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Study design | SUSTAIN-3, an ongoing phase 3, open-label, multicenter (SUSTAIN-3 has a 4-week induction phase (if applicable) and an optimization/maintenance phase of variable duration. Participants in 1 of 6 phase 3, “parent” studies of esketamine and for whom benefit versus risk was favorable were enrolled into either the 4-week induction phase or the long-term optimization/maintenance phase of SUSTAIN-3 based on their status at the end of the parent study (Fig. SUSTAIN-3 (clinical trials.gov identifier: NCT02782104) and the parent studies (identifiers: NCT02417064, NCT02418585, NCT02422186, NCT02493868, NCT02497287, NCT03434041) are registered at clinicaltrials.gov. | PMC10267177 |
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Study population | TRD, depression | The eligibility criteria of each parent study are reported elsewhere [10–14; clinical trials.gov: ID NCT03434041]. In brief, each parent study enrolled adults (≥18 years) who met the definition of TRD (i.e., non-response to an adequate trial of at least 2 antidepressants in the current episode of depression, one of which was observed prospectively). | PMC10267177 |
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Study drug | depression | In the induction phase, participants self-administered (under medical supervision) esketamine (28 mg [starting dose age ≥65 years], 56 mg, or 84 mg) as a flexible dose, twice-weekly therapy for 4 weeks. In the optimization/maintenance phase, participants received interval dosing of esketamine individualized to the severity of their depression based upon a clinical global impression - severity [CGI-S]-based algorithm (refer to Table Throughout the study, esketamine was dispensed only at clinical sites during each dosing session and dose administration occurred under direct supervision of site staff. | PMC10267177 |
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Evaluations of safety and efficacy | PMC10267177 |
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Safety | ADVERSE EVENTS, EVENTS, CYSTITIS | Treatment-emergent adverse events, including events of special interest (i.e., renal disorder/interstitial cystitis, hepatic) were monitored, and other safety assessments (i.e., hematology and serum chemistry, urinalysis, physical examination, pulse oximetry, vital signs, electrocardiogram, and Columbia-Suicide Severity Rating Scale [Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale was used to assess the level of post-dose sedation, and the Clinical Global Assessment of Discharge Readiness (CGADR), to assess participants’ discharge readiness, based on their overall clinical status.The Cogstate computerized test battery [ | PMC10267177 |
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Efficacy | Depression, disability, depressive illness | SHEEHAN | Montgomery–Åsberg Depression Rating Scale (MADRS) assessments [Participants rated the impact of the study treatments on socio-occupational disability using the Sheehan Disability Scale [Investigators rated severity of depressive illness using the CGI-S [ | PMC10267177 |
Statistical methods | depressive symptoms | ADVERSE EVENTS, EVENTS, REMISSION | The number (percentage) of participants with adverse events, including events of clinical interest, serious adverse events, and adverse events leading to premature discontinuation of study drug were summarized by preferred term. Descriptive statistics were provided for other safety parameters.Descriptive statistics and frequency distributions were used to summarize the efficacy data. Efficacy endpoints for both the induction and optimization/maintenance phases comprise the following: change from baseline in depressive symptoms (MADRS and PHQ-9), including response (≥50% improvement from baseline) and remission (MADRS total score ≤ 12; PHQ-9 total score < 5 [ | PMC10267177 |
Results | TRD | A total of 1148 adult patients with TRD were enrolled into SUSTAIN-3. Overall, 458 participants were enrolled into the induction phase, 38 (8.3%) of whom discontinued and 420 (91.7%) continued to the optimization/maintenance phase. In addition, 690 other participants were enrolled directly into the optimization/maintenance phase (Fig. | PMC10267177 |
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Safety | PMC10267177 |
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Dissociation | ADVERSE EVENTS, EVENTS | Dissociation included reports of perceptual disturbances where sounds, visual stimuli, and proprioception seemed exaggerated or altered, or by a sense of derealization or depersonalization. Overall, dissociation was reported in 24.4% of participants. Although no treatment for dissociation was recommended or specified in the study protocol, a few participants (0.8%) received treatment with concomitant medication(s) for dissociation, which primarily (4 of 8 participants) consisted of single doses of a benzodiazepine anxiolytic (alprazolam, diazepam, lorazepam). There were no serious adverse events of dissociation.Almost all (5358/5369, 99.8%) adverse events of dissociation occurred and resolved on the day of dosing. Seven (0.6%) participants had 1 or more dissociation events that resolved after the day of dosing, all within 2 days after dosing. No participant had esketamine dose changed due to dissociation. | PMC10267177 |
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Sedation | ADVERSE EVENTS, EVENTS, RESPIRATORY DEPRESSION, ADVERSE EVENT | Sedation was reported as an adverse event in 7.8% of participants. The majority (99.4%, 1073/1079) of sedation events occurred on a dosing day and resolved the same day. Five (0.4%) participants had 1 or more sedation events that did not resolve on the day of dosing. Sedation led to esketamine dose reduction for 1 of these participants.There were no serious adverse events of sedation or adverse events of sedation that led to withdrawal of study drug. No participant reported respiratory depression. An adverse event of oxygen saturation decreased was reported for four participants; all such events were transient and self-limited, none requiring any intervention. The four participants had MOAA/S scores of 5 (i.e., defined as participant readily responding to name spoken in normal tone [awake]).The MOAA/S scores of the study participants are summarized in the Supplement. Clinically-relevant sedation, defined by MOAA/S score ≤ 3 (i.e., moderate or greater sedation), occurred at least once among 6.1% (28/458) of participants in the induction phase and in 6.9% (77/1110) of participants in the optimization/maintenance phase. | PMC10267177 |
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Increased blood pressure | ADVERSE EVENT | The greatest mean (SD) change in systolic and diastolic blood pressure (BP) from predose values were +9.3 (12.01) mmHg at day 15 and +6.1 (7.84) mmHg at day 25, respectively, in the induction phase and +10.2 (9.25) mmHg at week 184 and +6.0 (6.36) mmHg at week 184, respectively, in the optimization/maintenance phase, all at 40 min post-dose. Participants who met the study criteria for markedly elevated BP (i.e., systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg) are summarized in the Supplement.Overall, investigators reported an adverse event related to increased BP for 17.9% of participants, with incidence generally similar at visits throughout both the induction and optimization/maintenance phases (Fig. | PMC10267177 |
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Adverse events of clinical interest | renal disorder, urinary incontinence, cholelithiasis, nephrolithiasis, dysuria, UTI, hematuria, pollakiuria, interstitial/ulcerative cystitis, hepatic adverse | CHOLECYSTITIS, URINARY TRACT INFECTIONS, RENAL DISORDER, ADVERSE EVENTS, EVENT, URINARY INCONTINENCE, CHOLELITHIASIS, NEPHROLITHIASIS, HEMATURIA, UTI, EVENTS | No case of treatment-related interstitial/ulcerative cystitis was identified. Urinary tract infections (UTI) were reported in 153 (13.3%) participants, 65 of whom had more than one episode of UTI (63 of 65 were female, mean age 53.7 years). Other adverse events (incidence ≥1%) related to a renal disorder included dysuria (2.7%), pollakiuria (2.4%), micturition urgency (1.3%), nephrolithiasis (1.3%), hematuria (1.0%), and urinary incontinence (1.0%).A minority (6.3%) of participants experienced 1 or more hepatic adverse events, the most common being gamma glutamyl transferase increased (2.1%), alanine aminotransferase (ALT) increased (1.4%), aspartate aminotransferase increased (1.0%), hepatic enzyme increased (1.0%), and cholelithiasis (1.0%). No participant manifested hepatic enzyme levels of ALT > 3 x upper limit of normal [ULN] and total bilirubin >2 x ULN. Nine hepatic events were considered serious, including 8 events of cholelithiasis and 1 event of cholecystitis, all classified by the site investigator as not related to esketamine. | PMC10267177 |
Discharge readiness | At the timepoints assessed, >89% of participants were ready to be discharged from clinic by 1.5 h post dosing. | PMC10267177 |
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Cognitive effects | Group mean performance on cognitive tests (Cogstate and HVLTR) from baseline through week 160 indicated that cognitive performance generally remained stable. There was no evidence of decline in cognition associated with long-term treatment among participants <65 years old from baseline to week 160 (Table | PMC10267177 |
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Suicidal ideation and behavior | TRD, illness, ideation | ADVERSE EVENTS, EVENT | Overall, 5.6% of participants experienced 1 or more adverse events potentially related to suicidality. Of these, one participant died by suicide. This individual was a 48-year-old male who did not respond to esketamine (MADRS total score was 35 at baseline and 41 and 25 on days 15 and 22, respectively). The participant died by suicide 4 days after the most recent esketamine dose. Considering this individual’s long history of mental illness and underlying TRD, the event was reported by the site investigator as not related to esketamine.In the C-SSRS assessment, 49 participants (of 1144; 4.3%) with no history of suicidal ideation reported new occurrences of suicidal ideation during the study. Ten (0.9%) participants reported new suicidal behavior, 9 of whom had a previous history of suicidal ideation. Improvement in severity category of C-SSRS assessment from baseline to postbaseline occurred in 14.0% of participants ( | PMC10267177 |
Efficacy | PMC10267177 |
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Depressive symptoms | Depressive | Depressive symptoms, as assessed by MADRS total score, decreased during the induction phase (Fig. | PMC10267177 |
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Mean (±SE) Montgomery–Åsberg Depression Rating Scale Total Score (Observed Cases). | depressive symptoms | REMISSION | IND Induction, OP/MA optimization/Maintenance. Note: Responders from the induction phase of the SUSTAIN-3 study and responders from parent studies were to enter the optimization/maintenance phase. The greater variability of the mean MADRS total score at later time points likely reflects the smaller number of participants at these timepoints, as reflected in the corresponding sample sizes.The proportion of responders (defined as ≥50% reduction in MADRS total score; observed cases) increased over time during the induction phase, from 15.0% (66/439) on day 8 to 50.6% (224/443) on day 28 and to 49.2% (224/455) at endpoint of the induction phase. A total of 35.6% (162/455) of participants were in remission (MADRS total score ≤12; observed cases) at the induction endpoint, and 50.9% (464/911) and 46.1% (511/1108) at year 1 and endpoint of the optimization/maintenance phase, respectively.Improvement in depressive symptoms was also noted based on decrease in PHQ-9 total score over the course of the induction phase (mean [SD] change from baseline to phase endpoint: −5.8 [5.84]; 95% CI: −6.32 to −5.24), with improvement maintained during the optimization/maintenance phase (change from phase baseline to endpoint: +0.9 [6.04]; 95% CI: 0.50 to 1.21) (Fig. Illness severity, as assessed by the CGI-S, improved from baseline (median of 5) to the endpoint of the induction phase (median [range] change from baseline, −1.0 [−5; 1]) and remained stable over the optimization/maintenance phase (median [range] change: 0.0 [−5; 4]), suggesting maintenance of the antidepressant effect. More than half of participants had CGI-S scores indicating normal/borderline/mild illness (scores of 1, 2, or 3) at endpoint of the induction phase (55.9%) and at endpoint of the optimization/maintenance phase (57.3%) (Fig. | PMC10267177 |
Functioning and associated disability | disability | REMISSION | The mean change (SD) from baseline to endpoint in SDS total score of −6.4 (7.14) indicates an improvement in functioning and associated disability during the induction phase. By endpoint of the optimization/maintenance phase, the mean change (SD) was +0.1 (8.23), suggesting maintenance of effect. The percentage of responders (defined as SDS scores ≤4 for each item and ≤12 for the total score) was 44.8% and 54.4% at endpoint of the induction and optimization/maintenance phases, respectively, and percentage of participants in remission (defined as SDS ≤ 2 for each item score and ≤6 for the total score) (Fig. | PMC10267177 |
Discussion | TRD, ideation, psychiatric, depressive symptoms, MDD, depression, drug abuse | ADVERSE EVENTS, REMISSION, ADVERSE EVENT | Long-term safety as well as remission and response with weekly or biweekly esketamine nasal spray, combined with an oral antidepressant, is being evaluated in SUSTAIN-3, a global multicenter study of participants with TRD. The results of this study extend those of a 1-year open-label study of esketamine nasal spray for TRD [The safety profile of esketamine, with continuous intermittent dosing for up to 4.5 years in SUSTAIN-3 (2,769 cumulative patient-years), is consistent with its established safety profile in participants with TRD treated for up to 1 year [While ketamine abuse could not have been detected if participants in SUSTAIN-3 surreptitiously obtained drug from illicit sources (the urine drug screen we used did not assay for the r-enantiomer of ketamine or its metabolites), the protocol represents a rigorous approach to estimating the abuse liability in a clinical population. In this regard, adverse events related to abuse of esketamine (or ketamine) were not reported by the site clinicians. Moreover, diversion or excess use was putatively prevented in the clinical trial setting as only one dose could be dispensed during each dosing session and each administration of esketamine occurred under clinical supervision. Additionally, a study drug reconciliation process was implemented.A minority of study participants discontinued esketamine treatment due to an adverse event. Likewise, few (1.5%, 4/259) serious adverse events were attributed to esketamine by the site investigators. Long-term exposure to esketamine yielded no additional concerns or trends related to suicidal ideation and/or behavior, drug abuse, or drug dependence.While up to 20% of patients with MDD attempt suicide over their lifetime [Cognition was assessed across multiple cognitive domains and remained stable, without changes over time, for the total sample and for the subgroup of participants <65 years of age. In participants ≥65 years, performance on all tests of higher cognitive function remained stable or slightly improved. However, among participants ≥65 years, slowing of simple and choice RT occurred during the optimization/maintenance period; mean change from baseline for z-score calculations indicated that the changes were in a range that would be characterized as a small effect. Slowing increased through approximately week 100, after which RT performance appeared to stabilize through week 160. The clinical relevance of the observed slowing of RT is unclear. Overall, attentional ability was not affected, and in the absence of a placebo group it is difficult to determine to what extent the slowing of RT reflects an effect of study drug. Slowing of RT/processing speed, possibly associated with increasing IIV of RT performance over time, has been observed in multiple longitudinal studies in older individuals, including patients with MDD [On average, the participants showed improvement in measures of depressive symptoms and other efficacy assessments during the induction phase (first 4 weeks of exposure), which appeared to be sustained during the optimization/maintenance phase. At the interim data cutoff, the majority of participants were receiving the 84 mg or 56 mg esketamine dose, either weekly or every other week, to maintain clinical stability. In the remainder, the every-4-week dosing interval was used only by about 14% of participants at the 1 year mark and close to 17% of participants at the 2 year mark, as shown in Table The generalizability of our findings is limited by the potential bias related to which participants chose to continue (or not continue) from the parent study into this study, the exclusion of participants with significant psychiatric or medical co-morbidities or substance dependence, and the relative lack of racial heterogeneity (86.8% white). Furthermore, sample size decreases at later study time points may have implications for representativeness and/or generalizability of findings. Notably, the data set includes current, interim data, which continues to be updated.In summary, no new safety signal was identified and improvement of depression appeared to be sustained with long-term, intermittently-dosed esketamine in this study of participants with TRD. | PMC10267177 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41386-023-01577-5. | PMC10267177 |
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Acknowledgements | The authors acknowledge Dr. Paul Maruff for his contribution to the interpretation of the cognition data. Drs. Abigail I. Nash, Qiaoyi Zhang, Tricia J. Lopena, Maju Mathews, and Jaskaran B. Singh authored posters in which early data from the SUSTAIN-3 study were presented (at the 2021 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP), June 2, 2021; 2021 Neuroscience Education Institute (NEI) Congress, November 5, 2021, Colorado Springs, CO; 2021 Psych Congress, San Antonio, TX, October 29-November 1, 2021). Dr. Sandra Norris (Norris Communications Group, LLC), supported by Janssen Research & Development LLC, provided writing assistance and Dr. Ellen Baum (Janssen Global Services, LLC) provided additional editorial support. The authors also thank the study participants, without whom this study would never have been accomplished and all the investigators for their participation in this study. RLM worked on this project during his employment by Janssen Research & Development, LLC and is now retired. | PMC10267177 |
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Author contributions | NZ and D-JF designed the study and wrote the protocol. GS helped design and conduct the study. NC and RL conducted the statistical analyses. RLM designed and supervised the cognition testing. All authors were involved in writing and/or revising the manuscript, and had final responsibility for the decision to submit for publication. | PMC10267177 |
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Funding | The SUSTAIN-3 study is supported by funding from Janssen Research & Development LLC, Titusville, NJ, USA. | PMC10267177 |
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Competing interests | Johnson & Johnson. | EMA | NZ, LC, TD, WCD, VP, D-JF, and RL are employees of Janssen Research & Development, LLC or Janssen Research & Development Belgium, and all are stockholders of Johnson & Johnson. RLM was an employee of Janssen Research & Development, LLC at the time this work was conducted. In the last 12 months. GS has provided consulting services to Ancora, Aptinyx, Axsome Therapeutics, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA Wellness, Engrail, Gilgamesh, Freedom Biosciences, Intra-Cellular Therapies, Janssen, miCure Therapeutics, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Perception Neuroscience, Praxis, Sage Pharmaceuticals, Seelos Pharmaceuticals, and XW Labs. He has received funds for contracted research from Janssen Pharmaceuticals, Merck, and Usona Institute. He holds equity in Biohaven Pharmaceuticals and has received royalties paid from patent licenses with Biohaven Pharmaceuticals. His employer, Yale University, has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. STW has received contract funding for clinical trials from Sage Therapeutics, Oui Therapeutics, and Janssen (administered through Yale University). He has received consulting fees from Sage Therapeutics, Oui Therapeutics, and Janssen. | PMC10267177 |
References | PMC10267177 |
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Subject terms | aphasia | People with aphasia (PWA) often present deficits in non-linguistic cognitive functions, such as executive functions, working memory, and temporal information processing (TIP), which intensify the associated speech difficulties and hinder the rehabilitation process. Therefore, training targeting non-linguistic cognitive function deficiencies may be useful in the treatment of aphasia. The present study compared the effects of the novel Dr. Neuronowski | PMC10462731 |
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Introduction | death, disability, Stroke | STROKE | Stroke is the second leading cause of death and disability in the worldPWA also have difficulties with temporal information processing (TIP). Some studies have demonstrated a link between TIP and language. Human speech is constrained by temporal organization in the millisecond and multisecond time domains. Millisecond TIP is related to phonological encoding/decoding and syllabification, while multisecond TIP is involved in lexical selection, sentence production, and perceptionThe present study focused mainly on millisecond TIP which seems essential for speech perception, especially for the processing of basic units of language—phonemes (e.g., stop-consonants limited in time up to ca. 40 msThe efficiency of millisecond TIP is determined by patients’ ability to accurately identify and process the order of stimuli that occur in rapid succession. It is often measured with the auditory Temporal-Order Judgment (TOJ) paradigmAccording to previous studies, TIP may be also considered as a neural frame for many non-linguistic cognitive functions that are characterised by specific temporal dynamics in the millisecond rangeMany speech and language trainings that directly train impaired linguistic functions are recognized as standard elements of rehabilitationSome pilot studies investigating the effects of millisecond TIP trainings in PWA have been conducted. Szymaszek et al.Dr. Neuronowski | PMC10462731 |
Methods | PMC10462731 |
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Participants | post-stroke, stroke, left-hemispheric stroke, head injuries, dementia, ExpG, comprehension impairment, post-stroke visual deficits, neurological or psychiatric diseases, aphasia, substance abuse | STROKE | Thirty four post-stroke patients (22 male) suffering from aphasia after their first left-hemispheric stroke (lesion age: Me = 32 weeks; min–max: 5–195 weeks) participated in the study. Participants’ ages ranged from 30 to 82 years (M ± SD: 59 ± 13 years). They were right-handed native speakers of Polish. Participants displayed normal hearing verified by pure-tone screening audiometry (Audiometer MA33, MAICO). The following exclusion criteria, verified during an interview with the caregivers of the patients, were applied: recurrent stroke, global aphasia, severe comprehension impairment, post-stroke visual deficits, prior neurological or psychiatric diseases, substance abuse, history of head injuries, and signs of dementia. Detailed characteristics for the patients are presented in Table Characteristics of the patient sample (This study was controlled, randomised, and single-blinded. The patients were classified into two groups: the experimental group (ExpG), who used the experimental training program, and the control group (ConG), who used the control training. For a detailed description of both trainings, see below. As PWA usually display huge inter-individual variability, ExpG and ConG were matched as closely as possible for age, lesion age and volume, gender, as well as pre-training levels of tested functions (i.e., speech difficulties, TIP, memory, and executive functions). It is worth noting that even though some of the abovementioned cognitive variables tended to be higher and lesion age tended to be shorter in ExpG, the statistical differences were nonsignificant. Descriptions of particular assessment procedures can be found in the Procedure section and a statistical comparison of the groups before training can be found in Table Characteristics of the two training groups in the pre-training assessment: mean and standard deviation values of demographic variables and scores of tests.t(32) = -0.827p = .415U = 100.0p = .129t(25) = -.174p = .863χp = 0.642U = 55.5p = 0.220t(32) = − 0.725p = 0.474U = 131.0p = 0.645U = 116.5p = 0.340U = 87.5p = 0.303U = 88.0p = 0.482U = 91.0p = 0.105U = 89.0p = 0.215t(31) = 0.89p = 0.382U = 99.5p = 0.584U = 115.5p = 0.856t(31) = − 0.161p = 0.873The location of the lesion was verified by CT or MRI in 27 out of 34 individuals (13 from ExpG, 14 from ConG; Fig. Lesion overlap maps of participants from ( | PMC10462731 |
Procedure | The study was comprised of both assessment and training procedures. The assessment procedures consisted of several neuropsychological measurements evaluating speech comprehension and production, TIP, memory, and executive functions (Fig. Schema of the study. | PMC10462731 |
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Training procedure | HAND PRESENTATION | The Overview of Dr. NeuronowskiIntroductory games to familiarise patients with the training, types of games, and sounds usedAuditory perceptionReaction speedResponse inhibitionAlertnessAuditory perception of nonverbal stimuliShort-term nonverbal auditory memorySelective attentionSustained attentionMillisecond TIP—processing of short sounds presenting in rapid successionNonverbal and verbal auditory short-term memory—memorising sequences of various lengthMillisecond TIP—processing of rapidly changing soundsPhonemic hearing based on phoneme change detection in syllables or in words differing in single consonant soundsVerbal auditory short-term memory based on artificially slowed verbal stimuliMillisecond and multisecond TIP—estimation of time intervalsDelay of responsesResponse inhibitionPhonemic hearing based on artificially modified voice onset timeMillisecond TIP—voice onset time perceptionThe task difficulty in particular games was modified by: number, length, and presentation rate of verbal and nonverbal stimuli, the rate of modified speech, various inter-stimulus intervals in sequentially presented stimuli, application of distractors, and time limits for the patient’s responses.The The protocols of both the experimental and control trainings involved 24 individual sessions of 45 min each, 3 times a week. All exercises were performed on a tablet. The training sessions were conducted with the assistance of a therapist, whose role was to monitor the patient’s performance and to provide technical assistance in handling the tablet. In both experimental and control trainings, the task difficulty in particular games changed adaptively on the basis of the actual level of the patient’s performance. | PMC10462731 |
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Statistical analyses | To verify the distributions of the resultant data, the Shapiro–Wilk Test was used and further statistical analyses were adjusted accordingly.To verify the effects of each training type on particular cognitive functions (To examine the stability of training effects | PMC10462731 |
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Results | PMC10462731 |
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Pre- vs post-training comparison of cognitive functions | POSITIVE | The effect of experimental and control training was evaluated for particular tasks. The profile of changes in Difference in z scores (post-training minus pre-training) for participants in the two training groups. The z scores for both post-training and pre-training were referred to pre-training performance of all participants (across both groups). The following formula was implemented: difference in z scores = [(X2—M1)/SD1] −[(X1—M1)/SD1], where X1 and X2 refer to an individual score for particular test in pre-training and post-training assessment respectively, M1 and SD1 refer to mean and standard deviation for all participants in this test in pre-training assessment. Positive values (right side from the 0 point) correspond to improved performance. Negative values correspond to worsened performance (left side from the 0 point). The significant differences between | PMC10462731 |
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Speech comprehension |
Sentence comprehension: the number of correct responses Grammar comprehension: the number of correct responses Word comprehension: the difference in the number of correct responses was nonsignificant between Phoneme discrimination: the number of correct responses | PMC10462731 |
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Speech production |
Naming: the number of correct responses Verbal fluency: the number of produced words was significantly higher (Z = − 2.626; p = 0.009) | PMC10462731 |
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Temporal information processing | ExpG |
Temporal order judgement: TOT values in ExpG were significantly lower (Z = -2.154; p = 0.031) | PMC10462731 |
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Memory | ExpG |
Verbal short-term memory: the number of correctly reproduced sequences in ExpG was significantly higher (Z = − 2.599; p = 0.009) Spatial short-term memory: the number of correctly reproduced sequences in | PMC10462731 |
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Executive functions | Verbal working memory, ExpG |
Planning ability: the difference between the number of correctly solved trials was nonsignificant (Z = − 0.595; p = 0.552) between Verbal working memory: the number of correctly reproduced sequences in ExpG was significantly higher (Z = -2.132; p = 0.033) Spatial working memory: the number of correctly reproduced sequences | PMC10462731 |
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Summary of results | The application of the experimental training in PWA improved all assessed functions, apart from word comprehension, spatial short-term and working memory and planning ability. On the other hand, following the control training, significant improvement was observed only in grammar comprehension and naming. All reported improvements were relatively stable for 3 months after the experimental and control trainings, apart from the significant improvement in ConG in phoneme discrimination and spatial short-term memory. | PMC10462731 |
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Discussion | ExpG | The present study measured the effects of the Dr. NeuronowskiSeveral cognitive functions were exercised in the experimental training, with a particular emphasis on TIP, which resulted in the lowering of participants’ temporal order thresholds (TOT), enhancement of phoneme discrimination (i.e., increased number of correct responses on the Phoneme Hearing Test), as well as improved maintenance of verbal stimuli in short-term memory (i.e., higher score on the Verbal Memory Test Forwards) in the post-training assessment. This improvement of the directly-trained functions may be considered as near transfer—improvement in tasks structurally similar to those trainedHowever, as phoneme hearing is also heavily rooted in millisecond TIPOf particular interest is the improvement of the following linguistic functions in ExpG: sentence comprehension, grammar comprehension, fluency, and naming. Experimental training did not provide practice for those functions, which may suggest more complex mechanisms of transfer. PWA improved in the comprehension of longer language units, as evidenced in better performance on sentence comprehension and grammar comprehension in post-training vs pre-training assessment. Similar effects were reported by Szeląg et al.It is an important and novel finding of this study that the Dr. NeuronowskiThis improvement of untrained functions following the experimental training may indicate a far-transfer effect—that is, the transfer of training benefits to a different domain that shares underlying mental processes with the trained oneAfter the Dr. NeuronowskiIt is, however, worth noting that, despite the emphasis on TIP, particular modules of Dr. NeuronowskiIn contrast, the control training resulted in improvement of only grammar comprehension and naming, which were directly practised. No significant improvement was observed in several linguistic measures: sentence comprehension, verbal fluency, and phoneme discrimination. As previously noted, sentence comprehension (measured with the Token Test) requires non-linguistic functions (e.g., working memory, which was not trained in this group), and therefore simple practice in sentence comprehension may have been insufficient to improve performance in this test. Similarly, tasks that assess verbal fluency, involving spontaneous generation of words from specific semantic categories, engage verbal working memory and semantic control as well as auditory attention and processing speed, which were not trained in the control groupAccording to Abikoff and RamseyIt is worth mentioning that we expected more widespread linguistic improvement in the control group. However, we speculate that the standardising and adjusting of experimental settings for both trainings resulted in a reduction of patient–therapist communication that occurred, which is typically associated with traditional speech training. This may have also hindered the effectiveness of this trainingIt is important to note that unequal number of patients participated in the following assessments (pre- and post- vs follow-up) was the limitation of the current study. Consequently, the main analyses were conducted only on the post- vs pre-training assessments as the follow up assessment was completed by a smaller number of patients (see “In summary, the current results are in line with previous studies regarding the use of training of TIP alone in PWA | PMC10462731 |
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Acknowledgements | We thank Tomasz Wolak for analysis and graphical presentation of neuroanatomical data as well as Anna Bombinska for her technical assistance during the data collection phase. | PMC10462731 |
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Author contributions | M.C. designed the study, recruited the participants, acquired, analysed, and interpreted the data, and wrote the manuscript. M.S. wrote the manuscript. A.S. conceptualised and designed the study, recruited the participants, acquired, analysed, and interpreted the data, wrote the manuscript, and is responsible for the final version of the manuscript. All authors approved the final version of the manuscript. | PMC10462731 |
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Funding | POLAND | Supported by the National Science Centre (Narodowe Centrum Nauki, NCN), Poland, Grant no 2016/21/B/HS6/03775. | PMC10462731 |
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Data availability | The datasets generated and/or analysed during the current study are available from the corresponding author on request. | PMC10462731 |
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Competing interests | AS is the co-creator of the Dr. Neuronowski | PMC10462731 |
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References | PMC10462731 |
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Purpose: | cancer | CANCER | These authors contributed equally to this work.While moderate-to-vigorous intensity physical activity (MVPA) is associated with various health improvements shortly after completion of exercise interventions, it remains unclear which health benefits can be expected when MVPA levels are maintained in the long term in cancer survivors. We aimed to assess the associations of (1) MVPA level at 12-month follow-up and (2) long-term MVPA patterns (from immediately post-intervention to 12-month follow-up) with different cancer-related health outcomes. | PMC10331773 |
Methods: | fatigue, anxiety, cancer, prostate, depression, Cancer | REGRESSION, CANCER, PROSTATE, CANCER | In the Physical training and Cancer (Phys-Can) RCT, 577 participants diagnosed with breast (78%), prostate (19%), or colorectal (3%) cancer were randomized to 6 months of exercise during curative cancer treatment. Accelerometer-assessed physical activity and outcome data (ie, cancer-related fatigue, health-related quality of life [HRQoL], anxiety and depression, functioning in daily life, cardiorespiratory fitness, sedentary time and sleep) were collected immediately post-intervention and at 12-month follow-up. Based on the sample’s median of MVPA immediately post-intervention (65 minutes/day) and the changes between the 2 measurement points, 4 categories with different long-term MVPA patterns were created: High & Increasing, High & Decreasing, Low & Increasing, and Low & Decreasing. Multiple linear regression analyses were performed for the analyses. | PMC10331773 |
Results: | fatigue | A total of 353 participants were included in the analyses. At 12-month follow-up, a higher MVPA level was significantly associated with lower fatigue in 3 domains (general fatigue [β = −.33], physical fatigue [β = −.53] and reduced activity [β = −.37]), higher cardiorespiratory fitness (β = .34) and less sedentary time (β = −.35). For long-term MVPA patterns, compared to the participants in the “Low & Decreasing” category, those in the “High & Increasing” category reported significantly lower fatigue in 3 domains (general fatigue [β = −1.77], physical fatigue [β = −3.36] and reduced activity [β = −1.58]), higher HRQoL (β = 6.84) and had less sedentary time (β = −1.23). | PMC10331773 |
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Conclusion: | cancer, Cancer | CANCER, CANCER | Our results suggest that long-term physical activity is essential for improving health outcomes post-intervention in cancer survivors. Cancer survivors, including those who reach recommended MVPA levels, should be encouraged to maintain or increase MVPA post-intervention for additional health benefits. | PMC10331773 |
Trial registration: | NCT02473003 (10/10/2014) | PMC10331773 |
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Introduction | cancer, anxiety/depression, fatigue, Cancer | CANCER, CANCER | Regular physical activity has proven safe and beneficial in cancer survivors.We recently reported the results from a 6-month exercise intervention study with a 2 × 2 factorial design, the Physical Training and Cancer randomized controlled trial (Phys-Can RCT).In the present study, we investigated MVPA in cancer survivors who previously participated in an exercise intervention during curative cancer treatment. The aims were to assess the associations of (1) MVPA level at 12-month follow-up and (2) long-term MVPA patterns (from immediately post-intervention to 12-month follow-up) with different cancer-related health outcomes (ie, cancer-related fatigue, HRQoL, anxiety/depression, function in daily life, cardiorespiratory fitness, sedentary time and sleep). We hypothesized that higher MVPA levels at 12-month follow-up and increased MVPA patterns after the end of an exercise intervention would be associated with improved health outcomes. | PMC10331773 |
Methods | PMC10331773 |
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Settings and Participants | Data included in the present study were collected as part of the Phys-Can RCT, a multicentre trial (NCT02473003). | PMC10331773 |
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Intervention | PMC10331773 |
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Exercise program | The exercise program has been described previously in detail. | PMC10331773 |
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Additional BCS | Additional BCS used in the Phys-Can RCT have been described previously in detail. | PMC10331773 |
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Measures | PMC10331773 |
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Physical activity | SWA | Two physical activity measures, MVPA level at 12-month follow-up and long-term MVPA patterns (from immediately post-intervention to 12-month follow-up) were assessed with SenseWear Armband mini (SWA) immediately post-intervention and at 12-month follow-up. The SWA is a monitor combining a tri-axial accelerometer with heat/skin sensors, and has previously been validated in healthy adultsThe first physical activity measure, MVPA level at 12-month follow-up, was assessed as | PMC10331773 |
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Cancer-related health outcomes | fatigue, Fatigue | -20 | All cancer-related health outcomes were assessed at 12-month follow-up. Cancer-related fatigue was assessed with the Multidimensional Fatigue Inventory questionnaire (MFI-20, range 4-20), | PMC10331773 |
Statistical Analyses | cancer | REGRESSION, CANCER | Descriptive characteristics are presented as mean and standard deviation (Multiple linear regression was performed to examine the associations of (1) MVPA level at 12-month follow-up and (2) long-term MVPA patterns with each cancer-related health outcome, respectively. For the analyses with long-term MVPA patterns as independent variable, the variable was included in models using dummy-coding (High & Increasing/ High & Decreasing/ Low & Increasing/ Low & Decreasing) and the category “Low & Decreasing” was used as reference in the analyses to test the hypothesis that high and/or increased MVPA after the end of an exercise intervention would be associated with improved health outcomes compared to those remaining less physically active. All cancer-related health outcomes were treated as continuous variables. All models included immediately post-intervention value of the health outcome to increase precision and were adjusted for age, gender, and cancer treatment. The results are presented as unstandardized regression coefficients (β) with 95% Confidence Intervals (95% CI). The unstandardized coefficients can be interpreted as the mean change in the outcome (1) per 30 minutes/day increase in MVPA for the analyses with MVPA level at 12-month follow-up and (2) when comparing the group “High & Increasing,” “High & Decreasing” or “Low & Increasing” with the reference group “Low & Decreasing” for the analyses with long-term MVPA patterns.Missing data were <10% in all cancer-related health outcomes, except for functioning in daily life (13% missing) and cardiorespiratory fitness (24% missing). Multiple imputation was used to handle missing data in the cancer-related health outcomes. | PMC10331773 |
Results | PMC10331773 |
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Discussion | fatigue, ’, breast cancer, cancer, lower cancer-related fatigue | CANCER, BREAST CANCER | In the present study, we investigated MVPA in cancer survivors who previously participated in an exercise intervention during curative cancer treatment. The aims were to assess the associations of (1) MVPA level at 12-months follow-up and (2) long-term MVPA patterns (from immediately post-intervention to 12-month follow-up) with different cancer-related health outcomes. We found that a daily increase of 30 minutes MVPA at 12-month follow-up was significantly associated with lower cancer-related fatigue, higher cardiorespiratory fitness, and less sedentary time at 12-month follow-up. Additionally, participants who had high MVPA levels immediately post-intervention and increased their MVPA levels at 12-month follow-up were those who had the greatest health benefits in terms of lower fatigue, higher HRQoL and less sedentary time.As hypothesized, both higher MVPA level at 12-month follow-up and increased long-term MVPA patterns, were significantly associated with improved cancer-related health outcomes. However, some differences between the 2 physical activity measures regarding the observed associations are worth noting. For example, both MVPA level at 12-month follow-up and long-term MVPA patterns were significantly associated with lower fatigue, but it is the most physically active participants (those in the “High & Increasing” category) who reported clinically relevant lower scores in physical fatigue compared to the least physically active participants (those in the “Low & Decreasing” category), as the difference in score exceeded the minimal clinically importance of 2 points.Results regarding sedentary time indicate that both MVPA level at 12-month follow-up and long-term MVPA patterns were significantly and negatively associated with this outcome. Notably, compared to the category with the least physically active participants (those in the “Low & Decreasing” category), all the other categories were superior suggesting that high and/or increased MVPA levels after the end of an exercise intervention may reduce time spent sedentary in cancer survivors. This is in line with an RCT where breast cancer survivors randomized to a 12-week of MVPA both significantly increased MVPA and reduced sedentary time compared with the control group.In general, participants in the “High & Increasing” category was superior to the other groups for most cancer-related health outcomes. These results suggest that having high MVPA levels immediately post-intervention and increasing these levels during the follow-up period may be optimal for health outcomes in the long term in cancer survivors. These results also reinforce a possible dose-response relationship between MVPA levels and different cancer-related health outcomes and support advice within existing international physical activity guidelines that exceeding recommended physical activity levels is likely to provide additional health benefits in cancer survivors.There are numerous strengths in this study. First, we extend current knowledge through (1) demonstrating the potential long-term benefits of increasing MVPA levels post-intervention for different cancer-related health outcomes and (2) providing evidence of such associations when physical activity levels are objectively assessed. Further, our findings add to the growing evidence that a dose-response relationship between MVPA levels and health benefits in cancer survivors exists. Strengths in this study also include a large sample, the longitudinal design and long-term follow-up. However, our study is not without limitations including the large number of participants lost to follow-up and the homogeneous study sample (ie, mainly women with breast cancer, highly educated and physically active when entering the study), limiting the generalizability of our results. Additionally, although our study design does not allow to determine the direction of causality, adjusting for several confounders and examining both MVPA levels at 12-month follow-up and long-term MVPA patterns strengthens our conclusions about the observed associations. Our multidimensional approach, combining absolute levels of physical activity (ie, MVPA level) with a relative measure of physical activity (ie, long-term MVPA patterns) also provides an accurate and well-rounded picture of cancer survivors’ long-term physical activity status. | PMC10331773 |
Conclusion | cancer, Cancer | CANCER, CANCER | Our results suggest that long-term physical activity is essential for improving health outcomes post-intervention in cancer survivors, even among those with high MVPA levels. Cancer survivors, including those who reach recommended MVPA levels, should therefore be encouraged to maintain or increase MVPA post-intervention for additional health benefits. | PMC10331773 |
Supplemental Material | PMC10331773 |
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sj-docx-1-ict-10.1177_15347354231178869 – Supplemental material for The Role of Long-Term Physical Activity in Relation to Cancer-Related Health Outcomes: A 12-Month Follow-up of the Phys-Can RCT | Cancer | CANCER | Click here for additional data file.Supplemental material, sj-docx-1-ict-10.1177_15347354231178869 for The Role of Long-Term Physical Activity in Relation to Cancer-Related Health Outcomes: A 12-Month Follow-up of the Phys-Can RCT by Anne-Sophie Mazzoni, Ann Christin Helgesen Bjørke, Andreas Stenling, Sussanne Börjeson, Katarina Sjövall, Sveinung Berntsen, Ingrid Demmelmaier and Karin Nordin in Integrative Cancer Therapies | PMC10331773 |
References | PMC10331773 |
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1. Introduction | precancerous lesions, CRC, adenomatous polyps, inflammation, cancer, adenomatous polyp, dysplasia, carcinoma, colon cancer, high-grade dysplasia, adenoma, deaths | PRECANCEROUS LESIONS, CARCINOGENESIS, ADENOMATOUS POLYPS, INFLAMMATION, DISEASE, ADENOMATOUS POLYP, DYSPLASIA, CARCINOMA, COLON CANCER, CANCER, INSULIN RESISTANCE, ADENOMA, COLORECTAL CANCER | These authors contributed equally to this work.Colorectal cancer prevention is crucial for public health, given its high mortality rates, particularly in young adults. The early detection and treatment of precancerous lesions is key to preventing carcinogenesis progression. Natural compounds like curcumin and anthocyanins show promise in impeding adenomatous polyp progression in preclinical models. We conducted a randomized, double-blind, placebo-controlled, phase II presurgical trial in 35 patients with adenomatous polyps to explore the biological effects of curcumin and anthocyanins on circulating biomarkers of inflammation and metabolism. No significant difference in biomarker changes by treatment arm was observed. However, the network analysis before treatment revealed inverse correlations between adiponectin and BMI and glycemia, as well as direct links between inflammatory biomarkers and leptin and BMI. In addition, a considerable inverse relationship between adiponectin and grade of dysplasia was detected after treatment (corr = −0.45). Finally, a significant increase in IL-6 at the end of treatment in subjects with high-grade dysplasia was also observed (Colorectal cancer (CRC) prevention plays a pivotal role in safeguarding public health and reducing the burden of this deadly disease. CRC, the second leading cause of cancer-related deaths worldwide and the third most commonly diagnosed, often develops silently and progresses rapidly [The adenoma–carcinoma sequence is a well-recognized mechanism for CRC development [Circulating biomarkers play a pivotal role in understanding the intricate mechanisms underlying colon cancer development and progression. Metabolic biomarkers, such as glycemia, insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) index, provide insights into the metabolic dysregulation that can fuel cancer growth [The use of natural compounds for CRC prevention has gained significant attention in recent years due to their potential health benefits [In the present study, we aim to further enhance our understanding of the biological implications of curcumin and anthocyanin in patients with adenomatous polyps investigating circulating biomarkers related to inflammation and metabolism, thus improving valuable biological insights into their potential effects. | PMC10537228 |
2. Materials and Methods | PMC10537228 |
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2.1. Study Design and Participants | flat serrated, polyp, adenomatous polyps, cancer, adenomatous polyp, blood coagulation, Status ≤, colorectal tract, adenomas | HYPERPLASTIC POLYPS, CANCER, ADENOMATOUS POLYP, ADENOMATOUS POLYPS | A randomized, double-blind, placebo-controlled, phase II presurgical trial in patients with adenomatous polyps of the colon was conducted (MiRACol trial). Participants received either anthocyanin plus curcumin or a placebo for 4–6 weeks before undergoing polypectomy. To be eligible for the trial, patients had to be between 18 and 85 years old, have one or more adenomatous polyp in the colorectal tract with a diameter of at least 1 cm, and have an ECOG Performance Status ≤ 1. Patients with hyperplastic polyps, flat serrated adenomas, and cancer diagnosis were excluded from the study, as were those who had taken experimental medications, bilberry-based dietary supplements, or curcumin in the 15 days leading up to enrollment.The duration of the experimental treatment was suited to current standard clinical practice. Polyps larger than 1 cm in diameter are typically removed in a subsequent colonoscopy, following the availability of blood coagulation test results, as a safety precaution. Additionally, the 4-week interval between polyp detection and polypectomy falls within the common waiting period observed in numerous national health system facilities.Participants were recruited from the Department of Gastroenterology at Galliera Hospital in Genoa, Italy, between March 2014 and December 2017. The study registered as NCT01948661, was conducted under the approval of the Liguria Region Ethical Committee and in accordance with the Declaration of Helsinki. All patients provided written informed consent before participating in the trial. | PMC10537228 |
2.2. Study Procedures | adenomatous polyp, polyp | ADENOMATOUS POLYP | During screening, subjects underwent colonoscopy with evaluation for the presence of adenomatous polyp ≥1 cm and collection of tissue biopsies of the polyp and perilesional normal tissue. Once the histological confirmation and eligibility criteria were verified, eligible patients were randomly assigned to either the active treatment group (active arm) or the control group receiving a placebo (control arm). Participants were instructed to take 1 tablet of 500 mg Mirtoselect | PMC10537228 |
2.3. Dietary Supplements | Indena SpA (Milan, Italy) generously contributed curcumin (MerivaMerivaMirtoselect | PMC10537228 |
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2.4. Circulating Biomarkers Assessment | TNF-α | BLOOD | Fasting blood samples were obtained at baseline and the end of the study after 4–6 weeks of intervention. Blood samples were processed into serum and aliquots were frozen at −80 °C until biomarkers measurements.We measured hs-CRP, glycemia, and insulin using the Abbott Alinity analyzer (Abbott Diagnostics, Abbott Park, IL, USA). We then calculated the HOMA-IR index as an indicator of metabolic status [Total IGF-I, IGFBP-3, and 25OHD concentrations were assessed by chemiluminescent immunometric assay on the IDS-iSYS analyzer (Immunodiagnostic Systems Limited, East Boldon, UK).Adiponectin, leptin, IL-10, IL-6, and TNF-α were measured on the automated platform ELLA (ProteinSimple, BioTechne, Minneapolis, MN, USA), as previously described [Samples from the same participant were analyzed in the same batch. The laboratory staff were blinded to the arm assignment. | PMC10537228 |
2.5. Statistical Analysis | The sample size calculation was based on data from our previous randomized trial on the same study population [We presented median values and interquartile ranges (IQR) of serum biomarkers at baseline and the end of the study, in changes in time from baseline and % changes, by treatment arm. Biomarker values below the limit of detection (LLOD) were obtained by dividing the LLOD by two. Correlations among biomarkers are measured through Spearman correlation coefficients, which are “joined” in a graphical representation to create a network. Differences by arms were evaluated by Wilcoxon rank tests and through ANCOVA models adjusted for baseline values and significant confounders. The normal distribution of residuals from the full model was graphically checked. Due to the exploratory nature of the study, adjustment for multiple testing was not performed.Two-tailed | PMC10537228 |
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4. Discussion | obesity, colorectal cancer, TNF-α, colorectal adenomas, inflammation, dysplasia, adenomatous polyp, carcinoma, colon carcinogenesis, Inflammation, satiety, adenoma | OBESITY, COLORECTAL CANCER, ADENOMATOUS POLYPS, INFLAMMATION, ABNORMAL CELL PROLIFERATION, ADENOMATOUS POLYP, CARCINOMA, DYSPLASIA, DYSPLASTIC, INFLAMMATION, ADENOMA, CHRONIC INFLAMMATION | The findings from our study provide valuable insights into the complex relationships between biomarkers and treatment outcomes of curcumin and anthocyanin in patients with adenomatous polyps. Notably, no significant differences in biomarker levels or their changes were observed across the treatment arms, indicating that the interventions may not have directly influenced these specific biomarkers. However, our network analysis revealed compelling patterns, including direct correlations between adiponectin and BMI and glycemia, as well as direct links between inflammatory biomarkers and between leptin and BMI. These correlations potentially reflect disruptions in metabolic regulation that could contribute to adenomatous polyp development or progression. The direct link between leptin and BMI might indicate a complex interaction between the excess of body weight and signaling related to adenomatous polyp growth. These connections shed light on the complex interplay between metabolic and inflammatory pathways that could contribute to adenomatous polyp development or progression. These findings offer avenues for further research into preventive or therapeutic strategies targeting metabolic and inflammatory pathways contributing to the adenoma–carcinoma sequence in CRC development.Moreover, we detected an inverse relationship between post-treatment adiponectin levels and Ki67 levels in dysplasia tissue, suggesting a potential role of this adipokine in dysplasia progression. Adiponectin is a hormone secreted by adipose tissue that plays a role in regulating glucose and lipid metabolism. It is also involved in various anti-inflammatory and anti-tumorigenic processes [The finding of an inverse correlation between adiponectin and Ki67 levels in dysplasia tissue suggests a potential relationship between adiponectin levels and the severity of dysplasia. One possible explanation for this correlation is the role of adiponectin in inflammation. Adiponectin has been shown to have anti-inflammatory effects by suppressing the production of pro-inflammatory molecules and promoting the release of anti-inflammatory factors. Inflammation plays a crucial role in the development and progression of dysplasia, and lower levels of adiponectin could contribute to a pro-inflammatory environment that facilitates dysplasia [Equally noteworthy was the observed increase in IL-6 at the end of treatment in subjects with high baseline dysplasia grade, suggesting a composite interplay between dysplasia severity and inflammatory processes. The expected outcome of treatment with the natural compounds curcumin and anthocyanins would be a reduction in dysplasia grade and a decrease in inflammation, given their anti-inflammatory properties. However, the observed increase in IL-6 could be counterintuitive, since IL-6 is associated with inflammation, and increased levels might suggest a pro-inflammatory response. The mechanism by which IL-6 could be involved in dysplasia progression is not fully understood. One possible explanation is that chronic inflammation sustained by granulocytes, plasma cells, lymphocytes, and macrophages results in high levels of pro-inflammatory cytokines. IL-6 in particular creates a microenvironment conducive to abnormal cell proliferation and promotes the survival of dysplastic cells, inhibiting apoptosis and possibly contributing to their progression toward cancerous changes [The observation of a greater IL-10 increase in subjects with BMI < 25 compared to BMI > 25 is an interesting finding that suggests a potential relationship between body weight and the immune response. IL-10 is an anti-inflammatory cytokine that plays a crucial role in dampening the immune response and reducing inflammation [Surprisingly, our study did not yield evidence of curcumin inhibiting TNF-α, which could be primarily attributed to the limitations of a small sample size. Notably, recent research through a systematic review and meta-analysis of randomized controlled trials, indicated that with increasing doses of curcumin, there was a trend towards a greater reduction in TNF-α levels [The finding that subjects with low anthocyanin food intake show a greater reduction in leptin levels suggests a potential relationship between anthocyanin dietary consumption and leptin regulation. Leptin is a hormone produced by adipose tissue that plays a central role in appetite regulation and energy balance. Higher leptin levels generally signal satiety and a reduced appetite, while lower levels may lead to increased hunger and food intake [It is interesting to note that subjects with a positive family history of colorectal cancer had greater circulating levels of IGFBP-3 at the end of the trial than subjects without a family history. IGFBP-3 is a multifunctional protein that regulates the activity of insulin-like growth factors (IGFs) and plays a crucial role in cell growth, differentiation, and apoptosis [The finding of a trend to lower adiponectin levels in subjects with colorectal adenomas taking curcumin and anthocyanins compared to placebo is an unexpected result. A comprehensive systematic review and meta-analysis of 60 randomized controlled trials found that curcumin/turmeric supplementation improved anthropometric indices of obesity and increased adiponectin levels in the general population [The study has several limitations, including the small sample size and the short duration of intervention, which may have precluded the achievement of a significant modulation of circulating biomarkers of colon carcinogenesis related to inflammation and metabolism. | PMC10537228 |
5. Conclusions | dysplasia, colorectal adenomas | DISEASE PROGRESSION, DYSPLASIA, DISEASE CHARACTERISTIC | In conclusion, the combined treatment of curcumin and anthocyanins in patients with colorectal adenomas did not directly modulate circulating biomarkers. While the expected changes in biomarker levels were not observed, our study yielded intriguing results, shedding light on the complex interplay between metabolic and inflammatory pathways. The uncovered correlations between adiponectin, BMI, glycemia, inflammatory markers, and leptin provided valuable insights into the intricate regulatory mechanisms within the body. Additionally, the findings of an inverse relationship between adiponectin levels and dysplasia grade post treatment, along with an increase in IL-6 in subjects with high baseline dysplasia grade, warrant further investigation into the potential roles of these biomarkers in disease progression. Our research underscores the importance of understanding the multifaceted interactions between metabolic and inflammatory pathways in patients with colorectal adenomas and may guide the development of novel treatment strategies tailored to individual disease characteristics. | PMC10537228 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10537228 |
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Author Contributions | Conceptualization, D.M., I.M.B., H.J. and A.D.; methodology, A.D., H.J. and S.G.; formal analysis, S.G. and O.D.; investigation, D.M., I.M.B., H.J., V.A., T.B.W., M.O., B.B. and A.D.; resources, H.J., M.O. and A.D.; data curation, D.M., I.M.B., H.J., V.A., O.D. and S.G.; writing—original draft preparation, D.M., I.M.B., H.J., O.D., S.G. and A.D.; writing—review and editing, V.A., T.B.W., M.O. and B.B.; supervision: A.D.; project administration, I.M.B. and H.J.; funding acquisition, A.D. All authors have read and agreed to the published version of the manuscript. | PMC10537228 |
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Institutional Review Board Statement | ICH | The study was carried out in accordance with the Declaration of Helsinki (1964) guidelines and its amendments and the general principles of ICH Harmonised Tripartite Guidelines for Good Clinical Practice (ICH Topic E6, CPMP/ICH/135/95). At the beginning of the study, written informed consent, reviewed by the ethics committee, was obtained from each subject, according to ICH-GCP, the ethical principles that have their origin in the Declaration of Helsinki, and the regulatory and legal requirements in Italy. The study (NCT01948661) was approved by the local Ethical Committee (Comitato Etico Regione Liguria), Genoa, Italy. | PMC10537228 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10537228 |
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Data Availability Statement | Data may be made available for collaborative studies upon reasonable request to the corresponding author. | PMC10537228 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10537228 |
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ABSTRACT | Shuwen Yu and Benjie Wang have served as speakers for Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Qiong Wu, Chao Pan, Xiangqing Yu, and Yuhui Liu are the employees of Jiangsu Hansoh Pharmaceutical Group Co., Ltd, the sponsor of the study, at the time of this study. The remaining authors declare no conflict of interest.Ibrexafungerp (code name in China: HS-10366) is a first-in-class and orally active triterpenoid antifungal agent with broad antifungal activity against | PMC10720486 |
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KEYWORDS | PMC10720486 |
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MATERIALS AND METHODS | PMC10720486 |
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Study design | SAD) stage | RECRUITMENT | This was a randomized, double-blind, placebo-controlled phase 1 study, aiming at assessing the safety, tolerability, and PK characteristics of ibrexafungerp in healthy Chinese subjects. Two stages, the single ascending dose (SAD) stage and the multiple ascending dose (MAD) stage, were launched sequentially.This study was conducted in the Qilu Hospital of Shandong University from 3 March to 9 October 2022 in line with ethical principles derived from the Declaration of Helsinki and in compliance with the International Council for Harmonization Guidelines for Good Clinical Practice. The protocol, informed consent form (ICF), recruitment materials, all subject materials, and any amendments were submitted and approved by the Ethics Committee of Qilu Hospital of Shandong University. Written informed consent was obtained before the implementation of any study-related procedures.Eligible subjects were randomly assigned in a 6:1 ratio to receive an ibrexafungerp citrate tablet (strengths: 150 mg and 250 mg) or matching placebo (Overall design, treatments, and numbers of subjects enrolled in single-ascending dose (Eligible subjects included in this study were healthy volunteers, male or female (those who were not in pregnancy or lactating), aged between 18 and 45 years old, with a body mass index (BMI) between 19 and 27 kg/m | PMC10720486 |
Safety and tolerability assessments | SAD | ADVERSE EVENTS | Safety and tolerability assessments included adverse events (AEs) and serious AEs (SAEs) assessments from the signing of ICF until finishing assessments in the last visit of follow-up. Time intervals between the last dose and last visit of follow-up in SAD and MAD stages were both 7 days. Severity of AEs was classified mainly according to the protocol of this trial, CTCAE (version 5.0) was also referred to verify the judgment. AEs were coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 term (MedDRA MSSO, Herndon, VA, | PMC10720486 |
Sample collection and bioanalytical assay | SAD | In all three cohorts of the SAD stage, blood samples for ibrexafungerp concentration were collected predose (0 hour), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours postdose. In 450 mg cohort of MAD stage, blood samples were collected predose (0 hour), and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose on day 1; predose (0 hour) from day 5 to day 7; at 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours postdose on day 7. In 750 mg cohort of MAD stage, blood samples were collected predose (0 hour), and at 2, 4, 6, and 8 hours postdose in the morning and evening on day 1; predose (0 hour) from day 2 to day 6; predose (0 hour), and 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose on day 7.A validated HPLC-MS/MS assay was used to quantify the concentrations of ibrexafungerp in human plasma. Samples were pretreated by protein precipitation extraction. The calibration range was 5.00–5,000 ng/mL. The sensitivity of this method was 5.00 ng/mL. The maximum of intra-run and inter-run precision (CV%) were 5.27 and 4.32, respectively. The range of intra-run and inter-run accuracy (Bias%) were −0.67 ~ 11.50 and 1.44 ~ 9.07, separately. Moreover, matrix effect, selectivity, dilution, carryover, and stability were also validated. All performance characteristics of the bioanalytical method met the acceptable requirement. All samples were collected, stored, and analyzed under conditions confirmed by analyte stability during validation studies. | PMC10720486 |
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Pharmacokinetic data analysis | PK data analyses were performed using the data from all enrolled subjects who had at least one plasma concentration post-dosing. PK parameters for ibrexafungerp were calculated with standard non-compartmental analysis using Phoenix WinNonlin (Certara USA, Inc., version 8.1) and were summarized by study part and cohort using SAS (version 9.4, SAS Institute Inc., NC, USA). Plasma concentrations of HS-10366 were summarized and plotted using Phoenix WinNonlin (Certara USA, Inc., version 8.1). | PMC10720486 |
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Statistical analysis | All analyses were performed by using SAS software (version 9.4, SAS Institute Inc., NC, USA) or Phoenix WinNonlin (version 8.0, Certara USA Inc., USA). Demographics and baseline characteristics as well as safety data were summarized descriptively for subjects who had received at least one dose of study drug. Mean (standard deviation) and count (percentage) were presented for continuous data and categorical data, respectively. | PMC10720486 |
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RESULTS | PMC10720486 |
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Demographic profile | SAD stage, SAD | In total, 70 subjects were randomized into this study (42 in the SAD stage and 28 in the MAD stage). For both stages, all subjects are Chinese with balanced distributions of age, sex, ethnicity, and BMI between ibrexafungerp and placebo groups (Demographic and clinical characteristics of subjects in the single ascending dose (SAD) stageDemographic and clinical characteristics of subjects in the multiple ascending dose (MAD) stage | PMC10720486 |
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Safety and tolerability | syncope, abdominal pain, diarrhea, TEAEs, SAD | ADVERSE EVENT | All 70 subjects received at least one dose of study drug and were included in the safety analysis sets. TEAEs were reported in 8 (66.7%), 11 (91.7%), 12 (100.0%), 12 (100.0%), and 12 (100.0%) subjects in SAD and MAD stages. All TEAEs were mild to moderate in severity. There were no SAEs, severe AEs, or AEs leading to withdrawal during this study. The most common TEAEs in SAD and MAD stages was diarrhea (69.4% and 91.7%, respectively). The most common ibrexafungerp-related TEAEs were also the most common TEAEs. The comparative analysis between SAD and MAD stages showed that the incidence of diarrhea gradually increased with increasing doses. Most TEAEs were resolved without corrective interventions except for three reports (two reports of abdominal pain and one report of syncope) from three subjects in 1,500 mg cohort, who recovered after being treated with an infusion of electrolyte balance solutions and anisodamine. All ibrexafungerp-related TEAEs in SAD and MAD stages were presented in Study drug-related TEAEs in the single ascending dose (SAD) stageStudy drug-related TEAEs in the multiple ascending dose (MAD) stageNote: The percentage was calculated using the number of subjects in each cohort of the safety analysis set as the denominator. Adverse events associated with the study drug were defined as those in which the association with the study drug during administration was “definitely relevant”, “probably relevant”, or “undetermined”. Adverse events were coded based on MedDRA 25.1. | PMC10720486 |
Pharmacokinetic properties | SAD stage, SAD) stage, SAD | Plasma concentrations of ibrexafungerp were available for analysis in 60 healthy Chinese subjects (36 in the SAD stage and 24 in the MAD stage), and these 60 subjects were included in the PK analysis.After a single oral dose in the fasting state, the mean plasma concentration of ibrexafungerp generally increased with increasing dose in a dose range of 300 to 1,500 mg (Plasma ibrexafungerp concentration (Mean ± SD, log plots) time profiles after a single dose. SAD, single ascending dose.Descriptive summary of pharmacokinetic parameters of ibrexafungerp in the single ascending dose (SAD) stage (fasting)Median (minimum, maximum).Note: Parameters were shown as Geometric Mean (coefficient of variability CV %), unless otherwise noted.Abbreviations: After multiple doses of 450 mg (fasting) or 750 mg (taken with a standard meal), mean trough plasma concentrations plateaued on days 5, 6, and 7, indicating reaching a steady state (Plasma ibrexafungerp concentration (Mean ± SD, log plots)-time curve after repeated doses. MAD, multiple ascending doses.Descriptive summary of pharmacokinetic parameters of ibrexafungerp in the multiple ascending dose (MAD) stageMedian (minimum, maximum).Note: Parameters were shown as Geometric Mean (coefficient of variability CV %), unless otherwise noted.Abbreviations: | PMC10720486 |
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DISCUSSION | diarrhea, abdominal pain, gastrointestinal degeneration, TEAEs, vomiting, SAD | GASTROINTESTINAL DISORDERS | This was the first study to assess the safety, tolerability, and PK of ibrexafungerp in healthy Chinese subjects. In the SAD stage, CWith respect to the safety of ibrexafungerp in healthy Chinese subjects, most TEAEs were mild to moderate, and resolved without medical interventions. The most common TEAEs in SAD and MAD stages were gastrointestinal disorders (including diarrhea, abdominal pain, and vomiting), which were similar to that in non-Asian populations. Moreover, no evidence of gastrointestinal degeneration or any significant clinical abnormalities was found in any biopsy of subjects in phase 1 studies overseas. These data indicated that the effect of ibrexafungerp on gastrointestinal mucosa was without significant functional or safety consequences and was completely reversible in humans.With access to two previous phase 1 studies overseas (FDA application review files of ibrexafungerp), the PK characteristics of ibrexafungerp could be compared between Asian and non-Asian subjects. In the present study, CIt is important to consider that the present study and phase 1 overseas studies were conducted with different populations and under different conditions, therefore, the comparison of PK parameters of ibrexafungerp should be interpreted with caution. The observed difference in AUC | PMC10720486 |
Conclusion | Following a single dose up to 1,500 mg and multiple doses up to 750 mg, ibrexafungerp was safe, well-tolerated, and displayed a favorable PK profile in healthy Chinese subjects, which was similar to those in the previous studies conducted overseas. These results support further clinical development of ibrexafungerp in China. | PMC10720486 |
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ACKNOWLEDGMENTS | We would like to thank all of the investigators, staffs, all of the subjects and their families for their support in completing this trial during the outbreak of the COVID-19 pandemic. We thank Jiayang Song for carefully analyzing and reviewing the data and also appreciate Wen Jia, Peng Xia, and Chaonan Jin for providing help with manuscript preparation.This study was funded by the Jiangsu Hansoh Pharmaceutical Group Co., Ltd.Guarantors of the article: S.W.Y. Specific author contributions: Study conception and design: X.Y.L.; B.J.W.; S.W.Y. Acquisition of data: the ibrexafungerp (HS-10366 in China) Study Group; Statistical analysis: J.Y.S.; Interpretation of the data and drafting of the manuscript: X.Y.L., P.X.; Critical revision of the manuscript for important intellectual content: all authors. | PMC10720486 |
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