Treatment-related Withdrawals Research Articles

Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies.

Although cannabinoid-based medications are increasingly used by older adults, their safety and tolerability in this age group remain unclear. The purpose of this systematic review was to examine the safety and tolerability of cannabinoid-based medications by conducting a meta-analysis of open-label observational studies of cannabinoid-based medications for all indications in individuals with a mean age of ≥50 years. A systematic search was conducted on PubMed, PsycINFO, MEDLINE, EMBASE and CINHAL. Study quality was assessed using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. We included studies that (a) were published from 1990 onwards; (b) included older adults (mean age ≥50 years); and (c) provided data on the safety and tolerability of medical cannabinoids. Data were pooled using a random-effects approach. Risk of adverse events, serious adverse events and withdrawals was computed as the incidence rate (IR). Separate analyses were conducted by the cannabinoid-based medication used, for delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and a combination of THC and CBD (THC:CBD). Thirty-eight studies were identified (THC = 23; CBD = 6; THC:CBD = 9; N = 2341, mean age: 63.19 ± 8.08 years, men: 53.86%). THC had a very low incidence of all-cause and treatment-related adverse events (IR: 122.18, 95% confidence interval [CI] 38.23-253.56; IR: 84.76, 95% CI 0.13-326.01, respectively) and negligible serious adverse events (IR = 0). Similar IRs for CBD (all cause, IR: 111.91, 95% CI 1.24-495.93; treatment related, IR: 1.76, 95% CI 4.63-23.05) and no serious adverse events (IR = 0). CBD was not associated with a risk of treatment-related withdrawals. THC had a low risk of all-cause and treatment-related withdrawals (IR: 25.18, 95% CI 12.35-42.52; IR: 7.83, 95% CI 3.26-14.38, respectively). The THC:CBD treatment had a low risk of all-cause and treatment-related adverse events (IR: 100.72, 95% CI 0.25-383.00; IR: 55.38, 95% CI 8.61-142.80, respectively), but reported a risk of all-cause and treatment-related serious adverse events (IR: 21.32, 95% CI 0.18-93.26; IR: 3.71, 95% CI 0.21-11.56, respectively), and all-cause and treatment-related withdrawals (IR: 78.63, 95% CI 17.43-183.90; IR: 34.31, 95% CI 6.09-85.52, respectively). Significant heterogeneity (I2 >55%) was present in most analyses. Although cannabinoid-based medications were generally safe and acceptable to adults aged over 50 years, these estimates are limited by the lack of a control condition and considerable heterogeneity. Nevertheless, they complement and are consistent with comparable evidence from randomised controlled trials.

Efficacy and safety of fenfluramine in patients with Dravet syndrome: A meta‐analysis

Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly controlled and nearly half of patients still experience at least four tonic-clonic seizure per month. Recently, several clinical trials demonstrated that fenfluramine may provide a significant reduction in convulsive seizure frequency in the treatment of Dravet syndrome. A computerized literature search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar was performed from inception until December 31, 2019. We included randomized placebo-controlled trials for the treatment of Dravet syndrome. We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model. Quality assessment of included studies was performed with the Cochrane Collaboration's tool. Two trials with a total of 206 patients were included. The pooled RR of 5.49 (95% CI 3.13-9.65) showed that a significantly greater proportion in the fenfluramine group achieved ≥50% reduction in monthly convulsive seizure frequency (MCSF). As for the complete seizure free rate, the pooled RR of 5.75 (95% CI 1.03-32.07) also demonstrated the favorable efficacy of fenfluramine, even though the difference was not statistically significant (p=0.046). However, a significantly greater proportion of patients in the fenfluramine group experienced no more than one seizure during the treatment period (RR 13.82, 95% CI 2.68-71.27, p=0.002). There were no significant differences in withdrawals and serious adverse events between the two treatment groups. No valvular heart disease or pulmonary arterial hypertension was observed in participants. The most common adverse events reported by included trials were diarrhea, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, decreased appetite, and weight loss. Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated.

ONCE DAILY ORAL DOSING OF RODATRISTAT ETHYL (RVT-1201) ACHIEVES REDUCTIONS IN SEROTONIN BIOSYNTHESIS COMPARABLE TO THOSE ASSOCIATED WITH REVERSAL OF VASCULAR REMODELING IN PAH ANIMAL MODELS

SESSION TITLE: Tuesday Electronic Posters 5 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: RVT-1201, a pro-drug for the tryptophan hydroxylase (TPH) inhibitor KAR5417, is being developed for PAH. TPH1 is the rate-limiting enzyme for peripheral biosynthesis of serotonin (5HT), which has been implicated as a causative factor in PAH. RVT-1201 decreased pulmonary vessel wall thickness in 2 PAH rodent models indicating potential to halt/reverse pulmonary remodeling in humans. The median effective dose (100 mg/kg QD) in PAH rat models yielded a ∼35% reduction in 5-HT biosynthesis (based on reduction in urinary 5-HIAA, a metabolite of 5HT). Divided-dose pharmacodynamic (PD) studies in healthy rats (QD vs BID vs TID) demonstrated KAR5417 AUC, rather than Cmax or Cmin, best correlated with lowering of 5-HT, indicating QD dosing was as effective as more frequent dosing. The purpose of this study was to compare reductions in 5-HIAA levels following QD and BID dosing in healthy subjects. METHODS: 24 healthy subjects received 800 mg total daily oral doses of RVT-1201 or placebo (PBO), either as single (800mg QD) or divided (400mg BID) doses for 14 days across two cohorts (9 active: 3 PBO per cohort). KAR5417 plasma levels and change from Baseline (BSL) PD biomarker data (plasma and urine 5-HIAA) were compared between QD and BID cohorts at Day 14. Safety and tolerability were assessed via adverse event (AE) monitoring and laboratory, vital signs and ECG assessments. RESULTS: At Day 14, KAR5417 mean (±SD) AUC0-24 at 800 mg QD (9180 ng*h/mL, ± 4280) was comparable to the mean pAUC0-24 for 400 mg BID (10400 ng*h/mL, ± 3260). 5-HT lowering was similar across both dose regimens, with 800 mg QD achieving mean (± SD) 40.0 (6.32) % and 45.8 (6.59) % reductions in plasma and urinary 5-HIAA at D14, respectively, compared to 49.9 (9.52) % and 55.5 (10.3) % reductions, respectively, with the 400 mg BID regimen. Plasma and urinary 5-HIAA levels were not reduced from BSL in the PBO arms. 5-HIAA reductions in both regimens exceeded those associated with efficacy in the rodent models. Both dose regimens were generally well-tolerated. The overall incidence of GI-related AEs was greater in the QD group (78%) compared to the divided dose group (33%); however, most AEs were mild in intensity and there were no treatment-related withdrawals in either cohort. CONCLUSIONS: Repeated QD dosing of RVT-1201, an investigational treatment for PAH, reduced 5-HT biosynthesis similarly to divided (BID) daily dosing. Reductions in 5-HIAA levels were comparable to those associated with reversal of vascular remodeling in animal PAH models. RVT-1201 was generally well-tolerated in both dose regimens. CLINICAL IMPLICATIONS: RVT-1201 has the potential to reduce serotonin production and impact vascular remodeling in PAH patients. If ultimately proven effective, the potential to dose RVT-1201 once-daily may help improve overall treatment adherence in a disease like PAH in which patients often take more than one drug in combination chronically. DISCLOSURES: Employee relationship with Altavant Sciences Please note: >$100000 Added 02/05/2019 by David Carpenter, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/15/2019 by Katelyn Crizer, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $1-$1000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Ownership interest Removed 03/20/2019 by Laurence Keller, source=Web Response Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Thomas Pack, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Michelle Palacios, source=Web Response, value=Salary No relevant relationships by Julie Rurka, source=Web Response No relevant relationships by Michele Snyder, source=Web Response Employee relationship with Altavant Sciences Inc Please note: >$100000 Added 03/18/2019 by Stephen Wring, source=Web Response, value=Salary

Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis.

Rheumatoid arthritis patients have a high level of pro-inflammatory interleukin-1. Augmenting the blockade of interleukin-1 receptors by external interleukin-1 receptor antagonist modifies the progression of the disease. Therefore, the aim of this study was to evaluate the clinical efficacy and safety of interleukin-1 receptor antagonist (anakinra) in the treatment of rheumatoid arthritis. Clinical trials and extension studies that compared anakinra with placebo or other medications were included. Electronic bibliographic databases: PubMed, Scopus, and Web of Sciences were searched from inception to November 2017. The American College of Rheumatology 20% (ACR20) improvement was the primary efficacy outcome measure. Total number of adverse drug events, serious adverse drug events, total treatment withdrawals, and treatment-related withdrawals were safety outcome measures. Ten studies were included in this review. One study did not fulfil quantitative criteria and was assessed qualitatively. Six clinical trials and three extension studies were included in meta-analysis. Patients treated with anakinra are 42% more likely to have ACR20 response than patients without IL-1Ra (pooled RR 1.42; 95% CI 1.01, 2.00). Patients on 30-150mg anakinra have lower Health Assessment Questionnaire (HAQ) score than patients without IL-1Ra (SMD - 0.28; 95% CI - 0.53, - 0.03). The inflammatory marker erythrocyte sedimentation rate (ESR) was significantly lower among patients treated with 30-150mg anakinra (SMD - 0.44; 95% CI - 0.65, - 0.23). Patients on anakinra have a 34% more risk of treatment-related withdrawal than placebo. The other parameters were not found to be statistically significant. Anakinra has a significant improvement in ACR20, HAQ, and ESR. The ACR20 response is maintained after 48weeks of treatment. Anakinra shows higher episodes of treatment-related withdrawals than placebo.

A Double-Blind, Randomized, Neoadjuvant Study of the Tissue Effects of POMx Pills in Men with Prostate Cancer Before Radical Prostatectomy

Pomegranates slow prostate cancer xenograft growth and prolong prostate-specific antigen (PSA) doubling times in single-arm human studies. Pomegranates' effects on human prostate tissue are understudied. We hypothesized that orally administered pomegranate extract (POMx; Pom Wonderful) would lower tissue 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress biomarker. Seventy men were randomized to two tablets, POMx or placebo, daily up to four weeks before radical prostatectomy. Tissue was analyzed for intraprostatic urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NF-κB, and Ki67. Primary endpoint was differences in 8-OHdG, and the study was powered to detect 35% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (P = 0.095), which was not statistically significant. POMx was well tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21 of the 33 patients in the POMx group versus 12 of the 35 in the placebo group (P = 0.031). Cancer pS6 kinase, NF-κB, Ki67, and serum PSA changes were similar between arms. POMx before surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary endpoint in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitively test whether POMx reduces prostate oxidative stress, as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology.

Efficacy and Safety of Pegylated Interferon Alfa-2b and Ribavirin Combination Therapy Versus Pegylated Interferon Monotherapy in Hemodialysis Patients: A Comparison of 2 Sequentially Treated Cohorts

Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. 2 prospective observational cohort studies. From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. Peginterferon alfa-2b monotherapy, 1.0 μg/kg/wk, versus peginterferon alfa-2b, 1.0 μg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. Comparison of 2 sequential cohorts rather than a randomized control study. Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

Pegylated interferon α-2a versus standard interferon α-2a for treatment-naïve dialysis patients with chronic hepatitis C: a randomised study

Background:Chronic hepatitis C virus (HCV) infection is prevalent in dialysis patients, and standard interferon monotherapy is the current standard of care for such patients.Aim:To investigate whether pegylated interferon has a...

Intranasal Fluticasone Once Daily Compared with Once-Daily Cetirizine in the Treatment of Seasonal Allergic Rhinitis

The efficacy and tolerability of fluticasone aqueous nasal spray, 200µg once daily for 21 days, was compared with cetirizine, 10mg once daily for 21 days, in a multicentre, randomised, double-blind, double-dummy, parallel group study. 237 evaluable patients aged 12 years and above, with seasonal allergic rhinitis (defined as having a positive skin test and a total symptom score of ≥ 6/15), received either fluticasone aqueous nasal spray (n = 119) or cetirizine (n = 118). Improvement in total symptom score was observed in patients from both treatment groups, with the improvement in the fluticasone treatment group being significantly greater (decrease in total symptom score from 9.23 to 2.13) than in the cetirizine treatment group (decrease in total symptom score from 9.36 to 4.31; p < 0.001). There was also a significantly greater improvement in the number of symptom-free days for all symptoms in favour of fluticasone aqueous nasal spray compared with cetirizine (p < 0.001). Furthermore, the percentage of days when patients did not require terfenadine as rescue therapy was significantly greater in the fluticasone group (87%) than in the cetirizine group (80%; p < 0.05). Five adverse events were reported during intranasal fluticasone treatment and 10 adverse events were reported during cetirizine therapy. There were no treatment-related withdrawals from therapy in the fluticasone group, but 5 treatment-related withdrawals were reported in the cetirizine group.This study demonstrated that fluticasone aqueous nasal spray, 200µg once daily, was significantly more effective than cetirizine, 10mg once daily, and had comparable (if not better) tolerability, in the treatment of seasonal allergic rhinitis.

Worldwide activity and safety of bicalutamide: a summary review

Objectives. To evaluate bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of bicalutamide. To evaluate bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy. Results. Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of bicalutamide plus an LHRH-A was superior ( P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly ( P <0.001) lower incidence of diarrhea and fewer withdrawals for adverse events among bicalutamide-treated patients. With longer follow-up and a 34% mortality, survival was equivalent between groups. Dose-related effects of bicalutamide on serum PSA concentrations were clearly demonstrated in the clinical trial program. With a total exposure of >2800 patient-years, bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals. Conclusions. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

Bicalutamide

Maximum androgen blockade, a relatively recent development in the treatment of prostate cancer, combines medical or surgical castration with antiandrogen therapy. A large randomized study comparing the non-steroidal antiandrogen, bicalutamide, with flutamide, each in combination with luteinizing hormone-releasing hormone (LHRH) analogs, showed that after a median follow-up of 49 weeks, the time to treatment failure was significantly longer for the bicalutamide patients compared with the flutamide patients (p = 0.005). After a median follow up to 95 weeks, bicalutamide in combination with LHRH analog therapy produced at least equivalent efficacy with flutamide in combination with LHRH analog therapy in terms of time to treatment failure and equivalent efficacy in terms of survival. The tolerability profile of bicalutamide, as based on reported findings and a literature review, indicates a superior tolerability to that of currently available antiandrogens, particularly with respect to diarrhea with a low incidence of treatment-related withdrawals.

Statistical analysis of cost outcomes in a randomized controlled clinical trial.

This paper suggests an approach to deal with an estimation problem which is often encountered in analyzing the longitudinal cost data gathered in a clinical trial. The source of that estimation problem is twofold: 1) a considerable number of missing data due to treatment-related withdrawal of severely affected patients with high health care costs in only one the treatment groups and 2) a heavily skewed cost distribution due to rare high-cost events. The approach is illustrated using data from a trial comparing 3 different drug regimes. In order to calculate costs per patient-year in case of selectively missing data we extrapolated the costs of patients with incomplete follow-up. Due to the skewness and the associated large variance in costs per patient-year, these costs cannot be analyzed using common parametric statistical methods relying on underlying normal distributions. A logarithmic transformation was performed to approximate a normal distribution, reduce the impact of extreme values and create similar size variances in the treatment groups. An ordinary least squares regression analysis of transformed data then standardized for differences in patient characteristics between the groups. For the retransformation, the so-called smearing estimate was used. This 'transformation-standardization-retransformation' approach enabled us to provide more consistent and efficient estimates of cost differences that were shown to be statistically significant and judged to be important.

Antihypertensive Effects of Tertatolol: A Comparative Study Versus Atenolol

The purpose of this study was to compare the antihypertensive efficacy and tolerance of tertatolol and atenolol. Sixty-one ambulatory patients with uncomplicated mild to moderate hypertension (diastolic blood pressure (DBP) between 95 and 120 mm Hg) received, following a randomized allocation, either 5 mg tertatolol (T) (n = 30) or 100 mg atenolol (A) (n = 31) in single daily dose. After a one-month single-blind placebo run-in period, the two drugs were administered double-blind over a 3 month period. Blood pressure (BP) and heart rate were measured before, and after the first and third months. Electrocardiographic and biological data were collected respectively before and at the third month. At each consultation, patients were asked to report any side effects. Atenolol and tertatolol were similar in controlling BP: the decrease in supine systolic blood pressure (SBP) reached 24.2 mm Hg (P less than .001) in group T and 21.7 mm Hg in group A (P less than .001), and the decrease in DBP reached 16.6 mm Hg in group T (P less than .001) and 16.8 mm Hg in group A (P less than .001). Supine heart rate (HR) fell by 15.5 beats/min and 14.8 beats/min in the T and A groups, respectively (P less than .001). At the end of the trial, blood pressure control (DBP less than or equal to 90 mm Hg) was obtained in 80% and 70% of the patients in the T and A groups, respectively. The clinical tolerance of both drugs was satisfactory with 8 slight and transient complaints in T group, and 14 complaints with one treatment-related withdrawal at the second month in A group. Electrocardiographic and biochemical variations were not significantly different in the two groups. We conclude that the antihypertensive efficacy of 5 mg tertatolol is comparable to that of 100 mg atenolol, with a similar clinical and biochemical tolerance.