Teratogenicity of zonisamide and other little-used antiseizure medications.

PURPOSE: To investigate the risk of teratogenesis occurring in relation to intrauterine exposure to infrequently used antiseizure medications in Australia. METHODS: Analysis of data contained in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs. RESULTS: There was statistically significant evidence that zonisamide, but not any other of nine infrequently used antiseizure medications in Australia, was associated with a risk of teratogenesis related to the maternal dose of the drug taken in at least the earlier half of pregnancy. CONCLUSIONS: The teratogenesis associated with zonisamide, like that associated with topiramate and possibly acetazolamide, may be an expression of a class effect shared among sulphonamide-derived carbonic anhydrase inhibitors that possess anti-seizure activity.

Immune-mediated polyarthritis and anterior uveitis secondary to zonisamide administration in a dog with refractory epilepsy.

The objective of this article is to describe a case of suspected zonisamide-induced immune-mediated polyarthritis (IMPA) and anterior uveitis in a dog. A 7-year-old male neutered Siberian Husky with a history of refractory idiopathic epilepsy was presented for cluster seizures. Following the addition of zonisamide to the antiepileptic regime, the dog developed new IMPA and anterior uveitis. Within a few weeks of discontinuation of the zonisamide, the dog's IMPA and anterior uveitis resolved. These immune-mediated conditions were thus presumed to be an idiosyncratic reaction to zonisamide. To our knowledge, this is the first report of IMPA and anterior uveitis in dogs associated with zonisamide administration at its recommended dose.

Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study.

PURPOSE: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). METHOD: In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range. RESULTS: Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study. CONCLUSIONS: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants. CLINICALTRIALS: GOV: NCT04106557.

Leflunomide exposure through second trimester of pregnancy: A case report.

Leflunomide is a commonly used disease modifying antirheumatic agent. However, its use is contraindicated in pregnancy. The American College of Rheumatology (ACR) guidelines recommend discontinuing Leflunomide at least 24 months before conception. If a woman is found to be pregnant while on Leflunomide, ACR suggests close monitoring and cholestyramine washout. We describe a case of a patient with a history of juvenile idiopathic arthritis who was on Leflunomide throughout the first and second trimester of her pregnancy. A cholestyramine washout regimen was started but not completed. The patient was induced at 37 weeks of gestation due to non-reassuring fetal heart rate. She ultimately delivered a healthy baby via emergency cesarian section.

The association between CYB5A gene rs1790834 polymorphism and clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.

INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) is a disease affecting around 1% of the population in developed countries and can be treated with leflunomide. The higher prevalence of RA among women and numerous previous studies suggested the crucial role of sex hormones. Cytochrome CYB5A regulates the synthesis of androgens. Therefore, the aim of this study was to determine the association between common CYB5A gene polymorphism and the response to leflunomide in women with RA. METHODS: This study included 111 patients. All of them received oral leflunomide monotherapy at a dose of 20 mg daily. Women were genotyped for the presence of CYB5A rs1790834 polymorphism and evaluated monthly for 6 months following the initiation of treatment. RESULTS: After 6 months of therapy, patients with the GG genotype had higher DAS28 values and less improvement in DAS28 compared to patients with the GA and AA genotypes (p = 0.04). No statistically significant differences were found in relation to other disease activity parameters. CONCLUSIONS: The results of the current study suggest a possible association of the CYB5A rs1790834 polymorphism with some disease activity parameters in RA patients treated with leflunomide during the initial therapy period. However, confirmation of the effect of this polymorphism on the efficacy of leflunomide treatment requires further studies. Key Points • Leflunomide is the synthetic disease-modifying anti-rheumatic drug used in the therapy of rheumatoid arthritis. • CYB5A rs1790834 gene polymorphism may influence the clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.

Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

PURPOSE: Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. METHODS: We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. RESULTS: Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. CONCLUSION: It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.

The Effect of Leflunomide as Adjunctive Therapy With a TNF Inhibitor in Pediatric Patients With Uveitis.

PURPOSE: To describe the effectiveness of leflunomide as adjunctive therapy with anti-tumor necrosis factor (anti-TNF) agents in pediatric patients with uveitis who are not able to tolerate methotrexate. METHODS: A retrospective case series was performed of pediatric patients who were receiving leflunomide in conjunction with anti-TNF agent therapy after intolerance to a combination of methotrexate with anti-TNF therapy. Dose and duration of methotrexate, leflunomide, and anti-TNF therapy were recorded. Extensive history, demographics, laboratory data, and uveitis flare rate were obtained. RESULTS: A total of five children were included in the study. Most patients were initially receiving methotrexate and an anti-TNF agent was added subsequently due to inadequate response to monotherapy. After discontinuation of methotrexate, leflunomide was initiated with anti-TNF therapy. The replacement of methotrexate with leflunomide showed decreased side effects and was associated with lower flare rates and steroid-free remission. CONCLUSIONS: Leflunomide was found to be well tolerated and effective at maintaining uveitis quiescence in conjunction with anti-TNF agents in pediatric patients who do not tolerate methotrexate. [J Pediatr Ophthalmol Strabismus. 2023;60(6):417-420.].

Leflunomide: Traditional immunosuppressant with concurrent antiviral effects.

Leflunomide is a classic disease-modifying anti-rheumatic drug that is widely used to treat autoimmune diseases. Studies also show its antiviral effects in in vitro and/or in vivo experiments. Considering glucocorticoids, immunosuppressants and newly emerged antibodies commonly used in autoimmune diseases and autoinflammatory disorders bring risk of infection such as viral infection, leflunomide with combination of anti-viral and immunosuppressive features to maintain the balance between infection and anti-inflammation are attractive. Here we summarize the actions and mechanisms of leflunomide in immunoregulatory and antiviral effects.

Therapeutic drug monitoring of teriflunomide: do plasma concentrations predict response to leflunomide in patients with rheumatoid arthritis?

OBJECTIVES: Leflunomide is a commonly used treatment for rheumatoid arthritis. It acts by inhibiting dihydroorotate dehydrogenase through its active metabolite teriflunomide. The objective of the study was to investigate the relation between plasma-concentration of teriflunomide and disease-activity in rheumatoid arthritis. METHODS: Data were collected from patients with rheumatoid arthritis on a stable leflunomide dose for at least 2 months. Socio-demographic data, disease characteristics and DAS28 score were recorded. Blood samples were taken for determination of teriflunomide concentration. RESULTS: A total of 32 serum concentration-time measurements were collected. The concentration of teriflunomide was positively correlated with disease duration of RA (r2=0.2264) and the number of swollen joints (r2=0.2413). There was a trend towards a positive correlation between Health Assessment Questionnaire (HAQ) and plasma teriflunomide concentration (r2=0.1699). Weight was negatively correlated with the residual plasma concentration of teriflunomide (r2=0.2483). However, there was no significant correlation between residual-plasma-concentration of teriflunomide and the following parameters: age, sex, number of tender painful joints, patient-global-assessment, C-reactive protein (CRP) and duration of prescription of leflunomide. We did not find association between disease-activity and residual-plasma-concentration of teriflunomide (r2=0.0021) and haven't been able to define the threshold value of residual-plasma-concentration of leflunomide predictive of a good-response. CONCLUSIONS: We did not find a concentration-effect-relationship. However, therapeutic drug monitoring of teriflunomide may be useful to ensure adherence and evaluate toxic-levels in case of adverse-events.

Paliperidone palmitate vs. paliperidone extended-release for the acute treatment of adults with schizophrenia: a systematic review and pairwise and network meta-analysis.

Is paliperidone palmitate (PP) a useful treatment option for adults with acute symptoms of schizophrenia? We conducted a systematic review and a random-effects pairwise and network meta-analysis that compared PP (25-150 mg equivalent) with paliperidone extended-release (PAL-ER, 3-12 mg/d) regarding their efficacy and safety in adults with acute symptoms of schizophrenia. The outcomes were the total score of the Positive and Negative Syndrome Scale (PANSS-T) at week 6 (the primary outcome for efficacy) and all-cause discontinuation(the primary outcome for acceptability), discontinuation due to inefficacy, discontinuation due to adverse events, discontinuation due to the withdrawal of consent, and the incidence of individual adverse events. Five studies on PP and seven studies on PAL-ER, which involved 4970 individuals in total, were included in this study. For the primary outcomes, we only included data from the treatment arms that used 100 or 150 mg equivalent as an initial dose of PP and data from the treatment arms that used 6, 9, or 12 mg as an initial dose of PAL-ER. The pairwise meta-analyses showed that both PP and PAL-ER outperformed placebo regarding PANSS-T at week 6 and all-cause discontinuation. However, there were no statistically significant differences in these outcomes between the effect sizes of PP and that of PAL-ER. Both PP and PAL-ER increased blood prolactin levels in both females and males compared with placebo. PAL-ER significantly increased blood prolactin in both females and males compared with PP. There were no statistically significant differences in other outcomes between the effect sizes of PP and that of PAL-ER. Similar results in all outcomes were observed in the network meta-analyses. In conclusion, PP might be a useful treatment option for adults with acute symptoms of schizophrenia. A noninferiority study that directly compares PP with PAL-ER for acute schizophrenia, conducted according to the recommended regimen, is required to provide solid evidence.

Paliperidone Extended Release Versus Olanzapine in Treatment-Resistant Schizophrenia: A Randomized, Double-Blind, Multicenter Study.

PURPOSE: Paliperidone is an atypical antipsychotic as effective as other atypical antipsychotics for schizophrenia. However, few studies have explored the efficacy of paliperidone for treatment-resistant schizophrenia. This study aimed to compare the efficacy and safety of paliperidone extended release (ER) versus olanzapine in schizophrenia patients with either poor treatment response or intolerable adverse effects due to standardized antipsychotic therapy. METHODS: This 12-week randomized, double-blind, multicenter study compared the treatment efficacy on psychotic symptoms, cognitive functions, and tolerance between paliperidone ER (6-15 mg/d, n = 45) and olanzapine (10-30 mg/d, n = 41) in treatment-resistant or treatment-intolerant patients with schizophrenia. The severity of psychotic symptoms was evaluated by the Positive and Negative Syndrome Scale and the Clinical Global Impression Severity of Illness Scale. The cognitive functions were assessed by the MATRICS Consensus Cognitive Battery. In addition, the metabolic impacts were evaluated by weight gain and waist circumference. RESULTS: Patients with either paliperidone ER or olanzapine treatment showed apparent improvement in psychotic symptoms, without significant intergroup difference. Twelve-week paliperidone ER or olanzapine treatment did not improve the cognitive functions. Both paliperidone ER and olanzapine treatment caused significant increase in weight and waist circumference, and olanzapine had a greater impact on waist circumference than paliperidone ER. In addition, both drugs were well tolerated. CONCLUSIONS: Paliperidone ER could be a safe alternative for treatment-resistant schizophrenia.

Presumed zonisamide-induced blood dyscrasias in four dogs.

OBJECTIVE: To describe 4 canine cases of presumed zonisamide-induced blood dyscrasias. CASE SUMMARY: From 2007 to 2018 at Angell Animal Medical Center and from 2014 to 2019 at the Cummings School of Veterinary Medicine at Tufts University, 4 dogs presented with febrile neutropenia while being administered zonisamide. No septic focus was found on workup for any of the dogs, and the clinical signs were attributed to an idiosyncratic drug reaction. All WBC counts returned to normal with drug withdrawal, and all dogs survived. NEW OR UNIQUE INFORMATION PROVIDED: Presumptive zonisamide-induced blood dyscrasias are a rare complication that has not previously been reported in the veterinary literature.

Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms.

CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 µM and Ki = 462 µM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin. METHODS: Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W). RESULTS: Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy. CONCLUSIONS: Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. CLINICAL TRIALS IDENTIFIER: NCT02157792.

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. METHODS: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. RESULTS: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. CONCLUSIONS: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. CLINICAL TRIAL IDENTIFIER: NCT02157792.

Effects of parecoxib after pancreaticoduodenectomy: A single center randomized controlled trial.

BACKGROUND: Parecoxib, a selective cyclooxygenase-2 inhibitor, is a potential alternative analgesic to reduce opioid consumption after Pancreaticoduodenectomy (PD). Further, the safety and efficacy of long-term use of parecoxib for patients after PD remain a major concern. MATERIALS AND METHODS: In this single-center, randomized clinical trial, 134 patients undergoing open PD were randomized into the parecoxib group (group P) and control group (group C) at a 1:1 ratio. Besides a routine patient-controlled epidural analgesia (PCEA) until 3 days postoperatively for both groups, patients in group P (n = 68) received parecoxib (40 mg, intravenously, Q 12 h) for the first 5 postoperative days and were encouraged to receive opioid analgesics to control severe pain as needed. Patients in group C (n = 66) received on-demand opioid analgesics (pethidine or morphine) postoperatively. The primary outcomes included the effectiveness of parecoxib in controlling pain (measured using the visual analog scale (VAS)) and reduction of opioid use (measured as accumulated doses). Secondary outcomes included the postoperative recovery process, rate of postoperative complications, and the anti-inflammatory effect of parecoxib. RESULTS: The VAS scores were not significantly different between the two groups. The number of doses of opioids for patients in group P (3.2 ± 0.3 doses) was significantly lower than in group C (8.5 ± 0.4 doses) (p = 0.0007). The incidence of opioid-related side effects was significantly lower in group P than in group C (p = 0.001). There were no significant differences in postoperative complications or readmission rates between the two groups. The postoperative time to first pass flatus, time to first mobilization out of bed, and time of removal of nasogastric tube in group P were significantly shorter than those in group C (P < 0.05). The postoperative serum IL-6 levels of patients in group P were significantly lower than those in group C at each time point (P < 0.05). CONCLUSIONS: Parecoxib effectively controls pain after PD. Prophylactic analgesia using parecoxib for up to 5 days after PD is safe, feasible, and can provide the same optimal pain control as opioids without adverse effects.

Leflunomide as a cause of collagenous colitis: an entity to consider.

Leflunomide belongs in the group of disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of psoriatic, rheumatoid, and reactive arthritis. Approximately 20 % of patients will experience some adverse event, mainly weight loss, abdominal pain, and diarrhea. We describe the clinical, endoscopic, and histological findings in a patient with psoriatic arthritis (PA) who developed severe chronic diarrhea after drug use.

Neuropsychiatric toxicity and cycloserine concentrations during treatment for multidrug-resistant tuberculosis.

BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited. METHODS: A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma. RESULTS: A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01). CONCLUSIONS: A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.

The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome.

OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression-Severity and Clinical Global Impression-Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13-45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALSGOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated.