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CompletedNCT03303079Updated Jun 15, 2021Results posted

Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Chronic Migraine

A Phase 2/3 interventional study of TEV-48125 and TEV-48125 or placebo in Migraine, sponsored by Otsuka Pharmaceutical Co., Ltd.. Completed at 1 site in Japan. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2021-06-15.

Sponsored by Otsuka Pharmaceutical Co., Ltd. · Phase 2/3, Interventional, and Treatment

Phase
Phase 2/3
Study type
Interventional
Enrollment
571
Allocation
Randomized
Ages
18 Years to 70 Years
Sex
All
01

Study summary

To evaluate the efficacy and safety of subcutaneous (SC) administration of TEV-48125 [monthly TEV-48125 225 mg (loading dose only: 675 mg) and TEV-48125 675 mg once over a period of 3 months] compared with placebo for preventive treatment in Chronic Migraine patients

02

Conditions studied

  • Migraine

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03

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Patient has a history of migraine (according to The International Classification of Headache Disorders, third edition [beta version] criteria) or clinical judgment suggests a migraine diagnosis
  • Patient fulfills the criteria for Chronic migraine in baseline information collected during the 28 day screening period
  • Not using preventive migraine medications for migraine or other medical conditions or using no more than 1 preventive migraine medication for migraine or other medical conditions if the dose and regimen have been stable for at least 2 months prior to giving informed consent.
  • Patient demonstrates compliance with the electronic headache diary during the screening period by entry of headache data on a minimum of 24 of 28 days and the entered data is judged appropriate by the investigator.

Exclusion criteria

Exclusion Criteria:

  • Patients who have previously failed (lack of efficacy) 2 or more of the clusters of the medications for treatment of migraine after use for at least 3 months at accepted migraine therapeutic doses
  • Patient suffers from unremitting headaches, defined as having headaches for more than 80% of the time that he/she is awake, and less than 4 days without headache per month. Daily headache is acceptable if the patient has headaches 80% or less of the time they are awake on most days.
  • Hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease considered clinically significant in the judgment of the investigator
04

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
571 participants (actual)

Study arms

  • Experimental
    TEV-48125 (675/225/225 mg) group

    TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).

    Drug: TEV-48125

  • Experimental
    TEV-48125 (675 mg/placebo/placebo) group

    TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).

    Drug: TEV-48125 or placebo

  • Placebo comparator
    Placebo group

    Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).

    Drug: Placebo

Interventions

  • DrugTEV-48125

    TEV-48125 will be subcutaneously administered once monthly for 3 months.

  • DrugTEV-48125 or placebo

    TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months.

  • DrugPlacebo

    Placebo will be subcutaneously administered once monthly for 3 months.

05

What researchers measure

Primary outcomes

  1. Mean Change From Baseline in the Monthly (28 Day) Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)

    Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.

    Time frame: Baseline, 12 weeks

Secondary outcomes

  1. Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP

    Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.

    Time frame: Baseline, 12 weeks

  2. Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP

    Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.

    Time frame: 12 weeks

  3. Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP

    Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).

    Time frame: Baseline, 12 weeks

  4. Mean Change From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP in Subjects Not Receiving Concomitant Preventive Migraine Medications

    Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications."

    Time frame: Baseline, 12 weeks

  5. Mean Change From Baseline in Disability Score, as Measured by 6-Item Headache Impact Test (HIT-6) at 4 Weeks After the Final (Third) Dose of IMP

    Subjects assessed the impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress, using the HIT-6. The HIT-6 total score will be obtained from summation of the 6 question points.Each question is answered on the scale ranging with the following response options: 6 points (never), 8 points (rarely), 10 points (sometimes), 11 points (very often), and 13 points (always).

    Time frame: Baseline, 4 weeks

06

Results

Posted Jun 15, 2021

Participant flow

Participant flow — Overall Study
MilestoneTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Started189191191
Completed182180179
Not completed71112
Withdrew: Adverse event013
Withdrew: Protocol violation547
Withdrew: Withdrawal by subject242
Withdrew: Other than specified020

Outcome measures

PrimaryMean Change From Baseline in the Monthly (28 Day) Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)

Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.

Time frame:
Baseline, 12 weeks
Reported as:
Mean · days/month
Mean Change From Baseline in the Monthly (28 Day) Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)
days/monthTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Mean Change From Baseline in the Monthly (28 Day) Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)-4.12 ± 0.43-4.14 ± 0.43-2.45 ± 0.43
SecondaryMean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP

Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.

Time frame:
Baseline, 12 weeks
Reported as:
Mean · days/month
Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP
days/monthTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP-4.90 ± 0.50-4.07 ± 0.49-2.79 ± 0.49
SecondaryProportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP

Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.

Time frame:
12 weeks
Reported as:
Number · percentage of participants
Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP
percentage of participantsTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP29.029.113.2
SecondaryMean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP

Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).

Time frame:
Baseline, 12 weeks
Reported as:
Mean · days/month
Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP
days/monthTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP-3.74 ± 0.44-3.87 ± 0.43-2.44 ± 0.43
SecondaryMean Change From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP in Subjects Not Receiving Concomitant Preventive Migraine Medications

Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who had experienced headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications). Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity. If headache was reported, then headache severity was subjectively rated by the subject as mild, moderate, or severe. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications."

Time frame:
Baseline, 12 weeks
Reported as:
Mean · days/month
Mean Change From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP in Subjects Not Receiving Concomitant Preventive Migraine Medications
days/monthTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Mean Change From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-week Period After the First Dose of IMP in Subjects Not Receiving Concomitant Preventive Migraine Medications-3.74 ± 0.44-3.87 ± 0.43-2.44 ± 0.43
SecondaryMean Change From Baseline in Disability Score, as Measured by 6-Item Headache Impact Test (HIT-6) at 4 Weeks After the Final (Third) Dose of IMP

Subjects assessed the impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress, using the HIT-6. The HIT-6 total score will be obtained from summation of the 6 question points.Each question is answered on the scale ranging with the following response options: 6 points (never), 8 points (rarely), 10 points (sometimes), 11 points (very often), and 13 points (always).

Time frame:
Baseline, 4 weeks
Reported as:
Mean · score on a scale
Mean Change From Baseline in Disability Score, as Measured by 6-Item Headache Impact Test (HIT-6) at 4 Weeks After the Final (Third) Dose of IMP
score on a scaleTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Mean Change From Baseline in Disability Score, as Measured by 6-Item Headache Impact Test (HIT-6) at 4 Weeks After the Final (Third) Dose of IMP-8.06 ± 0.70-8.03 ± 0.68-6.49 ± 0.68

Adverse events

Collected over Double-blind treatment period (12 weeks). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
TEV-48125 (675/225/225 mg) Group0/188 (0%)3/188 (1.6%)115/188 (61.2%)
TEV-48125 (675 mg/Placebo/Placebo) Group0/190 (0%)1/190 (0.5%)116/190 (61.1%)
Placebo Group0/191 (0%)1/191 (0.5%)117/191 (61.3%)
Most frequent serious events
Most frequent serious events
EventTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
Brain contusionInjury, poisoning and procedural complications1/1880/1900/191
AsthmaRespiratory, thoracic and mediastinal disorders1/1880/1900/191
Intestinal haemorrhageGastrointestinal disorders1/1880/1900/191
InfluenzaInfections and infestations0/1881/1900/191
Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/1880/1901/191
Most frequent other events
Showing 10 of 180
Most frequent other events
EventTEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo Group
NasopharyngitisInfections and infestations30/18840/19036/191
Injection site indurationGeneral disorders33/18823/19024/191
Injection site erythemaGeneral disorders29/18823/19021/191
Injection site painGeneral disorders14/18824/19017/191
Injection site pruritusGeneral disorders10/1883/1905/191
Back painMusculoskeletal and connective tissue disorders5/1881/1901/191
NauseaGastrointestinal disorders2/1885/1902/191
InfluenzaInfections and infestations4/1881/1903/191
DiarrhoeaGastrointestinal disorders3/1884/1900/191
CystitisInfections and infestations0/1884/1901/191

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)TEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo GroupTotal
<=18 years0000
Between 18 and 65 years187184190561
>=65 years27110
Age, Continuous
Age, Continuous(years)TEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo GroupTotal
Mean42.7 ± 10.243.5 ± 10.242.1 ± 10.242.8 ± 10.2
Sex: Female, Male
Sex: Female, Male(Participants)TEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo GroupTotal
Female163165163491
Male26262880
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)TEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo GroupTotal
Asian189191191571
Region of Enrollment
Region of Enrollment(participants)TEV-48125 (675/225/225 mg) GroupTEV-48125 (675 mg/Placebo/Placebo) GroupPlacebo GroupTotal
Japan159159161479
South Korea30323092
07

Study locations

1 site
  • Saitama Medical University Hospital
    Iruma, Japan
08

References and documents

Publications

  • Takeshima T, Nakai M, Shibasaki Y, Ishida M, Kim BK, Ning X, Koga N. Early onset of efficacy with fremanezumab in patients with episodic and chronic migraine: subanalysis of two phase 2b/3 trials in Japanese and Korean patients. J Headache Pain. 2022 Feb 9;23(1):24. doi: 10.1186/s10194-022-01393-0. PubMed 35139816 ↗

Study documents

  • Study protocol · Jul 8, 2019
  • Statistical analysis plan · Dec 12, 2019

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Undecided

09

Registry details

Key details

Study ID
NCT03303079
Lead sponsor
Otsuka Pharmaceutical Co., Ltd.
Responsible party
Sponsor
First posted
Oct 5, 2017
Start date
Dec 19, 2017
Primary completion
Nov 30, 2019
Completion
Nov 30, 2019
Results posted
Jun 15, 2021
Last update
Jun 15, 2021

Study contacts

Takehisa Matsumaru
study director · Otsuka Pharmaceutical Co., Ltd.

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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