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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
Declarations
PMC10150529
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 C...
PMC10150529
Consent for publication
Not applicable.
PMC10150529
Competing interests
The authors declare that they have no competing interests.
PMC10150529
References
PMC10150529
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-sp...
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 rehabili...
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 postoperat...
PMC10069348
Trial registration
MAY
NCT05046756. Registered on 11 May 2021.
PMC10069348
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-023-10728-2.
PMC10069348
Keywords
PMC10069348
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 prese...
PMC10069348
Methods
PMC10069348
Study design
This protocol will be a prospective multi-centered two-armed randomized controlled trial. The study design meets SPIRIT guidelines [
PMC10069348
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) ...
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 random...
PMC10069348
Interventions
PMC10069348
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 ar...
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 ...
PMC10069348
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 mon...
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 functiona...
PMC10069348
Sample size calculation
Based on a previous study [
PMC10069348
Data management
For systematic data management, electronic data capture of Medicallogic Company (
PMC10069348
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 com...
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 applyi...
PMC10069348
Trial status
MAY, RECRUITMENT
The first participant recruitment began on 11 May 2020.
PMC10069348
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 recu...
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...
PMC10069348
Acknowledgements
We thank Medi Plus Solution for their technical support and all of the hospital members who devoted their effort for the study.
PMC10069348
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 ...
PMC10069348
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 suppor...
PMC10069348
Data Availability
Not applicable.
PMC10069348
Declarations
PMC10069348
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
Consent for publication
Not applicable.
PMC10069348
Competing interests
The authors declare that they have no competing interests.
PMC10069348
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
References
PMC10069348
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 mitochondr...
PMC10382259
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...
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 sym...
PMC10382259
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
Trial Registration Information
Trial registered with
PMC10382259
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, a...
PMC10382259
Methods
PMC10382259
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 RePO...
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 boa...
PMC10382259
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 elami...
PMC10382259
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
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 ...
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 throughou...
PMC10382259
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...
PMC10382259
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).Be...
PMC10382259
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,...
PMC10382259
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 aggreg...
PMC10382259
Data Availability
Anonymized data not published within this article will be made available by request from any qualified investigator.
PMC10382259
Protocol and Statistical Analysis Plan
The study protocol and statistical analysis plan were published.
PMC10382259
Results
PMC10382259
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
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 elamipret...
PMC10382259
Efficacy
PMC10382259
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 ...
PMC10382259
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 partici...
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...
PMC10382259
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 2...
PMC10382259
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 Place...
PMC10382259
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 fun...
PMC10382259
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. MMP...
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...
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
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 DIS...
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 consultin...
PMC10382259
Authors
PMC10382259
Coinvestigators
PMC10382259
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 ...
PMC10382259
References
PMC10382259
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
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 ...
PMC9834365
Results
Patients with LSG exhibited massive cognitive improvement in postoperative 3 month without or with TAPB or QLB (
PMC9834365
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 bari...
PMC9834365
Graphical Abstract
PMC9834365
Supplementary Information
The online version contains supplementary material available at 10.1007/s11695-022-06319-y.
PMC9834365
Keywords
PMC9834365
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, periphera...
PMC9834365
Materials and Methods
PMC9834365
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...
PMC9834365
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
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
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
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 r...
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 c...
PMC9834365
Acknowledgements
The authors would like to express their appreciation for the postgraduate students supervised by Prof. Yong Wang for their invaluable assistance.
PMC9834365
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 Uni...
PMC9834365
Declarations
PMC9834365
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
Informed Consent
Informed consent was obtained from all individual participants included in the study.
PMC9834365
Conflict of Interest
The authors declare no competing interests.
PMC9834365
References
PMC9834365
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 popu...
PMC10069053