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Conflicts of Interest | The authors declare no conflict of interest. | PMC10001681 | ||
References | TG | Body weight (kg). Significantly different pre-vs. post-intervention at ** Body fat (%). Significantly different pre-vs. post-intervention at ** TC (mg/dL). TC, Total cholesterol; ** TG (mg/dL). TG, Triglyceride; ** LDL (mg/dL). LDL, Low-density lipoprotein; * HDL (mg/dL). HDL, High-density lipoprotein.Adiponectin. Significantly different pre vs. post at * Leptin (mg/dL). Significantly different pre vs. post at * Participant characteristics.Values are presented as mean ± standard error of the mean (SEM); RME, resistance and moderate aerobic exercise; RVE, resistance and vigorous aerobic exercise.Exercise program.TRX, total body resistance exercise.Change of lipid profiles.TC, Total cholesterol; TG, Triglyceride; LDL, Low density lipoprotein; HDL, High density lipoprotein. Significantly different pre-vs. post at * Change of adipokines.Significantly different pre-vs. post at * | PMC10001681 | |
Supplementary Information | Risdiplam | Risdiplam is an oral, survival of motor neuron 2 (The online version contains supplementary material available at 10.1007/s00415-023-11560-1. | PMC9897618 | |
Keywords | PMC9897618 | |||
Introduction | PMC9897618 | |||
Overview of SMA and the natural history of types 2 and 3 SMA | SMA, autosomal recessive neuromuscular disorder | SPINAL MUSCULAR ATROPHY 4 | Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by reduced levels of survival of motor neuron (SMN) protein due to homozygous deletions or loss-of-function mutations in the Patients with type 2 SMA develop symptoms between 6 and 18 months of age, achieve the ability to sit independently and occasionally stand or take a few steps with support, but are unable to walk independently [ | PMC9897618 |
Risdiplam overview | Risdiplam | Risdiplam (Evrysdi® [F. Hoffmann La-Roche Ltd/Genentech Inc.]) is an orally administered small molecule indicated for the treatment of patients in the USA [Risdiplam modifies | PMC9897618 | |
Overview of the SUNFISH study | risdiplam | SUNFISH (NCT02908685) [Part 1 was a dose-finding study in patients with type 2 or type 3 SMA (ambulant and non‑ambulant) to inform the dose for Part 2. In Part 1, risdiplam treatment led to a sustained increase in SMN protein in the blood, and exploratory efficacy analyses showed improvement or stabilization in motor function [Here, we report longer-term exploratory efficacy and safety results after 24 months of risdiplam treatment in SUNFISH Part 2 and contextualize these findings with external comparator groups. In addition, we investigate the efficacy and safety of 1 year of risdiplam treatment in patients who previously received placebo up to month 12. | PMC9897618 | |
Methods | PMC9897618 | |||
Study oversight | ADVERSE EVENTS | This trial was approved by an ethics committee at each study site and was conducted in accordance with Good Clinical Practice guidelines and the World Medical Association Declaration of Helsinki. Written informed consent was provided by the patient or by parents/caregivers. The sponsor, F. Hoffmann-La Roche Ltd, provided the study drug, study management and medical monitoring, drug safety management and analysis, data management and statistical analysis, and pharmacokinetic/pharmacodynamic analysis. Confidentiality agreements were in place between the authors and F. Hoffmann-La Roche Ltd. An external independent data monitoring committee monitored the safety of patients. All authors attest to adherence to the protocol, accuracy of analysis, and complete reporting of adverse events (AEs). | PMC9897618 | |
Patients and study procedures | non-ambulant | Eligible patients were non-ambulant and aged 2–25 years, with a genetically confirmed diagnosis of 5q-autosomal recessive SMA and clinical symptoms attributable to type 2 or type 3 SMA. Patients were excluded from the study if they had received treatment with an | PMC9897618 | |
Study design and outcomes | risdiplam | Patients were stratified by age (2–5, 6–11, 12–17, and 18–25 years) and randomized 2:1 with concealed allocation to receive either risdiplam or placebo daily for 12 months. The risdiplam dose was 0.25 mg/kg for patients weighing < 20 kg, and 5 mg for patients weighing ≥ 20 kg [The 24-month exploratory objectives and outcomes included the efficacy of risdiplam treatment with regard to motor function (as measured by MFM32 [Safety was assessed throughout the study by monitoring and recording AEs, including serious AEs (SAEs), laboratory assessments, electrocardiograms, vital signs, and ophthalmologic, neurologic, and anthropometric examinations. | PMC9897618 | |
Statistical methods | non-ambulant, risdiplam, scoliosis | REGRESSION, DISEASE CHARACTERISTIC, SCOLIOSIS | Exploratory efficacy analyses were conducted based on the all-exposure-to-risdiplam treatment period (the treatment period after receiving the first dose of risdiplam). Randomized patients who did not receive risdiplam treatment were not included in the exploratory efficacy analyses; this condition applied to one patient who was originally randomized to the placebo group but left the study early, and thus did not receive risdiplam treatment. For each efficacy endpoint, individuals who fulfilled the corresponding missing motor function scale item rules were excluded at the corresponding time point, as predefined in the statistical analysis plan.Efficacy endpoints were summarized by randomized treatment (risdiplam or placebo switched to risdiplam) for the all-exposure-to-risdiplam treatment period. For patients initially on risdiplam treatment, results at month 12, month 18, and month 24 were summarized. For patients initially on placebo, the adjusted baseline (defined as the last measurement prior to the first dose of risdiplam) was used for the analyses and results at month 12 on risdiplam treatment (i.e., month 24 in the study) were summarized.All patients who received at least one dose of risdiplam (After month 12, all patients in SUNFISH received risdiplam while maintaining blinding to the initial treatment randomization. An external comparator group of untreated individuals with Type 2 and Type 3 SMA was, therefore, used to give context to SUNFISH Part 2 results at month 24 for those initially randomized to the risdiplam treatment arm. The external comparator population comprised 81 patients from the NatHis-SMA study (NCT02391831) [For the external comparator analysis, MFM total score was used for all analyses to compare motor function at month 24. To calculate MFM total score (hereinafter referred to as MFM-derived total score), the external control data were compared with SUNFISH Part 2 data based on the 20-item MFM (MFM20) total score [Since the SUNFISH Part 2 study population consisted of non-ambulant patients with types 2 and 3 SMA, ambulant patients were not included in the external control comparison analysis. To ensure robust analysis, patients from the external comparator data set were selected based upon similarities to the SUNFISH Part 2 risdiplam arm patients in terms of demographics, the MFM version, and disease characteristics. After applying the missing item rule on the MFM scale and trimming to exclude patients with missing information on selected prognostic factors (age, SMA type, Patients in the external comparator group were weighted using inverse probability of treatment weighting based upon the selected prognostic factors at baseline, creating a pseudo-population with similar covariate distributions in the treated and untreated groups. A propensity score for each patient was estimated using logistic regression incorporating potential predictors of treatment assignment (risdiplam versus no risdiplam) as independent variables. The potential predictors included in the model were age at baseline (years), SMA type (type 2 or non-ambulant type 3), baseline MFM total score, presence of scoliosis at baseline (yes or no), Change from baseline in MFM-derived total score was analyzed as an independent variable using a mixed model for repeated measures (MMRM). The independent variables in the MMRM included baseline MFM-derived total score, treatment, time of assessment (i.e., the categorical study visit weeks 17, 26, 35, 52, 78, and 104), treatment-by-time interaction, baseline-by-time interaction, age at baseline, SMA type, | PMC9897618 |
Results | PMC9897618 | |||
Patients | risdiplam | A total of 180 patients were enrolled in SUNFISH Part 2 and were randomized to receive risdiplam (After month 12, all patients received risdiplam. A total of 176 patients entered the open-label treatment period (defined as months 12–24 in the study). Motor function scores from the 59 patients who switched from placebo to risdiplam at study month 12 (i.e., at adjusted baseline) are presented in Table S1. Patients and all individuals in direct contact with patients at the site remained blinded to the treatment group from randomization until completion of at least their second year in the study.During the open-label treatment period, two patients withdrew from treatment. One of these patients elected to withdraw from the study but completed the month 24 study visit. The other patient withdrew prematurely due to the COVID-19 pandemic and did not complete the month 24 visit. Data are available from 164 patients who were recorded as having completed the open-label treatment period at month 24 by the clinical cut-off date of 30th September 2020 (10 patients did not have a recorded date of completion for the open-label treatment period). The clinical cut-off date is the date at which it was estimated that the last patient in Part 2 would have completed the month 24 study visit. However, some patients missed this study visit due to COVID-19 pandemic restrictions. All patients remaining in the study entered the open‑label extension phase (≥ 24 months) for 3 years of further treatment. | PMC9897618 | |
Motor function | PMC9897618 | |||
RULM | risdiplam | At month 24, the mean change from baseline (95% CI) in RULM total score was 2.8 (1.9–3.6) (Table Change in RULM and HFMSE total score from baseline in patients receiving risdiplam for up to 24 months and those who previously received placebo up to study month 12. | PMC9897618 | |
HFMSE | At month 24, the mean change from baseline (95% CI) in HFMSE total score was 2.2 (1.1–3.2) (Table | PMC9897618 | ||
Respiratory function | PMC9897618 | |||
FVC | risdiplam | FVC was assessed in patients aged 6–25 years at screening. In patients who received risdiplam for 24 months, the mean change from baseline in the best percentage-predicted FVC (95% CI) was – 7.8% (– 11.6 to – 3.9%) after 24 months of risdiplam treatment (Table | PMC9897618 | |
Caregiver- and patient-reported independence | PMC9897618 | |||
SMAIS-ULM | risdiplam | In patients who received risdiplam for 24 months, the mean change from baseline (95% CI) in the caregiver-reported SMAIS-ULM total score was 2.7 (1.7–3.7) at month 24 (Table Change in caregiver- and patient-reported SMAIS upper limb total score from baseline in patients receiving risdiplam for up to 24 months and those who previously received placebo up to study month 12. In patients who initially received placebo, the mean change from baseline in the caregiver-reported SMAIS-ULM total score was 1.6 (0.4–2.8) after 12 months of risdiplam treatment (Table | PMC9897618 | |
Discussion | DISEASE | The natural history of types 2 and 3 SMA involves progression of disease and continued loss of function [ | PMC9897618 | |
Motor function and independence | Risdiplam, non-ambulant, risdiplam, prolonged disease, later-onset SMA | DISEASE | Risdiplam treatment in a clinically heterogeneous population of children, teenagers, and adults with later-onset SMA and varying disease duration resulted in continued stabilization or improvement in motor function. Although analyses are exploratory, overall, the gains in motor function after 12 months of risdiplam treatment were maintained or improved upon up to month 24—confirming the benefit of longer-term risdiplam treatment.In patients with prolonged disease duration, the improvement with treatment is not expected to be evident in the short term, as it requires the activation of multiple compensatory reinnervation processes. Furthermore, hip contractures in non-ambulant patients with prolonged disease duration limit functional gains in tasks that require full hip extension. Thus, a goal of treatment is the long-term stability of specific functions, many of which involve the hands or upper extremities, which are important for the autonomy of non-ambulant patients. The progressive improvement on the RULM scale (1.91 at month 12, 2.06 at month 18, and 2.79 at month 24) following risdiplam treatment in this study exemplifies the impact of risdiplam on upper limb function. Increases in the caregiver-reported SMAIS-ULM total score (1.68 at month 12, 2.10 at month 18, and 2.73 at month 24; available for the full population), which is strongly correlated with the RULM [The trajectories of MFM32 and RULM total scores changed in patients who switched from placebo to risdiplam at month 12, while decline was observed from baseline to month 12 (when patients received placebo). A trend toward improvement or stabilization in motor function was observed from months 12 to 24 (12 months after the switch to risdiplam treatment).The external comparator analysis showed that risdiplam administration led to significant improvements in motor function at months 12 and 24 (Table In the comparison, analyses of MFM-derived total scores showed that risdiplam treatment in SUNFISH Part 2 led to an increase in mean score from baseline to month 24, which was significantly different from the progressive decline observed in the untreated external comparator. After 24 months of treatment, a higher proportion of individuals treated with risdiplam showed improvement or stabilization (≥ 3- or ≥ 0-point change, respectively) in MFM total score compared with the untreated external comparator. These results provide further confirmation of the longer-term efficacy of risdiplam in a broad population of patients with type 2 and non-ambulant type 3 SMA compared with untreated patients.Importantly, although risdiplam increases levels of functional SMN protein [ | PMC9897618 |
Respiratory function | BEST | Best percentage-predicted FVC in this population declined at a rate consistent with natural history findings [ | PMC9897618 | |
Safety | toxicity, pneumonia, risdiplam, retinal toxicity | PNEUMONIA, EYE DISORDERS | The safety profile after 24 months of treatment was consistent with the safety results after 12 months of treatment (Table Initial observations in the double-blind period showed a slightly higher incidence of serious pneumonia in patients in the risdiplam arm (8%) compared with the placebo arm (2%). However, the incidence of serious pneumonia did not increase in those patients who switched to risdiplam at month 12 (0%) compared with the first year on placebo (2%). Furthermore, the incidence of pneumonia did not increase during the second year of risdiplam treatment (7%), compared with the first year of risdiplam treatment (8%).A review of laboratory parameters did not reveal any risdiplam-associated toxicity. There have been no clinically significant safety findings in patients reflective of potential risks previously identified from nonclinical toxicology studies (effects on epithelial tissues, retinal toxicity, or hematologic effects). AEs in the System Organ Class ‘eye disorders’ were not suggestive of risdiplam-induced effects. | PMC9897618 |
Conclusion | risdiplam, Risdiplam, later-onset SMA, upper limb motor function | DISEASE | Risdiplam treatment in a broad and clinically heterogeneous patient population of children, teenagers, and adults with later-onset SMA and varying disease duration resulted in continued clinically relevant gains in motor function. This was demonstrated by improvements (32% of patients) and stabilization (58% of patients) in MFM32 total score at month 24 and confirmed by progressive improvements on RULM—an additional, independent measure of upper limb motor function—as well as caregiver-reported SMAIS‑ULM. The gains in motor function observed after 12 months of risdiplam treatment were maintained or improved upon after 24 months, confirming the benefit of longer-term treatment with risdiplam. The safety profile after 24 months of treatment was consistent with that previously observed after 12 months of treatment [ | PMC9897618 |
Supplementary Information | SPINAL MUSCULAR ATROPHY 1 | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 49 kb)The authors would like to thank all individuals enrolled in the risdiplam studies, their families, and the site staff involved. The authors would also like to thank the Spinal Muscular Atrophy Foundation and PTC Therapeutics for their collaboration in the SUNFISH study. Jen Ciarochi of Nucleus Global, wrote the first draft of the manuscript based on an outline agreed by all authors and provided medical writing assistance with subsequent drafts in accordance with Good Publication Practice (GPP3) guidelines ( | PMC9897618 | |
Author contributions | CM | CV, KG, HK, CM, WYY, and PF contributed to the study conception and design. Data were collected by MO, ND, ESM, AN, KS, CV, GB, NG, JK, AK-P, LS, and EM. Analysis was performed by ND, AN, KG, TM, WYY, and PF. Interpretation was performed by all authors. All authors reviewed and edited drafts of the manuscript and approved the final submitted manuscript. All authors attest to the integrity of the data. All authors had full access to all the data in the study on request and had final responsibility for the decision to submit for publication. | PMC9897618 | |
Funding | This study is sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Medical writing and editing support were funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland in accordance with Good Publication Practice (GPP3) guidelines ( | PMC9897618 | ||
Data availability | For eligible studies, qualified researchers may request access to individual patient level clinical data through a data request platform. At the time of writing this request platform is Vivli. | PMC9897618 | ||
Declarations | PMC9897618 | |||
Conflicts of interest | CM, AveXis/Novartis | MO reports grants from F. Hoffmann-La Roche Ltd during the conduct of the study and has received grants as a clinical trial investigator from Biogen. JWD has received fees for serving on scientific advisory boards from Biogen, Novartis, Sarepta Therapeutics, and Avidity; has received consulting fees from Affinia Therapeutics and Shift Therapeutics for a therapeutic platform; and has received grant support for clinical trials from F. Hoffmann-La Roche Ltd, Biogen, Novartis Gene Therapies, Cytokinetics, Scholar Rock, and Sarepta Therapeutics. ND served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Biogen and Novartis Pharmaceuticals; he has received personal fees from Biogen and F. Hoffmann-La Roche Ltd for congress and travel support. ESM reports that she has served on advisory boards for Biogen and Scholar Rock. She has received consulting fees, travel support, and speaker honoraria as an independent contractor from F. Hoffmann-La Roche Ltd, Biogen, AveXis, and Scholar Rock. AN has received fees for serving on scientific advisory boards and speaker fees from F. Hoffmann-La Roche Ltd. KS reports grants from F. Hoffmann-La Roche Ltd/Chugai Pharmaceutical during the conduct of the study and grants from Biogen Japan and lecture fees from Novartis Pharmaceuticals, outside the submitted work. CV reports personal fees and financial support to her institution from F. Hoffmann-La Roche Ltd for activities outside the submitted work. GB received consultancy fees and speaker honoraria from F. Hoffmann-La Roche Ltd, AveXis/Novartis Gene Therapy, and Biogen, and grants from F. Hoffmann-La Roche Ltd. NG reports fees for serving on advisory boards and presentations at symposia from F. Hoffmann-La Roche Ltd, Biogen, AveXis, and Novartis. JK received grants or contracts from Novartis Gene Therapies and Biogen. He has received consulting and speaker fees from F. Hoffmann La Roche Ltd, Biogen, and Novartis Gene Therapies and consulting fees from Scholar Rock. AK-P reports that she received an institutional support grant from Biogen; serving on scientific advisory boards for and receiving speaker honoraria from Biogen, F. Hoffmann-La Roche Ltd, Novartis, and PTC Therapeutics; and receiving personal fees from Biogen and F. Hoffmann-La Roche Ltd for travel support. LS received grants and personal fees from F. Hoffmann-La Roche Ltd, Biogen, and AveXis/Novartis Gene Therapies and personal fees from Cytokinetics, BioHaven, and Scholar Rock, outside the submitted work. GP, KG, HK, CM, TM, RSS, HS, WYY, and PF report that they are current employees of and stockholders in F. Hoffmann-La Roche Ltd. EM has received fees for serving on scientific advisory boards; speaker fees from F. Hoffmann-La Roche Ltd, Biogen, AveXis/Novartis, Scholar Rock, and Cytokinetics; and grants from Biogen during the conduct of the study. | PMC9897618 | |
Ethical approval | This trial was approved by an ethics committee at each study site and was conducted in accordance with Good Clinical Practice guidelines and with the World Medical Association Declaration of Helsinki. | PMC9897618 | ||
Informed consent | Written informed consent was provided by the patient or by the patients’ legally authorized representative before participating in the study. | PMC9897618 | ||
References | PMC9897618 | |||
Subject terms | stress | AIDS | Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessation aids show only modest efficacy, new interventions are needed. Given the evidence that stress is a potent trigger for smoking, the present randomized clinical trial tested whether stress could augment the effects of a memory updating (retrieval-extinction) intervention. Non-treatment seeking smokers (Clinicaltrials.gov identifier: NCT04843969. | PMC9750979 |
Introduction | death, smoking behaviors, anxiety | DISORDERS | Tobacco use is the primary cause of preventable death worldwide [A fundamental feature of smoking is the learned associations between smoking behaviors and cigarette-related cues [In the past two decades, memory reconsolidation blockade interventions have shown promise as treatments for stress and anxiety related disorders [Memory updating might also be applied to substance use problems by weakening the ability of drug-associated triggers to elicit substance use [In the present study, we aimed to extend the previous findings and further decrease cigarette smoking using a novel procedure. Given the evidence that stress can potently trigger cigarette cravings [Based on the literature described above, we made two main predictions. First, compared to all other groups, the combined stress and cue procedure would induce greater craving and physiological responses during phase 1 and larger decreases in cue reactivity and cigarette use at two- and six-week follow-up. Second, the stress-based intervention alone would be at least as effective as the cue-based intervention alone. | PMC9750979 |
Methods | PMC9750979 | |||
Participants | Non-treatment seeking smokers were recruited through online advertisements, flyers posted around Montreal, and word-of-mouth. Study eligibility was determined from telephone interviews using the Fagerström Test for Cigarette Dependence (FTCD) [ | PMC9750979 | ||
Procedures | This randomized clinical trial took place between February 2019 and January 2020. The study comprised five in-person visits, including baseline, intervention, and three test sessions given 24 h, two weeks and six weeks post-intervention (Fig. | PMC9750979 | ||
Experimental design and timeline. | During the initial assessment and test sessions 1, 2 and 3, a novel smoking-related video was shown to participants. Physiological measures (heart rate (HR) and skin conductance (SC)) were collected prior to and during the last minute of each video presentation. During these same visits, blood pressure (BP) and self-reported cigarette craving and urge to smoke scores were collected pre- and post-video. On the day of the behavioral intervention, baseline physiological measures (HR, SC, and BP) and self-report data were gathered, followed by one of four conditions (phase 1): stress task and smoking cue, stress task and neutral cue, non-stressful task and smoking cue, or non-stressful task and neutral cue. Physiological and craving measures were collected and followed by a 10-minute break. All participants then went through the extinction protocol (phase 2) consisting of additional smoking videos, smoking images, and the manipulation of smoking-related paraphernalia. Immediately after phase 2, physiological and craving measures were gathered again. | PMC9750979 | ||
Baseline | During the first study visit, participants provided demographic information, including age, sex, ethnicity, level of education, employment status, and history of cigarette use. They completed the Contemplation Ladder [ | PMC9750979 | ||
Intervention | Prior to the baseline session, participants were randomized to one of four conditions (phase 1) using a 2 × 2 factorial design: (1) stress task and smoking cue, (2) stress task and neutral cue, (3) control task and smoking cue, or (4) control task and neutral cue. The stress task was the Montreal Imaging Stress Test (MIST) [The MIST (or its control version) was immediately followed by a five-minute video cue presentation. For participants in the smoking cue condition, these video clips were similar but non-identical to those presented at baseline. For participants in the neutral cue condition, cues consisted of ten 30-second clips depicting non-smoking activities (see Supplementary Methods). Neutral and smoking cues were matched on number of people in each clip, their approximate age, ethnicity, distance from the camera, and lighting.All four phase 1 conditions were followed by a 10-minute break during which participants remained seated in front of a black screen. They then underwent a 60-minute extinction protocol (phase 2). This entailed four rotations of: a five-minute video with smoking-related content (composed of similar but non-identical clips to those presented in the baseline visit), a five-minute presentation of smoking images (with each image presented for 3 seconds, see Supplementary Methods), and five minutes of manipulating smoking paraphernalia (e.g., lighter, cigarettes).Immediately prior to and after phase 1, and immediately after phase 2, HR, SC and BP were measured, and participants completed the TCQ-SF and QSU-Brief. Participants remained in the laboratory for one hour following completion of the questionnaires to minimize the chance that they would reengage the association between cigarette use and smoking-related cues. Participants who underwent the stressful MIST were debriefed. All participants were asked to see how long they could go without smoking after the session. | PMC9750979 | ||
Test sessions 1, 2 and 3 | Participants returned to the laboratory for cue reactivity test sessions 24 h, two weeks, and six weeks following the intervention. During each of these sessions, SC, HR and BP were measured, and the CWS-21, Contemplation Ladder, FTCD (for tests 2 and 3), TCQ-SF and QSU-Brief were administered. Participants then viewed a new five-minute smoking cue video with SC and HR measured for one minute before video presentation and again during the last minute of the video. Immediately after the video, BP was measured and the TCQ-SF and QSU-Brief were administered again.Between each of the test sessions, participants were asked to record their daily cigarette use in a journal provided by the experimenters. Data from the journals were collected at test sessions 2 and 3. | PMC9750979 | ||
Statistical analyses | SPSS 26.0.0.1 (Chicago, IL) was used for all statistical analyses. Preliminary analyses indicated less than 1% missing data on all variables. Multiple imputation was used to impute missing scores. Chi square tests and analyses of variance (ANOVAs) were used to examine group differences in study characteristics at baseline for categorical and continuous variables, respectively. Daily cigarette use at test sessions 2 and 3 was calculated as the mean number of cigarettes smoked per day in the week prior to each test session. Repeated measures analyses of variance (ANOVA) were used to examine group differences in physiological and craving measures, daily cigarette use, Contemplation Ladder and FTCD scores. Partial eta squared were used to assess the magnitude of these effects. Greenhouse-Geisser corrections were applied when the assumption of sphericity was violated. Post-hoc analyses consisted of paired samples t-tests with Bonferroni corrections. Correlational analyses tested for potential predictors of cigarette use changes, and the Benjamini-Hochberg procedure with a false discovery rate of 5% was applied to decrease the risk of false positives. | PMC9750979 | ||
Results | PMC9750979 | |||
Participant characteristics | Seventy-six volunteers were deemed eligible for the study (Fig. | PMC9750979 | ||
Experimental manipulation check | Since this was the first time stress and smoking cues were combined in a memory updating procedure, we initially examined whether they elicited their expected effects during phase 1 of the intervention session. As hypothesized, the stress task yielded the predicted effects within the smoking cue groups ( | PMC9750979 | ||
Responses during the intervention | PMC9750979 | |||
Phase 1 | When comparing scores obtained immediately pre- and post-phase 1, there were main effects of time reflecting anticipated decreases in HR ( | PMC9750979 | ||
The stress task-induced psychophysiological and craving responses during the behavioral intervention. | During phase 1 ( | PMC9750979 | ||
Phase 2 | Across groups, the extinction procedure significantly increased SC ( | PMC9750979 | ||
Cue reactivity assessments | PMC9750979 | |||
Baseline | As expected, exposure to a smoking-related video led to a main effect of time revealing significant increases in craving (QSU-Brief: | PMC9750979 | ||
Tests 1, 2 and 3 | Across groups, at each test session, exposure to a new smoking-related video led to increased SC response (all | PMC9750979 | ||
Across sessions | Across sessions, physiological responses to the video cues became less pronounced as shown by decreases in SC (( | PMC9750979 | ||
Smoking behavior | Over the period of the study, participants decreased their cigarette use as reflected by a significant main effect of session ( | PMC9750979 | ||
Predictors of decreased cigarette use | When participants from all groups were combined, higher systolic BP values following phase 1 of the intervention predicted larger decreases in cigarette use at test session 3 ( | PMC9750979 | ||
Discussion | The present study tested whether a laboratory stressor could augment the ability of a memory updating procedure to decrease cigarette use. While our predictions for the cue-based intervention were not supported, two hypotheses about the stressor were. First, during phase 1 of the intervention, greater craving and physiological responses were observed following exposure to the stressor as compared to the control task. Second, and more importantly, during the weeks following the intervention, larger decreases in cigarette use were seen in stress versus control group participants.The failure to reproduce the effect of a previous smoking cue-based intervention on cigarette use [The stress-based intervention reduced cigarette use but not craving and physiological responses during the follow-up sessions. This too differed from studies using cue-based memory updating interventions [Interestingly, the control procedure also conferred some benefit. Across groups, we observed decreased nicotine dependence scores, increased motivation to quit smoking, and decreased cigarette use. While this may in part be a byproduct of study participation (e.g., placebo or Hawthorne effect), it may also reflect individual differences in responsiveness to the intervention. Just as the stress task may not have been equally stressful to all participants, for some, the control arithmetic task may have been stressful. These individual differences in stress reactivity may account for the correlations between physiological responding at intervention and changes in cigarette use. Across all participants, greater decreases in cigarette use correlated with greater phase 1 systolic BP responses and greater decreases in systolic BP during phase 2. Systolic BP responses could potentially reflect both the reactivation of craving-related processes and the efficacy of the intervention.While this study was originally conceived as a memory updating paradigm, other interpretations are plausible. One possible interpretation is that phase 2 alone led to decreased cigarette use. However, although extinction procedures (often in the form of exposure therapy) can produce transient reductions in cigarette use [A more plausible alternative interpretation may be that the stress procedure enhanced extinction. Although no studies (to our knowledge) have investigated behavioral stress induction on extinction (as in the current study), cortisol has been used to induce a stress state. In fear-related studies, elevated stress hormones during extinction learning (either endogenously or through prior cortisol administration) can further reduce fear responses post-extinction and at follow-up [While it is not possible to determine which mechanism (i.e., memory updating or enhanced extinction) is involved, the present study nonetheless provides, to our knowledge, the first evidence that a single-session stress-based intervention can reduce cigarette use in non-treatment seeking smokers. Future studies may wish to examine neurobiological underpinnings and clarify differences between enhanced extinction and memory updating. | PMC9750979 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41386-022-01455-6. | PMC9750979 | ||
Acknowledgements | The authors would like to thank Rhonda Amsel for valuable statistical advice and Elena Pérez Gómez for assembling and editing the smoking and neutral video cues. We are also grateful to the large team of undergraduate students who assisted with screening and administrative tasks. | PMC9750979 | ||
Author contributions | AB, KG and ML had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AB, KG, KN, ML. Acquisition, analysis, or interpretation of data: All authors. Statistical analysis: AB, KG, ML. Drafting of the manuscript: AB, KG, ML. Critical revision of the article for key intellectual content: All authors. Final approval of the version to be published: All authors. | PMC9750979 | ||
Funding | JP | This research was funded by a James McGill Professor Research Award to KN and Canadian Institutes of Health Research operating funds to KN and ML (MOP-211696) and JP and KN (PJT-148728). The funders had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. | PMC9750979 | |
Competing interests | The authors declare no competing interests. | PMC9750979 | ||
References | PMC9750979 | |||
Abstract | PMC10240182 | |||
Background | hair loss, FAGA | HAIR LOSS, ANDROGENIC ALOPECIA, TELOGEN EFFLUVIUM | Oral supplementation with some amino acids (like methionine, taurine, and cysteine) could be useful in subjects with hair loss conditions such as androgenic alopecia (AGA or FAGA) or telogen effluvium (TE). Hydrolysed collagen (HC) oral supplementation has demonstrated to have beneficial effects on nail and skin health and could improve hair growth. A food supplement in tablet formulation containing hydrolysed fish‐origin collagen (300 mg/dose), taurine, cysteine, methionine, iron, and selenium has been recently available. To date no controlled data are available regarding the clinical efficacy of this product as adjuvant to hair loss specific treatments in these clinical conditions. | PMC10240182 |
Study aims | hair loss | HAIR LOSS | To evaluate and compare the efficacy and tolerability of an oral supplementation based on HC and amino acids in subjects with hair loss due to AGA/FAGA or chronic TE in combination with drug treatments in comparison with drug treatments alone. | PMC10240182 |
Methods and subjects | ±, hair loss | HAIR LOSS, LUDWIG | In a prospective, 12‐week, randomized, assessor‐blinded controlled trial 83 subjects (mean age 41 ± 16 years; 26 men and 57 women) were enrolled in the study. Fifty‐nine subjects suffered from AGA/FAGA (Hamilton I‐VA, Ludwig I‐1, II‐2) and 24 from chronic TE. Subjects were randomized to oral supplementation (1 tablet day) in combination with the specify drug treatment decided by the investigator according to the type of hair loss (AGA/FAGA or TE) (Group A; | PMC10240182 |
Results | ± | GROUP B | Seventy‐six participants (91.6%) completed the 12‐week study period. The GAS score at week 6 was 0.5 ± 0.2 in group A and 0.0 ± 0.1 in Group B ( | PMC10240182 |
Conclusion | An oral supplement containing hydrolysed fish‐origin collagen, taurine, cysteine, methionine, iron, and selenium has demonstrated to improve the clinical efficacy of specific anti‐hair loss treatments in subjects with AGA/FAGA or chronic TE.
| PMC10240182 | ||
INTRODUCTION | hair loss, alopecia, FAGA | HAIR LOSS, ALOPECIA, TELOGEN EFFLUVIUM, HAIR LOSS | Hair loss can be classified in several forms including male‐ or female‐androgenetic alopecia (AGA and FAGA, respectively), and telogen effluvium (TE). AGA is one of the most frequent hair loss causes, | PMC10240182 |
STUDY AIM | hair loss | HAIR LOSS | The aim of this study was to evaluate the efficacy and tolerability of an oral supplementation (based on HC, amino acids, and micronutrients) in combination with drug treatments (e.g., minoxidil or finasteride) in subjects with hair loss due to AGA/FAGA or TE in comparison with drug treatments alone. | PMC10240182 |
SUBJECTS AND METHODS | PMC10240182 | |||
Population and study design | mycosis, alopecia areata, ±, psoriasis, Hair loss, allergies, FAGA | HAIR THINNING, MYCOSIS, ALOPECIA AREATA, PSORIASIS, MAY, THINNING HAIR, IRON DEFICIENCY, HAIR LOSS, ALLERGIES, SEBORRHEIC DERMATITIS, LUDWIG | Between May 2022 and November 2022, 83 subjects with AGA, FAGA or chronic TE were assessed and screened for inclusion in the trial. Hair loss condition was confirmed by physical examination performed by a dermatologist that assigned a clinical diagnosis of AGA or chronic TE. AGA was diagnosed using the Hamilton or Ludwig scales by observing hair thinning and miniaturization in scalp region. Chronic TE was diagnosed considering subject history, self‐reported and investigator‐reported thinning hair. The study was designed as a 12‐week, prospective, randomized, assessor‐blinded trial. The trial took place in six different Dermatology clinics in Italy. The trial was conducted according to Good Clinical Practice Guidelines and Helsinki Declaration. All subjects provided signed informed consent. Eighty‐three subjects (mean age 41.2 ± 16.2 years) with AGA/FAGA (71.1%) or TE (28.9%) were enrolled. The main inclusion criteria were age >18 years, diagnosis of AGA/FAGA or chronic TE, eligible for the treatment with the oral supplement used in the study. The main exclusion criteria were acute inflammatory condition at the scalp, allergies to the components of the products used in the study, iron deficiency, clinically relevant alteration to thyroid function, presence of other scalp conditions (e.g., alopecia areata, seborrheic dermatitis, psoriasis, mycosis, lichenoid lesions). The study was conducted over 12 weeks, patients was evaluated at baseline and after 6 (facultative visit) and 12 weeks. Patients were randomly divided in two arms: Group A ( | PMC10240182 |
Study outcomes | The primary efficacy endpoint was evaluated in an assessor‐blinded fashion after 6 (facultative visit) and 12 weeks by a panel of six dermatologist (GFM‐O‐Trial Investigator Group) through the global assessment score (GAS), a 7‐point score from −3 (severe worsening) to +3 (excellent improvement) performed using standardized global photographs, taken with the head in a stereotactic positioning device.The second endpoints were represented by the global clinical efficacy and the global tolerability evaluated by the investigators after 12 weeks through a 5‐point score from −2 (very negative) to +2 (very positive). The global clinical efficacy was also evaluated by patients through a 5‐point score from −2 (severe worsening) to +2 (excellent improvement). The patients also evaluated the acceptability and tolerability of the products using a scale from 1 (very accepted) to 10 (not accepted). | PMC10240182 | ||
Statistical analysis and sample size calculation | A total of 83 participants were enrolled and randomized in two groups. Sample size calculation was performed considering the data of Panchaprateep and Lueangarun, | PMC10240182 | ||
RESULTS | hair loss, FAGA | MAY, HAIR LOSS | Between May 2022 and November 2022, 83 subjects with AGA, FAGA or chronic TE were assessed and screened for inclusion in the trial. Demographics and baseline characteristic were similar between groups (Table Demographics and baseline characteristics.Seventy‐six participants completed the trial (91.6%), and seven subjects stopped prematurely the trial for different reasons (Figure Study's flow.Patients, both in group A and group B received different drug treatments according to the type of hair loss. Topical Minoxidil (2% and 5%) was the treatment most used (Table Distribution of drug treatments, alone or in combination with the food supplement used in this study, decided by the investigators according to the type of hair loss. | PMC10240182 |
Primary endpoint | ± | The GAS was evaluated in an assessor blinded fashion after 6 (facultative visit) and 12 weeks by the investigators using a 7‐point score from −3 (severe worsening) to +3 (excellent improvement). After 6 weeks, the mean GAS increased only in Group A (0.5 ± 0.2 in Group A and 0.0 ± 0.1 in group B). After 12 weeks both the two groups showed an increase in the GAS, that was higher in group A compared to group B (1.67 ± 0.16 and 0.66 ± 0.20, respectively, mean difference 1.01 ± 0.25, 95% CI: 0.52–1.50) (Figure Global assessment score (GAS) evaluated after: (A) 6 weeks (group A Global photographs and macro‐photographs of some patients in group A (GFM+T), took at baseline and after 12 weeks were showed in Figures Global photographs of a patients in group A (GFM+T), took at baseline (A) and after 12 weeks (B).Global photographs and a macro‐photographs of a patients in group A (GFM+T), took at baseline (A and B), and after 12 weeks (C and D). | PMC10240182 | |
Secondary endpoints | ±, hair loss, gastro‐intestinal adverse | HAIR LOSS | Global clinical efficacy was evaluated in an open fashion both by investigators and patients trough questionnaires converted in a 5‐point score scale. The mean global clinical efficacy was higher in group A both for investigators (differences between means 0.33 ± 0.14, 95% CI: 0.05–0.62) and patients (differences between means 0.56 ± 0.20, 95% CI: 0.16–0.96) (Figure Mean score of global clinical efficacy evaluated by: (A) investigators (Group A, In Table Distribution of recorded global clinical efficacy.The tolerability of products was evaluated by investigators (Table Tolerability of products evaluated by investigators.Tolerability of products evaluated by patients through a questionnaire based on a 10 items scale: From 1 (none) to 10 (a lot).Both the oral supplement and the therapies generally used to treat the hair loss conditions were well tolerated, as reported by investigators and patients. The investigators reported that the 97.7% of patients in Group A and the 96.1% in the group B showed a good or very good tolerability.The 84.1% of subjects in group A and the 80.0% of patients in group B declare that the used of the product/s was not problematic. In addition, no gastro‐intestinal adverse effects were reported in 86.4% and 94.1% of subjects in Group A and B, respectively. | PMC10240182 |
DISCUSSION | anti‐hair loss | BLIND, HAIR LOSS | Hair loss is a common problem that affects up to 50 percent of men and women.Some limitations should be considered in evaluating our results. First, the two arms of the study were slightly unbalanced (48 subjects in group A and 35 subjects in group B). This could be explained by the randomization conducted using a block of six. Although the two groups are slightly unbalanced in term of participants, demographics and baseline characteristic were similar between groups. A second limitation of this study was the trial design which was not double blind. In order to increase the internal validity of our trial, we adopted an assessor‐blinded primary outcome evaluation. Another limitation of this study was related to the relatively short duration of the treatments. However, it was adequate to observe the role of oral supplementation in improving the efficacy of the anti‐hair loss treatments generally employed. | PMC10240182 |
CONCLUSIONS | hair loss disorders | This clinical trial demonstrated that the tested oral supplement, containing hydrolysed fish‐origin collagen, taurine, cysteine, methionine, iron and selenium was able to improve the clinical efficacy of specific anti‐hair loss treatments in subjects with hair loss disorders such as AGA/FAGA or TE. | PMC10240182 | |
CONFLICT OF INTEREST STATEMENT | MM | MM and FC are employees of Difa Cooper Catabria Labs that commercialized the food supplement. The authors report no other conflict of interest in this work. | PMC10240182 | |
ETHICS STATEMENT | All participants provided written informed consent and a photo consent statement before starting the study. | PMC10240182 | ||
DATA AVAILABILITY STATEMENT | SAID | The author has provided the required Data Availability Statement, and if applicable, included functional and accurate links to said data therein. | PMC10240182 | |
REFERENCES | PMC10240182 | |||
Subject terms | neurodevelopmental disorder, Rett syndrome | RETT SYNDROME | Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study (Results from the LAVENDER phase 3 study demonstrate that trofinetide, a synthetic analog of glycine–proline–glutamate, provides significant therapeutic benefits in the core symptoms of Rett syndrome | PMC10287558 |
Main | seizures, hand stereotypies, loss of verbal communication, neurodevelopmental disorder, Rett syndrome, RTT | RETT SYNDROME | Rett syndrome (RTT) is a rare, genetic neurodevelopmental disorder characterized by loss of verbal communication with limited nonverbal skills, loss of fine and gross motor function (including purposeful hand use), behavioral issues, seizures, hand stereotypies and gastrointestinal problemsRTT primarily affects females (1 in 10,000–15,000 live female births)Trofinetide ((2The main objective of this phase 3 study was to investigate the efficacy, safety and tolerability of trofinetide in a larger, randomized, double-blind, placebo-controlled study in RTT. | PMC10287558 |
Results | PMC10287558 | |||
Demographic and baseline characteristics | Enrollment occurred between 29 October 2019 and 28 October 2021, with 208 participants screened and 187 participants randomized to trofinetide ( | PMC10287558 | ||
Primary efficacy outcomes | The mean (s.e.m.) change from baseline to week 12 in the RSBQ total score was −5.1 (0.99) and −1.7 (0.98) in the trofinetide and placebo groups, respectively. Based on the mixed-effect model for repeated measure (MMRM) analysis, the LSM (s.e.m.) change from baseline to week 12 in the RSBQ total score was statistically significantly greater with trofinetide (−4.9 (0.94)) than with placebo (−1.7 (0.90)), with an LSM (s.e.m.) treatment difference of −3.1 (1.30) (95% confidence interval (CI), −5.7 to −0.6; | PMC10287558 | ||
Key secondary efficacy outcome | The mean (s.e.m.) change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist (CSBS-DP-IT) Social Composite score was −0.1 (0.28) and −1.1 (0.28) in the trofinetide and placebo groups, respectively. MMRM analysis showed a statistically significant difference between trofinetide and placebo, with an LSM (s.e.m.) treatment difference of 1.0 (0.37) (95% CI, 0.3 to 1.7; | PMC10287558 | ||
Secondary efficacy outcomes | SECONDARY | Results for the other secondary endpoints are shown in Extended Data Table | PMC10287558 | |
Post hoc efficacy analyses | diarrhea | The results for the coprimary endpoints were comparable irrespective of diarrhea TEAE status (Extended Data Table | PMC10287558 | |
Discussion | diarrhea, antiseizure, TEAEs, vomiting, constipation, neurodevelopmental disorders, RTT | SECONDARY, RARE DISEASE, SYNDROME, PATHOPHYSIOLOGY | In this phase 3 study in a large cohort of girls and women 5–20 years of age with RTT, trofinetide demonstrated a statistically significant improvement over placebo for both the coprimary and key secondary efficacy endpoints. Treatment with trofinetide improved key symptoms of the syndrome from the perspective of both the caregiver (RSBQ) and clinician (CGI-I). All RSBQ subscores were directionally in favor of trofinetide, suggesting broad improvement across key symptoms of the syndrome.Cohen’s The efficacy endpoints are complementary and reflect functionally important dimensions of RTT, including the ability to communicate. The RSBQ shows correlations with functioning, is validated across a range of ages (2–47 years) in RTTMild or moderate diarrhea was frequently associated with trofinetide and was responsible for the majority of discontinuations due to TEAEs; however, diarrhea was self-limited and resolved soon after withdrawal of trofinetide. The implementation of a diarrhea-management plan partway through the study, which involved the adjustment or discontinuation of laxative medications commonly taken for RTT-associated constipation, the initiation of fiber supplements and antidiarrheal medication and dose reduction or interruption of trofinetide, if necessary, appeared to mitigate this risk, as 75% of participants receiving trofinetide completed the study. Furthermore, analyses indicate that the risk of functional unblinding due to an imbalance of TEAEs of diarrhea did not bias the efficacy data in favor of trofinetide. Given that most participants were using concomitant antiseizure medication, many of which cause changes in liver enzymesThe exclusion of individuals without a documented disease-causing In conclusion, statistically significant differences were demonstrated between trofinetide and placebo for efficacy endpoints relevant to RTT, suggesting that trofinetide is potentially capable of modifying core symptoms consistent with the underlying pathophysiology of the syndrome. Furthermore, this study demonstrated an acceptable safety profile for trofinetide. When we evaluate the benefit versus risk associated with trofinetide, it is important to consider the medium effect size that was demonstrated for the efficacy endpoints, which can be interpreted as clinically meaningful, particularly as this is a rare disease with a high burden for patients and families. When we consider the risk element, it is important to note that diarrhea and vomiting were issues of tolerability, not safety. Almost all TEAEs of diarrhea and vomiting were mild or moderate in severity and can be managed with appropriate interventions. Given that numerous phase 2 and 3 studies in neurodevelopmental disorders including RTT have failed to meet efficacy endpoints | PMC10287558 |
Methods | PMC10287558 | |||
Study design | The study design and methods have been published previouslyA single dose level of trofinetide was tested using weight-based dosing to achieve the target exposure identified based on the results of the previous phase 2 studyThe study included a screening period of ≤3 weeks, a 12-week double-blind treatment period and a 30-day safety follow-up for participants who did not continue into the open-label extension study ( | PMC10287558 | ||
Study population | RTT | Girls and women 5–20 years of age with RTT, a score of 10–36 on the RTT Clinical Severity Scale | PMC10287558 | |
Intervention | Trofinetide (200 mg ml | PMC10287558 |
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