Effects of fremanezumab on the use of acute headache medication and associated symptoms of migraine in patients with episodic migraine.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody targeting calcitonin gene-related peptide, has demonstrated efficacy for the preventive treatment of migraine in adults. OBJECTIVE: To evaluate the effect of fremanezumab treatment on acute headache medication use and migraine-associated symptoms in patients with episodic migraine. METHODS: In the Phase 3 HALO trial, patients with episodic migraine were randomized to receive subcutaneous fremanezumab monthly (225 mg at baseline, weeks 4 and 8), fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), or placebo over a 12-week period. The secondary endpoint was change from baseline in the monthly number of days with use of any acute headache mediation or migraine-specific acute headache medication; exploratory endpoints were change from baseline in the monthly number of days with nausea or vomiting, photophobia, or phonophobia. RESULTS: Of 875 patients randomized, 865 were included in the analysis (monthly, n = 287; quarterly, n = 288; placebo, n = 290). Baseline mean ± standard deviation days with: Any acute headache medication use (monthly: 7.7 ± 3.4; quarterly: 7.8 ± 3.7; placebo: 7.7 ± 3.6), migraine-specific acute headache medication use (6.1 ± 3.1; 6.6 ± 3.1; 7.1 ± 3.0), nausea or vomiting (4.5 ± 3.6; 4.9 ± 3.7; 4.5 ± 3.3) and photophobia and phonophobia (5.5 ± 4.1; 6.3 ± 4.1; 6.0 ± 3.9) were similar among treatment arms. Fremanezumab reduced the number of days of acute headache medication use ([least-squares mean change vs. placebo] monthly: -1.4 [95% confidence interval: -1.84, -0.89], p < 0.001; quarterly: -1.3 [-1.76, -0.82], p < 0.001) and migraine-specific acute headache medication use (monthly: -2.2 [-2.80, -1.56], p < 0.001; quarterly: -2.2 [-2.81, -1.58], p < 0.001) compared with placebo. Fremanezumab also reduced nausea or vomiting, photophobia, and phonophobia compared with placebo. CONCLUSIONS: Fremanezumab reduced the need for acute headache medications, including migraine-specific medications, while treating migraine-associated symptoms in patients with episodic migraine. TRIAL REGISTRATION: Clinicaltrials.gov NCT02629861.

Early Onset of Efficacy With Fremanezumab for the Preventive Treatment of Chronic Migraine.

OBJECTIVE: To assess the onset of efficacy for fremanezumab in chronic migraine by evaluating pain-related clinical measures at different time points. BACKGROUND: Faster onset of efficacy of preventive treatments could benefit patients with migraine. Fremanezumab is a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine. In 12-week clinical trials, subcutaneous fremanezumab significantly reduced the frequency of migraine headaches, headache hours, and headaches in general, without serious treatment-related adverse events. New drug classes of migraine preventive treatment demonstrate markedly different clinical profiles from standard-of-care treatments. METHODS: In this double-blind phase III study, eligible patients were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline, 225 mg at weeks 4 and 8), or placebo at each time point. This study included secondary, exploratory, and post hoc analyses of the primary trial, evaluating the change in headache days of at least moderate severity or migraine days during the first 4 weeks of the trial. RESULTS: A total of 1130 patients were randomized (fremanezumab quarterly, n = 376; fremanezumab monthly, n = 379; or placebo, n = 375). During the 4-week period after the first dose, the mean number of monthly headache days of at least moderate severity was reduced for the all-fremanezumab group (mean reduction [95% confidence interval]: -4.6 days [-5.1, -4.1]) compared with the placebo group (-2.3 days [-2.9, -1.6]; P < .0001). Treatment effects were observed at Week 1 for the all-fremanezumab group (-1.1 days [-1.3, -1.0]) vs placebo (-0.5 days [-0.7, -0.3]; P < .0001), with separation from placebo by Day 2 (P = .003). Similar effects were observed for the monthly average number of migraine days and mean number of monthly headache hours. CONCLUSIONS: The early onset of efficacy of fremanezumab may have the potential to improve patient compliance and clinical outcomes.

Fremanezumab for preventive treatment of migraine: Functional status on headache-free days.

OBJECTIVE: To evaluate the effect of fremanezumab on the functional status on headache-free days in phase 2 episodic migraine (EM) and chronic migraine (CM) studies. METHODS: Functional status data were collected prospectively via the electronic headache diary on all headache-free days by patients answering questions regarding work/school/household chore performance, speed of work completion, concentration, and feeling of fatigue. Individuals with EM receiving monthly doses of fremanezumab 225 mg (n = 96) or 675 mg (n = 97) or placebo (n = 104) were compared. Individuals with CM receiving fremanezumab 675 mg followed by monthly 225 mg (n = 88) and 900 mg (n = 86) were also independently compared to those receiving placebo (n = 89). RESULTS: In patients with EM, compared to patients receiving placebo, those receiving fremanezumab experienced an increased number of headache-free days with normal function in work/school/household chore performance and concentration/mental fatigue measures compared to their baseline over the entire treatment period (all p < 0.005). An increased number of headache-free days with normal functional performance for some measures was also found in the CM group in those treated with fremanezumab. CONCLUSION: There was an increased number of headache-free days with normal functional performance on all measures for the patients with EM and some measures for patients with CM in the fremanezumab-treated groups. Further research is required to confirm these findings in a prospective study and to clarify the underlying mechanism(s). CLINICALTRIALSGOV IDENTIFIER: NCT02025556 and NCT02021773. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with migraine, fremanezumab increases normal functional performance on headache-free days.

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial.

Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and Setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main Outcomes and Measures: The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and Relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02629861.

Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective: To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design: Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting: One US site. Subjects: Healthy, adult, nondependent, recreational opioid users. Methods: Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on "at the moment" Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results: Mean maximum effect for "at the moment" Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled "at the moment" Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions: The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Fremanezumab for the Preventive Treatment of Chronic Migraine.

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .).

Evaluation of Quality of Life, Functioning, Disability, and Work/School Productivity Following Treatment with an Extended-Release Hydrocodone Tablet Formulated with Abuse-Deterrence Technology: A 12-month Open-label Study in Patients with Chronic Pain.

BACKGROUND: This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA® Abuse-Deterrence Technology platform. METHODS: Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory-Short Form (BPI-SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire-Short Form (HPQ-SF). RESULTS: Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI-SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ-SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. CONCLUSIONS: Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study.

Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective: To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA ® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design: Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients: One study site in the United States; adult nondependent, recreational opioid users. Methods: After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was "at the moment" drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results: Mean maximum effect (E max ) for "at the moment" drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (E max : 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective "at the moment" drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions: The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points.

OBJECTIVE: To evaluate the onset of efficacy of TEV-48125, a monoclonal antibody against calcitonin gene-related peptide, recently shown to be effective for the preventive treatment of chronic migraine (CM) and high-frequency episodic migraine. METHODS: A randomized placebo-controlled study tested once-monthly injections of TEV-48125 675/225 mg or 900 mg vs placebo. Headache information was captured daily using an electronic headache diary. The primary endpoint was change from baseline in the number of headache hours in month 3. Herein, we assess the efficacy of each dose at earlier time points. RESULTS: The sample consisted of 261 patients. For headache hours, the 675/225-mg dose separated from placebo on day 7 and the 900-mg dose separated from placebo after 3 days of therapy (p = 0.048 and p = 0.033, respectively). For both the 675/225-mg and 900-mg doses, the improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025 and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p = 0.0057). For change in weekly headache days of at least moderate intensity, both doses were superior to placebo at week 2 (p = 0.031 and p = 0.005). CONCLUSIONS: TEV-48125 demonstrated a significant improvement within 1 week of therapy initiation in patients with CM. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with CM, TEV-48125 significantly decreases the number of headache hours within 3 to 7 days of injection.

Six-month, open-label study of hydrocodone extended release formulated with abuse-deterrence technology: Safety, maintenance of analgesia, and abuse potential.

OBJECTIVE: To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA® Abuse-Deterrence Technology. DESIGN: Phase 3, multicenter, open-label extension. SETTING: Fifty-six US centers. PATIENTS: Adults with chronic low back pain completing a 12-week placebocontrolled study of abuse-deterrent hydrocodone ER were eligible. One hundred eighty-two patients enrolled and received ≥1 dose of study drug, 170 entered openlabel treatment, and 136 completed the study. INTERVENTIONS: Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n=78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment. SAFETY: adverse events (AEs). Maintenance of analgesia: worst pain intensity (WPI) and average pain intensity (API) at each study visit. Aberrant drug behavior: study drug loss and diversion. RESULTS: AEs were reported for 65/182 (36 percent) patients during dose titration/ adjustment and 88/170 (52 percent) during open-label treatment. No treatmentrelated serious AEs were reported. There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry. One patient receiving hydrocodone ER 30 mg twice daily experienced a severe AE of neurosensory deafness that was considered treatment related. Mean WPI and API remained steady throughout open-label treatment. Six (3 percent) patients reported medication loss, and 5 (3 percent) reported diversion. CONCLUSIONS: Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Twelve-month, open-label assessment of long-term safety and abuse potential of hydrocodone extended-release formulated with abuse-deterrence technology in patients with chronic pain.

OBJECTIVE: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA(®) Abuse-Deterrence Technology platform. DESIGN: Phase 3, open-label study. SETTING: Sixty-one US study centers. PATIENTS: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study. INTERVENTION: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received ≤ 52 weeks of open-label treatment. SAFETY: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control. RESULTS: Of 329 patients who received ≥ 1 hydrocodone ER dose, 284 (86 percent) reported ≥ 1 AE and 27 (8 percent) experienced ≥ 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low. CONCLUSIONS: Hydrocodone ER demonstrated acceptable safety when administered for ≤ 12 months in patients with chronic pain. Low occurrence of aberrant drugrelated behavior may support the abuse-deterrence properties of hydrocodone ER.

Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study.

BACKGROUND: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. METHODS: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. FINDINGS: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. INTERPRETATION: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. FUNDING: Teva Pharmaceuticals.

Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556. FINDINGS: Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively. INTERPRETATION: TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials. FUNDING: Teva Pharmaceuticals.

Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction--a 21-day treatment-randomized clinical trial.

Alvimopan has been shown to reverse the inhibitory effect of opioids on gastrointestinal transit without affecting analgesia. We evaluated oral alvimopan, 0.5 or 1 mg, versus placebo, once daily for 21 days, in 168 patients with opioid-induced bowel dysfunction (OBD) who were receiving chronic opioid therapy (minimum, 1 month) for nonmalignant pain (n = 148) or opioid dependence (n = 20). The primary outcome was the proportion of patients having at least one bowel movement (BM) within 8 hours of study drug on each day during the 21-day treatment period. Averaged over the 21-day treatment period, 54%, 43%, and 29% of patients had a BM within 8 hours after alvimopan 1 mg, 0.5 mg, or placebo, respectively (P < .001). Secondary outcomes of median times to first BM were 3, 7, and 21 hours after initial doses of 1 mg, 0.5 mg, and placebo, respectively (P < .001; 1 mg vs placebo). Weekly BMs and overall patient satisfaction were increased after the 1-mg dose (P < .001 at weeks 1 and 2 vs placebo, and P = .046, respectively). Treatment-emergent adverse events were primarily bowel-related, occurred during the first week of treatment, and were of mild to moderate severity. Alvimopan was generally well tolerated and did not antagonize opioid analgesia. Patients treated with chronic opioid therapy often experience opioid-induced bowel dysfunction as a result of undesirable effects on peripheral opioid receptors located in the gastrointestinal tract. Alvimopan, a novel peripheral opioid mu-receptor antagonist, has demonstrated significant efficacy for the management of opioid-induced bowel dysfunction without compromise of centrally mediated opioid-induced analgesia.