title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Introduction | migraine, RS, Migraine, neurological disease | MIGRAINE, MIGRAINE, NEUROLOGICAL DISEASE | Migraine is a common and highly disabling neurological disease [The application of advanced magnetic resonance imaging (MRI) techniques has markedly enhanced the understanding of migraine [Here, using a blinded, placebo-controlled design, we primarily aimed to confirm central modifications mediated by erenumab and resting state (RS) functional connectivity (FC) patterns of responders and non-responders after 12 weeks of therapy. Secondary and exploratory aims of the study were to: (1) explore whether central modulation of RS FC contributes to explain the therapeutic effect of erenumab; (2) identify imaging biomarkers of positive response to erenumab; and (3) investigate whether erenumab could lead to sustained central effects after 3-month treatment discontinuation.Gathering data on the effects of erenumab administration, their persistence and their relation with clinical response is crucial for a better understanding of the mechanism of action of this drug within migraine neurobiology. | PMC10576673 |
Materials and methods | PMC10576673 | |||
Study design and participants | migraine, Headache | MIGRAINE | This was a randomized, double-blind, placebo-controlled, crossover, phase 4 trial performed in five Italian Headache Centers from 30 July 2019 to 5 July 2021.The study included a screening (6 weeks), run-in (4 weeks) and a treatment phase (24 weeks). After run-in, patients were randomized to 12-weeks of subcutaneous erenumab 140 mg or masked placebo, followed by 12-weeks of the other treatment (Fig. Schematic description of study design and study procedures. Eligible patients had to be older than 18 years, have ≥ 4 and < 15 migraine days/month and have failed two or more previous migraine preventives. See supplementary methods for detailed inclusion/exclusion criteria. | PMC10576673 |
Randomisation and masking | Patients were randomized in a 1:1 ratio to erenumab or placebo using randomization and medication lists created by the Contract Research Organization’s statistician through a validated SAS program. Randomization was stratified by center. Patients, investigators and the clinical trial team remained blinded to treatment allocation. Erenumab and placebo were supplied in two 70 mg/1 mL pre-filled syringes. Treatments were identical in packaging, labeling and appearance. | PMC10576673 | ||
Procedures | RS, pain, headache, migraine, NRS | MIGRAINE, ADVERSE EVENTS | During the 24-week treatment phase, patients received erenumab 140 mg or placebo every 4 weeks. The treatment phase comprised a baseline visit and follow-up visits at week 4, 8, 12, 16 and 20. An end of study (EOS) visit was performed at week 24. At baseline visit, patients were randomized and received erenumab or placebo treatment which was continued for the following 12 weeks. At week 12, patients were switched to the other treatment (from erenumab to placebo or vice versa).During screening, patients’ underwent electrocardiogram, neurological examination, physical examination and a detailed clinical history, including prior headache characteristics, average headache and migraine days of the 3 months preceding study entry and prior migraine preventives failure history. From the run-in phase to the end of the study, patients were asked to complete a paper headache diary reporting the monthly migraine days (MMD), migraine attack duration, monthly headache days (MHD), monthly number of days with use of acute treatments (MAT), pain severity according the numerical rating scale (NRS) [At baseline, week 12 and week 24, all participants underwent a brain MRI including RS functional MRI (fMRI), fluid-attenuated inversion recovery, 3D T1-weighted and T2-weighted images, according to a prespecified protocol provided by the central reading facility (Neuroimaging Research Unit, IRCCS San Raffaele Scientific Institute, Milan). The baseline MRI was performed within three days prior to receiving the first dose of study treatment and at week 12 the MRI was performed within three days prior to administration of the fourth dose of treatment in order to explore the effect of 3-month of erenumab. To avoid measuring imaging changes related to acute migraine symptoms, all brain MRI were performed in a migraine/headache-free phase and at least 24 h after the last migraine attack.Vital signs, clinical laboratory parameters and occurrence of adverse events (AE) were investigated during the entire study. All patients who received at least one dose of study treatment were included in the Safety population. | PMC10576673 |
Outcomes | RS | Primary endpoints were RS FC changes between erenumab and placebo, as well as between clinical response groups within the two treatment groups. A clinical response was defined as the achievement of at least a 50% reduction of MMD [ | PMC10576673 | |
MRI acquisition protocol | RS | Using 3.0 T scanners at all sites, a T2*-weighted single-shot echo planar imaging (EPI) sequence was acquired at all timepoints for RS fMRI (repetition time [TR] = 2000 ms, echo time [TE] = 35 ms, flip angle = 90°, field of view [FOV] = 240 mm | PMC10576673 | |
RS fMRI preprocessing | RS | RS fMRI data processing was performed using the CONN toolbox [ | PMC10576673 | |
RS FC analysis | RS | Ten large-scale RS networks were created using a seed-region approach [For all networks, Z-score maps of RS FC with each seed region were obtained using the REST software ( | PMC10576673 | |
Sample size estimation | migraine, RS | MIGRAINE | At the time of the study design, no data were available to estimate the effect size for the primary endpoints of the study. Moreover, there were no data regarding a possible carryover effect and its duration upon discontinuation of erenumab (or placebo) on RS FC changes after 3 months of treatment. The sample size calculation for this study was therefore based on the conservative assumption that a relevant carry-over effect was present. As described in literature [Based on these scenarios, the sample size of 100 evaluable patients, 50 per treatment group, was chosen as the one which allowed solid results in each subgroup analysis. Considering observing at least a 15% of non-evaluable patients (i.e., fMRI not evaluable or dropout patient), 120 randomized are needed to obtain 100 evaluable patients. The target sample size for this study was therefore 120 patients randomized. In order to obtain 120 randomized patients, about 140 patients were to be screened.However, due to the COVID-19 pandemic, the study was interrupted balancing the number of available enrolled patients. In fact, the number of 60 randomized patients, 30 per group, guarantees a sufficient level of precision. In detail, considering the evaluation of the difference between treatment groups, about 25 patients are needed to detect a difference between treatment groups of 0.5%, with an intrasubject variability σW of 0.75%, a between-patient variability σB of 0.5%, a power of 90% and an alpha level of 0.002.With regards to the evaluation of whether the changes of the endpoint are different between the two groups of clinical response within treatment groups: (a) in the erenumab group, considering a percentage of clinical responders of about 30% in migraine patients with previous treatment failure [ | PMC10576673 |
Statistical analysis | migraine, RS | REGRESSION, DISEASE, MIGRAINE | The presence of a carry-over effect of treatment was tested, before proceeding with any analysis, by performing two-sample t tests on clinical variables and RS FC maps from all study subjects. Since the results of these analyses suggested the presence of a carry-over effect in the ereneumab/placebo sequence (supplementary results), all analyses were limited to data collected during the first 12-week treatment period, using a parallel group-like design.Between-group differences in clinical changes from baseline to week 12 were assessed using the Chi-square or Fisher exact test for categorical variables and ANCOVA models, including baseline value and treatment as covariates, for continuous variables (SAS, version 9.4). The difference in least square mean values was extracted as the measure of treatment effect along with corresponding two-sided 95% Confidence Interval (CI).A propensity score to be used as an independent covariate for statistical analysis of RS FC was created by entering in a logistic regression age, sex, migraine frequency in the 3 months preceding study entry, disease duration and number of previous preventives tried. Average maps of positive RS FC were obtained using scanner-adjusted one-sample t tests, including all time points from all study subjects. Longitudinal RS FC changes within study groups and comparisons of RS FC changes between erenumab and placebo, as well as between responders and non-responders were obtained using propensity score- and scanner-adjusted full factorial models. Results were masked with average maps of positive RS FC within each network. Correlation analyses of longitudinal RS FC changes with patients’ clinical response were run in all migraine patients, and in erenumab and placebo patients, separately, using propensity score- and scanner-adjusted multiple regression models. Results were masked with between-group differences of RS FC changes in the erenumab Average baseline RS FC Z-scores within the main effects of interest of each network were extracted using REX (Primary outcomes were analysed on the full analysis set (FAS), i.e., all patients randomized for study treatment, and on the per-protocol set (PPS), i.e., all patients who completed at least the first 3 months of double-blind treatment with no major protocol violation. Secondary outcomes were analysed only on the PPS population.The analysis protocol of this study was pre-registered with ClinicalTrials.gov, number NCT03977649. | PMC10576673 |
RS FC analysis | RS | Average maps of positive RS FC for all considered networks are shown in Supplementary Fig. 1. Regions showing significant RS FC changes, from baseline to week 12 of treatment, within the erenumab and placebo group in the FAS population are described in supplementary results. | PMC10576673 | |
Correlation analysis | RS, phonophobia, photophobia | CORTEX | In the entire group of patients, increased RS FC of the right calcarine cortex within the primary visual network correlated with reduction in MMD at week 12. Significant correlations were also found between decreased right thalamic RS FC with the left SFG and reduction in MMD and ASC-12 scores, decreased right thalamic RS FC with the right SFG and reduction in HIT-6 scores, and between the decreased right thalamic RS FC with the left SFG and middle cingulate cortex and reduction in the number of days with phonophobia. Increased RS FC of the left precuneus within the cerebellar network correlated with the reduction in the number of days with photophobia at week 12. No significant correlations were found in the erenumab and placebo group separately (Supplementary Table 6). | PMC10576673 |
Prediction analysis | A lower baseline Z-score in the right pontine network was associated with higher odds of a good clinical response to erenumab after 12 weeks of treatment (odds ratio = 0·95, 95% CI = 0·92–0·99, | PMC10576673 | ||
RS FC changes during erenumab discontinuation | RS | During erenumab discontinuation, patients showed increased RS FC of the left superior frontal gyrus within the primary visual network. Moreover, patients showed decreased RS FC between the left PAG and left SMA, between bilateral PAG and left cerebellum, and between the right pons and left superior temporal gyrus (Supplementary Table 7). | PMC10576673 | |
Safety | upper respiratory tract infections, femur fracture, constipation | ADVERSE EVENTS, UPPER RESPIRATORY TRACT INFECTIONS | No safety concerns emerged during the study. One serious AE was reported in a patient receiving erenumab (femur fracture), and treatment emergent AEs were essentially limited to constipation (10%) and upper respiratory tract infections (7%). Treatment emergent adverse events are described in Supplementary Table 13. No significant changes in laboratory parameters or physical findings were observed. | PMC10576673 |
Discussion | RS, cerebellar RS, pain, a reduced thalamic RS, peripheral nociceptive trigeminal inputs, migraine, thalamus | BRAIN, PATHOPHYSIOLOGY, SECONDARY, MIGRAINE, CORTEX | This study confirmed the efficacy of a 12-week erenumab treatment in episodic migraine and showed that the treatment is associated to RS FC changes within clinically relevant brain networks mediating migraine manifestations. In line with previous clinical studies [Compared to placebo, patients receiving erenumab showed increased cerebellar RS FC with the precuneus, an area implicated in sensory integration and mind wandering from pain [We also found a reduced thalamic RS FC with frontal brain areas involved in nociception in migraine patients treated with erenumab. The thalamus is a central area for pain modulation, where peripheral nociceptive trigeminal inputs converge before reaching the cortex [Clinical efficacy of erenumab was also linked to functional modulation of primary and secondary visual areas. We found that responders to erenumab experienced a higher RS FC between the calcarine cortex and extrastriate visual areas, like the cuneus, compared to non-responders. The role of the visual network in migraine, regardless the presence of aura, is well established [Only one previous observational study [Brain functional modifications observed after 12 weeks of erenumab at the level of PAG reversed when treatment was stopped. This finding is in line with clinical data [The identification of patients who might benefit more of a given treatment is an important goal of the expanding scenario of migraine treatment. In this perspective, we found that a lower RS FC of the pontine network contributes to identify patients with a higher probability of responding to erenumab. The pontine area is one of the key players of migraine pathophysiology. Several pieces of evidence [The mechanisms underlying the therapeutic benefit of anti-CGRP mAbs in migraine prevention are a matter of ongoing discussion. Given the large size of mAbs targeting the CGRP pathway, the most promoted idea is that their site of action is outside the BBB and may include meningeal receptors, trigeminal sensory fibers and the trigeminal ganglion [To our knowledge, this is the first study investigating erenumab central effects after 12 weeks of treatment using a randomized, double-blind, placebo-controlled design. Another strength of this study is the inclusion of only episodic migraine patients, who were not taking other migraine preventives and who were studied outside their migraine attack. In addition, we have applied a statistical approach corrected for multiple comparisons, thus limiting the number of false positives.We are aware that a limitation of this study is the lack of a healthy control group to serve as reference for RS FC findings. Information regarding the time elapsed between the MRI and the following migraine attack was also missing. Moreover, the sample size of the migraine subgroups was quite small, increasing the risk of false positive results, and our migraine sample was heterogeneous, including both patients with and without aura. Lastly, the software we used for our voxel-wise comparisons (i.e., SPM12) does not include a full implementation of mixed models. Larger studies are needed to confirm our findings. Although a peripheral mechanism of action of erenumab seems the most likely, this study suggests that clinical benefit of erenumab could derive from combined peripheral and central mechanisms. | PMC10576673 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 982 KB)Members of the RESET BRAIN Study Group are present in the Acknowledgement section. | PMC10576673 | ||
Acknowledgements | We would like to acknowledge Arianna Faggioli for MRI data acquisition. The authors thank Donatella Vassellatti of Novartis Farma for the oversight of all the aspects related to the conduction of the clinical study and OPIS for providing clinical trial support as CRO assigned to the study. | PMC10576673 | ||
Author contributions | MF, RM, MB, DR, RT, MAR contributed to the protocol design. RM, IC, BC, LG, DM, RO, AR, SS, CT, AC, VC, MS contributed to collection of data. RM, AP, AS, FB contributed to MRI data acquisition. RM, PV, RV, LDO contributed to MRI data analysis. RM and PV contributed to MRI statistical analyses, MB contributed to clinical statistical analyses. All authors were involved in the interpretation of the data. All authors critically reviewed and edited the manuscript. | PMC10576673 | ||
Funding | Novartis Pharma. | PMC10576673 | ||
Data availability | Data supporting the findings of this study are available from the corresponding author, upon reasonable request. | PMC10576673 | ||
Declarations | PMC10576673 | |||
Conflicts of interest | MF is Editor-in-Chief of the | PMC10576673 | ||
Ethical standards | This study was approved by institutional review board at all participating sites and all subjects provided written informed consent prior to study participation. | PMC10576673 | ||
References | PMC10576673 | |||
Background | death, ®, idiopathic PD, Parkinson’s disease, PD, neuronal dysfunction, mitochondrial dysfunction, REPAIR-MS | MULTIPLE SCLEROSIS (MS), MITOCHONDRIAL DYSFUNCTION, DISEASES, NEURODEGENERATIVE DISEASES | Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson’s disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively. | PMC10717868 |
Results | BRAIN | Brain metabolites were measured using 7-Tesla | PMC10717868 | |
Conclusions | PD | DISEASE | Our results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS. | PMC10717868 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12951-023-02236-z. | PMC10717868 | ||
Keywords | PMC10717868 | |||
Methods | PMC10717868 | |||
Standard protocol approvals, registrations, and patient consents | Study protocols were reviewed and approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and were conducted in accordance with Good Clinical Practice Guidelines of the International Conference on Harmonization and the ethical principles of the Helsinki Declaration of 1975, as revised in 2000 [ | PMC10717868 | ||
Participant selection | PD, REPAIR-MS, Parkinson’s disease | Detailed inclusion/exclusion criteria are given in Tables S1 (REPAIR-PD) and S2 (REPAIR-MS). Key entry criteria for each REPAIR cohort are provided below.REPAIR-PD: Participants were men or women aged 30–80 years old with a diagnosis of PD according to the MDS Clinical Diagnostic Criteria for Parkinson’s disease [REPAIR-MS: Participants were men or women aged 18–55 years old with a diagnosis of relapsing MS according to the revised McDonald Criteria [ | PMC10717868 | |
Interventions | REPAIR-MS | PROGRESSIVE MULTIPLE SCLEROSIS, BLIND | Participants took the assigned dose of CNM-Au8 once daily for at least 12 weeks. Study investigators and participants were blinded to the dose of CNM-Au8 selected by the sponsor, which could range from 7.5 mg to 60 mg CNM-Au8; the blind will be maintained until another companion cohort of the REPAIR-MS trial in non-active progressive multiple sclerosis, which is currently underway, is completed. | PMC10717868 |
Protocol deviation due to Covid-19 | REPAIR-MS | SECONDARY | Due to administrative suspension of in-person research visits at UT Southwestern in the Spring of 2020 during the COVID-19 pandemic, several patients continued treatment with the study drug for longer than the originally planned 12 weeks. Some study visit data that required an in-person visit was missing due to the COVID-19 related research suspension, but all participants had baseline and end-of-study primary and secondary outcome imaging assessments performed per protocol once in-person imaging was allowed. The end-of-study imaging assessment was performed 12–16 weeks post-baseline for all but two participants, one in REPAIR-PD (end-of-study imaging performed at 25 weeks) and one in REPAIR-MS (end-of-study imaging performed at 20 weeks). | PMC10717868 |
Statistical analysis | deaths | REGRESSION, ADVERSE EVENTS | The primary outcome was mean change from baseline to end-of-study visit for the NADSeveral bioenergetic metabolite exploratory outcomes, functional exploratory outcomes, and safety outcomes were also evaluated. Here, we report the regression of baseline values versus mean percentage change of the average brain β-ATP signal, which is regarded to reflect brain ATP levels due to the lack of overlap with overlapping phosphorous peaks [Safety was assessed via spontaneously reported adverse events, serious adverse events, discontinuations due to adverse events, deaths, and the Columbia Suicide Severity Rating Scale (C-SSRS).The sample size for this proof-of-concept study was calculated based on the observed variance in brain metabolite levels in a prior Paired t-tests were used to assess for change in NADPaired t-tests were also calculated for each individual gait or balance parameter reported by the APDM Mobility Lab Timed Up and Go (TUG), Walk, and Sway tests which were performed at baseline and on the end-of-study visit. Sidak’s correction for the APDM variables was employed to account for the large number of comparisons resulting in a significance threshold of 0.001. MDS-UPDRS parts 1, 2, and 4 were analyzed with ANOVA, while part 3 and total score was assessed using a mixed-effects model to account for the missing data caused by missed in-person visits related to the COVID-19 research suspension. Statistical analyses were performed using SAS 9.4 (SAS Institute, Inc., Cary, NC). Figures were generated in Prism 9.4.1 (Graphpad Software LLC, San Diego, CA). | PMC10717868 |
Results | PMC10717868 | |||
Participants | REPAIR-MS | Demographics, participant disposition and baseline clinical features of the 13 participants in REPAIR-PD are shown in Table
Baseline characteristics of participants in REPAIR-PD (n = 13)Values given are mean ± standard deviation. Levodopa dose is calculated as (mg immediate-release levodopa) + (mg controlled-release levodopa tablets)0.75 + (mg extended-release capsules)0.7.Demographics, participant disposition and baseline clinical features of the 11 participants in REPAIR-MS are shown in Table
Baseline characteristics of participants in REPAIR-MS (n = 11)Values given are mean ± standard deviation. | PMC10717868 | |
Exploratory endpoints | PD | MDS-UPDRS is a clinician-administered, validated instrument for measurement of both non-motor and motor aspects associated with PD for use in research and clinical trials [The APDM Mobility lab generated 32 unique parameters for the Sway test, 7 for the TUG test, and 51 for the Walk test. After Sidak correction, none of these demonstrated a statistically significant mean change from baseline to end of study. | PMC10717868 | |
Safety | ideation, sinusitis, paresthesia, nasopharyngitis, TEAEs, deaths, REPAIR-MS | SINUSITIS, ADVERSE EVENTS, DISEASE, NASOPHARYNGITIS, PARESTHESIA, ADVERSE EVENT | A total of 8 (61.5%) REPAIR-MS participants and 6 (46%) REPAIR-PD participants experienced at least one treatment emergent adverse event (TEAE). All TEAEs were reported as mild or moderate; no participants experienced TEAEs reported as severe. No participants experienced TEAEs that were considered related to study drug by the study investigators. There were no serious adverse events (SAEs), no TEAEs resulting in study discontinuation, and no deaths. TEAEs occurring in more than one participant across both disease cohorts included sinusitis (n = 3), nasopharyngitis (n = 3), and paresthesia (n = 2). Other safety parameters that were assessed included hematology, serum chemistry, urinalysis, physical exam, electrocardiogram, and the CSSRS. CSSRS data revealed no suicidal ideation from any participants across both studies. Of the laboratory assessments, only one clinically significant finding (elevated creatine kinase) was reported in the REPAIR-MS cohort for a participant at the baseline visit. The safety lab was collected prior to participant dosing with CNM-Au8 and was found to resolve within two weeks at this participant’s next visit, while treated with CNM-Au8. The participant’s creatine kinase remained within the normal range throughout the remainder of the study. In conclusion, CNM-Au8 was well-tolerated, and no safety signals were observed in either cohort. | PMC10717868 |
Discussion | PD, Parkinson’s disease | DISEASE | The objective of our study was to demonstrate brain target engagement of orally administered CNM-Au8 in participants with PD or MS using 7T Limitations of our study include the relatively small number of participants in the REPAIR trials. In addition, the studies had to be terminated after evaluating only one dose of CNM-Au8 due to enrollment challenges associated with the COVID-19 pandemic. While future studies with larger cohorts of participants using brain metabolite imaging to evaluate CNM-Au8 treatment effects are warranted, there were several important observations that these studies afforded, despite their small size.A previous The REPAIR studies also extend the findings of the recent NADPARK study, which reported that elevating brain total NAD levels by dietary supplementation with a high-dose NAD precursor in 30 participants with PD for 30 days was associated with mild clinical improvement, increased brain glucose metabolism, and decreased inflammatory cytokines in serum and CSF [The REPAIR studies also demonstrated significant effects of CNM-Au8 on ATP levels and on the phosphorylation potential using the full volume coil. Global assessment of brain metabolite changes may provide a measure of the overall burden of disease on the brain, independent of specific brain regions, and thus be more comparable across studies and disease states [We believe these observations demonstrate an important homeostatic energetic effect of CNM-Au8 in these patient populations. Both increased and decreased levels of brain ATP are indicative of disease state, in both PD and MS. In PD, a low ATP/Pi ratio is seen in Parkinson’s disease [This short-duration study was underpowered to detect clinical benefit with CNM-Au8 treatment, and thus the finding of no significant clinical benefit (as manifested by stable MDS-UPDRS total scores and APDM gait/balance parameters) was anticipated. We attribute the statistically significant improvement in MDS-UPDRS part 2 (driven by improvement at 4 weeks) to a placebo effect induced by expectation of benefit by subjects who knew they were taking active drug. Historically, symptomatic effects, i.e., effects with short-lived beneficial impact that converge to the level of placebo with time and that lack evidence of longer-term neuroprotection, have confounded outcome measure interpretation for putative neuroprotective drugs [ | PMC10717868 |
Conclusions | NEURODEGENERATIVE DISEASES | CNM-Au8 is a nanomedicine being developed to treat failures in energy metabolism associated with many neurodegenerative diseases. Its novel mechanism of action includes targeting the redox couple NAD | PMC10717868 | |
Acknowledgements | We are deeply grateful to the study participants and their families for their willingness to participate in clinical research. We thank Nasreen Sayed, Lisa Lamottte, and Jan Cameron-Watts of UT Southwestern for study coordination of REPAIR-PD, and Manuel Huichapa, Taylor Quance, and Ana Raicu of UT Southwestern for study coordination of REPAIR-MS. | PMC10717868 | ||
Author contributions | MTH | MTH, JR, RBD Jr, BMG, and KSH conceived and designed the study; RBD Jr, BMG, and PS were clinical trial lead researchers of this study; AR, JaE, JeE, RG, and MTH led trial operations for the study; RG served as safety monitor of the study; JR, RBDIII, RBD Jr, BMG and PS led data acquisition; all authors substantially participated in analysis and interpretation of data with SL and MTH leading the statistical analysis. KSH and MTH drafted the work and all authors participated in revising and editing. All authors read and approved the final manuscript. | PMC10717868 | |
Funding | Clene Nanomedicine, Inc., funded this study. | PMC10717868 | ||
Data availability | All datasets used and/or analysed during this study are either included in this published article and its supplementary information files, or are available as de-identified, HIPAA-compliant datasets upon reasonable request to the corresponding author. To protect the privacy of individuals who participated in this study, a fully executed data transfer agreement between Clene Nanomedicine, Inc., and the third party may be required.A control dataset used for power calculation and refinement of the | PMC10717868 | ||
Declarations | PMC10717868 | |||
Competing interests | MTH | JR, RBDIII, and RBD Jr have no competing interests to declare. AR, JaE, JeE, KSH, RG, MTH and BMG are employees of Clene and own stock in the company. At the time of study conductance, BMG was solely affiliated with UTSW. He was employed by Clene as a consultant after the conclusion of the described studies. SL is an employee of the contract research organization, Instat. PS has no disclosures related to this publication. He has received consulting fees from Medical Logix LLC, Genentech, and Bristol Myers Squibb. | PMC10717868 | |
Ethics approval and consent to participate | REPAIR-MS | Study protocols were reviewed and approved by the Institutional Review Board of the University of Texas Southwestern Medical Center (IRB# STU-2019-0992 and STU-2019-0625, for REPAIR-MS and REPAIR-PD, respectively). Trials were conducted in accordance with Good Clinical Practice Guidelines of the International Conference on Harmonization and the ethical principles of the Helsinki Declaration of 1975, as revised in 2000 [ | PMC10717868 | |
Consent for publication | Not applicable. | PMC10717868 | ||
References | PMC10717868 | |||
Background | OA, knee osteoarthritis | KNEE OSTEOARTHRITIS | A stratified approach to exercise therapy may yield superior clinical and economic outcomes, given the large heterogeneity of individuals with knee osteoarthritis (OA). | PMC9860430 |
Objective | To evaluate the cost-effectiveness during a 12-month follow-up of a model of stratified exercise therapy compared to usual exercise therapy in patients with knee OA, from a societal and healthcare perspective. | PMC9860430 | ||
Methods | An economic evaluation was conducted alongside a cluster-randomized controlled trial in patients with knee OA ( | PMC9860430 | ||
Results | knee pain | During 12-month follow-up, there were no significant between-group differences in clinical outcomes. The total societal costs of the experimental group were on average lower compared to the control group (mean [95% confidence interval]: € 405 [-1728, 918]), albeit with a high level of uncertainty. We found a negligible difference in QALYs between groups (mean [95% confidence interval]: 0.006 [-0.011, 0.023]). The probability of stratified exercise therapy being cost-effective compared to usual exercise therapy from the societal perspective was around 73%, regardless of the willingness-to-pay threshold. However, this probability decreased substantially to 50% (willingness-to-pay threshold of €20.000/QALY) when using the healthcare perspective. Similar results were found for knee pain and physical functioning. | PMC9860430 | |
Conclusions | Coronavirus disease | We found no clear evidence that stratified exercise therapy is likely to be cost-effective compared to usual exercise therapy in patients with knee OA. However, results should be interpreted with caution as the study power was lower than intended, due to the Coronavirus disease (COVID-19) pandemic. | PMC9860430 | |
Keywords | PMC9860430 | |||
Introduction | obesity, LMS, OA, ’, pain, TKR, Knee osteoarthritis | DISABLING DISEASE, OBESITY, KNEE OSTEOARTHRITIS | Knee osteoarthritis (OA) is one of the most common chronic health conditions (prevalence 3.8%) and one of the most disabling diseases among adults.Exercise therapy is recommended as a first-step treatment for knee OA, next to pain medication and diet, with TKR to be considered only after these conservative treatments fail.We recently conducted a randomized controlled trial (RCT) in knee OA to assess the clinical and cost-effectiveness of a stratified approach of exercise therapy – distinguishing a ‘high muscle strength subgroup’ (HMS), ‘low muscle strength subgroup’ (LMS) and an ‘obesity subgroup’ (OS) - compared to usual exercise therapy. As reported elsewhere,Therefore, the aim of the current study is to evaluate the cost-effectiveness of stratified exercise therapy compared to usual exercise therapy, from the societal and healthcare perspectives. | PMC9860430 |
Methods | PMC9860430 | |||
Design | obesity, knee Osteoarthritis | OBESITY | This economic evaluation was conducted alongside a 12-month pragmatic, parallel, 2-group cluster-randomized controlled trial (cRCT) in primary care: the OCTOPuS trial (Optimization of exerCise Therapy in patients with knee Osteoarthritis in a Primary care Setting).A total of 61 physical therapy practices (clusters) with 137 physical therapists were randomly allocated (1:2 ratio) to the experimental (23 practices with 54 physical therapists) or control arm (38 practices with 83 physical therapists), by using a web-based randomization program, with random sequence generation and concealment of randomization guaranteed. An independent researcher who was blinded to treatment allocation performed the randomization of physical therapy practices and supervised the blinded, primary (effectiveness) analyses. In addition, 21 dieticians (each of them linked to an experimental arm physical therapy practice) were recruited to provide the diet intervention in patients from the ‘obesity subgroup’. More details are reported elsewhere. | PMC9860430 |
Ethics approval and consent to participate | This study was approved by the Medical Ethical Committee of the VU University Medical centre (2018.563). We conducted this study in agreement with the declaration of Helsinki (2013), in accordance with the Dutch Medical Research Involving Human Subjects Act (WMO), and the General Data Protection Regulation (in Dutch: Algemene Verordening Gegevensbescherming, AVG). We obtained written informed consent from each participant, after the information letter was provided. The researchers made sure that the participants were given complete, adequate, written and oral information regarding the nature, aims, possible risks and benefits of the study. We explained to the participants that they were free to interrupt their participation in the study at any moment without any consequence, and that they were able to receive a digital copy of their personal data. Participants received a copy of the information letter and informed consent form. An independent clinician/epidemiologist was appointed to provide participants the opportunity to ask questions about the study. The research protocol and statistical analysis plan are accessible at the Netherlands National Trial Register ( | PMC9860430 | ||
Participants | knee pain, NRS | Participants were recruited by participating physical therapists in primary care. The following inclusion criteria applied: presence of knee pain with duration ≥3 months, severity of knee pain ≥2/10 on the Numeric Rating Scale (NRS), | PMC9860430 | |
Study procedures | Physical therapists screened patients for eligibility at their first consultation. After providing informed consent, eligible patients were included and asked to complete questionnaires on clinical outcomes and costs at baseline (T0), 3-month follow-up (T3), 6-month follow-up (T6), and 12-month follow-up (T12), in addition to a questionnaire at 9-month follow-up (T9) for costs only, to avoid recall bias. | PMC9860430 | ||
Interventions | PMC9860430 | |||
Experimental intervention | obesity, weight loss, LMS, ’ | OBESITY | Physical therapists were trained to provide the model of stratified exercise therapy and make:subgroup allocation into the HMS, LMS, or OS groups through a simple stratification algorithm with only two variables (body mass index [BMI] and upper leg muscle strength [30-seconds chair stand test]) (see Supplementary material – Fig. 1 and previous studiessubgroup-specific, protocolized exercise therapy interventions (see Baseline characteristics in OCTOPUS-trial.control arm was not aware and did not use stratification algorithm for subgroup allocation.Dieticians were instructed to deliver a dietary intervention aiming at 10% weight loss in 12 months, according to their clinical guideline to patients in the ‘obesity subgroup’ (see Supplementary material – | PMC9860430 |
Control intervention | Physical therapists were instructed to provide their usual care according to the Dutch physical therapy guideline (i.e., standard, ‘non-stratified’ exercise therapy accompanied by patient education).In the Netherlands, a maximum of 12 physical therapy sessions and a maximum of 180 min of dietician consultations per year are reimbursed from the ‘basic’ health insurance package for people with knee OA, from which patients are obliged to pay the first €385 themselves. In addition to the ‘basic’ health insurance package, people opt for supplementary health insurance to cover healthcare cost that are not (fully) covered by the basic health insurance package. | PMC9860430 | ||
Outcome measures | obesity, Osteoarthritis, Knee Injury, pain | OBESITY, OSTEOARTHRITIS |
Quality-Adjusted Life Years (QALYs), assessed by the EuroQol-5D-5 L (EQ-5D-5 L; 5 items), in which the patient can self-rate their level of severity on five domains (mobility, self-care, daily activities, pain/discomfort, and anxiety/depression).Average knee pain severity during walking in the past week, assessed by a NRS (score 0=no pain; 10=worst pain imaginable).Physical functioning, assessed by the subscale function in daily living (ADL) of the Dutch translation of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire (score 0=maximal problems; 100=no problem).Costs, valued in accordance with the Dutch Manual of Costing,health care utilization:intervention-related costs (i.e., costs from the physical therapy sessions (valued using the Dutch tariff of €35,69 for physical therapists or €41,00/hour for manual therapists), supplemented for the ‘obesity subgroup’ of the experimental arm by the costs of the dietician sessions (valued using the Dutch tariff of €32,09/hour).other medical costs (valued using Dutch tariffs and, if these were unavailable, prices of professional organizations) further subdivided into:primary health care, other than the (experimental or control) intervention (e.g., general practitioner, acupuncturist);secondary health care (e.g., hospital, rehabilitation center);(prescribed and over-the-counter) medication (for knee OA only);costs related to reduced work ability, with costs valued using Dutch sex-specific price weightsabsenteeism costs (i.e., costs of being absent from work), valued in accordance with the friction cost approach (friction period: 12 weeks)presenteeism costs (i.e., costs of being less productive while being at work, based on the participant's work ability, assessed by the Work Ability Index-Single Item Scale (WAS) on a 0–10 scaleunpaid productivity costs (i.e., volunteer work, and domestic and educational activities that the participant was not able to perform), valued using a recommended Dutch shadow price of €15,14/hourinformal care (i.e., care by family, friends, or other volunteers that was provided to the participant), valued using a recommended Dutch shadow price of €15,14/hour.sport costs (e.g. sport shoes, fees for fitness center).Discounting of costs was not necessary due to the 12-month follow-up period of the trial. | PMC9860430 |
Sample size | knee pain, pain | The sample size was based on the primary outcome measure of this trial (0–10 NRS knee pain). That is, based on an expected between-group difference of 0.5 on the 0–10 NRS pain scale, an estimated standard deviation (SD) of 1.4, α=0.05 (2-sided testing), power=90%, design effect of 1.05 and a 15% drop-out rate, 408 participants (204 per group) were desired. | PMC9860430 | |
Statistical analysis | obesity, SD, ’ | OBESITY | This economic evaluation was performed from a societal and a healthcare perspective, using a 12-month follow-up period. All participants included in the study were analyzed. Missing data were handled using Multivariate Imputation by Chained Equations (MICE) and the number of imputed datasets was determined using the loss of efficiency approach, where a loss of efficiency of <5% was deemed appropriate.In addition to the primary cost-effectiveness analysis, the following 5 a priori specified sensitivity analyses (SA) were performed. In SA1, the healthcare perspective was applied, meaning that only costs accruing to the formal Dutch healthcare system were included in the analyses. In SA2, the Human Capital ApproachClinical outcomes and knee-related health care utilization in OCTOPUS-trial.SD = standard deviation.based on data from patient-reported questionnaires after multiple imputation;.based on registration data from participating physical therapists and dieticians collected during study, without multiple imputation.only data from participants from ‘obesity subgroup’ in experimental arm (based on data from participants and/or therapists, without multiple imputation. | PMC9860430 |
Results | PMC9860430 | |||
Participants | In total, 335 patients with knee OA were included in our trial: 153 in the experimental arm and 182 in the control arm (see Supplementary material – Fig. 2 and previous studies | PMC9860430 | ||
Effects and health care utilization | No significant between-group differences in clinical outcomes were found, neither in the total sample ( | PMC9860430 | ||
Costs | upper leg muscle strength | As shown in Costs per arm and cost differences across arms.CI = confidence interval.adjusted for treatment arm, baseline costs, QALY, work status, sex, age, duration of knee symptoms, upper leg muscle strength, and BMI.primary health care, other than the (experimental or control) intervention (e.g., general practitioner, acupuncturist).secondary health care (e.g., hospital, rehabilitation center).(prescribed and over-the-counter) medication (for knee OA only). | PMC9860430 | |
Cost-effectiveness | NRS pain, LMS, pain | From a societal perspective (our main analysis), the ICER for QALYs was €−83,547/QALY, based on an adjusted mean cost difference of €−426 and an adjusted mean effect difference of 0.006 (Cost-effectiveness analysis.CI, confidence interval; C, costs; CE-plane, cost-effectiveness plane; E, effects; ICER, incremental cost-effectiveness ratio; SA, sensitivity analysis.0–10 scale for NRS pain transformed so that higher score means better (less pain) instead of worse outcome, similar as for the other outcome measures, to facilitate interpretation.Cost-effectiveness plane (a) and cost-effectiveness acceptability curve (b), for outcome measure QALYs using a societal perspective.Also the human capital approach (SA2) and per-protocol analyses (SA4) showed very similar results as the main analysis, while the results from the complete case analysis (SA3) were slightly more in favor of the control arm, but again with much uncertainty. The stratified analyses for each of the 3 subgroups of the OCTOPuS algorithm separately (SA5) indicated that – compared to the 73% likelihood of stratified exercise therapy being cost-effective in the total group – this likelihood is much larger in the LMS (95%) and much lower in the OS (37%). | PMC9860430 | |
Discussion | LMS | The current study showed no clear evidence that stratified exercise therapy is likely to be a cost-effective option compared to usual exercise therapy in patients with knee OA. As we did not demonstrate superiority for clinical effectiveness either,The present study indicates that – although cautious interpretation is warranted – the stratified exercise therapy approach could potentially result in (particularly work-related) cost-savings, with similar clinical effects compared to usual exercise therapy. Results from separate analyses in each of the 3 subgroups of the stratified model also suggest that cost savings are most likely to occur in the LMS and to a lesser extent in the HMS, while being least likely in the OS. However, we cannot draw firm conclusions from our study because all cost difference estimates were surrounded by very high levels of uncertainty (partly due to insufficient power) and cost differences disappeared when focusing only at the healthcare perspective. Decision-makers (as well as health care professionals and patients) should therefore balance the uncertain cost savings (in work-related costs) and the lack of superior clinical effects by the stratified exercise therapy on the one hand against the effort that comes with implementing the new treatment. In this perspective, the barriers for applying the new treatment (especially for the OS) as reported elsewhereOur inconclusive result seems to be consistent with the scarce and conflicting evidence regarding the cost-effectiveness of stratified approaches of physical therapy, with two trialsWe would like to highlight two potential reasons for the unexpected finding of stratified exercise therapy not resulting in healthcare costs savings. First, we a priori expected that our stratified approach would not only lead to superior clinical effects, but also in substantial cost savings due to less physical therapy sessions (especially in HMS), other healthcare utilization and work absenteeism. However, with regards to the physical therapy sessions, we found only a very small difference in number of sessions of 1.2 (8.4 vs 9.6) between our study arms. This can be attributed to the much lower amount of sessions in the control group than what was expected, which can be considered an indication for an (even further) improvement in efficiency by Dutch physical therapists. It could also be caused by the COVID-19 pandemic, as health care sites were closed or restricted to acute situations only. Finally, also work absenteeism occurred much less than expected in both study arms. It should be noted that half of our study group was already retired (i.e., 53% in experimental and 48% in control arm) and those wo still worked showed relatively high work ability and low sick leave rate already at baseline, so there was not much room for substantial group differences in work-related costs.A second reason for the lack of difference in healthcare costs between our study arms is the smaller than intended contrast between the interventions, as also reported in our clinical effectiveness study.We should address the following study limitations. First, as with nearly every clinical trial, our study was powered on the primary effect outcome, rather than on cost-effectiveness outcomes, such as costs. This is common practice in health economics, because costs are heavily right skewed and would therefore require extremely large sample sizes, which in turn might be infeasible and/or unethical. To deal with this issue, we used estimation (e.g. by reporting the probability of cost-effectiveness) rather than hypothesis testing for interpreting our outcomes. | PMC9860430 | |
Conclusion | We found no clear evidence that stratified exercise therapy is more cost-effective compared to usual exercise therapy in patients with knee OA. However, results should be interpreted with caution as the study power was lower than intended, due to the COVID-19 pandemic. Hence, it is up to policy-makers, whether they perceive the likelihood of stratified exercise therapy possibly generating societal cost savings while maintaining clinical effects, to determine if implementation of this intervention in clinical practice is warranted. | PMC9860430 | ||
Conflicts of interest | All authors declare that they have no competing interests. | PMC9860430 | ||
References | PMC9860430 | |||
Supplementary materials | PMC9860430 | |||
Acknowledgements | Vliet, der | DER | We thank all participating patients, physical therapists, and dieticians for their participation. We also thank the steering group members (prof.dr. T.P.M. Vliet Vlieland, prof.dr. K. Bennell, prof.dr. W.F. Lems, dr. Leti van Bodegom-Vos, dr. M. van der Leeden, dr. M. van der Esch, dr. M. de Rooij, dr. W.F.H. Peter) for their contribution to the OCTOPuS-project.This work was supported by the Scientific Board Physical Therapy (WCF) of the Trial registration: The Netherlands National Trial Register: NL7463 (date of registration: 8 January 2019)Supplementary material associated with this article can be found in the online version at | PMC9860430 |
Authors’ contributions | LGA | Conceptualization: DBA; Analyses: YJ-N and LGA; Writing original draft: YJ-N; Review and editing: DBA, LGA, ABS, CJV, MJR, RJH. All authors approved the final draft. | PMC10510221 | |
Funding | MOORE | Authors supported in part by NIH grants R25DK099080, R25HL124208, U24AG056053, P30AG050886, and the Gordon and Betty Moore Foundation. The opinions expressed are those of the authors and do not necessarily represent those of the NIH or any other organization. | PMC10510221 | |
Availability of data and material | Statistical code is available at Dr. Flo-Groeneboom (the senior author of 10.1186/s12888-021-03376-y) provided us with temporary remote access to the dataset used for this re-analysis. We did not have any special access privileges that others would not have. | PMC10510221 | ||
Declarations | PMC10510221 | |||
Ethics approval and consent to participate | Not applicable | PMC10510221 | ||
Consent for publication | Not applicable | PMC10510221 | ||
Competing interests | Dr. Allison and his institution (Indiana University) have received payments for consultation, grants, contracts, in-kind donations, and contributions from multiple for-profit and not-for-profit entities interested in statistical design and analysis of experiments, but not directly related to the research questions addressed in the paper question. | PMC10510221 | ||
Abbreviations | Dementia | Bright Light Treatmentcluster Randomized Controlled TrialBehavioral and Psychological Symptoms of Dementia | PMC10510221 | |
References | PMC10510221 | |||
1. Introduction | rhinitis, Allergic rhinitis, DLE, allergic diseases | DISEASE, ALLERGIC RHINITIS, RHINOCONJUNCTIVITIS, RHINITIS, DLE | Allergic rhinitis (AR) has considerable impact on the general health of individuals. Therefore, treatment trials should include an evaluation of quality of life. We aimed to determine changes in the quality of life of moderate/severe AR patients treated with standard treatment in addition to dialyzable leukocyte extract (DLE), a peptide-based immunomodulator. In a prospective, non-controlled trial, DLE was added to the standard treatment regimen for patients with moderate/severe AR. DLE was administered orally at 2 mg per day for 5 days, followed by 4 mg per week for 5 weeks, and then 2 mg per week for 5 weeks. The primary endpoints were overall improved Standardized Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, domain scores, and individual item scores of 0.5 points or higher. Statistical significance was defined as Clinical trials registration ID: NCT02506998Allergic rhinitis (AR) is a common disease worldwide.Although not life-threatening, AR considerably affects general well-being, absenteeism, work, and school performance.The T-helper cell balance in allergic diseases is skewed toward a Th2/Th17 response, and it has been proposed that Th1/Treg cytokines play a negative regulatory role in Th2 inflammatory predominance.This study aimed to determine changes in QoL of patients with moderate/severe AR, treated with standard treatment in addition to DLE. | PMC10328667 |
2. Materials and methods | PMC10328667 | |||
2.1. Subjects | Allergic Rhinitis | DISEASE, ASTHMA, ALLERGIC RHINITIS | We included 30 patients aged 14 to 60 years with a confirmed diagnosis of moderate/severe AR. The disease was confirmed, and the severity was classified based on the Allergic Rhinitis and its Impact on Asthma guidelines. | PMC10328667 |
2.2. Study design and treatment | nose symptoms, fever | DLE | This was a prospective, open-label, non-controlled trial. The standard treatment was continued without any modifications, and DLE (Transferon OralPatients responded to each of the 28 items in the 7-domain questionnaire on a scale of 0 (no affection) to 6 (very bothersome). The total score was calculated from the average score of all items. The scores from each of the 7 domains (activity limitation, sleep problems, nose symptoms, eye symptoms, non-hay fever symptoms, practical problems, and emotional function) were obtained from the average score of the items in each domain. The scores for each item were also obtained. The primary endpoint was a change from baseline in the RQLQ overall scores, domain scores, and individual item scores of at least 0.5, minimal important difference (MID).All patients who underwent DLE signed an informed consent form as part of the IC 13-001 approved by the University Ethics Committee. Patients younger than 18 years also provided oral assent. | PMC10328667 |
2.3. Statistical analysis | Statistical analysis was performed using GraphPad Prism software version 6.0f (San Diego, CA) and SPSS version 21 (IBM SPSS Statistics for Windows, Version 21.0, Armonk, NY). The normality of the data was checked for skewness and kurtosis, and was confirmed using the Shapiro–Wilk normality test. Dispersion and central tendency statistics were used to describe variables. A 2-tailed The sample size was calculated using G*power 3 (Heinrich Heine Universität Duesseldorf) according to the following parameters: Type I error 0.05, power 0.8, and effect size 0.43, based on previous observations. | PMC10328667 | ||
2.4. Patient safety | ADVERSE EVENTS | The presence of any adverse events (AE) associated with the medication was assessed as required by the Mexican Official Standard Norm. | PMC10328667 | |
3. Results | PMC10328667 | |||
3.1. Subject characteristics | ALLERGIC RHINITIS | Thirty patients (50% female) between the ages of 14 and 60 years (33.4 ± 11.9) were followed up for 11 weeks (Fig. Demographic characteristics of the subjects.Values are presented as n (%).# = number, AR = allergic rhinitis, SCIT = subcutaneous immunotherapy, SLIT = sublingual immunotherapy.Summary of patient enrollment and study phases.One patient abandoned the study after the first week and was excluded from the efficacy analysis. | PMC10328667 | |
3.2. Standard treatment | The patients received different standard treatments for AR in various combinations. Twenty-7 patients (90%) were taking antihistamines, 13 (43.3%) were taking nasal corticosteroids, 5 (16.7%) were taking montelukast, 5 (16.7%) were taking sublingual or subcutaneous immunotherapy, and 1 patient (3.3%) had ophthalmic sodium cromoglycate (Table | PMC10328667 | ||
3.3. Overall RQLQ scores | DLE, allergic rhinitis | DLE, ALLERGIC RHINITIS, RHINOCONJUNCTIVITIS | The median basal overall RQLQ score before DLE was 3.41 ± 1.22. One week after the addition of DLE, the mean RQLQ overall score was 2.89 ± 1.27 (RQLQ(S) score during intervention with DLE. (A) Violin plots showing the distribution of RQLQ(S) total score and the density of subjects expressing the QoL punctuation through DLE intervention. Probability There was no significant difference in the RQLQ results between sexes, age groups (teens vs adults), or the amount of AR medication taken (Table Differences in RQLQ scores between different groups in relation to sex, age group, and number of allergic rhinitis medications before and after 11 weeks of DLE.Probability P was calculated using a 2-tailed t test to determine differences in gender and age groups. For differences between groups regarding the number of AR medications, one-way analysis of variance was used.AR = allergic rhinitis, CI = confidence intervals, DLE = dialyzable leukocyte extract, RQLQ = Standardized version (Spanish-Mexico) of the Rhinoconjunctivitis Quality of Life Questionnaire. | PMC10328667 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.