Modis Therapeutics, a wholly owned subsidiary of Zogenix Inc.; this relationship is monitored by an unconflicted external academic researcher. Dr. Hirano is a coinventor of this patent. CUIMC has received royalty payments related to the development and commercialization of the technology; Dr. Hirano has received shares of the royalty payments following Columbia University policies. He is on the scientific and medical advisory board of the United Mitochondrial Disease Foundation and Barth Syndrome Foundation and the Research Advisory Committee of the Muscular Dystrophy Association. T. Klopstock: received clinical trial funding from Stealth BioTherapeutics, Santhera Pharmaceuticals, Khondrion, and GenSight Biologics; received reimbursement for travel and consulting payments from Santhera Pharmaceuticals, GenSight Biologics, and Chiesi GmbH; and is the Speaker of the German network for mitochondrial disorders (mitoNET). Thomas Klopstock is supported by the German Federal Ministry of Education and Research (BMBF, Bonn, Germany) through grants to the German Network for Mitochondrial Disorders (mitoNET, 01 GM1906A) and to the E-Rare project GENOMIT (01 GM1920B). M. K. Koenig: receives research/grant support from Stealth BT, EryDel S.p.A., Ultragenyx Pharmaceuticals, BioElectron Technology Corporation/PTC Therapeutics, NIH, People Against Leigh Syndrome, Marinus Pharmaceuticals, TEVA Pharmaceuticals, Esai Pharmaceuticals, and Reneo Pharmaceuticals; serves on speaker's bureau/advisory board for Novartis Pharmaceuticals, Greenwich Pharmaceuticals, Stealth BT, Taysha Gene Therapies, and Modis Therapeutics; serves on scientific and medical advisory board for the Mitochondrial Medicine Society, Tuberous Sclerosis Complex Alliance, TANGO2 Research Foundation, and People Against Leigh Syndrome; coinventor of “Topical Rapamycin Therapy” licensed to LAM Therapeutics. C. Kornblum: has received travel funding and/or speaker honoraria from Sanofi Genzyme, Novartis, Santhera, and Fulcrum Therapeutics, acknowledges financial support as advisory board member and/or primary investigator for Stealth BioTherapeutics, Inc., Sanofi Genzyme, Amicus Therapeutics, Roche Pharma AG, Hormosan, Fulcrum Therapeutics, receives research support from the German Federal Ministry of Education and Research (BMBF), and is a member of the European Reference Network for neuromuscular diseases (EURO-NMD) and cocoordinator of mitoNET (BMBF funded). C. Lamperti: received research grant from and is supported by the Telethon (GSP16001) and by the E-Rare project GENOMIT (01 GM1920B), Italian Ministry of health RF: 2016–02361495, and Chiesi faramceuticis, member of the European Reference Network for neuromuscular diseases (EURO-NMD. A. Lehman: has received research grants, reimbursement for travel, or consulting payments from Shire-Takeda, Sanofi-Genzyme, Ultragenyx, Horizon Pharma, and Amicus. N. Longo: has received speaker honoraria from Alnylam, Amicus Therapeutics, ACI Clinical trials, BioMarin, BridgeBio/CoA Ther, Censa/PTC Ther., Chiesi/Protalix, CTI-Clinical Trial, Genzyme/Sanofi, Hemoshear, Horizon Pharma, Jaguar Gene Therapy, Leadiant Biosciences, Moderna, Nestle’ Pharma, Recordati, Reneo, Shire/Takeda, Synlogic, and Ultragenix; also receives clinical trial support from Aeglea, Amicus Therapeutics, Audentes/Astellas, AvroBio, BioMarin, Censa/PTC Ther., Chiesi/Protalix, Genzyme/Sanofi, Hemoshear, Homology, Horizon Pharma, Moderna, Nestle’ Pharma, Pfizer, Reneo, Retrophin, Shire/Takeda, Stealth BioTherapeutics, Synlogic, and Ultragenix. M. Judit Molnar: received research grant, reimbursement for travel, and consulting payments from Stealth BT, Sanofi Genzyme, Biogen, Amicus Therapeutics, PTC Therapeutics, Novartis Pharma, Takeda, and Richter Gedeon Plc. Molnar MJ is supported by the National Brain Foundation 2.0. H.Phan: received research grant, reimbursement for travel, and consulting payments from Stealth BT, Shire, Sarepta, Fibrogen, Pfizer, Ovid, Emalex, GeneTx, Genetech, Applied Therapeutics, Teva, Italofarmaco, and Eisai. S. Parikh: has no relevant disclosures to report R. D.S. Pitceathly: received reimbursement for travel and consulting payments from Stealth BioTherapeutics; a research grant, reimbursement for travel, and consulting payments from Reneo Pharmaceuticals; and consulting payments from Abliva. F. Scaglia: has received research grants from Stealth BT, Reata Pharmaceuticals, PTC Therapeutics (Edison Pharma), Horizon Pharma (Raptor Pharma), Entrada Therapeutics, Astellas Pharma, Modis Therapeutics, and the NIH (U54 NS078059). He has received research support from the Mervar Foundation and the Courage for a Cure Foundation. He is on the Board of the Mitochondrial Medicine Society and is an investigator for the North American Mitochondrial Disease Consortium and the Frontiers in Congenital Disorders of Glycosylation Consortium. S. Servidei: responsible for an HCP that is part of the European Rare Neurologic (ERN) NMD network. R. P. Saneto: received research grant and reimbursement for travel and consulting payments from Stealth Bio Therapeutics, received clinical trial funding from Edison Pharmaceuticals, and served on the DSMB board for REATA Pharmaceuticals. M. Tarnopolsky: has received speaker honoraria from Sanofi-Genzyme. He is the President and CEO of Exerkine Corporation that produces nutraceuticals that target mitochondrial dysfunction in obesity and aging. A. Toscano: has received reimbursement for educational activities from Sanofi Genzyme and Amicus and honorarium as component of Sanofi Genzyme Pompe Disease European Board. J. Van Hove: has received reimbursement for travel and consulting payments from Stealth BT. J. Vissing: has received research and/or travel support and/or speaker honoraria from UCB Pharma, Edgewise Therapeutics, Sanofi/Genzyme, Fulcrum Therapeutics, Argenx, Biogen, Lupin Limited, and Alexion Pharmaceuticals and served on advisory boards or as a consultant for Argenx, Roche, Viela Bio, Biogen, Amicus Therapeutics, Genethon, PTC Therapeutics, Sanofi/Genzyme, Ultragenyx Pharmaceutical, Fulcrum Therapeutics, ML Bio Solutions, Sarepta Therapeutics, Novartis Pharma AG, Stealth Biotherapeutics, Zogenix, Regeneron, UCB Pharma, Viela Bio, Lundbeck Pharma, and Lupin Limited. J. Vockley: received research grant, reimbursement for travel, and consulting payments from Stealth BioTherapeutics. M. Mancuso: received research grant, reimbursement for travel, and consulting payments from Stealth BT, Shire, Sanofi Genzyme, Khondrion, Abliva, Reneo, and Zogenix. Mancuso is supported by the Telethon (GSP16001) and by the E-Rare project GENOMIT (01 GM1920B). Mancuso is part of the European Rare Neurologic (ERN) NMD network. B. H. Cohen: received research grant, reimbursement for travel, and consulting payments from Stealth BT; received research grants from Reata pharmaceuticals, BioElectron Technology (Edison Pharma), and Horizon Pharma (Raptor Pharma); received travel support from Reata; serves on the UMDF Board of Trustees; and is an investigator for the NAMDC. D. A. Brown is an employee of Stealth BioTherapeutics and receives compensation and benefits commensurate with full-time employment. J. Finman and James Schiffer are consultants for Stealth Biotherapeutics and receive compensation commensurate with their consulting activities. Go to | PMC10382259 |
Authors | PMC10382259 |
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Coinvestigators | PMC10382259 |
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Glossary | fatigue | MITOCHONDRIAL MYOPATHY | 6-minute walk testadverse eventclinician global impressionestimated glomerular filtration rateintention to treatLeber hereditary optic neuropathymixed-model repeated measuresmitochondrial DNAnuclear DNApatient global impressionprimary mitochondrial diseasesprimary mitochondrial myopathiesPrimary Mitochondrial Myopathy Symptom Assessmentper-protocolpatient-reported outcomesquality of lifereactive oxygen speciestotal fatigue score | PMC10382259 |
References | PMC10382259 |
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Background | peripheral inflammation, cognitive impairment | In addition to the analgesic effect, peripheral neural blocks also prevent cognitive impairment and peripheral inflammation induced by surgery. However, it is unknown if there is collateral impact on cognitive improvement after bariatric surgery. | PMC9834365 |
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Methods | quadratus lumborum block | SEVERE OBESITY | In this pilot study, 75 patients with severe obesity for selective laparoscopic sleeve gastrectomy (LSG) were recruited and randomized into three groups (1:1:1) as general anesthesia (GA) group, transverse abdominis plane block (TAPB) group, and quadratus lumborum block (QLB) group. Bilateral TAPB or QLB was performed (0.33% ropivacaine with dexmedetomidine 1 μg/kg) before the standardized general anesthesia. Cognitive test battery was completed before LSG and in 1-month and 3-month follow-up. The levels of peripheral inflammatory cytokines were determined at equivalent time points. | PMC9834365 |
Results | Patients with LSG exhibited massive cognitive improvement in postoperative 3 month without or with TAPB or QLB ( | PMC9834365 |
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Conclusion | Laparoscopic sleeve gastrectomy ideally improved memory and attention as early as postoperative 1 month. QLB promoted cognitive improvement in MoCA, which was negatively correlated with changes in IL-6. More precise trials are needed to determine the overall effect of peripheral neural block on cognition following bariatric surgery. | PMC9834365 |
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Graphical Abstract | PMC9834365 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s11695-022-06319-y. | PMC9834365 |
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Keywords | PMC9834365 |
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Introduction | quadratus lumborum block, postoperative pain, overweight, TAPB | SEVERE OBESITY | According to the definition by WHO, overweight is a body mass index (BMI) ≥ 25 kg/mBariatric surgery is a promising intervention for people with severe obesity. It profoundly improves the comorbidities and reduces the overall mortality during the long-term follow-up [To efficiently relieve postoperative pain, peripheral neural blocks have been applied in the multimodal analgesia management for bariatric surgery. Evidence suggests that transverse abdominis plane block (TAPB) and quadratus lumborum block (QLB) can significantly reduce postoperative pain following abdominal surgery [ | PMC9834365 |
Materials and Methods | PMC9834365 |
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Participants | obese | OBESE | This is a pilot study based on the effects of peripheral neural block (PNB) in cognitive improvement among severe obese patients after laparoscopic sleeve gastrectomy (LSG). The study design was described previously, one of the primary aims of this RCT was to compare the analgesic effect of TAPB and QLB during LSG [ | PMC9834365 |
Standardized Anesthesia Protocol | Before anesthesia, all patients were delivered to the pre-anesthesia room for the arterial intubation and ultrasound-guided PNB. In brief, TAPB and QLB were performed by an experienced anesthesiologist who was blinded to the trial. By using a convex array probe (Sonosite Micromaxx, Bothell, WA, USA) with a frequency of 2–5 MHz, bilateral TAPB or QLB was completed with the diffusion of 30 ml of 0.33% ropivacaine (including dexmedetomidine 1 ug/kg) or normal saline into the fascia plane.A standardized anesthesia protocol was conducted to all patients. Briefly, perioperative administration of dexmedetomidine was achieved by a bolus infusion at 2 μg/kg/h for 15 min and a continuous infusion at 0.4 μg/kg/h during the surgery, as well as the subsequent patient-controlled intravenous analgesia (PCIA) device after surgery. General anesthesia induction was accomplished with midazolam (0.025 mg/kg), propofol (1.5 mg/kg), cisatracurium (0.2 mg/kg), and remifentanil (2 μg/kg). General anesthesia was maintained with sevoflurane inhalation as well as continuous infusion of remifentanil (5–15 μg/kg/h) and cisatracurium (0.1–0.2 mg/kg/h). The doses of all intravenous anesthetics were calculated based on the ideal body weight for each patient. During the operation, vasoactive agents were applied to maintain the mean arterial pressure (MAP) and heart rate (HR) within a range of 20% more or less than the baseline. Parecoxib 40 mg and nalbuphine 10 mg were also used as analgesia complement. The same surgeon team performed all the surgical procedures by using five ports technique. | PMC9834365 |
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Cognitive Evaluation | To continuously evaluate patients’ cognition, a battery of clinical neuropsychological assessments was used before LSG, 1 month and 3 months after LSG. The cognitive battery consisted of Montreal Cognitive Assessment (MoCA) [ | PMC9834365 |
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Inflammatory Cytokines Assessment | Plasma was collected before surgery, 24 h after surgery, 1 month after surgery, and 3 months after surgery. The concentrations of TNF- | PMC9834365 |
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Statistical Analysis | Baseline characteristics of three groups were described as mean ± standard deviation (SD), median with interquartile ranges or numbers (percentages), which were analyzed with one-way analysis of variance, | PMC9834365 |
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Discussion | obesity, Obesity, age-related neurodegenerative disorders, inflammation, Chronic adipose tissue, cognitive dysfunction, Alzheimer’s disease, Inflammation, metabolic syndrome | OBESITY, OBESITY, INFLAMMATION, RESPIRATORY FAILURE, INFLAMMATION, CARDIAC COMPLICATIONS, METABOLIC SYNDROME, COMPLICATIONS | In this study, we successfully described the profiles of cognition and inflammation before and after bariatric surgery. Among adults with obesity, cognition was significantly improved in 3 months after LSG. QLB, as an adjunct to the general anesthesia, significantly promoted cognitive improvement in MoCA. Significant reductions of pro-inflammatory cytokines and an increase of BDNF were also observed during the postoperative follow-up. There were possible correlations between cognition and changes in peripheral inflammatory cytokines, especially pro-inflammatory cytokines in postoperative 3 months.Obesity itself is sufficient to impair cognition [On the other hand, according to the analysis of 122 studies from 1946 to 2020, PNB is associated with decreased occurrence of numerous complications after total hip and knee arthroplasties, such as cognitive dysfunction, respiratory failure, and cardiac complications [Chronic adipose tissue inflammation and associated increases of circulating pro-inflammatory adipokines are typically displayed in patients with obesity. Inflammation has been regarded as a critical mechanism of cognitive dysfunction in human [Brain-derived neurotrophic factor (BDNF), as a member of the neurotrophin family, originally supports the development, maintenance, and plasticity of the central and peripheral nervous systems. BDNF signaling also contributes to the development of the metabolic syndrome and obesity under a circumstance with chronic positive energy balance. At the same time, the reduction of BDNF enforces the susceptibility to Alzheimer’s disease and other age-related neurodegenerative disorders [Noteworthy, the addition of dexmedetomidine may partially participate in the changes of cognition and inflammation induced by TAPB or QLB in this study. Dexmedetomidine is a selective There are also some limitations in our study. Some bias might affect inflammatory cytokines assessments, especially BDNF measurements, such as physical exercise [ | PMC9834365 |
Conclusion | obesity, inflammation | OBESITY, INFLAMMATION | In sum, our clinical trial suggested that the bariatric surgery effectively improved the cognitive function and modified the inflammation in obesity patients. The application of regional neural block in the standardized general anesthesia could further improve patient’s memory and attention. Numerous pro-inflammatory cytokines and BDNF may contribute to the massive cognitive improvements. Therefore, obesity treatment should be individually tailored with multiple analgesic approaches. Our findings provided the first clue to what impact of PNB on cognition. | PMC9834365 |
Acknowledgements | The authors would like to express their appreciation for the postgraduate students supervised by Prof. Yong Wang for their invaluable assistance. | PMC9834365 |
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Funding | Financial support and sponsorship: this study was supported by basic and clinical cooperative research promotion plan of Anhui Medical University (2019xkjT026), the National Natural Science Foundation of China (NSFC 81801050), and Scientific Research Platform Base Construction and Promotion Project of Anhui Medical University (2020xkjT060). | PMC9834365 |
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Declarations | PMC9834365 |
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Ethics Approval | All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. | PMC9834365 |
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Informed Consent | Informed consent was obtained from all individual participants included in the study. | PMC9834365 |
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Conflict of Interest | The authors declare no competing interests. | PMC9834365 |
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References
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Objective | femoral neck fractures, postoperative pain, anxiety, pain, femoral neck fracture, depression | The majority of individuals with femoral neck fractures opt for total hip replacement to enhance their quality of life. However, this group frequently exhibits perioperative symptoms of pain, anxiety, and sadness, which extends recovery time to some extent. Esketamine, the right-handed monomer of ketamine, is more popular these days due to its sedative, analgesic, and antidepressant properties. There are currently few domestic and international research on the use of esketamine in elderly individuals who have undergone surgery for a femoral neck fracture. In order to further cut the length of the hospital stay and hasten postoperative recovery, this study investigates whether esketamine postoperative analgesia can lessen postoperative pain, anxiety, and depression in older patients having hip replacement. | PMC10069053 |
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