scholarly journals Safety Analysis of an Oral Testosterone Undecanoate (TU) Formulation Following 2 Years of Administration in Hypogonadal Men

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A815-A816
Author(s):  
Ronald S Swerdloff ◽  
John K Amory ◽  
Marc Gittelman ◽  
B Woun Seo ◽  
Nestor Rohowsky ◽  
...  
Keyword(s):  
Safety Profile ◽  
Liver Toxicity ◽  
Clinical Laboratory ◽  
Dose Titration ◽  
Term Therapy ◽  
Initial Increase ◽  
Open Label ◽  
Testosterone Undecanoate ◽  
Days Of Therapy

Abstract Introduction: An oral testosterone (T) replacement therapy (TRT) would be the preferred choice for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men for up to 2 years. Subjects and Methods: Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results: Overall, up to 81 subjects were available for evaluation. T concentration increased from 208.3 ± 102.4 ng/dL (Mean ± SD) at baseline (BL) to 470.1 ± 396.5 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests - ALT (28.0 ± 12.3 to 26.6 ± 12.8 U/L), AST (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL) throughout the two studies. At Day 270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on Day 290, and the level dropped to 87 U/L, < 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. There were not any significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (+2.52 ± 3.7% vs BL, p < 0.001) and cuff systolic BP (+5.6 ± 15.0 mmHg vs BL, p = 0.006). The change in prostate-related growth variables and CV endpoints changed initially and stabilized throughout the 2 trials. For example, systolic BP consistently showed a mean increase from BL between 3 - 6 mmHg. Conclusion: This oral TU formulation is an effective long-term therapy for hypogonadal men and has a safety profile consistent with other approved T products. Notably, no evidence of liver toxicity was observed. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children.

Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial

2020 ◽  
pp. 27-37
Author(s):  
Suresh Durgam ◽  
Willie Earley ◽  
Rui Li ◽  
Dayong Li ◽  
Kaifeng Lu ◽  
...  
Keyword(s):  
Safety Profile ◽  
Relapse Prevention ◽  
Controlled Trial ◽  
Fixed Dose ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Randomized Controlled ◽  
Time To Relapse

Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy in randomized controlled trials in schizophrenia. This multinational, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia; total study duration was up to 97 weeks. Schizophrenia symptoms were treated/stabilized with cariprazine 3—9 mg/d during 20-week open-label treatment consisting of an 8-week, flexible-dose run-in phase and a 12-week fixed-dose stabilization phase. Stable patients who completed open-label treatment could be randomized to continued cariprazine (3, 6, or 9 mg/d) or placebo for double-blind treatment (up to 72 weeks). The primary efficacy parameter was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, or suicidal risk); clinical measures were implemented to ensure safety in case of impending relapse. A total of 264/765 patients completed open-label treatment; 200 eligible patients were randomized to double-blind placebo (n = 99) or cariprazine (n = 101). Time to relapse was significantly longer in cariprazine — versus placebo-treated patients (P = .0010, log-rank test). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI] = 0.45 [0.28, 0.73]). Akathisia (19.2%), insomnia (14.4%), and headache (12.0%) were reported in ≥ 10% of patients during open-label treatment; there were no cariprazine adverse events ≥ 10% during double-blind treatment. Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia. The long-term safety profile in this study was consistent with the safety profile observed in previous cariprazine clinical trials. ClincalTrials.gov identifier: NCT01412060. Key words: schizophrenia; cariprazine; long-term treatment; relapse prevention; randomized controlled trial; oral antipsychotics

Short- and Long-Term Cardiovascular Effects of Mixed Amphetamine Salts Extended-Release in Adolescents With ADHD

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S15) ◽  
pp. 22-30 ◽  
Author(s):  
Timothy E. Wilens ◽  
Thomas J. Spencer ◽  
Joseph Biederman
Keyword(s):  
Extended Release ◽  
Cardiovascular Effects ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Once Daily ◽  
Open Label Extension ◽  
Short And Long Term ◽  
Clinically Significant

AbstractObjectiveAssess cardiovascular effects of once-daily mixed amphetamine salts extended release (MAS XR) in adolescents (13–17 years of age) with attention-deficit/hyperactivity disorder (ADHD).MethodsBlood pressure (BP), pulse, and electrocardiograms were assessed in 327 healthy subjects during a 4-week, randomized, double-blind, placebo-controlled, forced dose-titration study. Placebo (n=69) or once-daily MAS XR(10, 20, 30, or 40 mg) was administered to subjects ≤75 kg (n=233); 50- and 60-mg MAS XR was administered to subjects >75 kg (n=25). One hundred thirty-eight subjects participated in a 6-month, open-label extension study.FindingsChanges in BP and QTcB (Bazett's formula) intervals at 4 weeks with MAS XR were not significantly different from the placebo group. Pulse increased by 5.0 and 8.5 bpm after 3 weeks with MAS XR 20 and 50 mg/day, respectively (P≤.002). After 6 months of open-label MAS XR treatment, mean increases in systolic BP (1.7 mm Hg; P=.0252) and pulse (4.4 bpm; P<.0001) were statistically, but not clinically, significant diastolic BP was not significantly changed (0.6 mm Hg) A decrease in QTcB interval (-4.6±19.9 msec) was statistically (P=.009), but not clinically, significant. There were no serious cardiovascular adverse events.ConclusionCardiovascular effects of short- and long-term MAS XR treatment (≤60 mg/day) were minimal in otherwise healthy adolescents with ADHD.

scholarly journals SAT-044 Treatment of Hypogonadal Men with a New Oral Testosterone Undecanoate (TU) Formulation Improves Psychosexual, Well-Being and Body Composition and Bone Density Parameters

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ronald S Swerdloff ◽  
John K Amory ◽  
Adrian S Dobs ◽  
Christina Wang ◽  
Theodore M Danoff ◽  
...  
Keyword(s):  
Body Composition ◽  
Well Being ◽  
Clinic Visit ◽  
Dose Titration ◽  
Mineral Density ◽  
Open Label ◽  
Testosterone Undecanoate ◽  
Active Comparator ◽  
Sf 36 ◽  
The Impact

Abstract Introduction and Objective: A new, first-in-class oral testosterone (T) replacement therapy product [T-undecanoate (TU) capsules] was recently approved by FDA to treat hypogonadal men. Clinical trials were conducted to evaluate, in part, the impact of oral TU therapy on important secondary efficacy endpoints: Psychosexual and/or general well-being (Trial I and II); and body composition and bone mineral density (BMD) (Trial II). Subject and Methods: Hypogonadal men (AM serum T ≤ 300 ng/dL) age 18 to 65 (Trial I) or 75 years old (Trial II) were randomized into open-label, active-comparator (T-gel/solution) trials. Subjects received: Trial 1: Oral TU (n=166) or a topical T solution (n=55) for 4-6 mos.; or Trial II: Oral TU (n=162) or T-gel (n=163) for 12 mos. The starting oral TU dose (with food) was 237 mg, BID in Trial I and 316 mg, BID in Trial II; up to 2 dose-titration opportunities were available to achieve eugonadal T concentrations (assayed by LC-MS/MS). In Trial I, Psychosexual Daily Questionnaires (PDQ) were completed by study subjects for 7 days at baseline and prior to final clinic visit (Day 105-180). In Trial II, the SF-36 well-being questionnaire was completed on Days 0, 30, 90, 180, 270 and 365 and PDQs were completed for 7 days prior to clinic visits on these same days. In Trial II body composition and BMD was assessed by DEXA scan on Days 0, 180 and 365. Safety was monitored by physical exam and standard clinical lab tests. Results: Mean serum T in response to oral TU was 489 ± 155 ng/dL (mean ± SD) (Trial I) and 628 ± 342 ng/dL (Trial II); 84% of subjects in each trial achieved mean T concentrations in the eugonadal range. Statistically significant mean changes from baseline (p&lt;0.0001) for most SF-36 well-being parameters were observed in both oral TU and T-gel groups. Psychosexual questionnaire results also demonstrated statistically significant improvement over baseline (p&lt;0.0001) in most parameters at Day 30 and all timepoints thereafter in both trials. On Days 180 and 365 (v. baseline) oral TU was associated with a significant reduction in fat mass [-1.92 ± 2.79 (SD) and -2.4 ± 3.6 kg, respectively] (p&lt;0.0001) and an increase in lean body mass [+2.87 ± 2.73 and +3.15 ± 2.69 kg, respectively] (p&lt;0.0001). Oral TU increased mean BMD over baseline on Days 180 and 365 in spine [+0.013 ± 0.035 and +0.018 ± 0.042 g/cm2, respectively (p&lt;0.0001)] and hip [+0.006 ± 0.019 and +0.012 ± 0.023 g/cm2, respectively (p&lt;0.0001)]. Oral TU exhibited a safety profile consistent with commonly prescribed topical T-comparators. Modest increases in cuff sBP of 2.8 ± 11.84 (SD) mm Hg and 1.8 ± 10.76 mm Hg were observed in Trial I for both oral TU and the comparator T-solution. Conclusions: Treatment of hypogonadal men with oral TU yielded circulating mean T concentrations in the mid-eugonadal range and significantly improved psychosexual, general well-being, body composition and BMD parameters comparable to transdermal T administration.

THUR 173 Longterms: 10-year experience of fingolimod in RRMS patients

2018 ◽  
Vol 89 (10) ◽  
pp. A22.3-A22
Author(s):  
Cohen Jeffrey ◽  
Tenenbaum Nadia ◽  
Bhatt Alit ◽  
Pimentel Ron ◽  
Kappos Ludwig
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Brain Volume ◽  
Disability Progression ◽  
Open Label ◽  
T2 Lesions ◽  
Long Term Follow Up ◽  
Efficacy Measures

ObjectivesPresent results for up to 10 years of fingolimod treatment in RRMS patients.MethodsLONGTERMS is an open-label, single-arm, extension study evaluating the long-term safety, tolerability and efficacy of fingolimod in patients who previously participated in earlier fingolimod studies. Key efficacy measures: annualised relapse rate (ARR), proportion of patients free of 6 month confirmed disability progression (6 m-CDP), annualised rate of new or newly enlarging T2 lesions (ARneT2), and annualised rate of brain atrophy (ARBA). Safety analyses: adverse events (AEs) and serious AEs (SAEs) frequencies.Results3168 patients were included in the analysis. ARR decreased with longer exposure from 0.26 (Month [M] 0–12) to 0.20 (M0–60) and 0.19 (M0–120). Most patients remained free from 6 m-CDP at M60 (79.3%) and M120 (68.1%). ARneT2 decreased from 1.31 (M0–12) to 0.90 (M0–60), and 0.71 (M0–120). Change in brain volume was stable throughout the study (−0.37 [M12], −0.33 [M60] and −0.32 [M120]). Long-term exposure did not raise new safety concerns. No increase in frequencies of AEs or SAEs per year was observed over long-term fingolimod treatment.ConclusionsLong-term follow-up confirmed the established safety profile of fingolimod. Treatment was associated with a sustained low level of disease activity as expressed by clinical and MRI outcomes.DisclaimerPreviously presented at ECTRIMS 2017

Long-term tolerability of fentanyl effervescent buccal tablets: Interim analysis in patients with cancer-related breakthrough pain

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8567-8567
Author(s):  
N. Slatkin ◽  
V. Charu ◽  
G. Niebler ◽  
R. Rauck
Keyword(s):  
Interim Analysis ◽  
Breakthrough Pain ◽  
Safety Data ◽  
Dose Titration ◽  
Open Label ◽  
Patients With Cancer ◽  
Titration Phase ◽  
Term Tolerability ◽  
Buccal Tablets

8567 Background: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. Results reported here represent a pre-specified interim analysis of an open-label safety and efficacy study of FEBT in opioid-tolerant patients with cancer-related breakthrough pain (BTP). Methods: Patients with cancer-related BTP receiving around-the-clock and supplemental opioids were eligible to enroll. Patients who had participated in a previous dose-titration study of FEBT enrolled directly into the 1-year phase; new patients entered a titration phase to determine an effective FEBT dose before entering the 1-year phase. An effective FEBT dose was defined as the dose needed to provide adequate analgesia for BTP. By October 3, 2005, 170 patients (aged 24 to 95 years) received FEBT (100–800 μg) and had documented safety data. Results: Of the 112 new patients, 70.5% identified an effective FEBT dose and were eligible for enrollment. In the long-term phase, patients received FEBT for a mean of 109.8 days; 8% at 100 μg, 15% at 200 μg, 23% at 400 μg, 25% at 600 μg, and 29% at 800 μg. The FEBT dose remained reasonably stable during the long-term phase, but 43 patients had a dose increase and 6 had a dose decrease at the discretion of the investigator. Only 2 patients required a change in the FEBT dose because of tolerability. The most common adverse events (AEs) are given in the table. The incidence of AEs did not correlate with the effective FEBT dose. The 42 patient deaths that occurred were all attributed to cancer-related pathology or the progression of cancer. Conclusions: Overall, FEBT was well tolerated in opioid-tolerant patients with cancer-related BTP. [Table: see text] [Table: see text]

scholarly journals A Long-Term, Open-Label, Safety Study of Triple-Bead Mixed Amphetamine Salts (SHP465) in Adults With ADHD

2017 ◽  
Vol 24 (3) ◽  
pp. 434-446 ◽  
Author(s):  
Lenard A. Adler ◽  
Glen Frick ◽  
Brian Yan
Keyword(s):  
Rating Scale ◽  
Symptom Control ◽  
Vital Signs ◽  
Early Morning ◽  
Dose Titration ◽  
Open Label ◽  
Diagnostic And Statistical Manual ◽  
Open Label Extension ◽  
Higher Doses

Objective: The aim of this study was to evaluate the long-term safety of triple-bead mixed amphetamine salts (MAS) in adults with ADHD. Method: Adults meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) ADHD criteria and satisfying study criteria from one of two antecedent studies were enrolled in this 52-week (dose titration, 4 weeks; dose maintenance, 11 months) open-label extension. The protocol included 12.5- to 75-mg triple-bead MAS but was amended to a maximum of 50-mg triple-bead MAS. Safety evaluations included treatment-emergent adverse events (TEAEs) and vital signs. Clinical outcome measures included ADHD Rating Scale–IV (ADHD-RS-IV) total score changes. Results: Of 505 enrolled participants, 266 completed the study; the M ± SD daily dose during the study was 48.0 ± 15.96 mg. The most frequent TEAEs were insomnia (initial insomnia, insomnia, early morning awakening, middle insomnia; 38.2%), headache (25.7%), and dry mouth (20.2%). Study discontinuations were more frequent with higher doses of triple-bead MAS (37.5-75 mg) than with lower doses (12.5 and 25 mg). Blood pressure and pulse increases were observed at end-of-study. Mean ADHD-RS-IV total score decreases from antecedent study and open-label baselines at end-of-study were −23.3 ± 11.44 and −7.9 ± 13.19, respectively. Conclusion: Triple-bead MAS exhibited a long-term safety profile comparable with previous reports and demonstrated evidence of continued symptom control for up to 12 months.

scholarly journals 0641 Effects of Weight Loss During Long-Term Solriamfetol Treatment on Cardiometabolic Indices

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A245-A245
Author(s):  
A Malhotra ◽  
P Strollo ◽  
J Pepin ◽  
P Schweitzer ◽  
G Lammers ◽  
...  
Keyword(s):  
Weight Loss ◽  
High Glucose ◽  
Cardiometabolic Risk ◽  
Clinical Laboratory ◽  
Serum Glucose ◽  
Long Term Effects ◽  
Open Label ◽  
Obstructive Sleep ◽  
Open Label Extension

Abstract Introduction Increased prevalence of obesity has been reported in patients with narcolepsy and obstructive sleep apnea (OSA). Results from a 1-year open-label extension (OLE) study showed ≥5% weight loss in 4.5%, 17.3%, and 32.4% of participants with narcolepsy or OSA receiving solriamfetol 75, 150, or 300mg/d. We examined whether clinically significant weight loss (≥5%) in this population had favorable effects on biomarkers of cardiometabolic risk compared to no such weight loss. Methods We evaluated changes in weight and BP (parent study baseline to OLE week 40) and clinical laboratory assessments (OLE baseline to week 40) in participants with narcolepsy (n=124) or OSA (n=250) from the OLE study. Results Of 374 participants, 96 (25.7%) had ≥5% weight loss and 34 (9.1%) had ≥5% weight gain. Demographics were similar in those with and without (n=278) ≥5% weight loss. From baseline to week 40, among participants with weight loss, there were decreases in percentage with high (ie, &gt;ULN) serum glucose (36.6% to 28.1%) or triglycerides (26.6% to 21.9%), whereas among participants without weight loss, there was an increase in percentage with high glucose (43.3% to 50%) and no change in percentage with high triglycerides (37.1% to 37.2%). The percentage of participants with high total cholesterol was stable among participants with weight loss (22.3% to 22.9%) and increased (32.7% to 37.2%) in participants without weight loss. Participants with weight loss had mean±SD reductions in SBP (-2.6±11.4mmHg) and DBP (-1.0±9.0mmHg), whereas participants without weight loss had increases of +0.65±12.5mmHg and +1.2±8.7mmHg, respectively. Conclusion Among solriamfetol-treated participants with ≥5% weight loss, there were decreases in BP and percentage of participants with high glucose and triglycerides. Further research is required to examine prospective long-term effects of solriamfetol on specific biomarkers of cardiometabolic risk. Support Jazz Pharmaceuticals

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