MigrainePhase 3NorMigNCT07040813
The Nordic Chronic Migraine Trial of CGRP Monoclonal Antibody and Onabotulinumtoxin A Dual Therapy Compared to CGRP mAbs Monotherapy
A Phase 3 study testing CGRP mAbs and onabotulinumtoxin A in people with Migraine and Chronic Migraine Headache, run by Oslo University Hospital at 6 sites in Norway.
Trial summary
Migraine is characterized by attacks of throbbing, moderate or severe headache, often associated with nausea, vomiting, and/or sensitivity to light and/or sound. Chronic migraine, which occurs in 1-2 % of the population is characterized by 15 or more headache days/month for more than 3 months and at least 8 days/month… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Migraine, Chronic Migraine Headache
- What is being tested?
- CGRP mAbs and onabotulinumtoxin A
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 450 participants
- Where
- 6 sitesNorway
- Study dates
- 6 Jun 2025to 30 Apr 2029
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Informed and signed written consent.
- Individuals of any sex, 18-70 years at the time of signing the informed consent.
- Fulfilling the diagnosis chronic migraine criteria 1.3. according to the International Classification of Headache Disorders version 3 at time of inclusion.
- Indications for treatment with CGRP mAbs according to SmPCs.
- Indications for treatment with BTA according to SmPC.
- No previous use of CGRP inhibitors or BTA.
- Women of childbearing potential (WOCBP) can only be included if they use a highly effective contraception method
Who cannot join
- Contraindications, allergy or hypersensitivity reactions to BTA including infection at the injection site.
- Contraindications, allergy or hypersensitivity reactions to CGRP mAbs including serious cardiovascular illness such as myocardial infarction, stroke, unstable angina pectoris, revascularization procedures last 12 months.
- Concomitant medication overuse headache where drug withdrawal has not been done.
- Subject is unable to differentiate migraine from other concomitant headaches.
- Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months before study inclusion (Visit 2).
- Long-standing continuous headache with no headache free days or periods for a period of time >1 years.
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- Pregnancy, planning to get pregnant, inability to use contraceptives and lactating.
- High degree of comorbidity and/or frailty associated with reduced life expectancy or high likelihood of hospitalization, at the discretion of the investigator.
- Alcohol or illicit drug dependence.
- Investigators may exclude patients who, for various reasons (for example, severe psychiatric disorders), are considered unlikely to be able to complete the tasks required for participation in the study.
- Inability to understand study procedures and to comply with them for the entire length of the study, assessed at the discretion of the investigator.
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
6 sites in 1 country
Norway6 sites, 6 recruiting
- Not yet recruiting
Østfold Hospital Trust
Grålum
Zhilwan Gadan, MD, +47 69 86 00 00, Zhilwan.Gadan@so-hf.no
Zhilwan Gadan, MD
- Not yet recruiting
Sørlandet Hospital Kristiansand
Kristiansand
Kai Ivar Müller, MD PhD, +47 38073000, Kai.Ivar.Muller@sshf.no
Kai Ivar Müller, MD PhD
- Not yet recruiting
Innlandet Hospital Trust Lillehammer
Lillehammer
Mari Aalstad-Johansen, MD, +47 91 50 62 00, Mari.Aalstad@sykehuset-innlandet.no
Mari Aalstad-Johansen, MD
- Recruiting
Oslo University Hospital
Oslo, 0424
Anne Hege Aamodt, MD PhD Prof, +47 23 07 00 00, a.h.aamodt@medisin.uio.no
Burcu Bezgal, MD, +47 23 07 00 00, burbez@ous-hf.no
- Not yet recruiting
Telemark Hospital Trust Skien
Skien
Christoffer Haugen Melbye, MD, +47 35 00 35 00, Christoffer.Haugen.Melbye@sthf.no
Heidi Øyen Flemmen, MD PhD
- Not yet recruiting
St. Olav University Hospital
Trondheim
Krsitin Wesnes, MD PhD, +47 72 57 30 00, Kristin.Wesnes@stolav.no
Erling Tronvik, MD PhD Prof, +47 72 57 30 00, erling.tronvik@ntnu.no
About this study
Official title: A Randomized Placebo-controlled Double-blind Phase III Trial to Investigate the Reduction of Monthly Migraine Days (MMDs) Over 12 Weeks of Treatment With CGRP mAbs and Onabotulinumtoxin A Intramuscularly Compared With CGRP mAbs and Placebo in Chronic Migraine
Migraine is characterized by attacks of throbbing, moderate or severe headache, often associated with nausea, vomiting, and/or sensitivity to light and/or sound.
Chronic migraine, which occurs in 1-2 % of the population is characterized by 15 or more headache days/month for more than 3 months and at least 8 days/month with features of migraine headache.
Read more
The study will evaluate the efficacy of onabotulinumtoxin A when added to CGRP monoclonal antibody therapy in chronic migraine prevention. Adverse events and change in disease activity will be monitored.
Onabotulinumtoxin A and CGRP monoclonal antibody therapy are investigational drugs developed to prevent chronic migraine. Approximately 450 patients will be included from sites in Norway.
All participants will receive CGRP monoclonal antibody therapy. Additionally, the participants will be randomized to receive onabotulinumtoxin A or placebo injections.
Total study duration is 20 weeks including 3 on site visits and 3 telephone visits. After an inclusion visit the participants are registering data in an electronic headache diary using the application Brain Twin for a minimum of 4 weeks before the come to the randomization visit and the study medications are started. The duration of treatment is 12 weeks.
Read the detailed description
Despite an improved understanding of migraine pathophysiology and treatment in recent years, many responders for both BTA and CGRP mAbs still experience high burden of disease. Thus, there is still a great need for further improving migraine prevention therapy. At present, there are few effective treatment alternatives for chronic migraine patients and a combination therapy of CGRP mAbs and BTA is an excellent candidate that has not previously been tested in any trial to date. The combined inhibition of CGRP release in C fibres by BTA and the receptor function blockade by CGRP mAbs directed towards the ligand or the receptor in Aδ fibres is proposed to have a synergistic effect. Several observational studies, including pooled analysis of real-world evidence, supports a combination of CGRP mAbs and BTA, but the efficacy remains to be demonstrated in randomized controlled trials. Additionally, while the cost-effectiveness of pharmacological treatments of chronic migraine in the adult population-using CGRP mAbs and BTA-have been demonstrated, the cost-effectiveness of the combination therapy needs to be clarified. As both fatigue and cognitive symptoms are important for the migraine related disability and migraine related quality of life, we will also include these aspects in the endpoint evaluations
. Hypothesis : Combination of CGRP mAbs and BTA reduces Monthly Headache Days (MHDs) in chronic migraine compared to single therapy.
In this trial of chronic migraine the efficacy of dual therapy with CGRP monoclonal antibody and onabotulinumtoxin A compared with CGRP monoclonal antibody single therapy in participants aged 18 to 70 years with chronic migraine will be studied. The primary endpoint is the reduction of Monthly Migraine Days (MMDs) over 12 weeks.
Total study duration is 20 weeks including 3 on site visits and 3 telephone visits. After an inclusion visit the participants are registering data in an electronic headache diary using the application Brain Twin for a minimum of 4 weeks before the come to the randomization visit and the study medications are started. The duration of treatment is 12 weeks.
Participants will be divided into two equal groups using electronic randomization. One group will receive one treatment with botulinum toxin A, while the other group will receive injections of placebo (saline). Unblinded study personnel will prepare botulinum toxin A/placebo which will then be administered to the participants by blinded study personnel. Onabotulinum toxin A/placebo will be administered at 31 pre-defined injection sites (0.1 ml with 5 units per injection; total 3.1 ml and 155 units), in accordance with a modified version of the Phase III REsearch Evaluating (PREEMPT) protocol. At the same time, both groups will start monthly injections of CGRP inhibitors as background medication. The choice of type of CGRP inhibitor is made by the study physician or based on national guidelines.
Participants will keep daily headache diaries throughout the study period to record headache frequency, intensity, use of reliever medication and type of headache.
The participants have a telephone visit with a study nurse after 4 and 8 week with study medication to follow-up the administration of CGRP inhibitors, headache diary and safety.
After 12 week of treatment the 3rd clinical visit is performed where the primary and secondary endpoints are registered. The participants continue to register headache diary for 4 weeks until the 3rd telephone visit which is the the end of study.
Sample size estimation: A difference of 1.6 MMDs over 12 weeks of treatment between the two groups is expected with a common standard deviation of 6.0 days for the average number of MMDs over 12 weeks in the two groups. With 90% power and a two-sided significance level of 5% 450 participants (225 in each arm) are needed in the analysis to detect the above-mentioned difference.
- Conditions
- Migraine, Chronic Migraine Headache
- Being tested
- CGRP mAbs and onabotulinumtoxin A, CGRP mAbs and placebo
- Keywords
- Migraine, CGRP, Onabotulinumtoxin A, CGRP monoclonal antibody, Combination of CGRP mAbs and onabotulinumtoxin A
- Medical subject headings
- Migraine Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CGRP mAbs and onabotulinumtoxin ADrug
CGRP mAbs given subcutanously every 4th week and onabotulinumtoxin A 155 given once intramuscularly according to adjusted PREEMPT protocol in the 12 week period of study intervention.
CGRP mAbs and placeboDrug
CGRP mAbs given subcutanously every 4th week and placebo once intramuscularly according to adjusted PREEMPT protocol in the 12 week period of study
| Study group | Role | What they receive |
|---|---|---|
| CGRP and placebo | Placebo comparator | Combination of CGRP mAbs and placebo (NaCl 0.9% Braun, 0.1 ml at the same sites) in male and female participants with chronic migraine aged 18 to 70 years. Receives: Drug: CGRP mAbs and placebo |
| CGRP and onabotulinumtoxin A | Active comparator | Onabotulinumtoxin A given totally 155 units at 31 sites according to modified PREEMPT or placebo (NaCl 0.9% Braun, 0.1 ml at the same sites). The treatment period is 12 weeks long. Receives: Drug: CGRP mAbs and onabotulinumtoxin A |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changer of Monthly Migraine Days over 12 weeks of treatment with the study medication.
To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by reduction of Monthly Migraine Days (MMDs) over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3 - primary endpoint visit.
Measured: 12 weeks
Secondary outcomes (5)
Change of Monthly Headache Days** over 12 weeks of treatment with the study medication
To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by reduction of Monthly Headache Days (MHDs) over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3.
Measured: 12 weeks
Monthly number of days with rescue medication over 12 weeks of treatment with the study medication.
Headache diary (by using the mobile application Brain Twin) where all rescue medication is registered until Visit 3.
Measured: 12 weeks
Number of treatment responders (≥ 50%, ≥75% and 100 % reduction in Monthly Migraine Headache days in each group over 12 weeks of treatment) at 12 weeks post-randomization.
To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by number of treatment responders ≥ 50%, ≥75% and 100 % reduction in MHD and MMDs over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3.
Measured: 12 weeks
Number of weekly migraine days from baseline to 12 months post-randomization.
To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by weekly migraine days over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3.
Measured: 12 weeks
Total number of hours at moderate or severe pain over 12 weeks of treatment.
To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by total headache score per month over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2025
- Study start6 Jun 2025
- Primary completion31 Jan 2029 (estimated)
- Study completion30 Apr 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (35)Papers the sponsor has linked to this study.
- Other trials for MigraineStudies of the same condition, open and under way.
- More trials run by Oslo University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A randomized placebo-controlled double-blind phase III two-arm study.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 450 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Oslo University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- St. Olavs Hospital, Sykehuset Telemark, Sykehuset Innlandet HF, Sorlandet Hospital HF, Ostfold Hospital Trust
- Responsible party
- Principal investigator, Anne Hege Aamodt, Oslo University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07040813
- Sponsor's protocol ID
- EU CT number 2024-517981-40-00
- Acronym
- NorMig
- Status last verified
- Jun 2025
- First submitted
- 18 Jun 2025
- Last updated
- 27 Jun 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Munoz-Vendrell A, Campoy S, Caronna E, Alpuente A, Torres-Ferrus M, Nieves Castellanos C, Olivier M, Campdelacreu J, Prat J, Camina Muniz J, Molina Martinez FJ, Minguez-Olaondo A, Ruibal Salgado M, Santos Lasaosa S, Navarro Perez MP, Morollon N, Lopez Bravo A, Cano Sanchez LM, Garcia-Sanchez SM, Garcia-Ull J, Rubio-Flores L, Gonzalez-Martinez A, Quintas S, Echavarria Iniguez A, Gil Luque S, Castro-Sanchez MV, Adell Ortega V, Garcia Alhama J, Berrocal-Izquierdo N, Belvis R, Diaz-Insa S, Pozo-Rosich P, Huerta-Villanueva M. Effectiveness and safety of anti-CGRP monoclonal antibodies in patients over 65 years: a real-life multicentre analysis of 162 patients. J Headache Pain. 2023 Jun 2;24(1):63. doi: 10.1186/s10194-023-01585-2.
PubMed 37268904Zheng H, Koo EH. The amyloid precursor protein: beyond amyloid. Mol Neurodegener. 2006 Jul 3;1:5. doi: 10.1186/1750-1326-1-5.
PubMed 16930452de Vries Lentsch S, van der Arend BWH, Maassen VanDenBrink A, Terwindt GM. Blood Pressure in Patients With Migraine Treated With Monoclonal Anti-CGRP (Receptor) Antibodies: A Prospective Follow-up Study. Neurology. 2022 Oct 25;99(17):e1897-e1904. doi: 10.1212/WNL.0000000000201008. Epub 2022 Oct 4.
PubMed 36195452Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP. Development of a fatigue scale. J Psychosom Res. 1993;37(2):147-53. doi: 10.1016/0022-3999(93)90081-p.
PubMed 8463991Gil-Gouveia R, Oliveira AG, Martins IP. A subjective cognitive impairment scale for migraine attacks. The MIG-SCOG: development and validation. Cephalalgia. 2011 Jul;31(9):984-91. doi: 10.1177/0333102411408359. Epub 2011 May 31.
PubMed 21628438Stewart WF, Lipton RB, Whyte J, Dowson A, Kolodner K, Liberman JN, Sawyer J. An international study to assess reliability of the Migraine Disability Assessment (MIDAS) score. Neurology. 1999 Sep 22;53(5):988-94. doi: 10.1212/wnl.53.5.988.
PubMed 10496257Dodick DW, Silberstein SD, Lipton RB, DeGryse RE, Adams AM, Diener HC. Early onset of effect of onabotulinumtoxinA for chronic migraine treatment: Analysis of PREEMPT data. Cephalalgia. 2019 Jul;39(8):945-956. doi: 10.1177/0333102418825382. Epub 2019 May 21.
PubMed 31112399Diener HC, Tassorelli C, Dodick DW, Silberstein SD, Lipton RB, Ashina M, Becker WJ, Ferrari MD, Goadsby PJ, Pozo-Rosich P, Wang SJ, Mandrekar J; International Headache Society Clinical Trials Standing Committee. Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: Fourth edition. Cephalalgia. 2019 May;39(6):687-710. doi: 10.1177/0333102419828967. Epub 2019 Feb 26.
PubMed 30806518Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, Brin MF; PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010 Jul;30(7):793-803. doi: 10.1177/0333102410364676. Epub 2010 Mar 17.
PubMed 20647170Tassorelli C, Diener HC, Dodick DW, Silberstein SD, Lipton RB, Ashina M, Becker WJ, Ferrari MD, Goadsby PJ, Pozo-Rosich P, Wang SJ; International Headache Society Clinical Trials Standing Committee. Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine in adults. Cephalalgia. 2018 Apr;38(5):815-832. doi: 10.1177/0333102418758283. Epub 2018 Mar 4.
PubMed 29504482Carvalho IV, Fernandes CS, Damas DP, Barros FM, Gomes IR, Gens HM, Luzeiro I. The migraine postdrome: Clinical characterization, influence of abortive treatment and impact in the quality of life. Clin Neurol Neurosurg. 2022 Oct;221:107408. doi: 10.1016/j.clineuro.2022.107408. Epub 2022 Aug 4.
PubMed 35985096Gerstein MT, Wirth RJ, Uzumcu AA, Houts CR, McGinley JS, Buse DC, McCarrier KP, Cooke A, Touba NM, Nishida TK, Goadsby PJ, Dodick DW, Lipton RB. Patient-reported experiences with migraine-related cognitive symptoms: Results of the MiCOAS qualitative study. Headache. 2023 Mar;63(3):441-454. doi: 10.1111/head.14484. Epub 2023 Mar 10.
PubMed 36905166Lipton RB, Lanteri-Minet M, Leroux E, Manack Adams A, Contreras-De Lama J, Reed ML, Fanning KM, Buse DC. Pre- and post-headache phases of migraine: multi-country results from the CaMEO - International Study. J Headache Pain. 2023 Nov 8;24(1):151. doi: 10.1186/s10194-023-01683-1.
PubMed 37940856Khanal S, Underwood M, Naghdi S, Brown A, Duncan C, Matharu M, Mistry H. A systematic review of economic evaluations of pharmacological treatments for adults with chronic migraine. J Headache Pain. 2022 Sep 16;23(1):122. doi: 10.1186/s10194-022-01492-y.
PubMed 36114468Salim A, Hennessy E, Sonneborn C, Hogue O, Biswas S, Mays M, Suneja A, Ahmed Z, Mata IF. Synergism of Anti-CGRP Monoclonal Antibodies and OnabotulinumtoxinA in the Treatment of Chronic Migraine: A Real-World Retrospective Chart Review. CNS Drugs. 2024 Jun;38(6):481-491. doi: 10.1007/s40263-024-01086-z. Epub 2024 Apr 7.
PubMed 38583127