Head-to-head Study of Erenumab Against Topiramate in Patients With Episodic and Chronic Migraine (HER-MES)

Head-to-head Study of Erenumab Against topiRamate-a Double-blind, Double Dummy Migraine Study to Assess Tolerability and Efficacy in a patiEnt -Centered Setting

This study used a single-cohort, 2-treatment arm, parallel-group randomized, double-blind, double-dummy design in adult patients with episodic migraine and chronic migraine, who had to be either naïve or not suitable for or could have failed up to three prophylactic treatments out of: propranolol/metoprolol, amitriptyline, flunarizine. Patients were stratified into groups according to their number of migraine days during the baseline period.

Study Overview

• Status: Completed
• Conditions: Migraine
• Intervention / Treatment: Biological: Erenumab; Biological: Erenumab matching placebo; Drug: Topiramate; Drug: Topiramate matching placebo

Detailed Description

All patients completing the Baseline period and fulfilling baseline eligibility criteria were invited to participate to the Double-blind, double-dummy Treatment Epoch (DBTE, 24 weeks) .

Eligible patients were randomized to one of two treatment arms. DBTE started with a titration phase for topiramate of a maximum of 6 weeks to determine the maximal tolerated dose and aimed to reach the recommended treatment dose of 100 mg according to the German SmPC. After the titration phase, maintenance phase started (18 weeks). Topiramate dose had to be maintained until the end of the DBTE. Erenumab dose at beginning of the DBTE was determined patient individually by the investigator based on the guidance provided in the SmPC and was either 70 mg or 140 mg. Dose escalation from 70 mg to 140 mg in case of insufficient response was considered at anytime during the DBTE.

Dose reduction of topiramate and erenumab was not allowed during DBTE (Week 0 to Week 24). After Week 24 or if the patient discontinued study drug, a one week double-blind taper off phase followed to ensure proper down titration for topiramate. At the end of the DBTE (24 weeks) the final assessment occurred to address the objectives.

A Follow-Up Visit 4 weeks after last study visit (or 8 weeks after last IMP injection for discontinued patients) was required as part of routine safety monitoring. The primary analysis was triggered when all patients had completed their respective last visit of the DBTE.

The End of study occurred when the last patient completed last visit (LPLV).

• Study Type: Interventional
• Enrollment (Actual): 777
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Alzenau, Germany, 63755
    • Novartis Investigative Site
  • Bad Homburg, Germany, 61348
    • Novartis Investigative Site
  • Bad Honnef, Germany, 53604
    • Novartis Investigative Site
  • Bad Saarow, Germany, 15526
    • Novartis Investigative Site
  • Bayreuth, Germany, 95445
    • Novartis Investigative Site
  • Bergen, Germany, 18528
    • Novartis Investigative Site
  • Berlin, Germany, 10713
    • Novartis Investigative Site
  • Berlin, Germany, 14169
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Berlin, Germany, 120999
    • Novartis Investigative Site
  • Berlin, Germany, 12101
    • Novartis Investigative Site
  • Berlin, Germany, 12163
    • Novartis Investigative Site
  • Berlin, Germany, 12627
    • Novartis Investigative Site
  • Berlin, Germany, 13156
    • Novartis Investigative Site
  • Bielefeld, Germany, D 33647
    • Novartis Investigative Site
  • Boblingen, Germany, 71032
    • Novartis Investigative Site
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Bonn, Germany, 53111
    • Novartis Investigative Site
  • Bonn, Germany, 53177
    • Novartis Investigative Site
  • Celle, Germany, 29223
    • Novartis Investigative Site
  • Chemnitz, Germany, 09117
    • Novartis Investigative Site
  • Dillingen, Germany, 66763
    • Novartis Investigative Site
  • Erbach, Germany, 64711
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Essen, Germany, 45133
    • Novartis Investigative Site
  • Frankfurt, Germany, 60313
    • Novartis Investigative Site
  • Freiburg, Germany, 79098
    • Novartis Investigative Site
  • Gelsenkirchen, Germany, 45879
    • Novartis Investigative Site
  • Greifswald, Germany, 17475
    • Novartis Investigative Site
  • Haar, Germany, 85540
    • Novartis Investigative Site
  • Halle, Germany, 06120
    • Novartis Investigative Site
  • Hamburg, Germany, 20253
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Heidenheim, Germany, 89518
    • Novartis Investigative Site
  • Hoppegarten, Germany, 15366
    • Novartis Investigative Site
  • Ibbenbueren, Germany, 49477
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Juelich, Germany, 52428
    • Novartis Investigative Site
  • Kassel, Germany, 34121
    • Novartis Investigative Site
  • Kassel, Germany
    • Novartis Investigative Site
  • Kiel, Germany, 24149
    • Novartis Investigative Site
  • Koln, Germany, 50935
    • Novartis Investigative Site
  • Königstein im Taunus, Germany, 61462
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Leipzig, Germany, 04107
    • Novartis Investigative Site
  • Luenen, Germany, 44534
    • Novartis Investigative Site
  • Mannheim, Germany, 66163
    • Novartis Investigative Site
  • Marburg Wehrda, Germany, 35041
    • Novartis Investigative Site
  • Mittweida, Germany, 09648
    • Novartis Investigative Site
  • Muenchen, Germany, 81377
    • Novartis Investigative Site
  • Muenchen, Germany, 81675
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Neu-Ulm, Germany, 89231
    • Novartis Investigative Site
  • Neuburg an der Donau, Germany, 86633
    • Novartis Investigative Site
  • Osnabrück, Germany, 49074
    • Novartis Investigative Site
  • Pforzheim, Germany, 75172
    • Novartis Investigative Site
  • Quakenbrueck, Germany, 49610
    • Novartis Investigative Site
  • Regensburg, Germany, 93059
    • Novartis Investigative Site
  • Rostock, Germany, 18057
    • Novartis Investigative Site
  • Ruelzheim, Germany, 76761
    • Novartis Investigative Site
  • Schwerin, Germany, 19053
    • Novartis Investigative Site
  • Schwerin, Germany, 19055
    • Novartis Investigative Site
  • Seesen, Germany, 38723
    • Novartis Investigative Site
  • Siegen, Germany, 57076
    • Novartis Investigative Site
  • Sindelfingen, Germany, 71065
    • Novartis Investigative Site
  • Stadtroda, Germany, 07646
    • Novartis Investigative Site
  • Stuttgart, Germany, 70174
    • Novartis Investigative Site
  • Stuttgart, Germany, 70178
    • Novartis Investigative Site
  • Stuttgart, Germany, 70182
    • Novartis Investigative Site
  • Trier, Germany, 54292
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
  • Ulm, Germany, 89073
    • Novartis Investigative Site
  • Unterhaching, Germany, 82008
    • Novartis Investigative Site
  • Westerstede/Oldenburg, Germany, 26655
    • Novartis Investigative Site
  • Wiesbaden, Germany, 65191
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
  • Baden Wuertemberg
    • Stuttgart, Baden Wuertemberg, Germany, 70178
      • Novartis Investigative Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30159
      • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Aachen, Nordrhein-Westfalen, Germany, 52062
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Documented history of migraine in the 12 months prior to screen
2. at least 4 days per month of migraine symptoms
3. >=80% diary compliance during the Baseline period
4. Patients must be either naïve or not suitable or have failed previous migraine prophylactic treatments

Key Exclusion Criteria:

1. Older than 50 years of age at migraine onset
2. Pregnant or nursing
3. History of cluster or hemiplegic headache
4. History or evidence of major psychiatric disorder
5. Score of 19 or higher on Beck Depression Inventory (BDI)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Erenumab; 70 mg and 140 mg Erenumab	Biological: Erenumab; 70mg/1mL (70 mg) or 2x70mg/1mL (140 mg) in pre-filled syringe, administered every 4 weeks; Other Names: AMG334; Biological: Erenumab matching placebo; Erenumab matching placebo pre-filled syringue administered every 4 weeks
Active Comparator: Topiramate; Topiramate in the highest tolerated dose (50 - 100 mg/day)	Drug: Topiramate; Film-coated tablet taken orally: 25 mg administered once daily (first week of titration phase). After the first week, titration was done according to the summary of product characteristics (SmPC) in 25 mg increments each week and aimed to reach the recommended daily treatment dose of 100 mg (50/75/100 mg). 50/75/100 mg were administered twice daily during titration phase and maintenance phase.; Other Names: Topamax; Drug: Topiramate matching placebo; Topiramate matching placebo administered daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Treatment Discontinuation Due to an Adverse Event (AE) During the Double-blind Treatment Epoch/Period (DBTE)	The primary objective was to demonstrate the tolerability of 70 mg and 140 mg erenumab compared to topiramate in the highest tolerated dose assessed by the rate of patients discontinuing treatment due to AE during the double-blind epoch of the study.	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With at Least 50% Reduction From Baseline in Monthly Migraine Days (MMD) Over the Last Three Months (Month 4, 5, and 6)	The secondary objective of this study was to evaluate the effect of erenumab compared to topiramate on the proportion of patients with at least 50% reduction from baseline in MMDs. The Baseline period was defined as the period between Week -4 and the day prior to first dose. This was analyzed by logistic regression over the last 3 months (months 4, 5, and 6) of treatment. All the subjects' data collected regarding 50% response in MMD was used in the analysis regardless of whether subjects discontinue study treatment or not. Subjects with missing response information on this endpoint were imputed as non-response (non-responder imputation).	Baseline, Last three months (month 4, 5, and 6)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Reduction in the Headache Impact Test (HIT-6) From Baseline to Week 24	The HIT-6 is a widely used patient-reported outcome measure that assesses the negative effects of headaches on normal activity. Six items assess the frequency of pain severity, headaches limiting daily activity (household, work, school, and social), wanting to lie down when headache is experienced, feeling too tired to work or do daily activities because of headache, feeling "fed up" or irritated because of headache, and headaches limiting ability to concentrate or work on daily activities. Each of the 6 questions is responded to using 1 of 5 response categories: "never," "rarely," "sometimes," "very often," or "always." For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, are assigned to the response provided. These points are summed to produce a total HIT-6 score that ranges from 36 to 78. HIT-6 scores are categorized into 4 grades: little or no impact (49 or less), some impact (50 - 55), substantial impact (56 - 59), and severe impact (60 - 78) due to headache.	Baseline, Week 24
EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24	The SF-36 is a widely used and extensively studied instrument to measure health-related quality of life (HRQoL) among healthy subjects and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-36 has proven useful in monitoring general and specific populations, comparing the relative burden of different disease, differentiating the health benefits produced by different treatments, and in screening individual patients. The purpose of the SF-36 in this study was to assess the HRQoL of patients. Given the nature of this disease and the 4-weekly assessment, the SF-36 version 2, with a 4-week recall period, was used in this study.	Baseline, Week 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ehrlich M, Hentschke C, Sieder C, Maier-Peuschel M, Reuter U. Erenumab versus topiramate: post hoc efficacy analysis from the HER-MES study. J Headache Pain. 2022 Nov 15;23(1):141. doi: 10.1186/s10194-022-01511-y.
• Reuter U, Ehrlich M, Gendolla A, Heinze A, Klatt J, Wen S, Hours-Zesiger P, Nickisch J, Sieder C, Hentschke C, Maier-Peuschel M. Erenumab versus topiramate for the prevention of migraine - a randomised, double-blind, active-controlled phase 4 trial. Cephalalgia. 2022 Feb;42(2):108-118. doi: 10.1177/03331024211053571. Epub 2021 Nov 7.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2019
• Primary Completion (Actual): July 29, 2020
• Study Completion (Actual): July 29, 2020

Study Registration Dates

• First Submitted: February 1, 2019
• First Submitted That Met QC Criteria: February 1, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Actual): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Migraine; Headache; monoclonal antibody; Calcitonin Gene-related Peptide; Episodic migraine; Chronic migraine; erenumab; topiramate; CAMG 334; CGRP; CGRP receptor agonist; treatment failure
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Immunologic Factors; Anticonvulsants; Calcitonin Gene-Related Peptide Receptor Antagonists; Antibodies, Monoclonal; Erenumab; Topiramate
• Other Study ID Numbers: CAMG334ADE01; 2018-000943-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes