Dataset Information

Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels.

ABSTRACT: Objective:Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option. Materials and Methods:Patients with testosterone deficiency (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels on days 30 and 90, along with efficacy measurements, which were analyzed by comparison with baseline values. Baseline and/or predose TT values were used for patient stratification. Results:Prestudy and predose endogenous testosterone concentrations correlated. The maximal concentration of TT was nearly identical across all cohorts at days 30 and 90, whereas the average concentration over 24 hours had a slight positive dependence relative to predose levels. LH levels remained in the normal range but were decreased more in patients with higher starting baseline levels. These findings indicate that TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period. Patients with the lowest endogenous testosterone levels received maximum exposure impact from each TNG dose. Patients with severe testosterone deficiency had similar efficacy improvements as the remainder of the study population. Conclusion:All testosterone-deficient cohorts were successfully treated with TNG.

SUBMITTER: Gronski MA

PROVIDER: S-EPMC6694041 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Efficacy of Nasal Testosterone Gel (Natesto<sup>®</sup>) Stratified by Baseline Endogenous Testosterone Levels.

Gronski Matthew A MA Grober Ethan D ED Gottesman Irving S IS Ormsby Ross W RW Bryson Nathan N Bryson Nathan N

Journal of the Endocrine Society 20190626 9

<h4>Objective</h4>Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option.<h4>Materials and ...[more]

PMID: 31428719

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Project description:Background: General anesthesia in rabbits is associated with higher morbidity and mortality relative to other mammalian species commonly anesthetized. Unique challenges related to endotracheal intubation (ETI) in rabbits contribute to this risk. Objective: To improve the safety of ETI in rabbits, we developed two new ETI methods using a supraglottic airway device (v-gel®) to facilitate ETI and compared them to traditional "blind" technique. We hypothesized that relative to blind ETI, v-gel® guided ETI provides more successful placement of the endotracheal tube (ETT) in a shorter time. Outcomes included number of intubation attempts, time for achievement of ETI, endoscopic findings, and serial arterial blood gas (ABG) analysis. Study Design: Prospective, randomized, and crossover study. Methods: Ten female, New Zealand White rabbits aged 1-2 years old, weighing 4.3 ± 0.4 kg, were anesthetized four times. Each time, ETI was performed with one of the following techniques: Method 1: v-gel® guided, polypropylene catheter facilitated, intubation using a cuffed ETT; Method 2: v-gel® guided intubation using an uncuffed ETT directly inserted through the device airway channel; Method 3 and 4: Blind intubation with uncuffed or cuffed ETT. Upper airway endoscopy was performed before intubation attempts and after extubation. Serial ABG analysis was performed during the peri-intubation process. Results: V-gel® guided techniques allowed successful ETI on the initial attempt for 9/10 subjects using Method 1 and 10/10 using Method 2. Relative to the v-gel® guided techniques, the blind techniques required more intubation attempts. A median of 2 attempts (range 1-4, p < 0.007) were required for the uncuffed ETT, and a median of 4 (range 1-4, p < 0.001) attempts were performed for the cuffed ETT. The time to perform successful ETI was positively correlated with the number of attempts (ρ = 0.82), while successful ETI was negatively correlated with number of attempts (ρ = -0.82). Endoscopic findings showed mild to moderate laryngeal trauma. In the absence of oxygen supplementation, ABG analysis demonstrated low PaO2, while PaCO2 remained consistent. Conclusions: Facilitated ETI using the v-gel® guided techniques allows for the rapid establishment of a secure airway to provide ventilatory support for rabbits undergoing general anesthesia.

Project description:IntroductionNoninfectious keratitis is a painful corneal inflammation treated with topical cyclosporine and other immunosuppressants. Additional treatment options are needed for keratitis that does not improve with standard therapies. Repository corticotropin injection (RCI; Acthar® Gel) is approved to treat severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, including keratitis. This phase 4, multicenter, open-label study assessed the efficacy and safety of RCI for refractory severe noninfectious keratitis.MethodsPatients were ≥ 18 years old with persistent severe keratitis despite treatment with topical immunosuppressants. Patients received 80 U of RCI subcutaneously twice weekly for 12 weeks followed by a 4-week taper. Assessments included all domains of the Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire, Ocular Discomfort and 4-Symptom Questionnaire, and Visual Analog Scale (VAS). Corneal fluorescein and conjunctival lissamine green staining, Conjunctival Redness Scale, tear production (Schirmer's test), visual acuity, slit lamp examination, and intraocular pressure were also assessed. Safety was evaluated via treatment-emergent adverse events. Analyses were performed using the modified intent-to-treat (mITT) population (patients who received ≥ 1 dose of RCI and contributed any post-baseline efficacy data).ResultsIn the mITT population (N = 35), 50.0% (95% confidence interval, 33.2% to 66.8%) of patients experienced clinically important improvements in the symptom bother domain of the IDEEL Questionnaire at week 12 of RCI therapy. All domains of the IDEEL and the Ocular Discomfort and 4-Symptom Questionnaire showed improvements at week 12 of RCI treatment. The most pronounced improvements in the VAS at week 12 were for eye dryness and eye discomfort. Corneal staining, conjunctival staining, conjunctival redness, and tear production showed early improvements that were sustained through week 12. No new safety signals for RCI were identified.ConclusionsRCI is safe and effective for refractory severe noninfectious keratitis that has not improved with other approved therapies.Trial registration numberClinicalTrials.gov NCT04169061.

Project description:IntroductionThe Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted.MethodsTONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI).ResultsOverall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046).ConclusionIn patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone.Trial registrationTONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).

Project description:ContextMale hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy.ObjectiveThe aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl.MethodsThis is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA).ResultsMen with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed.ConclusionT therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.

Dataset Information

Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels.

Publications

Efficacy of Nasal Testosterone Gel (Natesto<sup>®</sup>) Stratified by Baseline Endogenous Testosterone Levels.

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