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Initial Assignment of Rett Clinical Severity Scale Scores and Symptoms to Clinical Global Impression-Severity Rating Score.
Source publication
Rett syndrome is a genetically based neurodevelopmental disorder. Although the clinical consequences of Rett syndrome are profound and lifelong, currently no approved drug treatments are available specifically targeted to Rett symptoms. High quality outcome measures, specific to the core symptoms of a disorder are a critical component of well-desig...
Contexts in source publication
Context 1
... first step provided an anchoring of the Clinical Glo- bal Impression-Severity ratings against an established clinical rating scale specific to Rett syndrome with excellent face valid- ity and extensive longitudinal use. This is shown in Table 2. ...
Context 2
... improvement scale scoring is shown in Table 3. The full set of anchors is shown in Table S2 in the Supplementary Materials. To ensure consistency in the application of the anchors, clin- ician raters participated in periodic calibration sessions in which they co-rated sample Rett syndrome vignettes. ...
Similar publications
Background: Rett Syndrome is a severe, neurodevelopmental disorder mainly caused by mutations in the MECP2 gene, affecting around 1 in 10,000 female births. Severe physical, language, and social impairments impose a wide range of limitations in the assessment of the abilities of Rett patients. This study proposes an analysis and first validation of...
Citations
... An assessment of individual symptom domains of RTT (hand use, ambulation, seizures, autonomic features, behavior, attentiveness, social interaction, and language/communication) was developed using a visual analog scale (RTT-DSC-VAS). The CGI-I is a measure of global clinical improvement that has been widely used in clinical trials of central nervous system disorders and neurodevelopmental disorders (Neul et al., 2015;Neul et al., 2022). RTT-specific scoring anchors were developed to make the CGI-I rating scale relevant to RTT (Neul et al., 2015). ...
... The CGI-I is a measure of global clinical improvement that has been widely used in clinical trials of central nervous system disorders and neurodevelopmental disorders (Neul et al., 2015;Neul et al., 2022). RTT-specific scoring anchors were developed to make the CGI-I rating scale relevant to RTT (Neul et al., 2015). Training and scoring calibration procedures were developed and used in the phase II studies to ensure consistency across the clinician raters. ...
... The CGI-I and RSBQ were chosen as the coprimary efficacy endpoints in the phase III clinical program to capture clinician and caregiver perspectives of the efficacy of trofinetide in patients with RTT . The CGI-I was chosen for clinicians to measure the overall improvement of patients with the same RTTspecific scoring anchors used in the phase II study (Neul et al., 2015;Neul et al., 2022). The RSBQ, a validated caregiver assessment accepted by the FDA as an endpoint in RTT clinical trials, was chosen for caregivers to measure improvement in specific behaviors and symptom domains associated with RTT. ...
Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases.
... All participants with RTT underwent genetic testing and phenotypic assessment accompanied by detailed medical history questionnaires completed by their caregivers. Symptom severity in RTT was measured using the Rett Syndrome Severity Scale (RSSS) which is the primary scale used by the Rett Syndrome Center of Monte ore Children's Hospital (Kaufmann, Tierney et al. 2012) (Kaufmann, Tierney et al. 2012, Neul, Glaze et al. 2015. This clinician-rated scale represents an aggregate measure of the severity of clinical symptoms, including motor function, seizures, autonomic function, ambulation, eye contact, and communication (Neul, Glaze et al. 2015). ...
... Symptom severity in RTT was measured using the Rett Syndrome Severity Scale (RSSS) which is the primary scale used by the Rett Syndrome Center of Monte ore Children's Hospital (Kaufmann, Tierney et al. 2012) (Kaufmann, Tierney et al. 2012, Neul, Glaze et al. 2015. This clinician-rated scale represents an aggregate measure of the severity of clinical symptoms, including motor function, seizures, autonomic function, ambulation, eye contact, and communication (Neul, Glaze et al. 2015). The RSSS score in the current RTT group ranged between 5 and 15 (Mean ± SD = 10.94 ± 2.8), with higher scores indicating more severe disease. ...
Background
In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials, recordings of sensory-perceptual functioning using event-related potential (ERP) approaches have emerged as potentially powerful tools. Considerable work points to highly anomalous auditory evoked potentials (AEPs) in RTT. However, an assumption of the typical signal-averaging method used to derive these measures is “stationarity” of the underlying responses – i.e. neural responses to each input are highly stereotyped. An alternate possibility is that responses to repeated stimuli are highly variable in RTT. If so, this will significantly impact the validity of assumptions about underlying neural dysfunction, and likely lead to overestimation of underlying neuropathology. To assess this possibility, analyses at the single-trial level assessing signal-to-noise ratios (SNR), inter-trial variability (ITV) and inter-trial phase coherence (ITPC) are necessary.
Methods
AEPs were recorded to simple 100Hz tones from 18 RTT and 27 age-matched controls (Ages: 6–22 years). We applied standard AEP averaging, as well as measures of neuronal reliability at the single-trial level (i.e. SNR, ITV, ITPC). To separate signal-carrying components from non-neural noise sources, we also applied a denoising source separation (DSS) algorithm and then repeated the reliability measures.
Results
Substantially increased ITV, lower SNRs, and reduced ITPC were observed in auditory responses of RTT participants, supporting a “neural unreliability” account. Application of the DSS technique made it clear that non-neural noise sources contribute to overestimation of the extent of processing deficits in RTT. Post-DSS, ITV measures were substantially reduced, so much so that pre-DSS ITV differences between RTT and TD populations were no longer detected. In the case of SNR and ITPC, DSS substantially improved these estimates in the RTT population, but robust differences between RTT and TD were still fully evident.
Conclusions
To accurately represent the degree of neural dysfunction in RTT using the ERP technique, a consideration of response reliability at the single-trial level is highly advised. Non-neural sources of noise lead to overestimation of the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially ameliorate this issue.
... Eligible females were five to 20 years of age with classic/typical RTT; had a documented disease-causing mutation in the MECP2 gene; had scores of 10 to 36 on the RTT Clinical Severity Scale [29], and ≥4 (moderate) on the Clinical Global Impression-Severity (CGI-S) scale [29]; were at least 6 months post-regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening); and had a stable pattern of seizures, or no seizures, within 8 weeks of screening. ...
... Eligible females were five to 20 years of age with classic/typical RTT; had a documented disease-causing mutation in the MECP2 gene; had scores of 10 to 36 on the RTT Clinical Severity Scale [29], and ≥4 (moderate) on the Clinical Global Impression-Severity (CGI-S) scale [29]; were at least 6 months post-regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening); and had a stable pattern of seizures, or no seizures, within 8 weeks of screening. ...
... It was developed based on previous research related to communication skills in RTT [15,33,34], with anchors based on existing, validated measures of early language development and social communication skills [19][20][21], and specific and applicable adaptations for RTT (e.g., use of real objects, photographs of real objects, and picture symbols to make choices). The RTT-COMC is also derived from the RTT-DSC-VAS that was used in a phase 2 trofinetide study [26] and from work done to support anchors for the CGI [29]. The RTT-COMC scale assesses the individual's ability to communicate nonverbally (and sometimes verbally) using the ability to make choices as a proxy. ...
... An approach that has been successfully used in other heterogenous conditions is the use of syndrome-specific Clinician Global Impression (CGI) scales [13][14][15]. These were introduced by Guy, et al. and have since been adapted to come in the form of a CGI -Severity (CGI-S) scale [16]. ...
... Given the heterogeneity of AS and limited COAs available, modified Global Impression items were deemed appropriate to assess symptom severity or impact and how symptoms have changed; a strategy employed by other researchers also working with heterogenous populations [14,15,17]. During the course of the SAS-CGI and CASS development, another AS-specific CGI was published [18]. ...
Background
Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable measures reporting key symptoms and functional impairments of AS are required to support development of patient-centered therapies. We describe the development of clinician- and caregiver-reported, AS-specific Global Impression scales for incorporation into clinical trials. Best practice US Food and Drug Administration guidance for measure development was followed with input from expert clinicians, patient advocates, and caregivers during content generation and refinement.
Results
Initial measurement domains for the Symptoms of AS—Clinician Global Impression (SAS-CGI) and the Caregiver-reported AS Scale (CASS) were identified from a conceptual disease model of AS symptoms and impacts, derived from interviews with caregivers and clinicians. Two rounds of cognitive debriefing (CD) interviews were performed; clinicians debriefed the SAS-CGI, with patient advocates and caregivers debriefing the CASS to ensure relevance and comprehension. Feedback was used to refine items and ensure wording was age-appropriate and captured AS-specific symptoms, as well as associated impacts and functional impairments. The SAS-CGI and CASS capture global assessments of seizures, sleep, maladaptive behaviors, expressive communication, fine and gross motor skills, cognition, and self-care, which were determined by clinicians, patient advocates, and caregivers to be the most challenging aspects of AS. Additionally, the measures include items for assessing overall AS symptoms and the meaningfulness of any change. In addition to ratings for severity, impact, and change, a notes field was included in the SAS-CGI to provide the rationale for the chosen rating. CD interviews confirmed the measures covered key concepts of AS from the perspective of clinicians and caregivers, and demonstrated that the measures’ instructions, items, and response options were clear and appropriate. Interview feedback informed adjustments to the wording of the instructions and the items.
Conclusions
The SAS-CGI and CASS were designed to capture multiple AS symptoms, reflecting the heterogeneity and complexity of AS in children 1 to 12 years old. These clinical outcome assessments have been incorporated into AS clinical studies, which will allow for the evaluation of their psychometric properties and inform further refinements if needed.
... Extensive information on the spectrum of clinical features and disease progression in RTT has been acquired from the US Natural History Study (NHS) of RTT and Related Disorders, which enrolled people with RTT and disorders with clinical and genetic relationships to RTT: MECP2 Duplication Syndrome (MDS); CDKL5 De ciency Disorder (CDD); and FOXG1 Syndrome (FS). This information, combined with other large disease databases [16], has been instrumental in establishing clinical trial readiness through the development of outcome measures [17,18] and identifying putative biomarkers [19][20][21]. While these efforts are essential for clinical trials, knowing what clinical issues and problems are most concerning and impactful for affected individuals is necessary to develop therapies that meaningfully address these concerns. ...
... Lack of hand use was of modest concern at CSS 6-10, was most prominent at CSS 11-15 and 16-20, and then declined thereafter. This pattern matched that seen using CGI-S as a measure of severity (especially since CSS and CGI-S are concordant [17]), with caregivers expressing less concern for functional hand use and gait for the most severely impaired individuals, despite these individuals being markedly impaired in these functional domains. In the most severely affected CSS groups, Frequent infections and GU issues concerns rise. ...
Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) has enabled development of novel therapeutic approaches that are currently undergoing clinical evaluation or are proposed to move into clinical development. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top clinical concerns in order to gain information to guide the development and selection of outcome measures for future clinical trials.
Methods: Caregivers of participants enrolled in the US Natural History Study of RTT and related disorders were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for Classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2.
Results: The top caregiver concerns for Classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The rank order of the frequency of the top caregiver concerns for Classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. The frequency of caregiver concern for seizures, hand use, and spoken language increased in relation to clinician assessed severity in these clinical domains, showing consistency between clinician assessments and caregiver concerns. Comparison across disorders found commonalities in the top caregiver concerns between Classic RTT, Atypical RTT, MECP2 Duplication Syndrome, CDKL5 Deficiency Disorder, and FOXG1 Syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features.
Conclusion: The top caregiver concerns for individuals with RTT and the RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.
... The clinician-rated Clinical Global Impression (CGI) scales are used to rate patients' global functioning before and after treatment in trials based solely on clinicians' judgement and knowledge of a patient's history [27]. Moreover, the RTT-specific version of the CGI offers the potential to capture changes to the seven core symptom domains in RTT [28]. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to differentiate the disorder from other severe intellectual disabilities [29] and has been widely used as an outcome measure in clinical trials of patients with RTT [15]. ...
Background: Rett Syndrome (RTT) is a rare, neurodevelopmental disorder characterised by a range of problematic symptoms. There is yet to be a robust instrument to adequately capture the range of disease severity across the lifespan. In this study, we aimed to develop and assess the validity of an RTT-specific electronic Observer Reported Outcome (eObsRO), the Multi-System Profile of Symptoms Scale (MPSS). Methods: The study was conducted in two phases. Phase 1 consisted of a systematic literature review, focus groups, expert feedback, and a pilot test of the new scale. Modifications were made based on preliminary analysis and feedback collected in the pilot phase. Phase 2 consisted of the validation of the questionnaire based on two samples (Sample 1, n = 18; Sample 2, n = 106). Participants were all parents or caregivers of individuals with RTT. Results: The MPSS consists of 12 validated sub-scales (mental health problems, autonomic problems, cardiac problems, communication problems, problems in social behaviour, problems in engagement, gastrointestinal problems, problems in motor skills, neurological problems, orofacial problems, respiratory problems, and sleep problems), which explore symptom frequency in the past month and a supplement to the scale consisting of five sub-scales (sensory problems, immune dysfunction and infection, endocrine problems, skeletal problems, and dermatological problems), which is designed to capture symptom changes over a longer time period. The frequency of symptoms was rated on a 10-point slider scale, which then was automatically transformed into a 0 to 5 Likert score. All 12 sub-scales showed strong internal consistency (α ≥ 0.700) and good stability, ranging from 0.707 to 0.913. Pearson’s correlation showed a statistically significant (r = 0.649) correlation between the MPSS and the Rett Syndrome Behaviour Questionnaire (RSBQ) total score and significant correlations between sub-scales with items that were presented in both the MPSS and RSBQ. Conclusions: The MPSS is a psychometrically validated eObsRO using the HealthTrackerTM platform and has the potential to be used in clinical trials.
... There is no 12 permanent cure for Rett syndrome in humans, and symptom management remains the 13 standard of care [4]. When new drugs are discovered to alleviate specific Rett trials, the Clinical Global Impression -Severity (CGI-S) is used to measure overall 23 disease severity in Rett subjects [5,6]. The CGI-S is a 7−point Likert rating scale that 24 reflects experts' clinical judgment of the patient based on the clinician's total experience 25 with the Rett syndrome population. ...
... The CGI-S ranges from 1 to 7 and each score 26 corresponds to the following patient states: (1) normal, not at all ill, (2) borderline ill, 27 (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, (7) amongst the most 28 extremely ill. It has been widely used as an outcome measure in Rett syndrome and 29 other neurodevelopmental disorders such as Autism and Fragile X Syndrome [5]. In our 30 work, we measured CGI-S in all our patients during all clinic visits included in our 31 experiments to assess their global clinical state. ...
... The copyright holder for this preprint this version posted March 22, 2022. ; , σ 2 LOOP 4 (5) and µ T RACE (10) ) and the rest five were MSTE-features. ...
Rett syndrome, a rare genetic neurodevelopmental disorder in humans, does not have an effective cure. However, multiple therapies and medications exist to treat symptoms and improve patients’ quality of life. As research continues to discover and evaluate new medications for Rett syndrome patients, there remains a lack of objective physiological and motor activity-based (physio-motor) biomarkers that enable the measurement of the effect of these medications on the change in patients’ Rett syndrome severity. In our work, using a commercially available wearable chest patch, we recorded simultaneous electrocardiogram and three-axis acceleration from 20 patients suffering from Rett syndrome along with the corresponding Clinical Global Impression - Severity score, which measures the overall disease severity on a 7-point Likert scale. We derived physio-motor features from these recordings that captured heart rate variability, activity metrics, and the interactions between heart rate and activity. Further, we developed machine learning (ML) models to classify high-severity Rett patients from low-severity Rett patients using the derived physio-motor features. For the best-trained model, we obtained a pooled area under the receiver operating curve equal to 0.92 via a leave-one-out-patient cross-validation approach. Finally, we computed the feature popularity scores for all the trained ML models and identified physio-motor biomarkers for Rett syndrome.
... The development of validated syndrome-specific anchors for distinct dimensions in schizophrenia (e.g., positive, negative, depressive, and cognitive) was among the first attempts to create syndrome-specific versions of the CGI scales [12]. More recently, the CGI has been adapted for rare neurodevelopmental disorders including Rett syndrome [13], Prader Willi syndrome (PWS) [14], and most recently for Angelman syndrome (AS) (NEPTUNE, NCT04106557). ...
... The first investigation of meaningfulness measured the frequency with which caregivers (parents of individuals with AS, aged [4][5][6][7][8][9][10][11][12][13][14] mentioned examples of behaviors within each domain as more or less challenging and their impact on QoL. The full set of interview questions appears in Supplemental Table 2. ...
Background
The Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales are widely accepted tools that measure overall disease severity and change, synthesizing the clinician’s impression of the global state of an individual. Frequently employed in clinical trials for neuropsychiatric disorders, the CGI scales are typically used in conjunction with disease-specific rating scales. When no disease-specific rating scale is available, the CGI scales can be adapted to reflect the specific symptom domains that are relevant to the disorder. Angelman syndrome (AS) is a rare, clinically heterogeneous condition for which there is no disease-specific rating scale. This paper describes efforts to develop standardized, adapted CGI scales specific to AS for use in clinical trials.
Methods
In order to develop adapted CGI scales specific to AS, we (1) reviewed literature and interviewed caregivers and clinicians to determine the most impactful symptoms, (2) engaged expert panels to define and operationalize the symptom domains identified, (3) developed detailed rating anchors for each domain and for global severity and improvement ratings, (4) reviewed the anchors with expert clinicians and established minimally clinically meaningful change for each symptom domain, and (5) generated mock patient vignettes to test the reliability of the resulting scales and to standardize rater training. This systematic approach to developing, validating, and training raters on a standardized, adapted CGI scale specifically for AS is described herein.
Results
The resulting CGI-S/I-AS scales capture six critical domains (behavior, gross and fine motor function, expressive and receptive communication, and sleep) defined by caregivers and expert clinicians as the most challenging for patients with AS and their families.
Conclusions
Rigorous training and careful calibration for clinicians will allow the CGI-S/-I-AS scales to be reliable in the context of randomized controlled trials. The CGI-S/-I-AS scales are being utilized in a Phase 3 trial of gaboxadol for the treatment of AS.
... Although the CGI-S and CGI-I were intended to allow the experienced clinician latitude in conceptualizing overall severity and change, 16,17,19 guidance surrounding the individual anchors has ranged from none, as in the original, to generic conceptualizations 18,19 and highly speci ed algorithmic anchor de nitions, requiring exact number and type of symptoms to equate for a severity level or clinical change. 25,26 Rather than specifying symptom combinations, some trials have included multiple CGI-S and CGI-I subscales, each associated with a particular symptom domain of interest (e.g., motor function, behavior, and sleep for Angelman Syndrome, 23 repetitive behavior and receptive language di culties for autism 27 ), which have been criticized for seeming to belie the concept of global impressions and for leaving the question of how to interpret drug response on only some, but not all, symptoms of a given disorder unanswered. 28 Patient global assessment. ...
Objective:
The International Society of CNS Clinical Trials Methodology (ISCTM) Working Group on Rare Disease/Orphan Drug Development is dedicated to improving and streamlining trials to best develop new treatments for rare diseases. The rarity of these disorders requires a drug development strategy that differs from those of nonrare conditions. Rare disease drug development programs are challenged with small sample sizes, heterogeneous clinical presentations, and few, if any, off-the-shelf endpoints. When disease-specific clinical endpoints exist, they might not be validated and are typically not well known or broadly used in clinical practice. This paper aims to provide an overview of the special issues surrounding endpoints in rare disease drug development, with guidance, practical applications, and discussion.
Discussion:
The paper covers regulatory considerations in endpoint selection; identification of relevant measurement domains; methods of quantifying clinical meaningfulness; incorporation of patient- and clinician-reported outcomes; considerations for global clinician- and patient-rated clinical assessments; cognition assessment challenges in rare diseases; translation considerations; training, standardization, and calibration of assessors; and endpoint quality assurance. Additionally, it provides guidance and resources for those involved in drug development for rare diseases.
Conclusion:
In keeping with the mission of ISCTM and the rare disease/orphan drug development working group, this article is designed to encourage thoughtful consideration and provide insight and guidance to promote and further efforts in in central nervous system (CNS) rare disease drug development efforts.
... The evaluation of the content validity of the CCSA-Clinician lays a strong foundation to then assess reliability and other aspects of validity. The CCSA-Clinician is ready for formal field testing and stands apart from other severity scales previously developed but not content validated, such as the severity assessments for RTT [24][25][26][27][28], FOXG1 [29 30], tuberous sclerosis [31] and other DEEs [32]. Other severity assessments have been content validated with a form that rated items on relevance [33]. ...
CDKL5 deficiency disorder (CDD) results in early-onset seizures and severe developmental impairments. A CDD clinical severity assessment (CCSA) was previously developed with clinician and parent-report items to capture information on a range of domains. Consistent with US Food and Drug Administration (FDA) guidelines, content validation is the first step in evaluating the psychometric properties of an outcome measure. The aim of this study was to validate the content of the clinician-reported items in the CCSA (CCSA-Clinician). Eight neurologists leading the USA CDD Center of Excellence clinics were interviewed using the "think aloud" technique to critique 26 clinician-reported items. Common themes were aggregated, and a literature search of related assessments informed item modifications. The clinicians then participated in 2 consensus meetings to review themes and finalize the items. A consensus was achieved for the content of the CCSA-Clinician. Eight of the original items were omitted, 11 items were added, and the remaining 18 items were revised. The final 29 items were classified into 2 domains: functioning and neurologic impairments. This study enabled refinement of the CCSA-Clinician and provided evidence for its content validity. This preliminary validation is essential before field testing and further validation, in order to advance the instrument toward clinical trial readiness.
