Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 217;377: DOI: 1.156/NEJMoa175848

2 1 Table of Contents METHODS 3 Study Sites 3 Study Exclusion Criteria 3 Term Definition 5 Trial Assessments and Safety Evaluations 5 Statistical Analysis 6 Sample size 6 Primary and Continuous Secondary Endpoint Analysis 7 Sensitivity Analysis 8 SUPPLEMENTARY FIGURES 9 S1: Patient disposition 9 S2: Changes from baseline in monthly acute migraine specific medication treatment days 1 S3: Change from baseline in monthly MPFID-EA score 11 S4: Change from baseline in monthly MPFID-PI score 12 SUPPLEMENTARY TABLES 13 Table S1: Supplementary baseline characteristics 13 Table S2: Change from baseline in mean monthly migraine days, mean monthly acute migraine specific medication treatment days, mean MPFID domain scores (MPFID-PI and MPFID-EA), and 5% responder rates at weeks 4, 8, 12, 16, 2, and 24 14

3 2 Table S3: Serious adverse events 16 Table S4: Liver function abnormalities during the double-blind treatment phase 18 Supplementary References 2

4 3 Methods Study Sites Patients were enrolled from 121 sites across North America (Canada, USA), Europe (Austria, Belgium, Czech Republic, Finland, Germany, Netherlands, Poland, Slovakia, Sweden, and United Kingdom), and Turkey. Study Exclusion Criteria Patients were excluded if they had no therapeutic response in migraine prevention after an adequate therapeutic trial of >2 of the following medication categories: Category 1: Divalproex sodium, sodium valproate Category 2: Topiramate Category 3: Beta blockers Category 4: Tricyclic antidepressants Category 5: Serotonin-norepinephrine reuptake inhibitors Category 6: Flunarizine, verapamil Category 7: Lisinopril, candesartan No therapeutic response was defined as no reduction in headache frequency, duration, or severity after administration of the medication for 6 weeks at the generally accepted therapeutic dose(s) based on the investigator s assessment. Lack of sustained response to a medication and failure to tolerate a therapeutic dose was not considered to be no therapeutic response.

5 4 The following medications, devices, or procedures were excluded: Botulinum toxin (in the head and/or neck region) is excluded within 4 months before the start of the baseline phase and throughout the study Ergotamine derivatives, steroids, and triptans used for migraine prophylaxis are excluded within 2 months before the start of the baseline phase and throughout the study Devices and procedures used for migraine prophylaxis are excluded within 2 months before the start of the baseline phase and throughout the study Investigational medications and devices are excluded throughout the study Patients also must not have used investigational medications or devices for at least 9 days prior to screening Patients who were concomitantly using 2 of the following medications for migraine prevention within 2 months before the start of the baseline phase and throughout the study were excluded: Divalproex sodium, sodium valproate, topiramate, carbamazepine, gabapentin Beta blockers Tricyclic antidepressants Venlafaxine, desvenlafaxine, duloxetine, milnacipran Flunarizine, verapamil, lomerizine Lisinopril, candesartan Clonidine, guanfacine

6 5 Cyproheptadine Methysergide Pizotifen Butterbur, feverfew, magnesium ( 6 mg/day), riboflavin ( 1 mg/day) Use of one medication was permitted if the dose was stable within 2 months before the start of the baseline phase and throughout the study. Term Definition A migraine day in this study was defined as follows: Any calendar day in which the patient experiences a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache is defined as a migraine with or without aura, lasting for 3 minutes, and meeting at least one of the following criteria (a and/or b): a) 2 of the following pain features: unilateral, throbbing, moderate to severe, exacerbated with exercise/physical activity b) 1 of the following associated symptoms: nausea and/or vomiting, photophobia, and phonophobia Trial Assessments and Safety Evaluations A central laboratory was used to process samples for serum chemistry, urinalysis, and hematology.

7 6 The following analytes were evaluated by the central laboratory: Serum Chemistry: Sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, magnesium, phosphorus, glucose, blood urea nitrogen or urea, creatinine, uric acid, total bilirubin, direct bilirubin, Alkaline phosphatase, aspartate aminotransferase (serum glutamic oxaloacetic transaminase), alanine aminotransferase (serum glutamic pyruvic transaminase), cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, creatine phosphokinase, estimated glomerular filtration rate modification of diet in renal disease Urinalysis: Specific gravity, ph, blood, protein, glucose, bilirubin, white blood cells (WBC), red blood cells (RBC), epithelial cells, bacteria, casts, crystals Hematology: RBC, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red cell distribution width, reticulocytes, platelets, WBC, WBC differential (bands/stabs, neutrophils, eosinophils, basophils, lymphocytes, monocytes, myeloblasts, promyelocytes, myelocytes, metamyelocytes, atypical lymphocytes), nucleated RBC Other laboratories were used to process further laboratory samples, including serum for antierenumab antibodies, urine for drug screening, and urine and serum for pregnancy testing. Statistical Analysis Sample Size A planned enrollment of 284 patients per treatment group provided 9% power to detect treatment differences of 1.12 monthly migraine days for erenumab 7 mg and 1.3 monthly

8 7 migraine days for erenumab 14 mg versus placebo, with a common standard deviation (SD) of 3.78, using two-sided tests at the 5% significance level. This sample size calculation assumed a 1% dropout rate. The assumed treatment effect was based on results observed in the phase 2 trial of erenumab in episodic migraine. 1 Primary and Continuous Secondary Endpoint Analysis The primary endpoint and continuous secondary endpoints were analyzed using a linear mixed-effects model including treatment group, baseline value, stratification factors, scheduled visit, and the interaction of treatment group with scheduled visit. Multiplicity Adjustment Method for the Primary and Secondary Endpoints To maintain the family-wise type 1 error rate of.5, a hierarchical gate-keeping procedure and Hochberg method was used. The primary endpoint was tested separately for each erenumab dose, at a significance level of.4 for erenumab 7 mg and.1 for erenumab 14 mg. The first-tier secondary endpoints were tested separately using the Hochberg method at a significance level of.4 for erenumab 7 mg and.1 for erenumab 14 mg, if the primary endpoint comparison was considered statistically significant. If the first tier secondary endpoints were significantly different from placebo for both doses of erenumab, the second tier secondary endpoints for the erenumab 14-mg group were tested at a significance level of.5. Otherwise, the erenumab 14-mg group was tested first at a significance level of.4 (if only 7 mg was significant) or.1 (if only 14 mg was significant), and the erenumab 7-mg group was tested only if both second tier endpoints for the erenumab 14-mg group were significantly different from placebo (significance levels carried over).

9 8 Sensitivity Analysis Sensitivity analyses for the primary endpoint and continuous secondary endpoints include the following: the same analysis using the per-protocol analysis set, the last observation carried forward to handle missing data with the analysis of covariance model, and multiple imputation with assumptions of missing at random and missing not at random to handle missing data. For the 5% reduction from baseline in mean monthly migraine days endpoint, sensitivity analyses include the following: Cochran-Mantel-Haenszel test using the per-protocol analysis set, generalized linear mixed-effects model without imputation of missing data, and logistic regression model for each visit after the missing data are imputed as nonresponse.

10 9 Supplementary Figures Figure S1. Patient disposition *Completing the study is defined as completing the 24-week double-blind treatment phase.

11 1 Figure S2: Changes from baseline in monthly acute migraine specific medication treatment days Figure S2 shows the least squares mean changes from baseline in monthly acute migraine specific medication treatment days during the double-blind treatment phase. Changes from baseline in mean monthly acute migraine specific medication treatment days over the last 3 months (months 4, 5, and 6) were significantly different from placebo for the erenumab 7-mg and 14-mg groups (P<.1 for both comparisons). Data were analyzed using a linear mixedeffects model including treatment group, baseline value, stratification factors, scheduled visit, and the interaction of treatment group with scheduled visit, and as observed with no imputation. Error bars represent 95% confidence intervals. Patients were dosed at day 1 (baseline) and months 1, 2, 3, 4, and 5. The figure is based on the efficacy analysis set.

12 11 Figure S3: Change from baseline in monthly MPFID-EA score Figure S3 shows the least squares mean change from baseline in monthly MPFID-EA score during the double-blind treatment phase. Changes from baseline in mean MPFID-EA score over the last 3 months (months 4, 5, and 6) were significantly different from placebo for the erenumab 7-mg and 14-mg groups (P<.1 for both comparisons). Data were analyzed using a linear mixed-effects model including treatment group, baseline value, stratification factors, scheduled visit, and the interaction of treatment group with scheduled visit, and as observed with no imputation. The error bars represent 95% confidence intervals. Patients were dosed at day 1 (baseline) and months 1, 2, 3, 4, and 5. The figure is based on the efficacy analysis set. MPFID-EA, Migraine Physical Function Impact Diary-Impact on Everyday Activities.

13 12 Figure S4: Change from baseline in monthly MPFID-PI score Figure S4 shows the least squares mean changes from baseline in monthly mean MPFID-PI score during the double-blind treatment phase. Changes from baseline in mean MPFID-PI score over the last 3 months (months 4, 5, and 6) were significantly different from placebo for the erenumab 7-mg and 14-mg groups (P<.1 for both comparisons). Data were analyzed using a linear mixed-effects model including treatment group, baseline value, stratification factors, scheduled visit, and the interaction of treatment group with scheduled visit, and as observed with no imputation. Error bars represent 95% confidence intervals. Patients were dosed at day 1 (baseline) and months 1, 2, 3, 4, and 5. The figure is based on the efficacy analysis set. MPFID-PI, Migraine Physical Function Impact Diary-Physical Impairment.

14 13 Supplementary Tables Table S1: Supplementary baseline characteristics Placebo (N = 319) Erenumab 7 mg (N = 317) Erenumab 14 mg (N = 319) Race no. (%) White 277 (86.8) 281 (88.6) 293 (91.8) Black or African American 24 (7.5) 24 (7.6) 18 (5.6) Other* 18 (5.6) 12 (3.8) 8 (2.5) Body mass index kg/m 2, mean±sd 27.14± ± ±6.22 *Other includes Asian, native Hawaiian and other Pacific Islander, multiple ethnic origins, American Indian or Alaska Native, or other.

15 14 Table S2: Change from baseline in mean monthly migraine days, mean monthly acute migraine specific medication treatment days, mean MPFID domain scores (MPFID-PI and MPFID-EA), and 5% responder rates at weeks 4, 8, 12, 16, 2, and 24

16 Month 1 Placebo (n = 316) Erenumab 7 mg (n = 312) Erenumab 14 mg (n = 318) Month 2 Placebo (n = 316) Erenumab 7 mg (n = 312) Erenumab 14 mg Monthly migraine days.9 ( 1.3,.5) 2.32 ( 2.73, 1.92) 2.72 ( 3.12, 2.32) 1.39 ( 1.8,.99) 2.93 ( 3.34, 2.52) 3.1 ( 3.5, 2.7) (n = 318) Month 3 Placebo (n = 316) 1.71 >5% responder rate Monthly acute migraine specific medication treatment days 49 (15.5).3 (.28,.22) 12 (32.7).78 ( 1.3,.53) 113 (35.5) 1.4 ( 1.65, 1.15) 77 (24.4).34 (.59,.9) 124 (39.7) 1.1 ( 1.35,.85) 143 (45.) 1.56 ( 1.81, 1.31) 83 (26.3).33 ( 2.12, 1.3) (.58,.8) Erenumab 7 mg (41.3) 1.12 (n = 312) ( 3.38, 2.56) ( 1.37,.87) Erenumab 14 mg (48.1) 1.56 (n = 318) ( 3.91, 3.1) ( 1.81, 1.31) Month 4 Placebo (28.8).19 (n = 316) ( 2.35, 1.52) (.45,.6) Erenumab 7 mg (41.) 1.8 (n = 312) ( 3.5, 2.67) ( 1.33,.82) Erenumab 14 mg (49.7) 1.56 (n = 318) ( 3.93, 3.11) ( 1.81, 1.31) Month 5 Placebo (29.1).4 (n = 316) ( 2.29, 1.46) (.66,.14) Erenumab 7 mg (47.1) 1.17 (n = 312) ( 3.75, 2.93) ( 1.43,.92) Erenumab 14 mg (48.1) 1.61 (n = 318) ( 4.15, 3.33) ( 1.87, 1.36) Month 6 Placebo (n = 316) (29.4).1 ( 2.8, 1.25) (.25,.26) Erenumab 7 mg (47.1) 1.14 (n = 312) ( 3.67, 2.84) ( 1.4,.89) Erenumab 14 mg (49.1) 1.67 (n = 318) ( 4.17, 3.35) ( 1.92, 1.41) Data are least squares mean (95% confidence interval) or no. (%). MPFID-PI score 1.58 ( 2.43,.73) 3.29 ( 4.15, 2.44) 3.72 ( 4.57, 2.88) 2.2 ( 2.87, 1.17) 4.15 ( 5.1, 3.29) 4.64 ( 5.49, 3.79) 2.39 ( 3.25, 1.53) 4.13 ( 4.99, 3.26) 4.87 ( 5.73, 4.2) 2.51 ( 3.38, 1.64) 4.13 ( 4.99, 3.26) 4.73 ( 5.58, 3.87) 2.61 ( 3.49, 1.74) 4.44 ( 5.31, 3.57) 4.96 ( 5.82, 4.9) 2.1 ( 2.89, 1.14) 4.15 ( 5.3, 3.28) 4.75 ( 5.62, 3.88) 15 MPFID-EA score 2.32 ( 3.16, 1.49) 4.24 ( 5.8, 3.4) 4.59 ( 5.43, 3.76) 2.89 ( 3.73, 2.5) 5.16 ( 6., 4.32) 5.6 ( 6.43, 4.76) 3.35 ( 4.2, 2.5) 5.35 ( 6.2, 4.5) 5.74 ( 6.58, 4.89) 3.52 ( 4.37, 2.67) 5.39 ( 6.24, 4.54) 5.77 ( 6.62, 4.93) 3.47 ( 4.32, 2.61) 5.68 ( 6.53, 4.82) 6.4 ( 6.88, 5.19) 2.9 ( 3.76, 2.4) 5.48 ( 6.34, 4.62) 5.78 ( 6.64, 4.93) MPFID-EA, Migraine Physical Function Impact Diary-Impact on Everyday Activities; MPFID-PI, Migraine Physical Function Impact Diary-Physical Impairment.

17 16 Table S3: Serious adverse events Placebo (N = 319) Erenumab 7 mg (N = 314) Erenumab 14 mg (N = 319) Number of patients reporting serious adverse events, n (%) 7 (2.2) 8 (2.5) 6 (1.9) Serious adverse events, n1 (%) Noncardiac chest pain Cholelithiasis 2 (<1) Ankle fracture Cerebral venous thrombosis * Clostridium difficile colitis * Viral gastroenteritis Kidney infection * Pyelonephritis * Sepsis * Spinal pain Vestibular neuronitis Back pain Migraine Ovarian cyst Post-traumatic neck syndrome Acute pyelonephritis Arthralgia Endometriosis Fall Hypersensitivity

18 17 Intentional overdose Osteoarthritis This table is based on the safety analysis set. N = number of patients in the analysis set; n = number of patients reporting at least one occurrence of the adverse event; n1 = number of serious adverse events reported. One or more adverse events could be reported by a single patient. *All 5 adverse events (cerebral venous thrombosis, Clostridium difficile colitis, kidney infection, pyelonephritis, and sepsis) were reported in a single patient.

19 18 Table S4: Liver function abnormalities during the double-blind treatment phase Erenumab Erenumab Placebo 7 mg 14 mg (N = 319) (N = 314) (N = 319) n/n1 (%) n/n1 (%) n/n1 (%) Patients with ALT or AST >3 ULN (post-baseline) 1/315 (.3) 1/312 (.3) /317 (.) Baseline value: 1 ULN 1/284 (.4) /288 (.) /291 (.) >1 ULN to 3 ULN /31 (.) 1/23 (4.3) /26 (.) >3 ULN / (-) /1 (.) / (-) Patients with ALT or AST >5 ULN (post-baseline) /315 (.) 1/312 (.3)* /317 (.) Baseline value: 1 ULN /284 (.) /288 (.) /291 (.) >1 ULN to 3 ULN /31 (.) 1/23 (4.3) /26 (.) >3 ULN to 5 ULN / (-) /1 (.) / (-) Patients with TBL >1 ULN (post-baseline) 1/315 (3.2) 9/312 (2.9) 1/317 (3.2) Baseline value: 1 ULN 4/37 (1.3) 4/37 (1.3) 4/31 (1.3) >1 ULN 6/8 (75.) 5/5 (1.) 6/7 (85.7) Patients with TBL >1.5 ULN (post-baseline) 1/315 (.3) 3/312 (1.) 1/317 (.3) Baseline value: 1 ULN /37 (.) 1/37 (.3) /31 (.) >1 ULN to 1.5 ULN 1/8 (12.5) 2/5 (4.) 1/7 (14.3) Patients with TBL >2 ULN (post-baseline) /315 (.) 1/312 (.3) /317 (.) Baseline value: 1 ULN /37 (.) 1/37 (.3) /31 (.) >1 ULN to 1.5 ULN /8 (.) /5 (.) /7 (.) Patients with ALP >1.5 ULN (post-baseline) /315 (.) 1/312 (.3) /317 (.)

20 19 Baseline value: 1.5 ULN /315 (.) 1/312 (.3) /317 (.) This table is based on the safety analysis set. *Occurred during safety follow-up, 16 weeks after the last dose of erenumab. The patient had to discontinue erenumab treatment after the week 12 dose due to use of a prohibited medication (prednisolone). No subject met the laboratory criteria for Hy s Law. 2 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; N, number of patients in the analysis set; n, number of patients who met the criteria; N1, number of patients with available data during post-baseline for all patients or by baseline subgroups; % = n/n1*1; TBL, total bilirubin; ULN, upper limit of normal.

21 2 Supplementary References 1. Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 216;15: US FDA. Guidance for Industry: Drug Induced Liver Injury: Pre-marketing Clinical Evaluation July 29 Drug Safety. Accessed 21 July 216.