Open-label Safety Study Research Articles

Oral Rimegepant 75 mg is Safe and Well Tolerated in Adults With Migraine and Cardiovascular Risk Factors: Results of a Multicenter, Long-Term, Open-Label Safety Study (1995)

Oral Rimegepant 75 mg is Safe and Well Tolerated in Adults With Migraine and Cardiovascular Risk Factors: Results of a Multicenter, Long-Term, Open-Label Safety Study (1995)

Acute Treatment of Migraine with Rimegepant Improves Health Related Quality of Life in Adults With a History of Triptan Treatment Failure: Results from a Long-Term, Open-Label Safety Study (5029)

Acute Treatment of Migraine with Rimegepant Improves Health Related Quality of Life in Adults With a History of Triptan Treatment Failure: Results from a Long-Term, Open-Label Safety Study (5029)

Rimegepant is Safe and Tolerable for the Acute Treatment of Migraine in Patients Using Preventive Migraine Medications: Results from a Long-Term Open-Label Safety Study (2370)

Rimegepant is Safe and Tolerable for the Acute Treatment of Migraine in Patients Using Preventive Migraine Medications: Results from a Long-Term Open-Label Safety Study (2370)

Preference for Rimegepant and Improved Clinical Global Impression of Change Among Adults With a History of Triptan Treatment Failure: Results from a Long-Term Open-Label Safety Study (5084)

Preference for Rimegepant and Improved Clinical Global Impression of Change Among Adults With a History of Triptan Treatment Failure: Results from a Long-Term Open-Label Safety Study (5084)

Post hoc analyses of an open-label long-term study of esketamine nasal spray plus an oral antidepressant comparing results in older versus younger adults with treatment-resistant depression

<h3>Introduction</h3> Major depressive disorder in the elderly is associated with lower response and remission rates, resulting in treatment-resistant depression (TRD). Furthermore, older patients are often more vulnerable to adverse drug effects. Recently published findings from a 4-week, phase 3 study of esketamine nasal spray (TRANSFORM-3), evaluated patients ≥65 years with TRD. SUSTAIN-2 was an up to one year, open-label safety and efficacy study of esketamine nasal spray in the same phase 3 program, which enrolled patients with TRD over 18 years old. In addition to patients directly enrolled in SUSTAIN-2, completers from TRANSFORM-3 (responders or non-responders) could continue into SUSTAIN-2. We present a post hoc comparison of depressive symptoms and safety between patients with TRD aged 18-64 years (younger) vs ≥65 years (older) in the SUSTAIN-2 study. <h3>Methods</h3> SUSTAIN-2 included 802 patients with TRD; 624 younger and 178 older. Patients received a new oral antidepressant and open-label, flexibly-dosed esketamine nasal spray (28 [only older patients], 56 or 84 mg) administered in two phases: induction (IND) (2X/week for 4 weeks; included direct-entry patients and transferred-entry non-responder patients) and optimization/maintenance (OP/MAINT) (weekly or bi-weekly for up to 48 weeks; included responders from the open-label IND phase of SUSTAIN-2 and transferred-entry responders from TRANSFORM-3). Post hoc analyses compared treatment outcomes and safety for both age groups for each study phase. Outcome measurements included change from baseline in each phase for the Montgomery–Åsberg Depression Rating Scale (MADRS) total score and patient-reported outcomes: Sheehan Disability Scale (SDS), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-Item (GAD-7). Remission (MADRS ≤12) and response (≥50% MADRS reduction from baseline) rates were also reported by phase. Key safety assessments included adverse events, labs, electrocardiograms (ECGs), blood pressure, and dissociation measured by Clinician-Administered Dissociative States Scale (CADSS). <h3>Results</h3> Baseline demographics, other than age (mean 49.0 [range: 18-64] and 69.0 [range: 65-86] for younger and older adults, respectively) and baseline hypertension (21.5% and 48.3% for younger and older adults, respectively), were similar between subgroups, including mean baseline MADRS total scores (IND: 31.4 and 30.7, in the younger and older groups respectively). The mean (SD) change from IND baseline in MADRS total scores following the IND phase was −16.6 (8.6) vs −15.4 (9.4), in younger and older patients respectively. Remission rates at the end of IND phase were 281/624 (46.5%) vs 76/155 (50.0%) and at the end of the OP/MAINT phase (up to week 48) rates were 270/477 (56.6%) vs 81/126 (64.3%) for younger and older patients respectively. Response rates at the end of IND were 485/624 (80.3%) vs 108/155 (71.1%) and at the end of OP/MAINT were 366/477 (76.7%) vs 95/126 (75.4%) for younger and older patients respectively. The mean (SD) change in the PHQ-9 following IND was –9.5 (6.4) vs −6.9 (7.2), in younger vs older patients respectively. Similarly, the mean change (SD) in the SDS following IND was –9.6 (7.8) vs –7.8 (8.4), in younger vs older patients respectively. The mean change (SD) in the GAD-7 following IND was –6.4 (5.9) vs –3.9 (5.3), in younger vs older patients respectively. In the IND phase, treatment emergent adverse events (TEAEs) ≥5% were seen in 537/624 (86.1%) and 116/155 (74.8%) of younger vs older patients respectively; TEAEs ≥10% included: dizziness (30.8% vs 23.2%), dissociation (24.0% vs 20.6%), nausea (22.9% vs 9.0%) headache (20.2% vs 7.1%), somnolence (12.3% vs 11.0%), hypoesthesia (11.5% vs <5%) in younger vs older patients respectively. In the OP/MAINT phase, TEAEs ≥5% occurred in 414/477 (86.8%) and 102/126 (81.0%) of younger vs older patients respectively; TEAEs ≥10% included: dizziness (22.0% vs 23.8%), headache (21.2% vs 10.3%), dissociation (19.3% vs 16.7%), nausea (15.3% vs 8.7%), somnolence (13.8% vs 15.1%) and viral upper respiratory infection (10.7% vs 15.1%), in younger vs older patients respectively. Treatment-emergent acute hypertension (defined as blood pressure ≥180/110 mm Hg) occurred in 13/624 (2.1%) vs 5/155 (3.2%) in the IND, and in 10/477 (2.1%) vs 8/126 (6.3%) in the OP/MAINT for younger vs older patients. <h3>Conclusions</h3> In this post hoc descriptive analysis, patients with TRD aged 18-64 and those ≥65 showed comparable treatment outcomes using esketamine nasal spray, including change in MADRS scores, response and remission rates. Safety and tolerability findings were comparable in both age groups, except for treatment-emergent acute hypertension, which was observed more often in the elderly. <h3>Funding</h3> Janssen Research & Development, LLC

Novel combined single dose anti-hepatitis C therapy: a pilot study

The new anti-hepatitis C virus (HCV) molecules improve treatment regimens and outcomes, but there are drawbacks. New combinations should target the HCV infectious cycle and be effective against all HCV genotypes. We developed the novel formulation Catvira, composed of epigallocatechingallate (EGCG) + sofosbuvir + ribavirin. Here, we compared Catvira to sofosbuvir + ribavirin tablets in patients with CHC genotype 4 in a randomized open-label efficacy and safety study. Treatment-naïve and treatment-experienced patients (n = 80) were randomly assigned to receive a single daily fixed dose of Catvira or sofosbuvir + ribavirin for 12 or 24 weeks. Both Catvira and sofosbuvir + ribavirin yielded similar outcomes of viral load (p < 0.001). Patients receiving Catvira had a significantly more rapid rate of viral load decline with sustained virologic response (SVR12) achieved by 90% of patients receiving 12 weeks of treatment. Catvira did not impact hemoglobin levels while sofosbuvir + ribavirin showed significant decline in hemoglobin levels after 24 weeks (p < 0.05). In this clinical trial (ClinicalTrials.gov Identifier NCT02483156), we found that Catvira administered daily for 12 or 24 weeks is safe, effective, and well-tolerated in both naïve and treatment-experienced patients with HCV genotype 4.

Cenobamate treatment of focal-onset seizures: Quality of life and outcome during up to eight years of treatment

A large proportion of patients with focal-onset epilepsy have frequent seizures despite treatment with newer anti-seizure medications (ASMs). We describe our experience optimizing cenobamate treatment for 49 patients treated at one center for up to eight years. We assessed the influence of treatment response on measurements of quality of life (QOLIE). Forty-nine patients were evaluated from three cenobamate regulatory trials: two open-label extensions of randomized placebo-controlled studies and one open-label safety study at the Johns Hopkins Hospital (JHU). Patients had focal-onset seizures despite treatment with one to three ASMs and were 18 years of age and older. Patients kept seizure diaries for the duration of the study and had tri-monthly evaluations. Seizure responder rates were determined, and patients with long-term seizure freedom (≥six months seizure free) were identified. Cenobamate doses were adjusted within the range of 100–400 mg/day. Johns Hopkins Hospital patients who were continuing treatment when the studies ended (n = 37) were administered the QOLIE-31 survey and a separate survey to assess changes in independence and epilepsy-linked disability at the end of the study at JHU. Thirty-seven of 49 (76%) patients continued treatment for three to eight years (median 5.6 years). In their final three months of treatment, 45% of patients achieved ≥75% seizure reduction, 29% had ≥90% reduction, and 16% were seizure free (responder rates computed with n = 49). Posttraumatic etiologies did not reduce treatment responses. Increased dosage of cenobamate across 150–400 mg/day range was significantly associated with higher responder rates (p < 0.001). High seizure responses—particularly ≥90% reduction—correlated with high QOLIE scores. Patients with drug-resistant focal-onset epilepsy had stable treatment responses during up to eight years of cenobamate treatment. Patients often tolerated high doses of cenobamate; high responders appeared to benefit with high QOLIE scores.

Cenobamate tablets as a treatment for focal-onset seizures in adults

ABSTRACT Introduction: Despite the introduction of numerous new antiseizure medications (ASMs) still about one-third of epilepsies remain drug-resistant. Therefore, new compounds with advanced efficacy are urgently needed. Cenobamate (CNB) is a new ASM that has been recently introduced in the United States for the treatment of adults with focal-onset seizures. The approval in Europe is under way. Areas covered: This review covers the pharmacological profile of CNB, the proof-of-concept trial, the two double-blind, placebo-controlled phase 2 trials investigating adjunct CNB in adults with focal-onset seizures, one open-label safety trial, and a variety of published abstract material that provided additional post hoc data. Expert opinion: In two placebo-controlled randomized multicenter phase 2 trials adjunct CNB showed unusually high efficacy with rates of seizure-free people with epilepsy (PWE) partially beyond 20%. However, during the clinical program cases of drug-related reactions with eosinophilia and systemic symptoms (DRESS syndrome) occurred. Therefore, an open-label safety study was performed in more than 1300 PWE with particularly slower titration schedules which did not add more cases with similar reactions. Taking into consideration the promising efficacy and the safety experience from the open-label trial, CNB applied according to the meanwhile recommended titration strategy, might offer a new prospect.

A long-term open-label safety study of galcanezumab in Japanese patients with migraine

ABSTRACT Background Because of the burden of migraine in Japan, there is a need for safe and effective preventive treatments. This study assessed the long-term safety and tolerability of galcanezumab in Japanese patients with episodic (EM) or chronic (CM) migraine. Research design and methods In this 12-month open-label study, adult patients with EM who previously completed a 6-month, double-blind, placebo-controlled trial were newly randomized to either galcanezumab dose from placebo or continued their assigned galcanezumab doses (all: 120 mg, n = 120; 240 mg, n = 126). Newly enrolled patients with CM were randomized to 120-mg (n = 32) or 240-mg (n = 33) galcanezumab. The primary outcome was long-term safety and tolerability. Results The incidence of TEAEs was similar between treatment groups. Nasopharyngitis was the most common TEAE, followed by injection site reactions. The discontinuation rate was low (EM = 9.3%; CM = 15.4%) and no deaths were reported. Patients with EM who received galcanezumab in the placebo-controlled trial had sustained efficacy. Both doses reduced the number of migraine headache days in patients with CM. Conclusions Long-term treatment with 120-mg or 240-mg galcanezumab was safe and effective in Japanese patients with EM or CM. Trial registration https://clinicaltrials.gov, identifier: NCT02959190.

18326 Results of a large open-label safety study of daxibotulinumtoxina for injection in glabellar lines

Introduction: A large open-label safety study of daxibotulinumtoxina for Injection (DAXI) assessed safety and efficacy with longer-term use and across successive glabellar lines (GL) treatment cycles.

Ten-year safety follow-up and post-explant analysis of an anterior chamber phakic IOL.

To assess endothelial cell loss (ECL) rate and collect safety data in patients with AcrySof L-series Cachet phakic intraocular lens (pIOL) up to 10 years post-implantation. Clinical settings in the United States, European Union, and Canada. Nonrandomized, observational, open-label safety study. Central and peripheral endothelial cell density was evaluated and compared with 6-month post-implantation baseline. Nonlinear analysis was performed to identify factors affecting post-explantation ECL. Additional evaluations included uncorrected visual acuity (UCVA), corrected distance visual acuity (CDVA), adverse device effects (ADEs), and serious adverse events (SAEs). The study included 1123 implanted eyes (mean age, 37.5 years). At 10 years, mean central and peripheral ECL was 16% (1.7% annualized). Explantations were performed in 10% of eyes (n = 136/1323). For eyes with pIOL explantation because of ECL (7%), annualized ECL rate post-explantation was numerically lower compared with the overall rate in eyes that underwent explantation for any reason (annualized rate, -1.65% vs -2.03%, respectively; n = 96) and compared with pre-explantation ECL. Mean ± SD CDVA and UCVA were -0.12 ± 0.11 and 0.03 ± 0.22 logarithm of the minimum angle of resolution, respectively. Common ocular ADEs included ECL (10%), pIOL extraction (9%), iris adhesion (7%), and pupillary deformity (2%). Common SAEs included pIOL extraction (11%), ECL (9%), and iris adhesions (8%). Cachet pIOLs were associated with long-term ECL in some cases. Overall, only 10% of all implanted eyes underwent explantation during 10-year follow-up. In patients requiring explantation because of ECL, the annualized ECL rates decreased post-explantation in some eyes. Continued monitoring of patients regardless of explantation is recommended.

Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study.

BackgroundPsilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss.MethodsSelf-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8–10 group therapy visits and one psilocybin administration visit (0·3–0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467)FindingsFrom 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp2 = 0·47, 90% CI 0·21–0·60).InterpretationWe demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs.FundingCarey Turnbull, Heffter Research Institute, NIMH R25 MH060482, NIH UL1 TR001872, River Styx Foundation, Saisei Foundation, Sarlo Foundation, Stupski Foundation, Usona Institute, US Department of Veterans Affairs (Advanced Neurosciences Fellowship and IK2CX001495).

682P Results from ADVANCE: A phase I/II open-label non-randomised safety and efficacy study of the viral vectored ChAdOx1-MVA 5T4 (VTP-800) vaccine in combination with PD-1 checkpoint blockade in metastatic prostate cancer

682P Results from ADVANCE: A phase I/II open-label non-randomised safety and efficacy study of the viral vectored ChAdOx1-MVA 5T4 (VTP-800) vaccine in combination with PD-1 checkpoint blockade in metastatic prostate cancer

Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy

ObjectiveCannabidiol (CBD) is a nonpsychoactive derivative of cannabis. Studies indicate that it is safe and effective in treating certain types of epilepsy. The present study examined the presence of adverse or beneficial cognitive or functional adaptive effects associated with CBD in the treatment of children, adolescents, and teenagers with treatment-resistant epilepsy (TRE) as part of an ongoing prospective, open-label safety study. MethodsParticipants (N = 38) between the age of 3 and 19 years with TRE were enrolled in an open-label study of a pharmaceutical formulation of CBD (Epidiolex®; GW Research Ltd.) as an add-on treatment. In addition to baseline physical, neurological, and laboratory testing, cognitive assessment was completed prior to initiating CBD and after one year, both using the NIH Toolbox Cognition Battery (NIHTB-CB). Many participants were unable to complete the NIHTB-CB because of the magnitude of their cognitive impairment (n = 24), and in these cases, the participant's caregiver was asked to complete the Adaptive Behavior Assessment System – Second Edition (ABAS-II) as a measure of functional adaptive skills. ResultsThere were no statistically significant changes in cognitive function, as measured by the NIHTB-CB, in those participants who were able to complete such testing, but there was a nonsignificant trend toward improvement in some cognitive domains. For participants who were unable to complete formal standardized cognitive testing because of the magnitude of their cognitive impairment, their functional adaptive skills, as measured by the ABAS-II, were unchanged after a one-year trial of CBD. SignificanceOur findings suggest that CBD, as an add-on drug for TRE in a pediatric sample, does not appear to cause adverse effects (AEs) involving cognition or adaptive function over one year of treatment.

Mitigation of Equine Recurrent Uveitis through topical Suppressor of Cytokine signaling-1 (SOCS1) mimetic peptide: Open Label Safety and Efficacy Pilot study

Abstract Recurrent Uveitis (RU), is a relapsing/remitting disease that accounts for more than 10% of severe visual handicaps in US patients per year, despite treatments that often include steroids. Even when effective, prolonged steroid use is accompanied by significant negative side effects. As such, there is a critical need for the development of novel therapeutic strategies to treat RU. Notably, equine recurrent uveitis (ERU) is the only spontaneous model of human recurrent uveitis, and is also a leading cause of equine blindness. RU is driven by aberrant inflammation from the immune system. Notably, the body naturally generates a family of intracellular proteins, known as suppressors of cytokine signaling (SOCS), which prevent excessive inflammatory responses. We have previously shown that topical application of an eye drop, containing a cell-penetrating peptide that mimics SOCS1 (SOCS1-KIR), could mitigate experimental uveitis in mice. In order to evaluate the ability to translate our preclinical findings we conducted a first in equine, open label study in which we evaluated the safety and efficacy of topical SOCS1 peptide administration in ERU patients. We found that topical SOCS1-KIR administration was well tolerated in equine patients. Moreover, topical administration of SOCS1-KIR peptide twice a day was associated with reductions in ocular discomfort, hyperemia, and aqueous flare. Additionally, biochemical analyses of SOCS1-KIR revealed an enrichment strategy that could potentially be utilized to optimize ocular peptide dosing. Together, these results prove justification for conducting larger additional treatment studies in horses, and exploring SOCS1-KIR use in humans.

Acute Treatment with Oral Rimegepant 75mg Reduces Migraine-Related Disability: Results from a One Year, Open-Label Safety Study (BHV3000-201) (1926)

Acute Treatment with Oral Rimegepant 75mg Reduces Migraine-Related Disability: Results from a One Year, Open-Label Safety Study (BHV3000-201) (1926)

Acute Treatment of Migraine with Oral Rimegepant 75 mg Improves Health Related Quality of Life: Results from a Long-Term, Open-Label Safety Study (BHV3000-201) (1943)

Acute Treatment of Migraine with Oral Rimegepant 75 mg Improves Health Related Quality of Life: Results from a Long-Term, Open-Label Safety Study (BHV3000-201) (1943)

Oral Rimegepant 75 mg Is Well-tolerated When Used Concomitantly with Injectable Anti-CGRP Monoclonal Antibodies: Results From a Multicenter, Long-term, Open-label Safety Study (4553)

Oral Rimegepant 75 mg Is Well-tolerated When Used Concomitantly with Injectable Anti-CGRP Monoclonal Antibodies: Results From a Multicenter, Long-term, Open-label Safety Study (4553)

Patient Preference and Improved Clinical Global Impression of Change with Rimegepant for the Acute Treatment of Migraine: Results from a Long-Term Open-Label Safety Study (Study 201) (2112)

Patient Preference and Improved Clinical Global Impression of Change with Rimegepant for the Acute Treatment of Migraine: Results from a Long-Term Open-Label Safety Study (Study 201) (2112)

186 Results From a 12-Month Open-label Safety Study of Lumateperone (ITI-007) in Patients with Stable Symptoms of Schizophrenia

Lumateperone (lumateperone tosylate, ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, and other disorders. Lumateperone has a unique mechanism of action that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This may provide advantages in the treatment of the broad symptoms associated with schizophrenia, including negative and depression symptoms. In 2 previous placebo-controlled trials in patients with acute schizophrenia, lumateperone 42mg (ITI-007 60mg) demonstrated statistically significant improvement in the Positive and Negative Syndrome Scale (PANSS) Total score compared with placebo. In these studies, lumateperone was well tolerated with a safety profile similar to placebo. This open-label long-term study evaluated the safety and effectiveness of lumateperone 42mg in patients with schizophrenia and stable symptoms. Patients with stable schizophrenia were treated for up to 1 year with lumateperone 42mg. Safety assessments included adverse events (AEs), body weight, laboratory parameters, and extrapyramidal symptoms (EPS)/motor symptom assessments. Efficacy analyses included evaluation of changes in PANSS Total score and in depression symptoms, as measured by the Calgary Depression Scale for Schizophrenia (CDSS). In the 1-year open-label study, 602 patients received at least 1 dose of lumateperone 42mg; at the time of this interim analysis, 107 patients had completed 1 year of treatment. Only 4 TEAEs occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderate-to-severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met CDSS response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy. In long-term treatment, lumateperone was associated with minimal metabolic, EPS, and cardiovascular safety issues relative to current SOC antipsychotic therapy. Lumateperone improved schizophrenia symptoms with continued long-term treatment. In patients with moderate-to-severe depression symptoms at baseline, lumateperone treatment was associated with marked improvement in CDSS scores. These data are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia treated with lumateperone. Supported by funding from Intra-Cellular Therapies, Inc.