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Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12–19 years) and adult (n = 148, aged 18–45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-CFX scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans.

Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.

To investigate the safety, tolerability and efficacy of rivastigmine capsules (3-12 mg/day) in a 26-week, multi-centre, open-label extension of a double-blind study.Patients with traumatic brain injury (TBI) and persistent cognitive impairment who had received rivastigmine (3-6 mg/day) or placebo for 12 weeks could enter the extension study and receive rivastigmine (or =12 mg/day). Patients were assessed using a range of cognitive tests including the Hopkins Verbal Learning Test (HVLT) and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing (CANTAB RVIP) A' sub-test. Safety measures included monitoring of adverse events.In the extension study (n = 127), the mean duration of rivastigmine treatment was 23.8 weeks and the mean final dosage was 7.9 mg/day. Approximately 40% of patients were responders (or =1.0 SD improvement from baseline) on CANTAB RVIP A' or HVLT total score at week 38 or endpoint. Statistically significant changes from week 12 at week 38 were observed for CANTAB-RVIP A' and HVLT-total word recall for the sub-group of ex-placebo patients with greater severity of initial impairment. The safety profile of rivastigmine capsules was consistent with the label.Treatment with rivastigmine for up to 38 weeks was safe in patients with TBI and cognitive impairment.

Objective: Switching patients with Alzheimer's disease from one cholinesterase inhibitor to another represents a viable option for patients not responding to current therapy. The objective of this large U.S.-based study was to evaluate the safety and efficacy of a treatment switch to rivastigmine in patients not responding adequately to or declining on treatment with donepezil. Method: In this 26-week, prospective, open-label, single-arm, multicenter study conducted from April 24, 2003, to June 25, 2004, patients with mild-to-moderate Alzheimer's disease (DSM-IV-TR criteria) who were not responding to donepezil were treated with rivastigmine 3–12 mg/day. Safety and tolerability were measured by the occurrence of adverse events and patient disposition. Treatment effects on global functioning were assessed using the Clinical Global Impression of Change (CGIC) scale. Results: Two hundred seventy patients with a mean age of 78.5 (SD = 7.56) years and a mean duration of dementia of 3.5 (SD = 2.06) years were included in the study. Sixty-nine percent of patients completed the study with 17.8% discontinuing due to adverse events. Eighty-three percent of patients reported at least 1 adverse event, with the most frequently occurring adverse events affecting the gastrointestinal system (54%). The majority of patients were reported to have either improvement or no decline on the CGIC. A limitation of the study is that the interpretation of the results is based on an overall completion rate of 69%. Conclusion: Immediately switching patients from donepezil to rivastigmine without a washout period was safe and well tolerated in the current study. Additionally, these results suggest that patients not responding adequately to or declining while taking donepezil may improve or stabilize after switching to rivastigmine.

Objective: To compare the efficacy and safety of rivastigmine (3 to 6 mg/day) vs placebo over 12 weeks in patients with traumatic brain injury and persistent cognitive impairment. Methods: This prospective, randomized, double-blind, placebo-controlled study was conducted in 157 patients at least 12 months after injury. The primary efficacy measures were the Cambridge Neuropsychological Test Automated Battery (CANTAB) Rapid Visual Information Processing (RVIP) A′ subtest and the Hopkins Verbal Learning Test (HVLT). The primary efficacy outcome was the proportion of patients who demonstrated 1.0 SD or greater improvement from baseline at week 12 on CANTAB RVIP A′ or HVLT. Results: The percentage of responders at week 12 on either the CANTAB RVIP A′ or HVLT was 48.7% for rivastigmine and 49.3% for placebo ( p = 0.940). Furthermore, for the overall study population, there were no significant differences for any of the secondary efficacy variables. In a subgroup of patients with moderate to severe memory impairment (n = 81), defined as 25% impairment or greater on HVLT at baseline, rivastigmine was significantly better than placebo for a number of measures, including the proportion of HVLT responders and CANTAB RVIP mean latency. Conclusions: Rivastigmine was safe and well tolerated in patients with traumatic brain injury with cognitive deficits. Rivastigmine shows promising results in the subgroup of patients with traumatic brain injury with moderate to severe memory deficits.

The two most common causes of dementia in the elderly are Alzheimer's disease (AD) and vascular dementia (VaD), which can coexist as mixed dementia. The object of this study was to assess the efficacy and safety of rivastigmine in patients with mixed dementia (AD with VaD).This 26-week open-label pilot study was conducted at 19 centres in the US. To reduce bias, the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) raters were blinded to all efficacy measures and to patient dosage information. Patients were treated with rivastigmine and titrated to their highest tolerated dose, up to 12 mg/day (6 mg twice daily). The primary efficacy measure was cognitive function assessed by the ADAS-Cog subscale (without the concentration/distractibility item, to be consistent with cognitive outcome measures used in previous rivastigmine trials).Forty-seven percent of patients treated with rivastigmine 6-12 mg/day demonstrated improvement on the ADAS-Cog at 26 weeks, with25% of patients having a clinically significant improvement ofor =4 points. Treatment with rivastigmine (6-12 mg/day) was well tolerated by the majority of patients. The most common adverse effects occurring in10% of patients were nausea, vomiting, dizziness and diarrhoea.This pilot study suggests that rivastigmine treatment may have beneficial effects in the treatment of patients with mixed dementia.

Objectives The Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) was used to study the impact of rivastigmine (Exelon; Novartis Pharmaceuticals Corporation, East Hanover, NJ), on occupational disruptiveness (OD), a proxy measure for professional caregiver burden. Methods The study was a prospective, multicenter, open-label, single-arm trial with NH residents prescribed rivastigmine (up to 6 mg bid) for Alzheimer’s disease (AD) treatment. The NPI-NH was completed by NH staff caregivers at time of initiation of treatment with rivastigmine (T1), at treatment weeks 10 to 14 (T2), at treatment weeks 24 to 28 (T3), and at treatment weeks 50 to 54 (T4). Results Observations ranged from 173 at baseline to 73 at week 52. All but one patient had either moderate or severe dementia. Total OD score means were 4.7 ± 6.1, 3.9 ± 5.0, 4.19 ± 5.6, and 2.79 ± 2.8 at baseline, and weeks 12, 26, and 52 (T1–T4), respectively, with significant difference found between T1 and T4. Except for euphoria and disinhibition at T3 and T4, all correlations between OD scores and the domain scores of the NPI, were significant. Rivastigmine dose was an independent variable that affected OD change. Conclusion Treatment with rivastigmine was associated with a reduction in the self-reported professional caregiver burden, as assessed by the NPI-NH OD scale.

Neuropsychiatric symptoms and behavioural disturbances occur in most patients with Alzheimer's disease (AD), are a source of stress for caregivers, and are the primary cause of patient institutionalisation. These symptoms often are treated with psychotropic medications. However, adverse drug interactions, adverse effects and nursing home regulations make reducing the use of psychotropic medications in elderly AD patients an important goal of therapy. Fifty-two-week data including data from a 26-week prospective open-label, multicentre study and its 26-week open-label extension were analysed.173 patients with moderate to severe AD residing in nursing homes were treated with rivastigmine 1.5-6mg twice daily. In the study, psychotropic drug use and behavioural symptoms were measured at baseline and at 52 weeks.Results showed that 40% of patients who were receiving psychotropic medications at baseline had discontinued use or reduced their dose of psychotropic medications at week 52. Furthermore, significant improvements were observed from baseline in 10 of the 12 behavioural domains of the Nursing Home version of the Neuropsychiatric Inventory, including delusions (mean change from baseline -2.0; p = 0.002), hallucinations (mean change -3.1; p0.001), anxiety (mean change -1.1; p = 0.014), and euphoria (mean change -3.2; p = 0.006).These data suggest favourable tolerability, behavioural and pharmacoeconomic outcomes in nursing home residents with AD who are treated with rivastigmine.

To evaluate the safety and efficacy of long-term treatment with rivastigmine (3-12 mg/day) and its effects on neuropsychiatric and behavioral disturbances in nursing home patients with moderate to severe probable Alzheimer's disease (AD).A prospective, multicenter 26-week open-label extension to a 26-week open-label study (52 week results) of rivastigmine treatment in patients with Mini-Mental State Examination (MMSE) scores of 6-15 inclusive, residing in nursing homes at 13 centers in the US. Effects of treatment with rivastigmine for up to 52 weeks on neuropsychiatric and behavioral symptoms were examined using the Neuropsychiatric Inventory-Nursing Home (NPI-NH) scale. Cognitive function was assessed by the MMSE, and the Naming Objects and Fingers Test (NOFT) subset of the Alzheimer's Disease Assessment Scale -- Cognitive subscale (ADAS-Cog). Global functioning was assessed using the simplified Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus).Rivastigmine (3-12 mg/day) significantly improved neuropsychiatric and behavioral symptoms compared to baseline (in patients with specific behavioral disturbances at baseline) in observed cases (OC) and last observation carried forward (LOCF) analyses. Over 52 weeks, treatment with rivastigmine significantly improved 10 of 12 individual NPI-NH domains from baseline in LOCF patients with symptoms present at baseline. Cognitive function was stable, indicated by the lack of decline in MMSE and the NOFT. Global function was stabilized or improved in greater than half of the patients as indicated by the simplified CIBIC-Plus scores.Rivastigmine showed potential benefit in the long-term treatment of behavioral symptoms as well as cognitive and global functioning in nursing home residents with moderate to severe AD with concurrent behavioral symptoms present at baseline. Although these results suggest that treatment with rivastigmine may have beneficial behavioral effects and cognitive benefits on patients with moderate to severe AD, they are subject to the limitations of an open-label study.

Objective Rivastigmine, a dual cholinesterase inhibitor (ChEI), is widely approved for the symptomatic treatment of both mild-to-moderate Alzheimer's disease (AD) and Parkinson's disease dementia. Orally administered ChEIs may be associated with gastrointestinal (GI) side effects and add-on therapy with memantine, an N-methyl-d-aspartate receptor antagonist, approved for moderate-to-severe AD, may ameliorate such side effects. This was a 26-week, prospective, multicenter, single-arm, open-label pilot study to assess the safety and tolerability of rivastigmine capsules plus memantine in patients with moderate AD. Methods The primary objective was to assess the safety and tolerability of rivastigmine capsules 6–12 mg/day plus memantine (5–20 mg/day) as measured by the incidences of vomiting and nausea compared with those reported in the rivastigmine United States Prescribing Information (US PI). A total of 117 patients were enrolled with 116 receiving at least one dose of study medication. Results The incidences of nausea and vomiting (30% and 13%, respectively) observed in patients who received 6–12 mg/day rivastigmine plus memantine were lower than those stated in the US PI for rivastigmine monotherapy 6–12 mg/day (47% and 31%, respectively). The most common adverse events were nausea, vomiting, and dizziness. Conclusion Results from this study suggest the combination of rivastigmine capsule and memantine in patients with moderate AD is safe and tolerable. A greater reduction in the GI tolerability of rivastigmine has been established with rivastigmine transdermal patch. Copyright © 2009 John Wiley & Sons, Ltd.

Objective: Evaluate safety and tolerability of switching from donepezil to rivastigmine transdermal patch in patients with mild to moderate Alzheimer's disease. Methods: Prospective, parallel-group, open-label study to evaluate immediate or delayed switch from 5-10 mg/day donepezil to 4.6 mg/24 h rivastigmine following a 4-week treatment period. Results: Rates of discontinuation due to any reason or adverse events were similar between groups. Incidences of gastrointestinal adverse events were 3.8% in the immediate and 0.8% in the delayed switch group. No patients discontinued secondary to nausea and vomiting. Discontinuations due to application site reactions were low (2.3%). Asymptomatic bradycardia was more common following the immediate switch (2.3% vs 0%); however, these patients had coexisting cardiac comorbidities. Conclusion: Both switch strategies were safe and well tolerated. The majority of patients may be able to switch directly to rivastigmine patches without a withdrawal period. Appropriate clinical judgment should be used for patients with existing bradycardia or receiving β blockers.

Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder characterized by a gradual progression of cognitive, functional, and behavioral deficits.1 The disease is currently estimated to affect 4 million people in the United States; however, the prevalence increases with age.2 In those aged 65 years, the prevalence is about 5%; beyond 65, the rate doubles approximately every 5 years.3,4 The typical duration of the disease from onset to death is about 8 to 10 years,5,6 hence affected patients generally require long-term symptomatic treatment. Consequently, long-term data on the safety and efficacy of therapeutic agents are essential in this patient population. Although the exact pathophysiology of AD has not been fully established, the cognitive deficits associated with the disease are primarily related to cholinergic deficits.7 Development of potential therapies has therefore focused on enhancing cholinergic neurotransmission. Cholinesterase inhibitors (ChEIs), which enhance cholinergic function, are the standard pharmacologic treatment for mild-to-moderate AD. The currently available ChEIs, donepezil, rivastigmine, and galantamine, enhance cholinergic function by inhibiting cholinesterases that degrade acetylcholine, thereby increasing the availability of the neurotransmitter to stimulate nicotinic and muscarinic receptors in the brain. They have been shown to improve the cognitive, functional, and behavioral symptoms of AD and are approved for the symptomatic treatment of mild-to-moderate disease8,9; however, donepezil has recently received U.S. Food and Drug Administration approval for the treatment of severe AD. The ChEIs differ in their affinity for acetylcholinesterase and butyrylcholinesterase; donepezil and galantamine are essentially selective for acetylcholinesterase, while rivastigmine inhibits both with similar affinity.10 Rivastigmine differs from the rapidly reversible cholinesterase inhibitors, donepezil and galantamine, in that it is a slowly reversible (pseudo-reversible) ChEI of the carbamate class with brain-regional specificity for the cerebral cortex and hippocampus.10 Although donepezil, rivastigmine, and galantamine belong to different chemical classes, they have shown similar levels of improvement in cognitive function in studies to date8; however, their differing pharmacologic, pharmacokinetic, tolerability, and drug interaction profiles may influence individual treatment response.8,10 It may, therefore, be beneficial to switch between ChEIs if patients fail to respond to treatment, deteriorate, or are unable to tolerate their current treatment.11,12 A recent 26-week open-label study13 showed that switching patients immediately (i.e., without a washout period) to rivastigmine 3 to 12 mg/day after poor response to donepezil improved or stabilized global functioning in almost 70% of patients. The immediate switch was also safe and well tolerated. Patients who completed the 26-week treatment period had the option to continue open-label treatment with rivastigmine for an additional 26 weeks. This report presents the final 52-week safety and tolerability data from this study, as well as outcomes data.

Alzheimer's disease (AD) is the most common form of dementia and is characterized clinically by a gradual decline in cognitive performance, an increasingly impaired ability to perform activities of daily living, and neuropsychiatric and behavioral disturbances.The goal of this study was to assess the effect of rivastigmine on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable AD and to evaluate the safety and tolerability of rivastigmine in this population.This prospective, 26-week, open-label study was conducted in 13 centers in the United States and involved a total of 29 nursing homes. The effects of rivastigmine 3 to 12 mg/d for 26 weeks were assessed in nursing home residents with moderate to severe probable AD. Efficacy was evaluated using the Neuropsychiatric Inventory-Nursing Home (NPI-NH) scale for neuropsychiatric and behavioral disturbances; the Mini-Mental State Examination and the naming subset of the Alzheimer's Disease Assessment Scale-Cognitive subscale for cognitive performance; and the simplified Clinician's Interview-Based Impression of Change Plus Caregiver Input for global functioning.A total of 173 patients (141 women, 32 men; mean [SD]age, 82.6 [5.9] years) were enrolled. After 26 weeks of rivastigmine treatment, the mean (SD) change from baseline for all treated patients in the observed cases population was -2.5 (16.4) (n = 100; P = 0.138); it was -0.8 (16.5) (n = 149; P = 0.576) for the last-observation-carried-forward population. Patients with at least 1 neuropsychiatric symptom present at baseline showed a 3.2-point mean improvement in NPI-NH total score (n = 92; P = 0.062), with 49% of these patients demonstrating a clinically meaningful (ie,or = 30%) reduction from baseline. At 26 weeks, scores for 8 of the 12 neuropsychiatric and behavioral disturbances in patients with the specific symptom present at baseline showed statistically significant improvements from baseline (delusions [n = 32; P = 0.007], hallucinations [n = 15; P0.001], agitation [n = 58; P = 0.044], apathy/indifference [n = 37; P0.001], irritability/lability [n = 50; P0.001], aberrant motor behavior [n = 32; P0.001], nighttime disturbances [n = 22; P0.001], and appetite/eating changes [n = 28; P = 0.002]) in the observed cases population. Limitations of this study include that it was open label and not restricted to patients with behavioral disturbances at baseline.In the current study, rivastigmine treatment for 26 weeks in nursing home residents with moderate to severe probable AD was associated with decreased NPI-NH item scores for a wide range of behavioral disturbances in the subgroup of patients with behavioral symptoms at baseline.

Background: Transitioning patients between cholinesterase inhibitors was thought to require a washout period to avoid cholinergic toxicity; however, evidence suggests that abrupt discontinuation of donepezil may lead to cognitive decline. We evaluated the safety and tolerability of an immediate switch from donepezil to rivastigmine.Method: This is an analysis of the safety and tolerability data from the first 28 days of an open-label, multicenter, prospective trial, conducted from August 2002 to August 2003, in which patients satisfying NINCDS-ADRDA criteria for probable Alzheimer's disease were administered rivastigmine 1.5 mg b.i.d. within 24 to 36 hours of donepezil discontinuation. Results are compared with adverse event rates from a retrospective analysis of a pivotal, placebo-controlled trial examining patients not previously treated with a cholinesterase inhibitor.Results: Fifty-eight of 61 patients completed the first 28 days, with no suspected drug-related discontinuations during this period. Incidence of overall gastrointestinal adverse events at day 7 was 8.2%, and at day 28 was 11.5%. The corresponding rate for rivastigmine-treated patients in the retrospective analysis of the pivotal trial for day 7 was 3.3%.Conclusion: These study results suggest that transitioning patients from donepezil to rivastigmine without a washout period is safe and well tolerated.

Background Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. Objective To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. Design and Methods Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog). Results The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n = 17) compared with the rivastigmine 6- to 12-mg/d group (n = 33) at week 26 (MMSE score, −8.2 vs −3.0;P= .009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n = 38) compared with the rivastigmine 6- to 12-mg/d group (n = 88) at week 26 (MMSE score, −5.69 vs −2.5;P= .004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P= .007,P= .009) and the pooled studies (P= .002,P= .017). Conclusions After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.

A phase II randomized, placebo-controlled, double-blind study and subsequent open-label extension study evaluated the efficacy, safety, and tolerability of mavoglurant (AFQ056), a selective metabotropic glutamate receptor subtype-5 antagonist, in treating behavioral symptoms in adolescent patients with fragile X syndrome (FXS). A novel method was applied to analyze changes in symptom domains in patients with FXS using the narratives associated with the clinician-rated Clinical Global Impression-Improvement (CGI-I) scale. In the core study, patients were randomized to receive mavoglurant (25, 50, or 100 mg BID) or placebo over 12 weeks. In the extension, patients received 100 mg BID mavoglurant (or the highest tolerated dose) for up to 32 months. Global improvement, as a measure of treatment response, was assessed using the CGI-I scale. Investigators assigning CGI-I scores of 1 (very much improved), 2 (much improved), 6 (much worse), or 7 (very much worse) were provided a standard narrative template to collect further information about the changes observed in patients. Investigator feedback was coded and clustered into categories of improvement or worsening to identify potential areas of improvement with mavoglurant. Treatment effect in each category was characterized using the Cochran–Mantel–Haenszel test. A total of 134 and 103 patients had reached 2 weeks or more of core and extension study treatment, respectively, by the pre-assigned cutoff date for investigator feedback. In the core study, 34 CGI-I scores of 1 or 2 were reported in 28 patients; one patient scored 6. Analysis of the CGI-I narratives did not indicate greater treatment response in patients receiving mavoglurant compared with placebo in any specific improvement domain. There were 54 CGI-I scores of 1 or 2 in 47 patients in the extension study. The most frequently reported categories of improvement were behavior and mood (79.3 and 76.6 % in core and extension studies, respectively), engagement (75.9 and 78.7 %), and communication (69.0 and 61.7 %). A method was established to capture and categorize FXS symptoms using CGI-I narratives. Although this method did not show benefit of drug over placebo, narratives from investigators were mostly based on parental report and thus do not represent a completely objective alternative assessment. The studies described are registered at ClinicalTrials.gov with clinical trial identifier numbers NCT01357239 and NCT01433354 .