Efficacy of lasmiditan for the acute treatment of perimenstrual migraine.

BACKGROUND: Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT1F receptor agonist, for perimenstrual attacks. METHODS: Patients from two randomized, double-blind, placebo-controlled clinical trials (MONONOFU and CENTURION) were instructed to treat an attack with a single dose of study medication within four hours of pain onset. After dosing, the proportion of patients who achieved freedom from migraine-related head pain, most bothersome symptom, and disability was reported at baseline up to 48 hours after dose and pooled data were evaluated. RESULTS: A total of 303 patients (MONONOFU N = 78; CENTURION N = 225) treated perimenstrual migraine attacks with lasmiditan 50 mg (N = 24), 100 mg (N = 90), 200 mg (N = 110), and placebo (N = 79). More patients achieved migraine-related head pain freedom with lasmiditan 200 mg versus placebo at all time points assessed. At 2 hours, 33.6% of patients in the 200-mg group (p < 0.001), and 16.7% of patients in the 100-mg (p = 0.11) and 50-mg (p = 0.19) groups were pain free, compared with 7.6% in the placebo group. CONCLUSIONS: Lasmiditan treatment of perimenstrual migraine attacks was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy.Clinical Trial registration: NCT03962738 and NCT03670810.

Lasmiditan for Patients with Migraine and Contraindications to Triptans: A Post Hoc Analysis.

INTRODUCTION: As 5-HT1B receptor agonists, triptans produce vasoconstriction and have cardiovascular contraindications and precautions. Lasmiditan, a selective 5-HT1F receptor agonist, has a low affinity for 5-HT1B receptors, does not cause vasoconstriction, and is free of cardiovascular contraindications and precautions. The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without at least one triptan contraindication. METHODS: Patient subgroups, with and without triptan contraindications, were analyzed from pooled patient data from four randomized, double-blind, placebo-controlled clinical trials (SAMURAI, SPARTAN, CENTURION, and MONONOFU). Patients experiencing a single migraine attack of moderate or severe intensity were treated with lasmiditan 50 mg (SPARTAN and MONONOFU only), 100 mg, 200 mg, or placebo, and efficacy data were recorded in an electronic diary. RESULTS: Of 5704 patients, 207 (3.6%) patients had at least one contraindication to triptans. Overall subgroup analysis revealed that the effects of lasmiditan on pain freedom, pain relief, freedom from most bothersome symptom, disability freedom, and Patient Global Impression of Change at 2 h post-dose did not differ in patient groups with and without triptan contraindications. These outcomes generally showed a similar benefit pattern for lasmiditan in both subgroups, with all results being statistically significant in patients without contraindications, and pain relief being statistically significant in patients with contraindications. The safety and tolerability profiles of patients with triptan versus without triptan contraindications were similar, including dizziness in 18.3 to 22.8% and somnolence in 7.9 to 9.9% of patients at the highest dose of lasmiditan. CONCLUSIONS: In pooled analyses from four trials, patients with and without triptan contraindications did not differ in their patterns of lasmiditan efficacy. Lasmiditan may be a treatment option in patients with contraindications to triptans. TRIAL REGISTRATION NUMBERS: SAMURAI, NCT:02439320; SPARTAN, NCT:02605174; CENTURION, NCT:03670810; and MONONOFU, NCT:03962738.

Migraine history and response to lasmiditan across racial and ethnic groups.

OBJECTIVE: The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT1F) receptor agonist, in racial and ethnic subgroups. METHODS: Descriptive data from racial (White [W](n = 3471) and Black or African American [AA](n = 792)) and ethnic (Hispanic or Latinx [HL](n = 775) and Non-Hispanic or Latinx [Non-HL](n = 3637)) populations are presented on pooled data from two double-blind, placebo-controlled, randomized Phase 3 studies (SAMURAI [NCT02439320] and SPARTAN [NCT2605174]). Patients were treated with lasmiditan (50 (SPARTAN only), 100, or 200 mg) or placebo for a single migraine attack of moderate-to-severe intensity. Efficacy data were recorded in an electronic diary at baseline, 30, 60, 90, and 120 min. Safety was evaluated and reported by occurrences of adverse events. RESULTS: Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes. CONCLUSIONS: There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN.

BACKGROUND: While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing. METHODS: Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom. RESULTS: Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time. CONCLUSIONS: This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint. TRIAL REGISTRATION: SAMURAI ( NCT02439320 ); SPARTAN ( NCT02605174 ).

Antenatal and perinatal factors influencing neonatal blood pressure: a systematic review.

OBJECTIVE: A comprehensive understanding of the factors contributing to perinatal blood pressure is vital to ensure optimal postnatal hemodynamic support. The objective of this study was to review existing literature on maternal and perinatal factors influencing blood pressure in neonates up to 3 months corrected age. METHODS: A systematic search of published literature in OVID Medline, OVID Embase and the COCHRANE library identified publications relating to maternal factors affecting blood pressure of neonates up to corrected age of 3 months. Summary data were extracted and compared (PROSPERO CRD42018092886). RESULTS: Of the 3683 non-duplicate publications identified, 44 were eligible for inclusion in this review. Topics elicited were sociodemographic factors, maternal health status, medications, smoking during pregnancy, and cord management at birth. Limited data were available for each factor. Results regarding the impact of these factors on neonatal blood pressure were inconsistent across studies. CONCLUSIONS: There is insufficient evidence to draw definitive conclusions regarding the impact of various maternal and perinatal factors on neonatal blood pressure. Future investigations of neonatal cardiovascular therapies should account for these factors in their study design. Similarly, studies on maternal diseases and perinatal interventions should include neonatal blood pressure as part of their primary or secondary analyses.

Tolerability and Safety of Lasmiditan Treatment in Elderly Patients With Migraine: Post Hoc Analyses From Randomized Studies.

PURPOSE: Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population. METHODS: These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing). FINDINGS: Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period. IMPLICATIONS: The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study.

This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient's current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with pulmonary arterial hypertension. Patients received tadalafil 20 mg or 40 mg based on their weight (heavy-weight: ≥40 kg; middle-weight: ≥25 to <40 kg) or placebo orally once daily for 24 weeks. Primary endpoint was change from baseline in six-minute walk distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results showed that patient demographics and baseline characteristics (N = 35; tadalafil = 17; placebo = 18) were comparable between treatment groups; median age was 14.2 years (6.2-17.9 years) and majority (71.4%, n = 25) of patients were in the heavy-weight cohort. Least square mean (standard error) changes from baseline in six-minute walk distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 (20.41) vs 36.60 (20.78) meters; placebo-adjusted mean difference (standard deviation) 23.88 (29.11)). Safety of tadalafil treatment was as expected without any new safety concerns. During study Period 1, two patients (one in each group) discontinued due to investigator's reported clinical worsening, and no deaths were reported. In conclusion, the statistical significance testing was not performed between the treatment groups due to low sample size; however, the study results show positive trend in improvement in non-invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with pulmonary arterial hypertension. Safety of tadalafil treatment was as expected without any new safety signals.

Lasmiditan efficacy in migraine attacks with mild vs. moderate or severe pain.

OBJECTIVE: To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity. METHODS: Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain. RESULTS: In SAMURAI and SPARTAN, most treated attacks were of moderate (N = 2768) or severe (N = 1147) intensity, compared to mild (N = 65). Numerically greater 2-h PF and 24-h SPF response rates were observed in attacks treated at mild compared to moderate or severe pain. Analysis of GLADIATOR data included 273 (1.5%), 11,644 (65.1%), and 5948 (33.3%) attacks treated when pain was mild, moderate, and severe, respectively. In general, a significantly greater proportion of attacks treated at mild pain achieved 2-h PF and MBS freedom, as well as 24-h SPF. The incidence of treatment-emergent adverse events in LTN treatment groups were similar regardless of baseline head pain intensity. CONCLUSIONS: Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials.

OBJECTIVE: Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT1F receptor agonist approved in the United States for the acute treatment of migraine. METHODS: In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). RESULTS: Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. CONCLUSIONS: The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

Method of Blood Pressure Measurement in Neonates and Infants: A Systematic Review and Analysis.

OBJECTIVES: To determine the recommended blood pressure (BP) measurement methods in neonates after systematically analyzing the literature regarding proper BP cuff size and measurement location and method. STUDY DESIGN: A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on BP in neonates <3 months of age (PROSPERO ID CRD42018092886). Study data were extracted and analyzed with separate analysis of Bland-Altman studies comparing measurement methods. RESULTS: Of 3587 nonduplicate publications identified, 34 were appropriate for inclusion in the analysis. Four studies evaluating BP cuff size support a recommendation for a cuff width to arm circumference ratio of approximately 0.5. Studies investigating measurement location identified the upper arm as the most accurate and least variable location for oscillometric BP measurement. Analysis of studies using Bland-Altman methods for comparison of intra-arterial to oscillometric BP measurement show that the 2 methods correlate best for mean arterial pressure, whereas systolic BP by the oscillometric method tends to overestimate intra-arterial systolic BP. Compared with intra-arterial methods, systolic BP, diastolic BP, and mean arterial pressure by oscillometric methods are less accurate and precise, especially in neonates with a mean arterial pressure <30 mm Hg. CONCLUSIONS: Proper BP measurement is critical in neonates with naturally lower BP and attention to BP cuff size, location, and method of measurement are essential. With decreasing use of intra-arterial catheters for long-term BP monitoring in neonates, further studies are urgently needed to validate and develop oscillometric methodology with enhanced accuracy.

Lasmiditan for the acute treatment of migraine: Subgroup analyses by prior response to triptans.

BACKGROUND: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. METHODS: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). RESULTS: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. CONCLUSIONS: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. TRIAL REGISTRATION: SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials.

OBJECTIVE: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications. BACKGROUND: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives. METHODS: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes. RESULTS: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications. CONCLUSIONS: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications. TRIAL REGISTRATION: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.

Enrollment of Neonates in More Than One Clinical Trial.

Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks' gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.

Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation.

Children represent a large underserved population of "therapeutic orphans," as an estimated 80% of children are treated off-label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or "borrowing") of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure-response information for antiepileptic drugs to pediatrics.

Use of Structural Equation Modeling to Demonstrate the Differential Impact of Storage and Voiding Lower Urinary Tract Symptoms on Symptom Bother and Quality of Life during Treatment for Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia.

PURPOSE: Lower urinary tract symptoms associated with benign prostatic hyperplasia typically respond well to medical therapy. While changes in total I-PSS (International Prostate Symptom Score) are generally accepted as measurement for treatment response, I-PSS storage and voiding subscores may not accurately reflect the influence of symptom improvement on patient bother and quality of life. MATERIALS AND METHODS: Structural equation modeling was done to evaluate physiological interrelationships measured by I-PSS storage vs voiding subscore questions and measure the magnitude of effects on bother using BII (Benign Prostatic Hyperplasia Impact Index) and quality of life on I-PSS quality of life questions. Pooled data from 4 randomized, controlled trials of tadalafil and placebo in 1,462 men with lower urinary tract symptoms/benign prostatic hyperplasia were used to investigate the relationship of storage vs voiding lower urinary tract symptoms on BII and quality of life. RESULTS: The final structural equation model demonstrated a sufficient fit to model interdependence of storage, voiding, bother and quality of life (probability for test of close fit <0.0001). Storage aspects had a twofold greater effect on voiding vs voiding aspects on storage (0.61 vs 0.28, each p <0.0001). The direct effect of storage on bother was twofold greater than voiding on bother (0.64 vs 0.29, each p <0.0001). Bother directly impacted quality of life by the largest magnitude of (-0.83), largely driven by storage lower urinary tract symptoms (p <0.0001). CONCLUSIONS: Total I-PSS is a reliable instrument to assess the therapeutic response in lower urinary tract symptoms/benign prostatic hyperplasia cases. However, an improvement in storage lower urinary tract symptoms is mainly responsible for improved bother and quality of life during treatment. Care should be taken when evaluating the accuracy of I-PSS subscores as indicators of the response to medical therapy.

Impact of Baseline Total Testosterone Level on Successful Treatment of Sexual Dysfunction in Men Taking Once-Daily Tadalafil 5 mg for Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: An Integrated Analysis of Three Randomized Controlled Trials.

INTRODUCTION: Controversy exists as to whether erectile response to phosphodiesterase type 5 inhibitors is compromised in men with low total testosterone (TT) levels. This is amplified by reports of improved response to phosphodiesterase type 5 inhibitor therapy after coadministration of testosterone replacement therapy in hypogonadal men unresponsive to phosphodiesterase type 5 inhibitors. AIM: To determine whether TT and luteinizing hormone levels influence efficacy of tadalafil for erectile dysfunction in men with concomitant lower urinary tract symptoms and benign prostatic hyperplasia. METHODS: This integrated analysis included 1,075 men randomized to once-daily tadalafil 5 mg (n = 540) or placebo (n = 535) for 12 weeks in three prospective clinical trials who had not received concomitant testosterone replacement therapy. Subjects were categorized at baseline by low vs normal TT levels (n = 1,049; <300 vs ≥300 ng/dL) and normal vs high luteinizing hormone levels (n = 1,058; ≤9.4 vs >9.4 mIU/mL). Treatment-group differences in International Index of Erectile Function (IIEF) by hormone subgroups were assessed using analysis of covariance. MAIN OUTCOME MEASURES: Changes in IIEF erectile function domain and other domain scores. RESULTS: The overall study population was comprised primarily of white men (>86%) with a mean age range of 64 to 70 years. Median baseline TT level in the integrated population was 355 ng/dL; levels were lower than 300 ng/dL (cutoff for normal) in 32.4% of men. Men with low TT levels reported diabetes (21.8%), cardiovascular disease (54.1%), and hypertension (49.1%) numerically more often than men with normal TT levels (10.6%, 43.2%, and 36.7%, respectively). Low TT and high luteinizing hormone levels were associated with numerically, but not statistically significantly, lower 12-week IIEF domain scores compared with those with normal levels. Changes in most 12-week IIEF domain scores showed that tadalafil was significantly more effective than placebo (P < .02). CONCLUSION: Low TT levels at baseline did not negatively influence response to tadalafil in men of advancing age with concomitant lower urinary tract symptoms and benign prostatic hyperplasia and erectile dysfunction.

Treatment satisfaction of men and partners following switch from on-demand phosphodiesterase type 5 inhibitor therapy to tadalafil 5 mg once daily.

INTRODUCTION: Treatment satisfaction of men receiving phosphodiesterase 5 inhibitors (PDE5) for erectile dysfunction (ED) and their partners is essential to successful long-term therapy. AIM: This study aims to assess treatment satisfaction, in men with a partial response to on-demand (PRN) PDE5 and their female partners, following tadalafil 5 mg once daily or placebo. METHODS: The study was randomized, double-blind, parallel, and placebo-controlled in men primarily with mild to moderate ED. Treatment satisfaction was assessed following a 4-week maximum dose PRN lead-in, 4-week nondrug washout, and treatment through 12 weeks. Men were ≥18 years old with ED for ≥3 months and International Index of Erectile Function Erectile Function score of ≥17 and <26 at screening and <26 following PRN lead-in. MAIN OUTCOME MEASURES: Treatment satisfaction was assessed using the Treatment Satisfaction Scale (TSS) for patients and partners. TSS domain scores range from 0 to 100, with higher values indicating greater satisfaction. Statistical comparisons were made using analysis of covariance. RESULTS: Treatment satisfaction was significantly greater with tadalafil once daily vs. placebo across all TSS domains for both patients and their partners (all P < 0.001). For patients, mean scores for the TSS domains Confidence to Complete Sexual Activity and Satisfaction with Orgasm ranged from 53.7 to 57.8 after the PRN lead-in and 26.7 to 31.9 following the nondrug washout. Following randomized treatment, scores for tadalafil and placebo were 55.4 and 32.6, respectively, for Confidence to Complete Sexual Activity and 57.5 and 37.9, respectively, for Satisfaction with Orgasm. Results were comparable for other TSS domains and between men and their partners. CONCLUSIONS: Treatment satisfaction was comparable for tadalafil 5 mg once daily and PRN PDE5 for both patients and female partners, suggesting that tadalafil once daily is a viable therapy option for men with ED who had a partial response to PRN PDE5 therapy.

Time to onset of clinically meaningful improvement with tadalafil 5 mg once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled from 4 pivotal, double-blind, placebo controlled studies.

PURPOSE: Tadalafil once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia consistently shows statistically significant I-PSS improvements. However, physicians and patients wish to know whether tadalafil provides rapid, clinically meaningful improvement in lower urinary tract symptoms. In this post hoc analysis we integrated results from 4 placebo controlled studies to determine the duration of tadalafil once daily required to achieve clinically meaningful improvement. MATERIALS AND METHODS: We performed post hoc analysis of data integrated from 4 double-blind studies of tadalafil 5 mg and placebo once daily in 742 and 735 men, respectively, 45 years old or older with total I-PSS 13 or greater. Two clinically meaningful improvement categories were assessed, including 1) 3-point or greater baseline to end point total I-PSS improvement and 2) 25% or greater baseline to end point total I-PSS improvement. I-PSS was assessed at weeks 4, 8 and 12 in all studies, week 1 in 2 and week 2 in 1. Results in men treated with tadalafil who showed clinically meaningful improvement (responders) were further examined to determine the earliest time to clinically meaningful improvement. RESULTS: Of 742 tadalafil treated patients 513 (69.1%) and 444 (59.8%) demonstrated category 1 and 2 clinically meaningful improvement, respectively, at the study end point. Of 234 category 1 responders with week 1 assessments 140 (59.8%) achieved clinically meaningful improvement by week 1 and 407 of the total of 513 category 1 responders (79.3%) showed it by week 4. Of the 205 category 2 responders with week 1 assessments 103 (50.2%) achieved clinically meaningful improvement by week 1 while 322 of the 444 category 2 responders (72.5%) did so by week 4. CONCLUSIONS: Tadalafil 5 mg once daily led to clinically meaningful improvement in approximately two-thirds of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. More than half of this group of tadalafil treated responders achieved clinically meaningful improvement after 1 week of therapy and more than 70% did so within 4 weeks.

Comparative efficacy of tadalafil once daily in men with erectile dysfunction who demonstrated previous partial responses to as-needed sildenafil, tadalafil, or vardenafil.

OBJECTIVE: Phosphodiesterase type-5 inhibitors (PDE5Is) are first-line therapies for erectile dysfunction (ED). Sildenafil (SIL) and vardenafil (VAR) are approved for as-needed (PRN) dosing; tadalafil (TAD) is approved for both PRN and once-a-day (OaD) dosing for ED. Recent evidence suggests that TAD-OaD may be effective as therapy in men with an incomplete response to PRN-PDE5I therapy. This study evaluated whether TAD-OaD provides similar efficacy in men with ED who had previously demonstrated a partial response to PRN-PDE5I therapy. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled trial, men with a ≥3 month ED history received SIL 100 mg, TAD 20 mg, or VAR 20 mg during a 4 week open-label lead-in period. Those with International Index of Erectile Function - Erectile Function (IIEF-EF) domain scores <26 following lead-in treatment completed a 4 week washout period, then randomized to TAD 2.5 mg up-titrated to 5 mg, TAD 5 mg, or placebo (PBO) OaD for 12 weeks. MAIN OUTCOME MEASURES obtained from patients treated with TAD-OaD were compared to PBO-treated patients. Additionally, results of treatment with TAD-OaD were compared to results obtained from 4 week PRN-PDE5I therapy to determine whether OaD and PRN regimens provided comparable efficacy. CLINICAL TRIAL REGISTRATION: NCT01130532. MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF) domain scores; Sexual Encounter Profile (SEP) questions 2-5. RESULTS: Endpoint data was obtained from 590 men (391 TAD; 199 PBO). RESULTS for all IIEF and SEP measures were significantly better for TAD-OaD (p < 0.001 for all) compared to PBO and were comparable to those observed during PRN-PDE5I treatment. TAD 2.5 mg and TAD 5 mg OaD therapy were safe and generally well tolerated. CONCLUSION: Tadalafil once daily is a viable alternative to as-needed PDE5I therapy in men with ED. Key limitations include the lack of a PRN PDE5I study group during the double-blind period, and that many more patients took tadalafil than sildenafil or vardenafil during the PRN period.

Comparability of single measurements of serum testosterone to the 24-hour C(avg) in patients using testosterone 2% solution.

INTRODUCTION: Efficacy of testosterone replacement therapy is determined by the proportion of men with 24-hour average serum testosterone concentration (Cavg ) in the normal range. In clinical practice, monitoring and dose adjustments are based on single testosterone measurements; however, how single measurements reflect Cavg is unclear. AIM: This post-hoc analysis evaluated whether single serum testosterone measurements and Cavg from the same day are both in the normal range in men receiving testosterone replacement therapy. METHODS: In an open-label, multicenter, titration trial, androgen-deficient men (N = 155) were started on 60-mg daily morning dose of testosterone 2% solution (Axiron®, Eli Lilly and Company, Indianapolis, Indiana, USA) applied to axillae (30 mg/axilla). Serum testosterone Cavg was determined on Days 15, 60, and 120. If necessary, dose was adjusted to maintain Cavg in the normal range (300-1,050 ng/dL). This analysis included subjects (n = 105) whose Cavg was within the normal range on Days 15, 60, and 120. MAIN OUTCOME MEASURES: Proportion of men with normal serum testosterone levels at 2, 4, or 8 hours post-dose on Days 15, 60, and 120. RESULTS: Greater than 93% of subjects had testosterone serum levels within the normal range 2, 4, or 8 hours post-dose on at least 1 day. In subjects with blood samples available from Days 15 and 60 or Days 15 and 120, 71.1% to 79.8% had normal levels at 2, 4, or 8 hours post-dose on both days, and in subjects with blood samples available from Days 15, 60, and 120, 63.9% to 68.8% had normal levels at 2, 4, or 8 hours post-application on all 3 days. CONCLUSION: Less than 70% of single testosterone measurements made on 3 separate days were concordant with same-day Cavg for all 3 days. These findings, which are specific for testosterone 2% solution, indicate that single measurements do not always reflect the 24-hour Cavg , and may possibly lead to inappropriate dose adjustments.