CRISPR-Cas9 Gene Editing for Sickle Cell Disease and ß-Thalassemia.

Transfusion-dependent ß-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).

Evaluation of Homology-Independent CRISPR-Cas9 Off-Target Assessment Methods.

The ability to alter genomes specifically by CRISPR-Cas gene editing has revolutionized biological research, biotechnology, and medicine. Broad therapeutic application of this technology, however, will require thorough preclinical assessment of off-target editing by homology-based prediction coupled with reliable methods for detecting off-target editing. Several off-target site nomination assays exist, but careful comparison is needed to ascertain their relative strengths and weaknesses. In this study, HEK293T cells were treated with Streptococcus pyogenes Cas9 and eight guide RNAs with varying levels of predicted promiscuity in order to compare the performance of three homology-independent off-target nomination methods: the cell-based assay, GUIDE-seq, and the biochemical assays CIRCLE-seq and SITE-seq. The three methods were benchmarked by sequencing 75,000 homology-nominated sites using hybrid capture followed by high-throughput sequencing, providing the most comprehensive assessment of such methods to date. The three methods performed similarly in nominating sequence-confirmed off-target sites, but with large differences in the total number of sites nominated. When combined with homology-dependent nomination methods and confirmation by sequencing, all three off-target nomination methods provide a comprehensive assessment of off-target activity. GUIDE-seq's low false-positive rate and the high correlation of its signal with observed editing highlight its suitability for nominating off-target sites for ex vivo CRISPR-Cas therapies.

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.

BACKGROUND: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours. METHODS: Tumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. RESULTS: Patients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients. CONCLUSIONS: Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm.

Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease.

OBJECTIVE: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. METHODS: This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3). RESULTS: The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (-0.41, 2.94), preladenant 10 mg = 0.40 (-1.29, 2.11), and rasagiline 1 mg = 0.30 (-1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%). CONCLUSIONS: No evidence supporting the efficacy of preladenant as monotherapy was observed in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT01155479. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study.

Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.

Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting.

To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had >80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo- and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.

Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization.

Purpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib.Experimental Design: A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as <3 months. Molecular analyses included germline BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort.Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (>42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation.Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. Clin Cancer Res; 23(15); 4086-94. ©2017 AACR.

Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial.

CONTEXT: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS. OBJECTIVE: The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS. DESIGN: This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial. SETTINGS: University hospitals and private clinical research centers were included. PARTICIPANTS: Women with PCOS aged 18-45 years participated. INTERVENTION: Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days. MAIN OUTCOME MEASURE: Change from baseline in the area under the LH serum concentration-time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured. RESULTS: Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6-67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9-40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0-5.1) (all nominal P < .05). CONCLUSIONS: The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

AIM: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. METHODS: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and ≥ 5 moderate or severe migraines per month prior to entering the trial. RESULTS: Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥ 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥ 8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001). CONCLUSIONS: Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.

IMPORTANCE: Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. OBJECTIVE: To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations. INTERVENTIONS: In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in off time from baseline to week 12. RESULTS: In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo). CONCLUSIONS AND RELEVANCE: In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01155466 and NCT01227265.

Outcomes and endpoints in cancer trials: bridging the divide.

Cancer is not one disease. Outcomes and endpoints in trials should incorporate the therapeutic modality and cancer type because these factors affect clinician and patient expectations. In this Review, we discuss how to: define the importance of endpoints; make endpoints understandable to patients; improve the use of patient-reported outcomes; advance endpoints to parallel changes in trial design and therapeutic interventions; and integrate these improvements into trials and practice. Endpoints need to reflect benefit to patients, and show that changes in tumour size either in absolute terms (response and progression) or relative to control (progression) are clinically relevant. Improvements in trial design should be accompanied by improvements in available endpoints. Stakeholders need to come together to determine the best approach for research that ensures accountability and optimises the use of available resources.

Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.

Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention.

OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom). RESULTS: The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥ 1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all in the telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥ 3 × the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥ 3 × the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2-6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = -2.9, 280 mg = -3.1, placebo = -1.7; p < 0.05) and migraine/probable migraine days (month 1: 140 mg = -2.7, 280 mg = -3.0, placebo = -1.6; p < 0.05). CONCLUSIONS: These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of telcagepant for daily administration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

Long-term open-label safety study of rizatriptan acute treatment in pediatric migraineurs.

OBJECTIVE: To evaluate the safety/tolerability of rizatriptan in the long-term acute treatment of migraine in pediatric patients. BACKGROUND: Acute migraine treatment options for children are limited. A recent single-attack trial demonstrated that rizatriptan is effective in eliminating migraine headache pain in this population. We evaluated the long-term safety and efficacy of rizatriptan when used for intermittent acute treatment. METHODS: Open-label study in pediatric migraineurs ages 12-17 years. Patients weighing <40 kg received rizatriptan (orally disintegrating tablet) 5 mg, and those weighing ≥40 kg received 10 mg. Patients could treat up to 8 mild/moderate/severe migraine attacks per month for up to 12 months. One dose of study medication was allowed in a 24-hour period. RESULTS: A total of 674 patients were enrolled, and 606 patients were treated with study medication (N = 583 for 10 mg, N = 23 for 5 mg). The mean duration in the study was 292 days, and the mean number of doses of study medication taken was 20. Over the course of the study within 14 days post-any-dose, 66.0% (400) of the 606 treated patients had any adverse event, 2.3% (14) discontinued due to an adverse event, 2.6% (16) had a serious adverse event, and 23.4% (142) had a triptan-related adverse event. Of the 16 patients with serious adverse events within 14 days post-any-dose, the adverse events in 3 were considered drug-related; all 3 patient's adverse events were classified as serious only because they were associated with an overdose (use of >1 dose of study medication in a 24-hour period). The mean percentage of patient's attacks with pain freedom at 2-hours post-dose was 46.3%; this was relatively consistent over time (Months 1-3 = 43.7%, Months 4-6 = 51.9%, Months 7-9 = 49.9%, Months 10-12 = 49.5%). CONCLUSION: Rizatriptan was generally safe and well tolerated in the long-term acute treatment of migraine in pediatric patients aged 12-17 years and demonstrated a consistent treatment effect over time.

Results of a 2-year retrospective cohort study of newly prescribed triptan users in European nationwide practice databases.

OBJECTIVE: This study was conducted to characterize prescription refill patterns for triptans among European patients with new prescriptions of triptans. BACKGROUND: Persistency with prescriptions of triptan monotherapy for migraine headache among newly prescribed users in European primary-care practices has not been well described. METHODS: Using electronic medical databases in the UK (N = 3618), France (N = 2051) and Germany (N = 954), we conducted a retrospective cohort analysis to identify refill patterns over 2 years among migraineurs receiving new prescriptions of triptan monotherapy in 2006. RESULTS: Of all patients, >33% of migraineurs with new triptan prescriptions received ≥1 refill of their index triptan prescriptions (UK, 44.3%; France, 34.2%; Germany, 37.7%). More than 50% never received index-triptan refill prescriptions (UK, 55.7%; France, 65.8%; Germany, 63.3%). Small proportions of patients (<7.0%) switched to alternative triptans, and even fewer switched to different prescription-medication classes (UK and Germany, 2.3%; France, 4.0%). More than 48% of patients received no further prescriptions for migraine after index prescriptions (UK, 48.5%; France, 54.9%; Germany, 54.7%). After the second year, >83.0% of patients in each country had no further prescriptions for migraine medications, <14.0% remained persistent with index prescriptions, <4.0% switched to other triptans, and <3.0% switched to alternative medication classes. CONCLUSIONS: In migraine patients who received new prescriptions of triptan monotherapy from their primary-care physicians, poor triptan prescription refill frequency was observed in Europe. Although consistent with potential clinical challenges in migraine management, our findings should be interpreted with caution given certain inherent limitations associated with the database study design. Further research is warranted to confirm our findings and to identify reasons for, or predictors of, triptan discontinuation.

Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design.

BACKGROUND: Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for < 40 kg, 10 mg for ≥ 40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12-17-year-olds. RESULTS: A higher proportion of 12-17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12-17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6-17-year-olds. CONCLUSION: Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12-17 and 6-17 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001234.

Randomized clinical trial of the efficacy and safety of preservative-free tafluprost and timolol in patients with open-angle glaucoma or ocular hypertension.

PURPOSE: To compare the efficacy and safety of tafluprost, a preservative-free (PF) prostaglandin analogue, with PF timolol in patients with open-angle glaucoma or ocular hypertension. DESIGN: Randomized, double-masked, multicenter clinical trial. METHODS: After discontinuation and washout of existing ocular hypotensive treatment, patients who had intraocular pressure (IOP) ≥23 and ≤36 mm Hg in at least 1 eye at the 08:00 hour time point were randomized 1:1 to 12 weeks of treatment with either PF tafluprost 0.0015% or PF timolol 0.5%. IOP was measured 3 times during the day (08:00, 10:00, 16:00 hours) at baseline and at weeks 2, 6, and 12. It was hypothesized that PF tafluprost would be noninferior to PF timolol over 12 weeks with regard to change from baseline IOP. The trial was powered for a noninferiority margin of 1.5 mm Hg at each of the 9 time points assessed. RESULTS: A total of 643 patients were randomized and 618 completed (PF tafluprost = 306, PF timolol = 312). IOPs at the 3 time points assessed during the baseline visit ranged from 23.8 to 26.1 mm Hg in the PF tafluprost group and 23.5 to 26.0 mm Hg in the PF timolol group. IOPs at the 3 time points assessed during the 12-week visit ranged from 17.4 to 18.6 mm Hg for PF tafluprost and 17.9 to 18.5 mm Hg for PF timolol. At all 9 time points, the upper limits of the 2-sided 95% confidence intervals for the difference between treatments in IOP lowering were less than the prespecified noninferiority margin. Similar percentages of PF tafluprost and PF timolol patients reported ocular pain/stinging/irritation (4.4% vs 4.6%) and pruritus (2.5% vs 1.5%). The percentages of PF tafluprost and PF timolol patients reporting conjunctival hyperemia were 4.4% vs 1.2% (nominal P = .016). CONCLUSIONS: The IOP-lowering effect of PF tafluprost was noninferior to that of PF timolol. PF tafluprost is an efficacious and generally well-tolerated ocular hypotensive agent.

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease.

OBJECTIVE: To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. BACKGROUND: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. METHODS: Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. RESULTS: One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. CONCLUSION: The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.

Rizatriptan for treatment of acute migraine in patients taking topiramate for migraine prophylaxis.

OBJECTIVE: To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis. BACKGROUND: There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication. METHODS: This was a worldwide, randomized, placebo-controlled, double-blind, multiple-attack study in adults with a >1-year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10-mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2-hour pain relief. RESULTS: Two-hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2-24 hours (32.6% vs 11.1%, P < .001), 2-hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 [15.8%] with rizatriptan, 3 [3.2%] with placebo); none were serious. CONCLUSION: Rizatriptan 10-mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.