Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND: In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets. METHODS: In this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers. RESULTS: The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period. CONCLUSIONS: Among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317 .).

Efficacy and safety of sublingual tablets of house dust mite allergen extracts: Results of a dose-ranging study in an environmental exposure chamber.

BACKGROUND: In a natural field study, sublingual tablets of house dust mite (HDM) allergen extracts (STG320) were efficacious in treating HDM-associated allergic rhinitis. OBJECTIVES: We sought to assess the efficacy and safety of 3 doses of STG320 in an environmental exposure chamber. METHODS: In this randomized, double-blind study, adults with HDM-associated allergic rhinitis were given a daily sublingual tablet containing placebo or STG320 at a dose of 500IR, 300IR, or 100IR (IR, index of reactivity) for 6 months. Participants recorded their rhinitis symptoms during 4-hour HDM EEC challenges at randomization and months 1, 2, 4, and 6. The primary efficacy end point was the change from baseline to end of treatment in the area under the curve of the rhinitis total symptom score (ChBLAUCRTSS 0-4h). Differences from the placebo group were analyzed by analysis of covariance. Adverse events (AEs) and routine safety parameters were recorded. RESULTS: A total of 355 subjects were randomized to 1 of 4 groups: 500IR (n = 93), 300IR (n = 86), 100IR (n = 89), or placebo (n = 87). The least squares mean differences from placebo in ChBLAUCRTSS 0-4h for the 500IR, 300IR, and 100IR groups indicated a dose-dependent effect, with reductions in symptom scores of 33%, 29%, and 20%, respectively. The most frequent AEs were throat irritation and oral pruritus. There were no reports of anaphylaxis or reports consistent with severe laryngopharyngeal disorders and no use of epinephrine. AEs leading to premature discontinuations were more common in the 500IR group. CONCLUSIONS: A dose-dependent effect of sublingual HDM immunotherapy was demonstrated in this environmental exposure chamber study, supporting further development of this treatment.

Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis.

BACKGROUND: Preliminary studies have suggested the efficacy of sublingual tablets of house dust mite (HDM) extracts in adults with allergic rhinitis. OBJECTIVES: We sought to assess the efficacy and safety of 2 doses of HDM sublingual tablets over 1 treatment year and the subsequent immunotherapy-free year. METHODS: Adults with HDM-associated allergic rhinitis were randomized in a double-blind, placebo-controlled study to receive 500 index of reactivity (IR) tablets, 300IR tablets, or placebo administered once daily for 1 year and were followed for the subsequent year. The primary efficacy variable was the Average Adjusted Symptom Score over the year 1 primary period (ie, October 1 to December 31). Symptoms and rescue medication scores, onset of action, patient-reported outcomes, and safety were secondary variables. The same end points were evaluated during the immunotherapy-free year. The primary efficacy end point was analyzed by using analysis of covariance. RESULTS: Five hundred nine participants were randomized, and 427 continued in the immunotherapy-free year. Both the 500IR and 300IR HDM sublingual tablets significantly reduced mean Average Adjusted Symptom Scores compared with placebo by -20.2% (P = .0066) and -17.9% (P = .0150), respectively. Efficacy of both doses was maintained during the treatment-free follow-up phase. The onset of action was at 4 months. Participants' global evaluation of treatment success was significantly higher in the 500IR and 300IR groups compared with the placebo group (P = .0206 and P = .0001, respectively). Adverse events were generally application-site reactions. There were no reports of anaphylaxis. CONCLUSIONS: Twelve months of treatment with 500IR and 300IR sublingual tablets of HDM allergen extracts was efficacious and well tolerated. Efficacy was maintained during the treatment-free follow-up year.

Guideline for referral of patients with suspected lung cancer by family physicians and other primary care providers.

OBJECTIVE: The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicions about the presence of lung cancer in their patients. COMPOSITION OF THE COMMITTEE: Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network and from among the members of the Cancer Care Ontario Lung Cancer Disease Site Group. METHODS: This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations. REPORT: Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of lung cancer within the Canadian context. CONCLUSION: Earlier identification and referral of patients with lung cancer might ultimately help improve lung cancer morbidity and mortality. These guidelines might also be of value for informing the development of lung cancer diagnostic programs and for helping policy makers to ensure appropriate resources are in place.

Systematic review of guidelines for the management of suspected lung cancer in primary care.

OBJECTIVE: To systematically review the literature and provide an update and integration of existing peer-reviewed guidelines with recent systematic reviews and with primary studies related to the early recognition and management of lung cancer in primary care. DATA SOURCES: MEDLINE and EMBASE were searched for relevant articles. The quality of the evidence to support existing guideline recommendations, and the consistency of recommendations with updated evidence, were assessed. Applicability in a Canadian primary care setting was also evaluated. STUDY SELECTION: All studies that explored signs or symptoms of or risk factors for lung cancer in the primary care setting were included. All diagnostic studies in which symptomatic primary care patients underwent 1 or more investigations were also searched. SYNTHESIS: Recommendations were consistent among guidelines despite a paucity of supporting evidence. Updated evidence provided further support for the recommendations. Recommendations for identifying signs and symptoms of lung cancer presenting in primary care and for initial management can be adopted and applied within a Canadian primary care setting. CONCLUSION: This updated review of recommendations might help promote evidence-based practice and, ultimately, more timely management and improved prognosis for lung cancer patients. It might also assist in the development of lung cancer diagnostic assessment programs.

Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa.

PURPOSE: To assess the safety and efficacy of AAV5-hRKp.RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP). DESIGN: Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847). METHODS: Males (≥5 years old) with XLRP-RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR (low: 1.0 × 1011 vg/ml; intermediate: 2.0 × 1011 vg/ml; high: 4.0 × 1011 vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants. RESULTS: AAV5-hRKp.RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52. CONCLUSIONS: AAV5-hRKp.RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial.

Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE.

BACKGROUND: Previous trials have demonstrated the efficacy, safety, and optimal dosage of the 5-grass pollen sublingual tablet for adults and children with grass pollen-induced allergic rhinoconjunctivitis. OBJECTIVES: We sought to evaluate the efficacy and safety of 300 index of reactivity (IR) 5-grass pollen sublingual tablet in US adults. METHODS: Adults with grass pollen allergy and Rhinoconjunctivitis Total Symptom Scores of 12 or greater (scale, 0-18) during the previous grass pollen season were randomized in a double-blind, placebo-controlled study to receive 300IR 5-grass pollen sublingual tablet or placebo starting 4 months before and continuing through the pollen season. The primary efficacy end point was the daily Combined Score (CS; scale, 0-3), which integrates symptoms and rescue medication use. RESULTS: Four hundred seventy-three participants were randomized. The mean daily CS over the pollen period was significantly lower in the active treatment group versus the placebo group (least-squares mean difference: -0.13; 95% CI, -0.19 to -0.06; P = .0003; relative reduction: 28.2%; 95% CI, 13.0% to 43.4%). In placebo-treated participants, the daily CS least-squares mean was 0.32 in the subgroup with baseline timothy grass-specific serum IgE of less than 0.1 kU/L (n = 23) and 0.46 in those with baseline timothy grass-specific serum IgE of 0.1 kU/L or greater (n = 204). The most frequent reported adverse events were oral pruritus, throat irritation, and nasopharyngitis. There were no reports of anaphylaxis, and no actively treated participant received epinephrine. CONCLUSION: In US adults with grass pollen-induced allergic rhinoconjunctivitis, preseasonal and coseasonal treatment with 300IR 5-grass pollen sublingual tablet demonstrated clinically meaningful efficacy, especially in study subjects with measurable timothy grass-specific serum IgE. Use of 300IR 5-grass pollen sublingual tablet was safe and well tolerated. A requirement for a measurable level of allergen-specific serum IgE should be considered in future studies in this field.

Automated telecommunication to obtain longitudinal follow-up in a multicenter cross-sectional COPD study.

BACKGROUND: It can be challenging to maintain longitudinal follow-up of subjects in clinical studies. COPDGene is a multicenter, observational study designed to identify genetic factors associated with COPD and to characterize COPD-related phenotypes. To obtain follow-up data on patient's vital status and outcomes, the COPDGene Longitudinal Follow-up (LFU) Program was developed to supplement its parent study. METHODS/RESULTS: We used a telecommunication system that employed automated telephone contact or web-based questions to obtain longitudinal follow-up data in our subjects. A branching questionnaire asked about exacerbations, new therapies, smoking status, development of co-morbid conditions, and general health status. Study coordinators contacted subjects who did not respond to one of the automated methods. We enrolled 10,383 subjects in the COPDGene study. As of August 29, 2011, 7,959 subjects completed 19,955 surveys. On the first survey, 68.8% of subjects who completed their survey did so by electronic means, while 31.3% required coordinator phone follow-up. On each subsequent survey the number of subjects who completed their survey by electronic means increased, while the number of subjects who required coordinator follow-up decreased. Despite many of the patients in the cohort being chronically ill and elderly, there was broad acceptance of the system with over half the cohort using electronic response methods. CONCLUSIONS: The COPDGene LFU Study demonstrated that telecommunications was an effective way to obtain longitudinal follow-up of subjects in a large multicenter study. Web-based and automated phone contacts are accepted by research subjects and could serve as a model for LFU in future studies.

A Standardized Minimal Opioid Prescription Post-Thoracic Surgery Provides Adequate Pain Control.

BACKGROUND: Given the national opioid crisis, postoperative analgesia at discharge must be thoughtfully prescribed. Data specifically related to thoracic procedures remain scarce. This study assessed adequacy of pain control with standardized and limited opioids after thoracic procedures. METHODS: A standardized prescription comprised 15 hydromorphone tabs, 7 days of acetaminophen, and 3 days of ibuprofen was provided on discharge to elective thoracic surgery patients. On the first postoperative visit, patients completed a questionnaire regarding the number of hydromorphones used, use of additional opioids, pain-related limitation to function, and adequacy of pain control. RESULTS: A total of 122 patients undergoing thoracic surgery procedures were surveyed. Twelve underwent open procedures and were excluded. An additional 6 patients who used opioids chronically preoperatively were also excluded. The remaining 104 patients were included in the study. Median age was 66 years (age range, 17-90 years) and median length of stay was 2 days (range, 1-15 days). Seventeen (16%) patients used all prescribed hydromorphone and 56 (54%) used none, 18 (17%) asked for additional or other opioid, and 14 (13%) felt that their pain significantly limited their function. Nine (9%) felt that that their pain was inadequately controlled. CONCLUSIONS: Pain after thoracic procedures, especially video-assisted thoracoscopic surgery, is adequately controlled with minimal opioid doses (combined with adjuncts), with less than 1 in 5 patients requiring additional prescriptions and very few patients complaining of pain that significantly limited their function. This study shows that a standardized limited opioid prescription is safe, is adequate, and can easily be implemented for the majority of thoracic surgery patients.

Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma.

BACKGROUND: Although specific immunotherapy is a valuable treatment option for patients with allergic asthma, the potential for systemic allergic reactions has limited its use, especially for patients with symptomatic disease. OBJECTIVE: To evaluate omalizumab's effect on the tolerability of specific immunotherapy in patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids. METHODS: This multicenter, double-blind, parallel-group study randomized patients to treatment with omalizumab or placebo, after which they received specific immunotherapy to at least 1 of 3 perennial aeroallergens (cat, dog, and house dust mite) according to a 4-week, 18-injection cluster regimen, followed by 7 weeks of maintenance therapy. The primary efficacy variable, a systemic allergic reaction after immunotherapy, was analyzed by using the Cochrane-Mantel-Haenszel test. RESULTS: A total of 248 randomized patients (126 omalizumab, 122 placebo) received at least 1 dose of immunotherapy and were evaluated for efficacy. Patients receiving omalizumab experienced significantly fewer systemic allergic reactions to immunotherapy than those receiving placebo (17/126 [13.5%] vs 32/122 [26.2%]; P = .017; 95% CI, 2.91% to 22.56%) and had fewer respiratory-related (grade 3) systemic allergic reactions (6 vs 24, respectively). Grade 4 reactions were reported in 2 patients in each group. More omalizumab patients were able to reach the target maintenance immunotherapy dose (110 [87.3%] vs 88 [72.1%], respectively; P = .004). CONCLUSION: Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose.

Effectiveness of omalizumab in reducing corticosteroid burden in patients with moderate to severe persistent allergic asthma.

BACKGROUND: Asthma guidelines advocate maintaining asthma control while minimizing corticosteroid exposure. OBJECTIVE: To assess the reduction in corticosteroid burden during long-term treatment and the corresponding impact of this reduction on asthma control, lung function, and inflammation in patients with moderate to severe allergic asthma. METHODS: We conducted a pooled analysis (N = 1,071) of 2 similarly designed, randomized, double-blind, placebo-controlled omalizumab trials and their extension phases. Each study included a 16-week steroid-stable phase, a 12-week steroid-reduction phase, and a 24-week extension phase. Patients received subcutaneous omalizumab (minimum, 0.016 mg/kg/IU (IgE/mL) every 4 weeks) or placebo every 2 or 4 weeks. Outcomes included change from baseline in inhaled corticosteroid dose, number of oral corticosteroid bursts, and other clinical measures, including asthma exacerbations and change in asthma quality-of-life score (questionnaire), lung function, and eosinophil count. RESULTS: The median reduction from baseline in inhaled corticosteroid dose (beclomethasone dipropionate equivalent dose) by the completion of the extension phase was greater for the omalizumab group than for the placebo group (-420.0 vs -252.0 µg/d; P < .001). During that time, omalizumab-treated patients required fewer oral corticosteroid bursts overall for treatment of acute exacerbations (mean, 0.2 vs 0.3; relative risk, 0.56; 95% confidence interval, 0.41 to 0.76; P < .001) and demonstrated greater improvements in measures of asthma control. CONCLUSION: The addition of omalizumab to baseline therapy in patients 12 years or older with moderate to severe persistent allergic asthma resulted in a durable reduction in the overall steroid burden and improvement in other clinical measures of asthma control.

Efficacy of omalizumab in cat-allergic patients with moderate-to-severe persistent asthma.

Cat allergen (Fel d 1) is a pervasive and common trigger of exacerbations in sensitized patients with IgE-mediated asthma. This study was designed to evaluate the effect on asthma-related outcome measures of adding omalizumab to current treatment in patients with moderate-to-severe persistent asthma and cat allergen sensitivity. A pooled analysis was conducted of two double-blind, placebo-controlled, 28-week pivotal U.S. registration trials. In all patients, asthma was inadequately controlled with moderate-high dose inhaled corticosteroids. Patients were randomized to receive subcutaneous omalizumab (minimum, 0.016 mg/kg per IgE IU/mL every 4 weeks) or matched placebo. The effects of omalizumab on asthma-related outcomes were assessed for patients with cat allergen sensitivity (n = 811), identified by positive skin-prick test. The mean number of asthma exacerbations requiring treatment with systemic steroid bursts in cat allergen-sensitive patients was lower in those receiving omalizumab versus placebo (0.6 versus 1.3, respectively; relative risk = 0.50, p < 0.001). Compared with placebo, omalizumab treatment led to significantly lower asthma symptom scores (least squares means (LSMs) treatment difference [95% confidence interval {CI}]: -0.57 [-0.77, -0.37]; p < 0.001), less rescue medication use (LSMs treatment difference [95% CI]: -0.75 puffs of rescue beta-agonist per day [-1.04, -0.46]; p < 0.001), and improvement in forced expiratory volume in 1 second (LSMs treatment difference [95% CI]: 100.84 mL [51.86, 149.81]; p < 0.001). Patient and investigator global evaluations of treatment effectiveness paralleled these outcomes. Omalizumab improved asthma control by reducing exacerbations and decreasing symptoms in cat-allergic patients with moderate-to-severe persistent IgE-mediated asthma.

Treatment of chronic autoimmune urticaria with omalizumab.

BACKGROUND: Approximately 45% of patients with chronic urticaria have an IgG autoantibody directed to the alpha-subunit of the high-affinity IgE receptor (chronic autoimmune urticaria, CAU) leading to cutaneous mast cell and basophil activation. Treatment of allergic asthma with omalizumab produces rapid reduction in free IgE levels and subsequent decrease in Fc epsilon RI expression on mast cells and basophils. If this occurs in CAU, cross-linking of IgE receptors by autoantibody would be less likely, reducing cell activation and urticaria/angioedema. OBJECTIVE: To investigate the efficacy of omalizumab in patients with CAU symptomatic despite antihistamine therapy. METHODS: Twelve patients with CAU, identified by basophil histamine release assay and autologous skin test, with persistent symptoms for at least 6 weeks despite antihistamines, were treated with placebo for 4 weeks followed by omalizumab (>or=0.016 mg/kg/IU mL(-1) IgE per month) every 2 or 4 weeks for 16 weeks. Primary efficacy variable was change from baseline to the final 4 weeks of omalizumab treatment in mean Urticaria Activity Score (UAS, 0-9 scale). Changes in rescue medication use and quality of life were assessed. RESULTS: Mean UAS declined significantly from baseline to the final 4 weeks of omalizumab treatment (7.50 +/- 1.78 to 2.66 +/- 3.31, -4.84 +/- 2.86, P = .0002). Seven patients achieved complete symptom resolution. In 4 patients, mean UAS decreased, but urticaria persisted. One patient did not respond. Rescue medication use was reduced significantly, and quality of life improved. No adverse effects were reported or observed. CONCLUSION: This exploratory proof of concept study suggests omalizumab is an effective therapy for CAU resistant to antihistamines.

Hyperhidrosis: what is it and why does it occur?

Hyperhidrosis is excessive sweating in response to heat or emotional stimuli beyond physiologic need. The ailment is not new and has been described in the literature dating back several centuries. It can be classified as either primary or secondary based on its etiology. Mechanisms that cause excessive sweating can be traced to the sympathetic nervous system, part of the autonomic nervous system. It has been speculated that the primary abnormality is central, and that the hypothalamic sweat center that controls the palms, axillae, and soles is distinct in hyperhidrosis individuals.

A multicenter, randomized, double-blind, placebo-controlled, 8-week trial of the efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 25 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg in the treatment of moderate-to-severe essential hypertension.

BACKGROUND: Many patients with moderate-to-severe hypertension require multiple drug therapy to achieve blood-pressure goals. Fixed-dose combination therapy with losartan and hydrochlorothiazide may be useful in this population. OBJECTIVE: This study was conducted to obtain additional data on the antihypertensive efficacy and tolerability of once-daily, fixed-dose combinations of losartan and hydrochlorothiazide. METHODS: This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patients > or = 21 years of age with moderate-to-severe essential hypertension, defined as a mean trough sitting diastolic blood pressure (SiDBP) of 105 to 115 mm Hg, were randomly assigned in a 2:2:1 ratio to receive losartan 100 mg/hydrochlorothiazide 25 mg (L100/25), losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/12.5), or placebo (PBO) once daily for 8 weeks. The primary efficacy measurement was the mean change from baseline in trough SiDBP in the L100/25 versus L50/12.5 treatment groups. Responders were defined as patients with mean trough SiDBP <90 mm Hg or a > or = 10-mm Hg decrease in mean trough SiDBP. RESULTS: A total of 446 patients were randomly assigned to receive L100/25 (n = 173), L50/12.5 (n = 184), or PBO (n = 89). At week 8, mean trough SiDBP was significantly lower than at baseline in the L100/25 (-17.5 mm Hg), L50/12.5 (-15.2 mm Hg), and PBO groups (-8.5 mm Hg) (all P < 0.001). The difference between the active-treatment groups was statistically significant (-2.2 mm Hg; 95% Cl, range -3.8 to -0.6) (P = 0.006), as was the difference between the L100/25 and PBO groups (-9.0 mm Hg; 95% CI, range -I1.0 to -7.0) (P < 0.001) and the L50/12.5 and PBO groups (-6.7 mm Hg; 95% CI, range -8.7 to -4.8) (P < 0.001). At week 8, the percentages of responders were 86.7% (144 of 166), 78.9% (142 of 180), and 50.0% (42 of 84) in the L100/25, L50/12.5, and PBO groups, respectively. The incidence of adverse experiences (AEs) was 34.7% (60 of 173) in the L100/25 group, 23.9% (44 of 184) in the L50/12.5 group, and 32.6% (29 of 89) in the PBO group. The incidence of drug-related AEs was similar among the treatment groups (L100/25, 7.5% [13 of 173]; L50/12.5, 7.1% [13 of 184]; and PBO, 11.2% [10 of 89]). CONCLUSIONS: This study demonstrates the antihypertensive efficacy and tolerability of the once-daily, fixed-dose combination L50/12.5 in patients with moderate-to-severe essential hypertension. In this study, L100/25 provided additional anti-hypertensive efficacy beyond that of L50/12.5 (and both were more efficacious than PBO). Approximately 4 of 5 patients (78.9%) treated with L50/12.5 responded to therapy, as did nearly 9 of 10 patients (86.7%) treated with L100/25. The tolerability profiles of L50/12.5 and L100/25 were similar to that of PBO.

The effect of a losartan-based treatment regimen on isolated systolic hypertension.

This study was conducted to compare the antihypertensive efficacy and tolerability, over 12 weeks, of a losartan-based treatment regimen and placebo in patients with isolated systolic hypertension. Three hundred eight patients > or =35 years of age with isolated systolic hypertension, defined as trough sitting blood pressure between 140 and 200 mm Hg systolic and between 70 and 89 mm Hg diastolic, were randomized to losartan 50 mg (n=157) or placebo (n=151) once daily, with titration as necessary to achieve a goal trough sitting systolic blood pressure (SBP) <140 mm Hg. At baseline, mean trough sitting SBP was 140-159 mm Hg in 20.5% of patients, 160-179 mm Hg in 62.7%, and 180-200 mm Hg in 16.9%, and was similar in the two groups (losartan, 165.3 mm Hg; placebo, 166.1 mm Hg). At 12 weeks, mean trough sitting SBP decreased significantly (p<0.001) in both the losartan-based treatment group (by 19.2 mm Hg) and in the placebo group (by 7.6 mm Hg). The reduction in sitting SBP was significantly greater for losartan than placebo (-11.6 mm Hg; 95% confidence interval, -14.8 to -8.4). In patients with isolated systolic hypertension, a once-daily losartan-based treatment regimen significantly lowered SBP. The losartan-based regimen exhibited antihypertensive efficacy that was superior to that of placebo, with a similar tolerability profile.

Sustained efficacy and safety of a 300IR daily dose of a sublingual solution of birch pollen allergen extract in adults with allergic rhinoconjunctivitis: results of a double-blind, placebo-controlled study.

BACKGROUND: Allergic rhinoconjunctivitis (ARC) due to birch pollen is a growing health concern in Europe. Here, we report the efficacy and safety of 300IR birch pollen sublingual solution administered discontinuously for 2 consecutive years to patients with birch-associated allergic rhinoconjunctivitis. METHODS: Birch pollen-allergic adults were randomized in this double blind study to 300IR birch pollen sublingual solution or placebo, daily, starting 4 months before and continuing through the pollen season for two pollen seasons. Randomization was stratified according to the presence or absence of oral allergy syndrome (OAS). The primary efficacy endpoint was the Average Adjusted Symptom Score (AAdSS) over the second pollen season and was analyzed by ANCOVA. Secondary efficacy endpoints included the AAdSS over the first pollen period. Safety was evaluated by means of adverse event monitoring. RESULTS: 574 patients (284 in the active group and 290 in the placebo group) were randomized and 496 completed the study. Over the second pollen period, the least square (LS) mean AAdSS was significantly lower in the 300IR group than in the placebo group (LS mean difference -2.04, 95% CI [-2.69, -1.40], (p <0.0001) with a relative reduction of 30.6%. Results were consistent in patients with and without OAS (-33.6% and -28.4%, respectively). A significant reduction in LS mean AAdSS was also observed over the first pollen season. The most frequently reported adverse events were application site reactions: oral pruritus, throat irritation, and mouth edema. There were no reports of anaphylaxis. CONCLUSIONS: Pre- and co-seasonal treatment with 300IR birch pollen sublingual solution demonstrated sustained clinical efficacy over 2 pollen seasons and was well tolerated in adults with birch pollen-associated allergic rhinoconjunctivitis. Efficacy results were consistent in patients with and without oral allergy syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01731249.

Time to treat: a system redesign focusing on decreasing the time from suspicion of lung cancer to diagnosis.

INTRODUCTION: Multiple investigations often result in a lengthy process from the onset of lung cancer-related symptoms until diagnosis. An unpublished chart audit indicated suboptimal delays in patients' courses from onset of symptoms until diagnosis of cancer. METHODS: The Time to Treat Program was designed for patients with clinical or radiographic suspicion of lung cancer. Pre- and postimplementation data on median wait times were compared. RESULTS: From April 2005 to January 2007, 430 patients were referred. After Time to Treat Program implementation, the median time from suspicion of lung cancer to referral for specialist consultation decreased from 20 days to 6 days, and the median time from such referral to the actual consultation date decreased from 17 days to 4 days. The median time from specialist consultation to computed tomography scan decreased from 52 days to 3 days, and the median time from computed tomography scan to diagnosis decreased from 39 days to 6 days. Overall, the median time from suspicion of lung cancer to diagnosis decreased from 128 days to 20 days. Of all patients in the Time to Treat Program, 33% were eventually diagnosed with lung cancer. CONCLUSIONS: Time to Treat Program was effective in shortening the time from suspicion of lung cancer to diagnosis and reduced time intervals at each step in the process. Earlier diagnosis of lung cancer may allow increased treatment options for patients and may improve outcomes.