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Progression-free survival | EVENTS | PFS events occurred in 6/26 patients in Part A (median follow-up, 35.8 months; range, 3.5–46.1) and in 10/45 patients in Part B (median follow-up, 25.3 months; range, 1.5–32.8). Median PFS for the entire cohort was not reached (NR; interquartile range [IQR]: 28.6 months to NR) (Fig. | PMC10264885 | |
Overall survival | EVENTS | OS events (any cause) occurred in 2/26 patients in Part A (median follow-up, 37.9 months; range, 4.6–47.0) and in 7/45 patients in Part B (median follow-up, 26.2 months; range, 9.5–33.1). Median OS estimates for Parts A and B separately and for the entire cohort were NR (range, NR–NR) (Fig. | PMC10264885 | |
Pharmacokinetics | Based on results from the PK population for NCA on Cycle 1, when given in combination with VRd, isatuximab PK parameters (area under the plasma concentration versus time curve from 0 to 1 week [AUC | PMC10264885 | ||
Immunophenotyping | Flow cytometry experiments were conducted to explore changes in the immune microenvironment upon treatment. Data from Parts A and B were obtained from peripheral blood collected at Day 1 of Cycle 1 (27 and 43 patients, respectively), Day 1 of Cycle 3 (20 and 38 patients), and end of treatment (8 and 9 patients) for the all-treated population.For the all-treated population, at Day 1 of Cycle 3 compared with baseline, the percentages of CD19 + B cells (2.33% to 0.66%), CD4 + T cells (15.56% to 11.27%), CD3 + T cells (23.56% to 19.00%), NK cells (CD56As all patients except 1 responded to the treatment, no correlation with parameters of clinical response was performed. | PMC10264885 | ||
Discussion | This Phase 1b study was designed to investigate Isa-VRd for the first time in adult patients with NDMM who were ineligible/had no intent for immediate transplantation. Treatment with isatuximab plus triplet bortezomib-lenalidomide-dexamethasone resulted in deep and durable responses, with an MRD- rate of 51% at a sensitivity of 10Median PFS in the overall population of the current study was not reached (NR; interquartile range [IQR], 28.6 months to NR). The PFS probability at 1 and 2 years for the entire cohort was 91.0% (95% CI: 81.0–95.9) and 83.1% (95% CI: 71.5–90.3), respectively. Examined separately, median PFS estimates were NR (IQR: 28.9 months to NR) for Part A (median follow-up, 35.8 months) and NR (IQR: 28.4 months to NR) for Part B (median follow-up, 25.3 months). Results from the Phase 3 SWOG S0777 study demonstrated significantly improved PFS with VRd vs Rd (43 vs 30 months; stratified HR 0.712 [95% CI: 0.56–0.906]) [Daratumumab is another anti-CD38 monoclonal antibody used for the treatment of patients with NDMM. In the Phase 3 MAIA study, after a median follow-up of 28.0 months, median PFS was NR in the daratumumab-Rd group vs 31.9 months in the Rd group (HR 0.56; 95% CI, 0.43–0.73) [In the MAIA and ALCYONE studies, daratumumab plus Rd or bortezomib-melphalan-prednisone (VMP) led to increased MRD- rates, assessed using NGS at a sensitivity of 10In the combined population of Parts A and B, there were no new safety concerns related to isatuximab compared with the results of the ICARIA-MM and IKEMA studies in RRMM [Overall, the incidence and severity of IRs were comparable to those reported with isatuximab in RRMM patients [Based on PK results from Parts A and B, when given in combination with VRd, isatuximab PK exposure was within the range of those previously reported, suggesting that VRd does not alter the PK of isatuximab [This study also evaluated isatuximab infusion duration. With the fixed-volume infusion, patients in Part A who switched from the weight-based infusion method and all patients in Part B exhibited a larger decrease in the median infusion time from ~3 h 40 min during the first infusion to ~1 h 20 min after the third infusion compared with patients in Part A with the weight-based infusion method ( ~ 3 h 40 min to ~2 h 35 min), with no increase in IRs reported.Stem cell collection showed adequate yield of cells/kilogram of body weight, which is required for further successful engraftment.Descriptive analysis of blood immune cell subpopulations in our study showed a decrease in CD3 and CD4 T cells, NK cells, regulatory T cells, and B cells at Cycle 3, in agreement with previous observations following single-agent treatment with an anti-CD38 antibody [In conclusion, this Phase 1b study demonstrated for the first time that a quadruplet regimen of isatuximab, an anti-CD38 monoclonal antibody, plus VRd led to deep responses in patients with NDMM ineligible/with no immediate intent for ASCT, including a 51% MRD- rate. In addition, Isa-VRd exhibited a safety profile consistent with that of each individual drug, suggesting that this quadruplet combination is both feasible and effective in this patient population. The ongoing Phase 3 BENEFIT study (NCT04751877) was designed to investigate isatuximab-based triplet (Isa-Rd) vs quadruplet (Isa-VRd) regimens in patients with NDMM ineligible for ASCT. This study will help determine any added value of the quadruplet vs triplet regimen in this patient population, considering the safety profile of each regimen. | PMC10264885 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41375-023-01936-7. | PMC10264885 | ||
Acknowledgements | The authors thank the participating patients and their families, and the study centers and investigators for their contributions to the study. Medical writing support was provided by Erin Burns-Tidmore, PhD, of Envision Pharma Group, contracted by Sanofi for publication support services. | PMC10264885 | ||
Author contributions | EMO, AP, PB, JFSM, IWB, LK, JM-L, WP, SB, MM, M-VM, PRO, and PM were investigators in the study and contributed to data acquisition. LD, SM, TF, NLR, and MG contributed to the analysis, verification, and interpretation of data for the work. All authors revised the work for important intellectual content and assume responsibility for data integrity and the decision to submit this manuscript for publication, had full access to the study data, edited and reviewed manuscript drafts, and approved the final version for submission. EMO had final responsibility for the decision to submit for publication. | PMC10264885 | ||
Funding | This study was sponsored by Sanofi. | PMC10264885 | ||
Data availability | Qualified researchers can request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report forms, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data-sharing criteria, eligible studies, and process for requesting access are at: | PMC10264885 | ||
Competing interests | MM | EMO: Honoraria – Amgen, BMS/Celgene, GSK, Janssen, MSD, Oncopeptides, Sanofi, Takeda. AP: Honoraria – AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Sanofi, Takeda. PB: nothing to disclose. JFSM: Honoraria – AbbVie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen, Karyopharm, MSD, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda. IWB: nothing to disclose. LK: Honoraria – AbbVie, Amgen, Celgene, Janssen, Sanofi, Takeda; Advisory Role: Amgen, Celgene, GSK, Janssen, Takeda. JM-L: Honoraria – Janssen, BMS, Incyte, Roche, Novartis, Amgen, Adaptive, Gilead, Sanofi. WP: nothing to disclose. SB: Honoraria – Janssen, Takeda, Amgen, Sanofi, Celgene, Oncopeptides, GSK, Bristol Myers Squibb. MM: nothing to disclose. M-VM: Honoraria – Sanofi. PR-O: Honoraria – Celgene-BMS, Janssen, Sanofi, AbbVie, GSK, Oncopeptides, Kite Pharma, Amgen. LD, SM, and TF are employed by Sanofi and may hold stock and/or stock options in the company Sanofi. NLR and MG are contractors for Sanofi on behalf of Altran and Excelya. PM: Consulting – AbbVie, Amgen, Celgene, Jansen, Oncopeptides, Sanofi; Honoraria – AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Sanofi; Advisory Role – AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Sanofi. | PMC10264885 | |
References | PMC10264885 | |||
Introduction | Symptoms reported following the administration of investigational drugs play an important role in decisions for registration and treatment guidelines. However, symptoms are subjective, and interview methods to quantify them are difficult to standardise. We explored differences in symptom reporting across study sites of a multicentre antimalarial trial, with the aim of informing trial design and the interpretation of safety and tolerability data. | PMC10476314 | ||
Methods | Data were derived from the IMPROV trial, a randomised, placebo-controlled double blinded trial of high dose primaquine to prevent | PMC10476314 | ||
Results | anorexia, fever | ANOREXIA | A total of 2,336 patients were included. The greatest variation between sites in the proportion of patients reporting symptoms was for anorexia between day 0 and day 13: 97.3% (361/371) of patients in Arba Minch, Ethiopia, reported the symptom compared with 4.7% (5/106) of patients in Krong Pa, Vietnam. Differences attenuated slightly after adjusting for treatment arm, age, sex, day 0 parasite density and fever; with the adjusted proportion for anorexia ranging from 4.8% to 97.0%. Differences between sites were greater for symptoms graded as mild or moderate compared to those rated as severe. Differences in symptom reporting were greater between study sites than between treatment arms within the same study site. | PMC10476314 |
Conclusion | Despite standardised training, there was large variation in symptom reporting across trial sites. The reporting of severe symptoms was less skewed compared to mild and moderate symptoms, which are likely to be more subjective. Trialists should clearly distinguish between safety and tolerability outcomes. Differences between trial arms were much less variable across sites, suggesting that the relative difference in reported symptoms between intervention and control group is more relevant than absolute numbers and should be reported when possible. | PMC10476314 | ||
Trial registration | Clinicaltrials.gov: NCT01814683; March 20 | PMC10476314 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12874-023-02022-3. | PMC10476314 | ||
Keywords | PMC10476314 | |||
Background | vivax malaria | ADVERSE EVENTS, VIVAX MALARIA | Clinical trials are designed to evaluate drug safety and efficacy. The assessment of safety usually involves identifying adverse events (AEs), that can be detected either by laboratory testing, clinical assessment or patient questioning for symptoms. While laboratory tests can be standardised, patient questioning methods are more complex and difficult to standardise. Placebo controlled double-blinded designs are important to ensure questioning is independent of treatment allocation. Patient symptoms questioning relies on individual patient reporting and information that can rarely be corroborated through other means. Investigators usually grade symptoms reported by the trial participant on a scale from mild, through moderate, to severe; however, grading matrices are variable between different studies and often specifically defined within a study protocol. Subjective assessments rely on the perceptions of the trial participants and the same question may trigger a range of responses in different individuals [The ‘improving the radical cure of vivax malaria’ (IMPROV) trial (NCT01814683) compared the efficacy, safety, and tolerability of two primaquine regimens for the radical cure of vivax malaria in 8 sites across 4 countries [In this analysis, we aimed to explore potential differences in symptom reporting across study sites and whether study site variation could be adjusted for, to inform future clinical trial designs and the interpretation of safety and tolerability data. | PMC10476314 |
Methods | PMC10476314 | |||
Study design | Data used in this analysis were derived from the IMPROV trial. The design of the trial [ | PMC10476314 | ||
Study sites | This study included patients recruited in eight study sites across four countries: Afghanistan, Ethiopia, Indonesia and Vietnam [ | PMC10476314 | ||
Data collection of symptoms | diarrhoea, itching, abdominal pain, pain, dizziness, skin rash, nausea,, headache, aches, shortness of breath | At each follow up visit a symptom questionnaire was completed. Patients were encouraged to report to the study centre if they became unwell between scheduled visits. The symptom questionnaire consisted of a 13-point symptom checklist for fever/hot body, headache, muscle/joint aches and pain, abdominal pain, poor appetite, nausea, vomiting, diarrhoea, passing red/brown/black urine, skin rash, dizziness, shortness of breath and itching. The questionnaire was available in English at all sites, except for the Indonesian sites where it was translated into Bahasa. Each symptom could be either present at the time of the interview or reported as occurring since the last visit and was graded according to study specific standard operating procedures (SOP) as either mild, moderate, severe or potentially life threating using definitions outlined in Table Severity grading scale for symptom reportingNausea/vomitingNo interferencewith activity or 1 – 2 episodes/24 hSome interferencewith activity or > 2episodes/24 hPrevents daily activity, requiresoutpatient IV hydrationEmergency department visit orhospitalisation forhypotensive shock4 – 5 stools or400 – 800 g/24hoursEmergency department visit orhospitalisationSome interferencewith activity notrequiring medicalinterventionPrevents dailyactivity andrequires medicalinterventionEmergency department visit orhospitalisation | PMC10476314 | |
Data analysis | diarrhoea, nausea, fever, abdominal pain, malaria, vomiting, dizziness, parasitaemia, anorexia | REGRESSION, MALARIA, ANOREXIA | The number and proportion of patients who had the most clinically relevant symptoms (vomiting, diarrhoea, anorexia, nausea, abdominal pain and dizziness) following the administration of primaquine or placebo are presented by study site and treatment. The confounder-adjusted proportion of the presence of each symptom at least once between day 0 and 13 for each study site was estimated following multivariable logistic regression with each confounder (age, sex, day 0 parasitaemia, treatment arm, and presence of fever on day 0) set at the population mean/prevalence value of the overall trial. Schizontocidal treatment was not adjusted for due to collinearity with study site (chloroquine for all patients in Ethiopia, Vietnam and Afghanistan, dihydroartemisinin-piperaquine for patients in Indonesia). A sensitivity analysis was performed excluding patients less than 5 years, whose parents or guardians may have reported their symptoms.To explore whether the observed variation between study sites may be due to differences in acute malaria symptoms the analyses were repeated for each symptom restricted to the time after acute malaria symptoms are expected to subside (days 3 to 13). To further explore whether the reported presence or absence of symptoms in an individual on day 0 or 1 could explain the variation between study sites, the models were repeated including symptom presence on day 0 or 1 as a covariate.To investigate whether variation in symptom reporting was impacted by severity, the presence of severe symptoms (grade 3) was compared between study sites. The confounder-adjusted proportion of symptoms between day 3 and 13 was described for each treatment arm using the previous multivariable logistic regression model and compared across sites to explore within and between-study site variation in symptoms.All statistical analyses were performed using Stata version v17.0 (StataCorp, US). Confounder-adjusted proportions of symptoms were estimated using the margins command. | PMC10476314 |
Variation across study sites | anorexia, fever | REGRESSION, ANOREXIA | The widest range of the proportion of patients reporting a specific symptom across the sites was for anorexia. A total of 97.3% (361/371) of patients in Arba Minch, Ethiopia reported anorexia between day 0 and day 13 compared with 4.7% (5/106) of patients in Krong Pa, Vietnam. The proportion of patients at the remaining sites reporting anorexia fell between these maximum and minimum values (Table Participants reporting symptoms at least once between day 0 and day 13 by study siteAfter adjusting for treatment arm, age, sex, day 0 parasite density, and day 0 fever in separate multivariable analyses for the presence of each symptom between day 0 and day 13, substantial heterogeneity remained between study sites for the covariate-adjusted estimated proportion of patients reporting a symptom (Fig. Covariate-adjusted estimate (95% CI) of proportion of patients reporting symptoms between day 0 and 13 and day 3 and 13 Legend: Covariate-adjusted site-specific estimated proportions were generated from logistic regression models adjusting for treatment arm, age, sex, day 0 parasite density and day 0 fever, with all covariates set at mean/prevalence values for all trial patients | PMC10476314 |
Variation between treatment arms | parasitaemia, anorexia, fever | REGRESSION, ANOREXIA | At the study site in Arba Minch, Ethiopia, anorexia between day 3 and day 13 was reported in 87.3% (62/71) of patients receiving placebo, 76.2% (112/147) of patients receiving low dose primaquine, and 83.3% (120/144) patients receiving high dose primaquine. In contrast, in Krong Pa, Vietnam, none (0/21) of the patients receiving placebo or low dose primaquine (0/43) reported anorexia compared with 7.3% (3/41) receiving high dose primaquine. In separate multivariable analyses for the presence of each symptom between day 3 and day 13, after adjusting for treatment category, age, sex, baseline parasitaemia and fever at presentation, the differences in symptom reporting were greater between study sites than between treatment arms within the same study site (Fig. Covariate-adjusted estimate (95% CI) of proportion of patients reporting symptoms at least once between day 3 and day 13 by treatment arm Legend: PQ – primaquine; PQ14 – 14-day course of primaquine; PQ7 – 7-day course of primaquine; Covariate-adjusted site-specific estimated proportions for each treatment arm were generated from logistic regression models adjusted for treatment arm, age, sex, day 0 parasite density and day 0 fever, with all confounders (except treatment arm) set at mean/prevalence values for all trial patients | PMC10476314 |
Variation in severity of symptoms across study sites | diarrhoea, nausea, abdominal pain, vomiting, dizziness, anorexia | ANOREXIA | Of 1,747 patients reporting vomiting, diarrhoea, anorexia, nausea, abdominal pain or dizziness, 1,033 (59.1%) reported only mild symptoms (grade 1), 682 (39.0%) reported their most severe symptom as moderate (grade 2) and 32 (1.8%) reported their most severe symptom as severe (grade 3). For all reported symptoms, less than 2.5% of all patients reported severe symptoms across all study sites (Supplementary file | PMC10476314 |
Discussion | diarrhoea, nausea, fever, abdominal pain, malaria, vomiting, pain, dizziness, anorexia | MALARIA, EVENTS, DISEASE, ANOREXIA | The overall number of symptoms reported in the IMPROV study varied significantly between sites, and this difference remained apparent after adjusting for demographics, disease severity estimated by presence of fever and parasite density at enrolment, and treatment arm. One site in Ethiopia reported almost 100% of study patients suffering from anorexia compared to other sites where less than 5% patients reported anorexia. There were less extreme but still relevant differences in the reporting of other symptoms including vomiting, diarrhoea, nausea, abdominal pain and dizziness. Critically the differences in symptom reporting were greater between study sites than between treatment arms, suggesting that symptoms are best interpreted in relation to the control arm.Differences in the circumstances under which symptoms were elicited may explain the variation between sites. Despite standardised training on how to complete the symptom questionnaire, the approach of study centres is likely to have differed in practice. At one extreme, investigators may have encouraged study participants to report every symptom, while in other sites the investigators may have been less explicit. This would be in line with previously reported differences showing that more specific questioning of study subjects resulted in more events reported compared to open-ended questioning [There are several alternative explanations for these findings. Cultural differences between study sites and countries may play a role. Observed differences could be explained by variations in expression and reporting of symptoms, such as pain, between different groups of people [Data on self-reporting of symptoms versus reporting by parents on behalf of a paediatric patient was not available and could have contributed. However, the proportion of children under the age of 5 was overall small and a sensitivity analysis excluding patients under 5 showed similar results. The effect of schizontocidal treatments on symptoms could not be assessed due to collinearity with study site. However, results remained heterogeneous on day 3–13, following cessation of the schizontocidal treatment.Gastro-intestinal tolerability of primaquine can be improved with food. While it was recommended to patients to take primaquine with food, patient level data on food uptake during treatment was not available and practices might have varied between sites. However, the difference in the proportion of patients reporting symptoms between the control arm and the treatment arms at each site were much smaller than between sites, suggesting that other explanations are more likely.Finally, a large number of patients in the placebo arm reported symptoms following drug administration, this could in part be explained by symptoms attributable to malaria. In addition it seems likely that the ‘nocebo’ effect (negative consequences following the administration of a placebo) may have played a role in the perception of symptoms by some participants [While the data collection tools for determining antimalarial efficacy have generally been well standardised [ | PMC10476314 |
Conclusions | EVENTS | The findings from our analysis suggest three pragmatic approaches to how symptom reporting in antimalarial trials could be improved. Firstly, the reporting of more severe symptoms is less skewed between sites and more likely to be reproducible compared to mild and moderate events. Trialists should therefore distinguish clearly between safety outcomes (severe symptoms) and tolerability outcomes (mild and moderate symptoms), with the latter needing to be interpreted with caution given greater heterogeneity of reporting. Secondly in multi-site studies with varied proportions of reported symptoms between sites, trialists should be clear in the reporting of the uncertainty surrounding their estimates. The range of proportions (rather than or in addition to the mean or median) may be a better way to report pooled results, reflecting the variability. Thirdly symptoms recorded in an intervention arm should be reported in relation to the control arm. A relative change in symptoms in the intervention arm compared to the control arm is much more relevant than simply recording the absolute occurrence of symptoms. | PMC10476314 | |
Acknowledgements | We wish to express our sincere gratitude to the patients for volunteering to join this study and to the nurses and laboratory staff. | PMC10476314 | ||
Authors’ contributions | MR, TTH | TSD | LvS, KT, RJC and MR conceived the idea for this study. LvS, JKB, NJW, NPD, and RNP conceived the IMPROV trial. TSD, KC, NHC, AA, MNN, APP, AGR, IS, NCT, TTH, AH, MAH, LLE, AW and TT were responsible for data collection. KT, RJC, MR and LvS did the data analyses and interpretation and wrote the first draft of the manuscript. All authors critically reviewed the paper and approved the final submitted version for publication. | PMC10476314 |
Funding | The IMPROV study was funded by the UK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404). KT is funded through an CSL Centenary Fellowship. RJC is funded by an Australian National Health and Medical Research (NHMRC) Emerging Leader Investigator Grant (1194702), JAS by a NHMRC Leadership Investigator Grant (1196068) and RNP by a NHMRC Leadership Investigator Grant (2008501). The study funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to the data in the study and had final responsibility for the decision to submit for publication. | PMC10476314 | ||
Availability of data and materials | The data are available for access via the WorldWide Antimalarial Resistance Network (WWARN.org). Requests for access will be reviewed by a Data Access Committee to ensure that use of data protects the interests of the participants and researchers according to the terms of ethics approval and principles of equitable data sharing.Requests can be submitted via the Data Access Form available at WWARN.org/accessing-data and by email to the following address: malariaDAC@iddo.org. The WWARN is registered with the Registry of Research Data Repositories (re3data.org). | PMC10476314 | ||
Declarations | PMC10476314 | |||
Ethics approval and consent to participate | The study received full ethical approval from the Human Research Ethics Committee of the Northern Territory Department of Health (HREC), the Oxford Tropical Research Ethics Committee (OxTREC), the Institutional Review Board at the Ministry of Public Health of the Islamic Republic of Afghanistan, the National Research Ethics Review Committee (NRERC) in Ethiopia, the Health Research Ethics Committee of the Faculty of Medicine University of Indonesia and the Ministry of Health Evaluation Committee on Ethics in Biomedical Research in Vietnam. All study activities were carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all subjects and/or their legal guardian(s). | PMC10476314 | ||
Consent for publication | Not applicable. | PMC10476314 | ||
Competing interests | The authors declare no competing interests. | PMC10476314 | ||
References | PMC10476314 | |||
Background | tightness, knee osteoarthritis, KOA | KNEE OSTEOARTHRITIS | The association between hamstring tightness and knee osteoarthritis (KOA) is significant because tight hamstrings can put more strain on the knee joint, reduce its range of motion, and cause compensatory movements that worsen the KOA. | PMC10695107 |
Objective | proprioceptive neuromuscular, KOA | To compare the effects of instrument-assisted soft tissue mobilization (IASTM) and proprioceptive neuromuscular (PNF) on hamstring flexibility in patients with KOA. | PMC10695107 | |
Methods | Data for the randomized controlled trial (NCT05110326) was collected from | PMC10695107 | ||
Results | The study found a significant interaction ( | PMC10695107 | ||
Conclusions | pain | Both the IASTM technique and PNF stretching resulted in increased hamstring flexibility, decreased pain, and enhanced general health. The IASTM technique, however, showed potential benefits over PNF stretching in terms of flexibility, pain relief, and public health enhancement. Physical therapists and manual therapists may prioritize the usage of the IASTM technique for patients who want to make significant changes in these areas. | PMC10695107 | |
Introduction | injury or overuse damages the articular cartilage, osteoarthritis, muscle flexibility, musculoskeletal disease, knee osteoarthritis, KOA, overweight, articular cartilage loss, Knee osteoarthritis, disability, proprioceptive neuromuscular facilitation, trauma | DEGENERATION, CONTRACTIONS, OSTEOARTHRITIS, MUSCULOSKELETAL DISEASE, KNEE OSTEOARTHRITIS, KNEE OSTEOARTHRITIS | Knee osteoarthritis (KOA) is a painful musculoskeletal disease caused by degeneration and articular cartilage loss over time. KOA mostly affects the elderly population and commonly causes disability throughout the world (Age, congenital and acquired deformity, trauma and female gender are all risk factors that have been linked to the development of KOA. The overweight population is more prone to develop osteoarthritis. Joint injury or overuse damages the articular cartilage leading to osteoarthritis (Knee joint movements occur by the two primary muscles including the quadriceps and hamstrings and assist the smooth and accurate ambulatory growth factors in the knee joint (There are different conventional approaches for the management of knee osteoarthritis including medical, surgical, and rehabilitative strategies. Physiotherapy includes the application of modalities, exercise therapy, and different manual therapy technique (In those with knee osteoarthritis (KOA), proprioceptive neuromuscular facilitation (PNF) stretching might be an effective technique to improve hamstring flexibility. This stretching method combines isometric contractions with passive stretching to increase joint range of motion and muscle flexibility (Enhancing hamstring flexibility through exercise and stretching can aid in symptom relief and lessen pressure on the knee joint, making it a crucial component of managing and treating KOA. IASTM and PNF stretching are two therapies that have been utilized to improve muscle flexibility and range of motion in joints. However, it is unclear how well they perform compared to one another when it comes to enhancing hamstring flexibility in knee osteoarthritis patients. It was hypothesized that IASTM techniques are more effective than PNF stretching in improving hamstring flexibility among KOA patients. Therefore, the study aimed to compare the effectiveness of IASTM and PNF stretching on hamstring flexibility in patients with KOA. | PMC10695107 |
Methods | PMC10695107 | |||
Study design & setting | It was a single-blinded, randomized clinical trial (NCT05110326) conducted at the RHS Rehabilitation Centre (RHS/EC/28-06-2021-03), Islamabad, Pakistan. The study was completed within 1 year from July 2021-June 2022 and approval was taken from the research and ethical committee (REC) of the Faculty of Rehabilitation and Allied Health Sciences (with Ref# Riphah/RCRS/REC-01055) Riphah International University. | PMC10695107 | ||
Participants | tightness, knee osteoarthritis, KOA | KNEE OSTEOARTHRITIS | The 35–50 years patient having grade 1&2 knee osteoarthritis (KOA), according to the Kellegren and Lawrence criteria, hamstring tightness of more than 20° from the active knee extension test (AKET) ( | PMC10695107 |
Sample size | A total of | PMC10695107 | ||
CONSORT diagram. | PMC10695107 | |||
Randomization | The sealed enveloped method using a computerized random number generator was used for randomization. An individual who was not directly involved in the study did the random allocation. The random numbers were then written on the index cards and placed in a thick and opaque sealed envelope before the start of the study. After obtaining written informed consent, the physical therapist opened the envelope and provided the respective interventions to the patients. As the assessing physical therapist was blinded to the intervention so the study was single-blinded. | PMC10695107 | ||
Intervention | A 30-minute session was given to each patient 3 times per week and was given for 6 weeks. Baseline assessments were made prior to beginning the intervention and re-assessment was done after 6 weeks. The detail intervention protocol for group A ( | PMC10695107 | ||
Intervention protocol. | PMC10695107 | |||
Assessments | Arthritis, knee osteoarthritis, pain | ARTHRITIS, KNEE OSTEOARTHRITIS | The researchers considered the ethical, legal and regulatory norms and standards for this research according to the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.The visual analog scale (VAS) was used to determine the severity of pain. The patient marked a point on a 100-mm horizontal line that indicated a continuum between “no pain” and “worst discomfort” (The hamstring flexibility was assessed by active knee extension test (AKET) using a goniometer (The Western Ontario and McMaster Universities Arthritis Index (WOMAC) index was also used to assess the health status of individuals with knee osteoarthritis including three subscales of pain, stiffness, and physical function. It consisted of 24 questions with a total score ranging from 0–96 ( | PMC10695107 |
Statistical methods | The descriptive statistics, such as frequency (n), percentage (%), mean, standard deviation (SD), and mean differences (MD), used to summarize the study’s findings and subsequently presented in tables and graphs. A two-way mixed ANOVA with partial eta squared ( | PMC10695107 | ||
Results | The mean age and BMI of the study participants were 45.14 ± 4.67 years and 28.53 ± 5.65 kg/m | PMC10695107 | ||
Frequency distribution (BMI). | PMC10695107 | |||
Frequency distribution knee OA grades. | PMC10695107 | |||
Interaction effect. | To find the interaction effect between intervention and level of assessment, two-way mixed ANOVA was applied. As the sphericity was assumed, the results showed that there was a significant interaction effect between both interventions and time factor in all dependent variables with large effect size, including hamstring flexibility on AKET {F =32.13(1,55), As there was a significant interaction effect for all the dependent variables, paired samples | PMC10695107 | ||
Discussion | tightness, reduced functional disability, knee osteoarthritis, pain | PATELLOFEMORAL PAIN SYNDROME, KNEE OSTEOARTHRITIS, ADHESIONS | This study was conducted to determine the effectiveness of the Instrument-Assisted Soft Tissue Mobilization (IASTM) technique and PNF stretching in improving hamstring flexibility, pain, and health status in knee osteoarthritis. In the present study within group analysis showed that participants in both groups had significant improvement in pain, hamstring flexibility, and health status throughout the treatment duration. Between group analysis showed that IASTM technique showed more significant improvement in hamstring flexibility, pain, and health status on WOMAC scores (pain, stiffness and physical functions) as compared to PNF stretching.A study comparing the effects of static stretching with PNF stretching in patients with knee osteoarthritis showed significant improvement in pain and hamstring flexibility in the PNF group (Within-group analysis showed that PNF stretching had significant results in reducing pain and improving health status. A study had similar results showing that PNF stretching significantly reduced pain intensity and improved functional performance in patients with knee osteoarthritis and chronic non-specific low back pain (An RCT showed that IASTM reduced pain and reduced functional disability in the patellofemoral pain syndrome (The present study showed that IASTM had significantly improved hamstring flexibility compared to PNF stretching. This difference could be attributed to IASTM’s ability to directly target specific areas of tightness or adhesions, stimulate fibroblastic activity, induce tissue reattachment, and lead to greater improvements in hamstring flexibility (The limitations of this study were that it was conducted in only one clinical setting. Another limitation that may affect the prognosis of the results, is the inclusion of both unilateral and bilateral knee osteoarthritis including different grades of knee osteoarthritis. | PMC10695107 |
Conclusion | knee osteoarthritis, pain | KNEE OSTEOARTHRITIS | This study indicated those with knee osteoarthritis benefited from both the IASTM technique and PNF stretching, resulting in increased hamstring flexibility, decreased pain, and enhanced general health. The IASTM technique, however, showed potential benefits over PNF stretching in terms of flexibility, pain relief, and general health enhancement. These benefits could be attributed to the IASTM technique’s improved hamstring flexibility. Multicentered future studies are recommended on the bases of BMI, gender differences as well as retention effects of the intervention. | PMC10695107 |
Supplemental Information | PMC10695107 | |||
CONSORT Checklist | Click here for additional data file. | PMC10695107 | ||
Trial Protocol | Click here for additional data file. | PMC10695107 | ||
Raw data | pain | SPSS or PSPP is required to view the datasetClick here for additional data file.Thanks to the participants of this study for sharing their personal experiences with pain. | PMC10695107 | |
Additional Information and Declarations | PMC10695107 | |||
Competing Interests | The authors declare there are no competing interests. | PMC10695107 | ||
Human Ethics | The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):The Research and ethical Committee (REC) of Faculty of Rehabilitation and Allied Health Sciences of RIphah International University approval to carry out the study (with Ref# Riphah/RCRS/REC-01055). | PMC10695107 | ||
Clinical Trial Ethics | The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):The Research and ethical Committee (REC) of Faculty of Rehabilitation and Allied Health Sciences of RIphah International University approval to carry out the study (with Ref# Riphah/RCRS/REC-01055). | PMC10695107 | ||
Data Availability | The following information was supplied regarding data availability:The raw data is available in the | PMC10695107 | ||
Clinical Trial Registration | The following information was supplied regarding Clinical Trial registration:NCT05110326 | PMC10695107 | ||
References | PMC10695107 | |||
Abstract | The authors declare no competing financial interests.Author contributions: N.F. and C.J.P. designed research; N.A.S.F. and C.J.P. performed research; N.A.S.F. contributed unpublished reagents/analytic tools; N.A.S.F. and Z.Z. analyzed data; N.A.S.F., Z.Z., and C.J.P. wrote the paper.This work was supported by a Research Intramural Funding Program (RIFP) award from the School of Nursing at the University of Washington and by the National Institutes of Health (NIH) National Center for Advancing Translational Sciences Grant UL1 TR002319. Data analysis infrastructure and trainee salary was supported by the Canadian Natural Sciences and Engineering Council (NSERC) Discovery Grant RGPIN-2015-05901.Interoception, the representation of the body’s internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoceptive attention are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions ( | PMC10295813 | ||
Significance Statement | CORTEX | Interoception, the representation of the body’s internal state, is poorly understood compared with the external senses, with existing neuroimaging studies failing to match task difficulty between interoceptive and exteroceptive tasks. The present study used a novel fMRI task to compare interoceptive and exteroceptive attention and explore whether this distinction was moderated by self-reported interoceptive awareness. The results implicate three novel interoceptive mechanisms: interoceptive attention reduces widespread cortical activity while increasing prefrontal connectivity, wherein greater self-reported interoceptive awareness is linked to preserved activation of the anterior cingulate cortex (ACC) and language regions. Rather than increasing activation of interoceptive cortex, interoceptive attention to the breath may involve attending to body representations typically ignored in favor of exteroceptive information and other forms of cognition. | PMC10295813 | |
Introduction | RECRUITMENT | Interoception, the sense of the body’s internal state, is central to human experience, providing homeostatic cues (Our understanding has been limited by a focus on interoceptive accuracy by the research community. For example, heartbeat detection paradigms model the ability to detect a liminal cardiac signal (Research confirms that interoceptive accuracy may not be especially relevant for emotion regulation and wellbeing. Clinical populations often show normal interoceptive accuracy (Interoceptive attention tendency, and specifically the ability to sustain interoceptive attention remains a compelling if underexplored determinant of mental health (Interoceptive attention seems to recruit a distinct neural network from exteroception that features the middle insula (Yet neuroimaging studies characterizing interoceptive attention to the breath have been confounded by nonequivalent task demands. We therefore developed a novel fMRI paradigm for characterizing the neural dynamics of breath-focused interoception compared with a closely balanced exteroception task. We hypothesized (H1) that interoception would result in greater somato-insular recruitment than exteroception, but reduced DAN activation. We further hypothesized (H2) that greater self-reported interoceptive sensibility would correlate with greater SLN activity during interoception, consistent with the SLN’s ascribed role in sensory monitoring and integration ( | PMC10295813 | |
Materials and Methods | PMC10295813 | |||
Experimental design | This fully within-participant study was conducted to validate a novel interoceptive attention task as part of an NIH-funded pilot study, a two-group randomized control trial to examine the neural correlates of interoceptive awareness in the context of mindful awareness in body-oriented therapy (MABT) training ( | PMC10295813 | ||
Participants | Twenty-two right-handed study participants (11 male and 11 female), of adult age (mean: 36.1 years, range: 18–62) completed both baseline and postintervention assessments. Eleven participants (50% of the sample) were randomly allocated to receive eight MABT sessions, delivered individually once per week for eight weeks. Twenty participants self-identified as White or European American, one as African American, and two as Hispanic. Their highest education levels were high school (Sample size for the study was determined by simulation-based power analysis. Given the difficulties in a priori registration of all fMRI contrasts, power analysis was conducted to determine minimum sample size for up to 10 focal contrasts while maintaining familywise power ≥0.90; this required a per-test power of Twenty-five healthy individuals with self-reported elevated stress were initially recruited through advertisements in a local newspaper and through the University of Washington research volunteer website and flyers posted on campus. Inclusion criteria were: (1) being over 18 years of age; (2) Perceived Stress Scale ( | PMC10295813 | ||
Ethics statement | All participants provided informed consent. The study procedures were reviewed and approved by the institutional review board at the University of Washington in accordance with the World Medical Association Declaration of Helsinki. | PMC10295813 | ||
The Interoceptive/Exteroceptive Attention Task (IEAT) | The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel paradigm for exploring the neural dynamics of respiratory attention and awareness. The IEAT consisted of five conditions: Passive Exteroception, Passive Interoception, Active Interoception, Active Exteroception, and Active Matching (a paced breathing condition), as shown in Schematics for the Interoceptive/Exteroceptive Attention Task (IEAT). In Exteroceptive conditions, participants attended to a circle expanding and contracting; in Interoceptive conditions, participants attended to their respiratory inhalation and exhalation. In Passive conditions, participants simply observed the circle or their breath. In Active conditions, participants pressed buttons to track the circle or breath. In the Matching condition, participants tracked the circle’s movements while synchronizing their respiration cycle with the circle. PasExt = Passive Exteroception; PasInt = Passive Interoception; ActExt = Active Exteroception; ActInt = Active Interoception; ActMatch = Active Matching. | PMC10295813 | ||
Passive conditions | During Passive Exteroception, participants were asked to visually monitor a circle as it expanded and contracted periodically on the MRI-compatible visual display without making any behavioral responses. The circle’s pulse frequency was set to match participants’ in-scanner breathing frequency, obtained from a respiration belt worn by participants in the scanner (usually ∼12 Hz). During Passive Interoception, participants viewed a stationary circle on the screen while attending to sensations of the breath. | PMC10295813 | ||
Active conditions | CONTRACTION | During Active Exteroception, participants reported on the expansion and contraction of the circle on the screen, which again was set to pulse at participants’ in-scanner respiratory frequency. During Active Interoception, participants reported on inhalations and exhalations by making button box key presses with their right-hand index and middle fingers respectively. The circle on the screen expanded and contracted with these key presses, approximating the frequency of circle movement during Passive Exteroception. During Active Matching, participants reported on the expansion and contraction of the circle as in Active Exteroception, while synchronizing their inhalation to the circle’s expansion and their exhalation to the circle’s contraction. | PMC10295813 | |
Interoceptive attention tendency | Perhaps the most common dispositional index of subjective interoceptive engagement is the Multidimensional Assessment of Interoceptive Awareness (MAIA), which in validation has demonstrated strong associations to subjective wellbeing (Here, the MAIA was used to provide a subjective report of the ability to adaptively engage interoceptive attention. The MAIA has an updated version to improve the reliability of the two reverse-coded subscales ( | PMC10295813 | ||
Procedures | Participants completed the IEAT during fMRI acquisition at two timepoints, baseline and three-month follow-up. The MAIA self-report questionnaire was administered to assess interoceptive awareness at both timepoints. Training effects are the subject of separate reports. | PMC10295813 | ||
Data analysis | PMC10295813 | |||
Respiration confounds | Changes in breathing depth and rate modulate CO | PMC10295813 | ||
Respiration frequency | Respiration data were acquired using a MR-compatible respiration belt sampling at 500 Hz (Philips model 452213117812). Respiration data were first smoothed using a 1 s zero phase low-pass filter window and then mean-corrected. Breath frequency was then estimated using a fast Fourier transform (FFT) of the respiration period. As a first level covariate, frequency was estimated using a 10 s sliding window across the time series, generating a frequency value for each volume acquired in the timeseries. Trial-specific frequencies were also estimated across each task period to serve as covariates at the second (group) level of analysis. | PMC10295813 | ||
Respiration volume/time | RVT | The respiratory signal is influenced by changes in respiratory volume in addition to frequency, with respiratory volume/time (RVT) predicting widespread changes in BOLD activity (To correct for RVT influence, belt amplitude signal was used to calculate RVT as recently recommend ( | PMC10295813 | |
Stimulus and behavior timeseries | RVT | CONTRACTION | The three active localizer conditions, Active Exteroception, Active Interoception, and Active Matching required button-presses to track the sensory target, i.e., inhalation/exhalation during the respiratory cycle, or expansion/contraction during the visual circle cycle. Each active condition therefore produced three periodic timeseries: (1) the circle radius, as measured by timestamps in the participant log files, (2) respiration belt amplitude, as measured by pressure transduction on an MR-compatible respiration belt, and (3) a waveform generated from participant button presses, with button presses indicating inflection points (peaks and troughs) of the response waveform.The respiration belt waveform was obtained directly from a physiological logfile for each fMRI run. Respiration data were sampled at 500 Hz and included a scanner-generated timestamp to precisely indicate the beginning and end of the functional run. Respiration data were segmented into task trials using timestamps from participant logfiles. The ‘pracma’ library (Respiration and behavior tracking. Effects of the respiratory volume/time (RVT) covariate on BOLD activity. Contrasts maps were generated from the five-condition model corrected using threshold-free cluster estimation (TFCE) to the familywise Behavioral keypress waveforms were generated using linear interpolation of behavioral logfile timestamps for button presses using the The circle stimulus waveform was obtained from the stimulus presentation software. The circle period was matched to participant-specific breathing frequencies obtained via respiration belt during structural MRI acquisition. For each trial, the timeseries began at an arbitrary unit of 0. The expansion/contraction period was symmetrical and defined as half the participant respiratory period. The circle value was then extrapolated as increasing from −1 for the expansion period to reach a value of 1 by the end of the period; the circle then paused for 0.2 * the expansion period; the circle then decreased at the same rate for the contraction period to reach a value of −1 by the end of the period, and then paused again for 0.2 * the contraction period, repeating the cycle the end of the task block. | PMC10295813 |
Tracking accuracy | NCC | To calculate trial-specific tracking accuracy in the active tracking conditions (Active Interoception, Active Exteroception, and Active Matching), the appropriate sensory stimulus waveform (respiration in Active Interoception, the visual circle in Active Exteroception) was first phase-corrected to maximally align with the keypress waveform; this correction served to compensate for systematic signal transduction lags between the three types of signals. Phase correction was performed using a normalized cross-correlation (NCC) analysis using the ‘dtwclust’ library in R to estimate the maximum correlation between behavior and respiration/circle timeseries (Following phase correction, tracking accuracy was assessed by computing the deviation from the respiration/circle inflection points to the nearest keypress, as tracking keypresses were cued by changes in circle/respiration phase (the switch from expansion/inhalation to contraction/exhalation). The average deviation in milliseconds was then calculated for each trial and used as a measure of tracking accuracy, with lower scores indicating more accurate tracking ( | PMC10295813 | |
Neuroimaging data acquisition | PAD | Neuroimaging was performed using a 3T Philips Achieva scanner (Philips Inc.) at the Diagnostic Imaging Sciences Center, University of Washington. Imaging began with the acquisition of a T1-weighted anatomic scan (MPRAGE) to guide normalization of functional images (∼6 min) with TR = 7.60 ms, TE = 3.52 ms, TI = 1100 ms, acquisition matrix = 256 × 256, flip angle = 7°, shot interval = 2530 ms, and 1-mm isotropic voxel size. Functional data were acquired using a T2∗-weighted echoplanar imaging (EPI) sequence with TR = 2000, TE = 25 ms, flip angle α = 79°, field of view = 240 × 240 × 129 mm, 33 slices, and a voxel size of 3 × 3 × 3.3 mm with 3.3-mm gap. Button presses were registered using a two-button MR-compatible response pad. | PMC10295813 | |
Preprocessing | A set of preprocessing steps was performed using the consortium-developed fMRIprep robust preprocessing pipeline for fMRI data ( | PMC10295813 | ||
First-level analysis | RVT | Within-participant statistical models were used to characterize the neural distinction between task conditions. Participant time series data from the IEAT was submitted to separate first-level general linear statistical models using Statistical Parametric Mapping software (v12). Task-specific boxcar stimulus functions were convolved with the canonical hemodynamic response function, separately modeling the onsets of the interoceptive and visual control conditions for each participant. To control for motion and physiological confounds, six standard movement parameters, the root mean square of temporal change (DVARS), framewise displacement, respiration rate, and RVT were all included as nuisance covariates. | PMC10295813 | |
Second-level analysis | Participant first-level maps for each experimental condition [Passive Interoception, Passive Exteroception, Active Interoception, Active Exteroception, Active Matching] were analyzed at the second level using a full-factorial mixed-model ANOVA in SPM12 (Familywise control for multiple comparisons (corrected | PMC10295813 | ||
Trial-level confounds | RVT | The current study comes from an exploratory clinical trial, the results of which are the subject of a separate report. We combined data across the trial to power the comparison of IEAT task conditions and modelled any effects of trial Group (MABT vs Control), Time (Baseline vs Postintervention) and their interactions as nuisance covariates. All models also contained condition-averaged respiration rate and RVT as covariates, to further control for variation in respiration between experimental conditions. | PMC10295813 | |
Region of interest (ROI) analysis | For region of interest (ROI) analysis, all signal extractions were taken from models containing the nuisance covariates. Using the built-in SPM12 function, the median value of the raw, unwhitened signal was extracted from all voxels within the ROI, yielding one value per participant at each scanning session. These values were entered into a linear mixed-effects model with restricted likelihood estimation was applied using the ‘lme4’ library ( | PMC10295813 | ||
Hypothesis testing | RVT | Hypothesis 1 aimed to compare interoceptive and exteroceptive attention. To this end we first evaluated a whole-brain interaction between reporting demand [active vs passive] and attentional target [interoception vs exteroception] to evaluate whether the effects of attentional target should be evaluated separately for the active and passive reporting conditions. Subsequent analyses compared the simple effects of attentional target within each reporting demand condition, i.e., [Passive Interoception vs Passive Exteroception] and [Active Exteroception vs Active Interoception]. To perform these contrasts, all five task conditions were estimated separately at the first (individual session) level of analysis and entered into a full factorial design in SPM12.Hypothesis 2 aimed to investigate whether the differences between exteroception and interoception were moderated by individual differences in subjective interoceptive awareness (MAIA scores). Focusing on the contrast of [Active Interoception vs Active Exteroception], we first created contrast maps at the first (within session) level of analysis. These first level maps were then entered into a second (group)-level analysis that included normalized (z-scored) MAIA scale total scores as a covariate of interest. The MAIA covariate was subjected to TFCE correction in the same fashion as other whole-brain analyses, and respiration rate and RVT change between the two conditions was included in the factorial model as a nuisance covariate to control for variation associated with physiological changes. Exploratory analyses of each MAIA subfactor are also available as Extended Data Hypothesis three tested the potential moderating factor of endogenous versus exogenous control of the respiratory cycle by contrasting each of Active Exteroception and Active Interoception against Active Matching using the same five condition model from testing Hypothesis 1.Hypothesis four aimed to understand how engaging in Active Interoception changes brain connectivity relative to Active Exteroception. To accomplish this aim, a psychophysiological interaction (PPI) analysis was conducted in SPM12 using the Generalized PPI Toolbox (v. 13.1), which improves on standard PPI analyses by estimating the effect each task condition has on connectivity independently (To define a region of interest (ROI), the conjunction of the [Active Exteroception – Active Interoception] contrast and the positive MAIA contrast was evaluated, using a threshold of | PMC10295813 | |
Test-retest reliability | The fact that each participant was scanned twice offered a unique opportunity to test the reliability of study effects across two independent scanning sessions. A conjunction analysis for the four main contrasts reported in this paper was conducted. As the TFCE algorithm does not currently perform conjunction analysis, and halving the sample size reduces experimental power, the baseline and postintervention sessions were each analyzed separately at | PMC10295813 | ||
Data and code availability | The full study protocol was preregistered with the Open Science Framework ( | PMC10295813 | ||
Results | PMC10295813 |
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