34Efficacy and safety of various doses of the new dual endothelin receptor antagonist aprocitentan in the treatment of hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Danaietash ◽  
P Verweij ◽  
B Flamion ◽  
J Menard ◽  
M Bellet
Keyword(s):  
Dose Response ◽  
Study Drug ◽  
Positive Control ◽  
Digital Ulcers ◽  
Maximal Effect ◽  
Endothelin Receptor ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Parallel Group ◽  
Treatment Of Hypertension

Abstract Background Endothelin Receptor Antagonists (ERAs) have been investigated for the treatment of a variety of cardiovascular conditions because of their potent vasodilating properties. However, until now, ERAs have only been registered for the treatment of pulmonary arterial hypertension and scleroderma-induced digital ulcers. This class of drugs may also be useful in the treatment of difficult to control hypertension with a medical need. Purpose To investigate the efficacy and safety of various doses of the new dual ERA, aprocitentan, in the treatment of hypertension in order to determine the most appropriate dose(s) for further clinical development using an unattended, automated office BP (AOBP) device (BpTRU). This Phase 2 trial was registered at ClinicalTrials.gov [NCT02603809]. Methods Eligible patients with hypertension (mean sitting systolic/diastolic BP 149.7/97.6 mmHg) received aprocitentan 5, 10, 25 or 50 mg, matching placebo or lisinopril 20 mg as a positive control, once daily for 8 weeks using a randomised, double-blind, parallel-group study design. AOBP was assessed at baseline and weeks 2, 4, 8, and 10 (withdrawal) by recording multiple BP readings with the patient resting quietly. Additionally, 24 h ambulatory BP monitoring was performed at baseline and week 8. Results A total of 490 eligible patients were randomised to the double-blind phase with 430 subjects successfully completing 8 weeks of treatment. Decreases in sitting systolic/diastolic AOBP, from baseline to week 8 were 10.3/6.3, 15.0/9.9, 18.5/12.0 and 15.1/10.0 mmHg for aprocitentan 5, 10, 25, and 50 mg, respectively vs. 7.7/4.9 mmHg for placebo and 12.8/8.4 mmHg for lisinopril. No changes in heart rate or body weight were observed for any dose of aprocitentan. Modelling the dose-response suggested that the maximal effect of aprocitentan is achieved at a dose of approximately 25 mg and that 70% of this effect is already observed at a dose of 10 mg. Aprocitentan treatment was associated with decreases in haemoglobin, haematocrit, and albumin which exhibited a monotonic dose-response relationship, in line with its known vasodilating effects. Estimated increases in plasma volume were 3.0%, 5.1%, 6.9%, and 9.5% for aprocitentan 5, 10, 25, and 50 mg, respectively, vs. 1.6% for lisinopril and a decrease of 0.3% for placebo. All these values are below the accepted pathophysiological threshold of 10%. The overall incidence of adverse events observed in the aprocitentan groups (ranging from 22.0% to 40.2%) was similar to that seen in the placebo group (36.6%). Overall, the most common events were hypertension, headache, and nasopharyngitis. Conclusions These findings support the use of aprocitentan at doses between 10 and 25 mg for further investigation as a potential treatment for hypertension. Acknowledgement/Funding Actelion conducted study. Drug discovery & early clinical pipeline demerged during Johnson & Johnson acquisition. Idorsia supported abstract.

506 Samelisant: Baseline Characteristics from a Phase 2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A199-A199
Author(s):  
Ramakrishna Nirogi ◽  
Jyothsna Ravula ◽  
Pradeep Jayarajan ◽  
Satish Jetta ◽  
Gopinadh Bhyrapuneni ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Demographic Data ◽  
Fixed Ratio ◽  
Study Drug ◽  
Eligibility Criteria ◽  
Double Blind ◽  
Healthy Humans ◽  
Parallel Group ◽  
Secondary Endpoints ◽  
Baseline Characteristics

Abstract Introduction histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile. Methods The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of < 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021. Support (if any):

Effect of Infusion Rate on the Pharmacokinetics and Tolerance of Intravenous Dolasetron Mesylate

1998 ◽  
Vol 32 (1) ◽  
pp. 39-44
Author(s):  
Dan C Dimmitt ◽  
Thomas L Hunt ◽  
Anthony J Spalitto ◽  
Michael B Cramer ◽  
Ajit K Shah ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Vital Signs ◽  
Correlation Coefficients ◽  
Study Drug ◽  
Pharmacokinetic Parameters ◽  
Least Squares Regression ◽  
Double Blind ◽  
Elimination Half ◽  
Parallel Group ◽  
Before And After

OBJECTIVE To evaluate the safety, tolerance, and pharmacokinetics of dolasetron mesylate and its active metabolite hydrodolasetron when dolasetron mesylate was administered intravenously at increasing infusion rates. DESIGN: A double-blind, placebo-controlled, parallel-group study. METHODS: Forty-nine healthy nonsmoking male volunteers were randomly assigned to receive intravenous doses of dolasetron mesylate 100 mg or placebo. Three groups of 16 subjects each (12 dolasetron mesylate, 4 placebo) received escalating infusion rates (50, 100, then 200 mg/min). Physical examinations, vital signs, laboratory tests, and adverse events were recorded before and after administration of the study drug. Serial blood samples and 12-lead electrocardiogram measurements were obtained for 24 hours after the infusion. Plasma samples were analyzed for dolasetron and hydrodolasetron. RESULTS Dolasetron mesylate was well tolerated, with no apparent differences in vital signs or adverse event profiles among the different rates of infusion. In general, the pharmacokinetics of dolasetron and hydrodolasetron were superimposable among the three infusion rate groups. Plasma dolasetron concentrations declined rapidly in all three infusion rate groups, with mean elimination half-life (t1/2) of less than 10 minutes. The reduced metabolite hydrodolasetron, which accounts for most pharmacologic activity, formed rapidly, with maximum concentrations occurring between 0.4 and 0.5 hours and disappeared with a mean t1/2 of 8–9 hours. The correlation coefficients of least-squares regression analysis between the pharmacokinetic parameters and the infusion rate of dolasetron were less than 0.083 and the slopes were not significantly different from 0, suggesting that none of the hydrodolasetron pharmacokinetic parameters were affected by rate of infusion. CONCLUSIONS The intravenous administration of dolasetron 100 mg over 0.5–2 minutes did not significantly alter the pharmacokinetic profiles of either dolasetron or hydrodolasetron. In addition, the safety profile of dolasetron did not change with increasing rate of infusion. Therefore, the rate of infusion of dolasetron mesylate appears to have no pharmacokinetic or clinical implications when assessed over a 0.5- to 2-minute time period. OBJETIVO Evaluar la seguridad, tolerabilidad, y farmacocinética del dolasetrón mesilato y la de su metabolito activo hidrodolasetrón cuando se administra dolasetrón mesilato por vía intravenosa a una frecuencia de infusión creciente. DISEÑO Estudio a doble-ciego, controlado con placebo, y grupos paralelos. MÉTODO Cuarenta y nueve hombres voluntarios sanos no fumadores fueron asignados de forma aleatorizada para recibir el tratamiento intravenoso con la dosis de 100 mg de dolasetrón mesilato o con placebo. Tres grupos de 16 sujetos cada uno (12 tratados con dolasetrón mesilato y 4 con placebo) recibieron frecuencias de infusión crecientes (50, 100, y 300 mg/min). La exploración física, signos vitales, analítica de laboratorio, y efectos adversos se registraron antes y tras la administración del fármaco. Se tomaron muestras seriadas de sangre y se determinó el electrocardiograma de 12 derivaciones durante 24 horas tras la infusión. Se analizaron los niveles plasmáticos de dolasetrón y de hidrodolasetrón. RESULTADOS Dolasetrón mesilato fue bien tolerado sin diferencias aparentes en el perfil de los signos vitales o efectos adversos entre las diferentes frecuencias de infusión. En general la farmacocinética del dolasetrón e hidrodolasetrón resulte superponible entre los tres grupos de infusión. Las concentraciones plasmáticas de dolasetrón disminuyeron rápidamente en los tres grupos, con una vida media de eliminación (t1/2) inferior a 10 minutos. El metabolito reducido hidrodolasetrón que posee la mayor parte de la actividad aparece con rapidez, con una concentración máxima alcanzada entre 0.4 y 0.5 horas y desaparece con una t1/2 de 8 a 9 horas. El coeficiente de correlación (r) del análisis de regresión por mínimos cuadrados entre los parámetros farmacocinéticos y la frecuencia de infusión de dolasetrón, fue inferior a 0.083 y las pendientes no difirieron significativamente de cero, súgiriendo que ninguno de los parámetros farmacocinéticos de hidrodolasetrón resultó afectado por la frecuencia de infusión. CONCLUSIONES La administración intravenosa de 100 mg de dolasetrón entre 0.5 a 2 minutos no altera significativamente el perfil farmacocinético del dolasetrón ni del hidrodolasetrón. Además, el perfil de seguridad del dolasetrón no cambia con el aumento de la frecuencia de infusión. Así pues, la frecuencia de infusión del dolasetrón mesilato parece carecer de implicaciones farmacocinéticas o clínicas cuando se administra en un período de tiempo comprendido entre 0.5 y 2 minutos.

Topiramate in the Treatment of Chronic Migraine

Cephalalgia ◽  
2003 ◽  
Vol 23 (8) ◽  
pp. 820-824 ◽  
Author(s):  
M Silvestrini ◽  
M Bartolini ◽  
M Coccia ◽  
R Baruffaldi ◽  
R Taffi ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Study Drug ◽  
Maintenance Phase ◽  
Headache Frequency ◽  
Double Blind ◽  
Baseline Phase ◽  
Titration Phase ◽  
Parallel Group ◽  
To Receive ◽  
Phase Number

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of chronic migraine. This was a double-blind, randomized, placebo controlled, parallel-group study. Patients suffering from chronic migraine with analgesic overuse were randomly assigned in a 1 : 1 ratio to receive topiramate or placebo. Following a baseline phase of eight weeks, the study drug was titrated in 25-mg increments over one week to 50 mg daily. Titration phase was followed by a 8-week maintenance phase. Number of days with headache during a 28-day period was the efficacy variable. At baseline, there was no difference in the number of days with headache between patients treated with topiramate and those treated with placebo (mean ± SD: 20.9 ± 3.2 and 20.8 ± 3.2, respectively). During the last 4 week-maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency in comparison to those treated with placebo (mean number of days with headache ± SD: 8.1 ± 8.1 vs. 20.6 ± 3.4, P < 0.0007). Topiramate at low doses proved to be an effective therapeutic approach to reduce headache frequency in patients with chronic migraine and analgesic overuse.

scholarly journals Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double blind dose response study in Lagos

2021 ◽  
Author(s):  
OE Babalola ◽  
CO Bode ◽  
AA Ajayi ◽  
FM Alakaloko ◽  
IE Akase ◽  
...  
Keyword(s):  
Platelet Count ◽  
Dose Response ◽  
Repeated Measures ◽  
Standard Of Care ◽  
Double Blind ◽  
Parallel Group ◽  
Clinical Benefits ◽  
Randomised Controlled

ABSTRACTIntroductionIn vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS - CoV-2 viral replication, but questions remained as to In-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19.MethodsWe conducted a translational proof of concept (PoC) randomized, double blind placebo controlled, dose response, parallel group study of IV efficacy in RT - PCR proven COVID 19 positive patients. 62 patients were randomized to 3 treatment groups. (A) IV 6mg regime, (B)IV 12 mg regime (given Q84hrs for 2weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care.ResultsThe Days to COVID negativity [DTN] was significantly and dose dependently reduced by IV (p = 0.0066). The DTN for Control were, = 9.1+/−5.2, for A 6.0 +/− 2.9, and for B 4.6 +/−3.2. 2 Way repeated measures ANOVA of ranked COVID 19 + / − scores at 0, 84, 168, 232 hours showed a significant IV treatment effect (p=0.035) and time effect (p <0.0001). IV also tended to increase SPO2 % compared to controls, p = 0.073, 95% CI - 0.39 to 2.59 and increased platelet count compared to C (p = 0.037) 95%CI 5.55 - 162.55 × 103/ml. The platelet count increase was inversely correlated to DTN (r = −0.52, p = 0.005). No SAE was reported.Conclusions12 mg IV regime may have superior efficacy. IV should be considered for use in clinical management of SARS-Cov-2, and may find applications in community prophylaxis in high-risk areas.

Efficacy and Safety of Tonabersat, a Gap-Junction Modulator, in the Acute Treatment of Migraine: A Double-Blind, Parallel-group, Randomized Study

Cephalalgia ◽  
2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 7-16 ◽  
Author(s):  
CGH Dahlö ◽  
AW Hauge ◽  
J Olesen
Keyword(s):  
Acute Treatment ◽  
Randomized Study ◽  
Vital Signs ◽  
Positive Control ◽  
Efficacy And Safety ◽  
Severe Attack ◽  
Double Blind ◽  
Parallel Group ◽  
Efficacy Measures ◽  
Slow Absorption

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.

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