Study of Sustained Benefit of AMG334 in Adult Episodic Mi... | NCT03927144

ID	Type	Description	Link
2018-001228-20	EudraCT Number
CAMG334A2401	Other Identifier	Novartis

Name	Class
Novartis	INDUSTRY

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
AMG334 70 mg/140 mg	Experimental	Participants were randomized to receive 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Participants who completed visits through Week 52 of the Core Phase were eligible to participate in the 52-week Extension Phase of the study.	Drug: AMG334 Drug: Oral Prophylactic
Oral Prophylactic	Active Comparator	Participants were randomized to receive a standard of care (SOC) locally approved oral prophylactic migraine medication once per day for 52 weeks in the Core Phase, as prescribed per local country labels. Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Participants who completed visits through Week 52 of the Core Phase were eligible to participate in the 52-week Extension Phase of the study.	Drug: AMG334 Drug: Oral Prophylactic

Name	Type	Description	Arm Group Labels	Other Names
AMG334	Drug	Subcutaneous Injection	AMG334 70 mg/140 mg Oral Prophylactic

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Who Completed Initially Assigned Treatment and Achieved at Least a 50% Reduction From Baseline in Monthly Migraine Days at Month 12	A migraine day was defined as any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined as a migraine with or without aura, lasting for ≥ 30 minutes, and meeting at least one of the following criteria: ≥2 of the following pain features: Unilateral Throbbing Moderate to severe Exacerbated with exercise/physical activity ≥1 of the following associated symptoms: Nausea and/or vomiting Photophobia and phonophobia If the participant took a migraine-specific medication (ie, triptan or ergotamine) during aura, or to treat a headache on a calendar day, then it was counted as a migraine day regardless of the duration and pain features/associated symptoms. In addition to achieving at least a 50% reduction from baseline in monthly migraine days, participants must have also completed their initially assigned treatment through Month 12.	Baseline and Month 12

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants Who Completed Initially Assigned Treatment at Month 12		Month 12
Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52	A migraine day was defined as any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). The mean of monthly migraine days was obtained cumulatively every 4 weeks across 52 weeks (for example, at Week 8 the mean will be based on data from Week 1 to Week 8; and at Week 12 the mean will be based on data from Week 1 to Week 12). The cumulative mean change from baseline in monthly migraine days was derived using difference between cumulative average of each month and baseline monthly migraine days.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Written informed consent must be obtained before any assessment is performed.
Adults greater than or equal to 18 years of age upon entry into screening.
Documented history of migraine (with or without aura) greater than or equal to 12 months prior to screening according to the International Classification of Headache Disorders-3rd Edition (ICHD-3).
Greater than or equal to 4 and less than 15 days per month of migraine symptoms (based on ICHD-3 criteria) on average across 3 months prior to screening based on retrospective reporting.
Less than 15 days per month of headache symptoms (i.e., migraine and non-migraine).
Subjects in need for switching by documented failure of 1 or 2 prophylactic treatments in the last 6 months due to either lack of efficacy or poor tolerability. For subjects with 1 prior treatment failure, the failure should have occurred in the last 6 months. For subjects with 2 prior treatment failures, the second treatment failure should have occurred in the last 6 months.
During baseline: Confirmed migraine frequency of 4 to 14 migraine days and less than 15 days of headache symptoms.
During baseline: greater than or equal to 80% compliance with the headache diary.

Exclusion Criteria:

Subjects meeting any of the following criteria are not eligible for inclusion in this study.
- Older than 50 years of age at migraine onset.
- History of cluster headache or hemiplegic migraine headache.
- Unable to differentiate migraine from other headaches.
- Lack of efficacy or poor tolerability with greater than 2 treatments from the 7 medication categories for prophylactic treatment of migraine after an adequate therapeutic trial.
Efficacy failure is defined as no meaningful reduction in headache frequency, duration, and/or severity after administration of the medication for at least 6 weeks at the generally accepted therapeutic dose(s) based on the investigator's assessment.
Tolerability failure is defined as documented discontinuation due to adverse events of the respective medication during the last 6 months prior to screening.
The following scenarios do not constitute lack of therapeutic response:
Lack of sustained response to a medication.
Patient decision to halt treatment due to improvement.
Used a prohibited medication from the 7 categories of prior prophylactic medications within 3 months prior to the start of and during baseline for a non-migraine indication if dose is not stable
Exposure to botulinum toxin in the head and/or neck region within 4 months.
Taken the following for any indication in any month during the 2 months prior to the start of the baseline period:
- Ergotamines or triptans on greater than or equal to 10 days per month, or Simple analgesics (non-steroidal anti-inflammatory drugs [NSAIDs], acetaminophen) on greater than or equal to 15 days per month, or
- Opioid- or butalbital-containing analgesics on greater than or equal to 4 days per month.
Device, or procedure that potentially may interfere with the intensity or number of migraine days within 2 months prior to the start of or during baseline.
History of major psychiatric disorders (such as schizophrenia or bipolar disorder) or current evidence of depression. Subjects with anxiety disorder and/or major depressive disorders are permitted in the study if they are considered by the investigator to be stable and are taking no more than 1 medication for each disorder. Subjects must have been on a stable dose within the 3 months prior to the start of the baseline period.
History of seizure disorder or other significant neurological conditions other than migraine. Note: a single childhood febrile seizure is not exclusionary.
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
Human immunodeficiency virus (HIV) infection by history.
History or evidence of any other unstable or clinically significant medical condition or clinically significant vital sign, laboratory, or electrocardiogram (ECG) abnormality during that could pose a risk to subject safety or interfere with the study evaluation.
Myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary artery bypass surgery or other re-vascularization procedures within 6 months prior to screening.
Score "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self-Injurious Behavior" (item also included in the Suicidal Behavior section), if this behavior occurred in the past 2 years.
Evidence of drug or alcohol abuse or dependence, based on Investigator discretion within 12 months.
Pregnant or nursing (lactating) women.
Women of child-bearing potential must use contraception during dosing with study treatment.
Use of other investigational drugs within 5 half-lives of enrollment, or until the expected pharmacodynamic effect has returned to baseline, whichever is longer.
History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes.
Previous exposure to AMG334 or exposure to any other prophylactic CGRP-targeted therapy (prior to the study).

Name	Affiliation	Role
MD	Amgen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Stanford Headache Center		Stanford	California	94305	United States
Yale Center for Clinical Research

PubMed Identifier	Type	Citation	Retractions
38526461	Derived	Pozo-Rosich P, Dolezil D, Paemeleire K, Stepien A, Stude P, Snellman J, Arkuszewski M, Stites T, Ritter S, Lopez Lopez C, Maca J, Ferraris M, Gil-Gouveia R. Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial. JAMA Neurol. 2024 May 1;81(5):461-470. doi: 10.1001/jamaneurol.2024.0368.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	AMG334 70 mg/140 mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 15, 2020	Sep 29, 2022

Arm/Group Information

ID	Title	Description
BG000	AMG334 70 mg/140 mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.
BG001	Oral Prophylactic	Participants received a standard of care (SOC) approved oral prophylactic once per day for 52 weeks in the Core Phase, as prescribed per local country labels. Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were in need of a treatment switch) entered the Extension Phase to receive 70 mg or 140 mg AMG334 for up to 52 weeks.
BG002	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants Who Completed Initially Assigned Treatment and Achieved at Least a 50% Reduction From Baseline in Monthly Migraine Days at Month 12

A migraine day was defined as any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined as a migraine with or without aura, lasting for ≥ 30 minutes, and meeting at least one of the following criteria:

≥2 of the following pain features:
- Unilateral
- Throbbing
- Moderate to severe
- Exacerbated with exercise/physical activity
≥1 of the following associated symptoms:
- Nausea and/or vomiting
- Photophobia and phonophobia

If the participant took a migraine-specific medication (ie, triptan or ergotamine) during aura, or to treat a headache on a calendar day, then it was counted as a migraine day regardless of the duration and pain features/associated symptoms.

In addition to achieving at least a 50% reduction from baseline in monthly migraine days, participants must have also completed their initially assigned treatment through Month 12.

FAS: Included all participants to whom study treatment had been assigned.

Posted

Count of Participants

Participants

Baseline and Month 12

ID	Title	Description
OG000	AMG334 70 mg/140 mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.
OG001	Oral Prophylactic	Participants received a standard of care (SOC) approved oral prophylactic once per day for 52 weeks in the Core Phase, as prescribed per local country labels. Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were in need of a treatment switch) entered the Extension Phase to receive 70 mg or 140 mg AMG334 for up to 52 weeks.

Units	Counts
Participants	OG000413 OG001208

Title

Denominators

Categories

Title	Measurements
	OG000232 OG00135

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Cochran-Mantel-Haenszel	Adjusted for stratification factor (no. of prior prophylactic migraine treatment failures=1 vs 2) after missing data were imputed as non-response.	<0.0001		Odds Ratio (OR)	6.48			2-Sided	95	4.28	9.82					Superiority

Secondary

Number of Participants Who Completed Initially Assigned Treatment at Month 12

FAS: Included all participants to whom study treatment has been assigned.

Posted

Count of Participants

Participants

Month 12

ID	Title	Description
OG000	AMG334 70 mg/140 mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.
OG001	Oral Prophylactic	Participants received a standard of care (SOC) approved oral prophylactic once per day for 52 weeks in the Core Phase, as prescribed per local country labels. Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were in need of a treatment switch) entered the Extension Phase to receive 70 mg or 140 mg AMG334 for up to 52 weeks.

Secondary

Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52

A migraine day was defined as any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). The mean of monthly migraine days was obtained cumulatively every 4 weeks across 52 weeks (for example, at Week 8 the mean will be based on data from Week 1 to Week 8; and at Week 12 the mean will be based on data from Week 1 to Week 12). The cumulative mean change from baseline in monthly migraine days was derived using difference between cumulative average of each month and baseline monthly migraine days.

Participants in the FAS with data available at each time point. The FAS included all participants to whom study treatment had been assigned. All participants included in the overall number of participants analyzed contributed to the post-baseline data for this endpoint.

Posted

Mean

Standard Error

migraine days per month

Baseline and Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52

ID	Title	Description
OG000	AMG334 70 mg/140 mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.

Secondary

Number of Responders as Measured by the Patient's Global Impression of Change (PGIC) Scale at Week 52

The PGIC scale consists of one item which measures the participants' perception of change in their condition relative to the beginning of the study. Responses are rated on a 7-item response scale ranging from very much improved (7) to no change or worsened condition (1). A responder was defined as a participant with a PGIC score of at least 5 (5=moderately better, 6=better, 7=a great deal better), at Week 52 for participants who completed the treatment period at Week 52 on the initially assigned treatment.

FAS: Included all participants to whom study treatment had been assigned.

Posted

Count of Participants

Participants

Baseline and Week 52

ID	Title	Description
OG000	AMG334 70 mg/140 mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.
OG001	Oral Prophylactic	Participants received a standard of care (SOC) approved oral prophylactic once per day for 52 weeks in the Core Phase, as prescribed per local country labels. Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Eligible Core Phase completers (completed Week 52 and were in need of a treatment switch) entered the Extension Phase to receive 70 mg or 140 mg AMG334 for up to 52 weeks.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Core Phase: AMG334 70mg/140mg	Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase. Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Includes 9 participants who switched from AMG334 to SOC oral prophylactics during the core phase; only AEs prior to the treatment switch to SOC oral prophylactics are reported.	408	15	408	131	408
EG001	Core Phase: Oral Prophylactics	Participants received a SOC approved oral prophylactic once per day for 52 weeks in the Core Phase, as prescribed per local country labels. Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion. Includes 9 participants who switched from AMG334 to SOC oral prophylactics during the core phase; only AEs following the treatment switch to SOC oral prophylactics are reported.	206	9	206	91	206
EG002	Extension Phase: AMG334 70mg/140mg Continuing on AMG334 70mg/140mg	Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks.	343	9	343	106	343
EG003	Extension Phase: Oral Prophylactics Then AMG334 70mg/140mg	Eligible Core Phase completers (completed Week 52 and were in need of a treatment switch) who received a SOC approved oral prophylactic in the Core Phase entered the Extension Phase to receive 70 mg or 140 mg AMG334 for up to 52 weeks.	118	4	118	47	118

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Tympanic membrane perforation	Ear and labyrinth disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG0031 affected118 at risk
Goitre	Endocrine disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Ulcerative keratitis	Eye disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Umbilical hernia	Gastrointestinal disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Medical device pain	General disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Anaphylactic reaction	Immune system disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Food allergy	Immune system disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
COVID-19 pneumonia	Infections and infestations	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Diverticulitis	Infections and infestations	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Pyelonephritis acute	Infections and infestations	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Ankle fracture	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Hand fracture	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Hip fracture	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Ligament sprain	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Meniscus injury	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Muscle hernia	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Procedural pain	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Radius fracture	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Wound	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Diastasis recti abdominis	Musculoskeletal and connective tissue disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Femoroacetabular impingement	Musculoskeletal and connective tissue disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Joint stiffness	Musculoskeletal and connective tissue disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Metatarsalgia	Musculoskeletal and connective tissue disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Papillary thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Salivary gland neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Headache	Nervous system disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Migraine	Nervous system disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Mood altered	Psychiatric disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Suicide attempt	Psychiatric disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Hydronephrosis	Renal and urinary disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Nephrolithiasis	Renal and urinary disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Ureteric rupture	Renal and urinary disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0021 affected343 at risk EG003
Breast fibrosis	Reproductive system and breast disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Endometrial hyperplasia	Reproductive system and breast disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Endometriosis	Reproductive system and breast disorders	MedDRA (25.1)	Systematic Assessment	EG0001 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Menometrorrhagia	Reproductive system and breast disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0011 affected206 at risk EG0020 affected343 at risk EG003
Ovarian cyst	Reproductive system and breast disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003
Skin laxity	Skin and subcutaneous tissue disorders	MedDRA (25.1)	Systematic Assessment	EG0000 affected408 at risk EG0010 affected206 at risk EG0020 affected343 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Constipation	Gastrointestinal disorders	MedDRA (25.1)	Systematic Assessment	EG00053 affected408 at risk EG0012 affected206 at risk EG00210 affected343 at risk EG00316 affected118 at risk
Fatigue	General disorders	MedDRA (25.1)	Systematic Assessment	EG00018 affected408 at risk EG00133 affected206 at risk EG0024 affected343 at risk EG003
COVID-19	Infections and infestations	MedDRA (25.1)	Systematic Assessment	EG00020 affected408 at risk EG00112 affected206 at risk EG00261 affected343 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (25.1)	Systematic Assessment	EG00036 affected408 at risk EG00115 affected206 at risk EG00228 affected343 at risk EG003
Vaccination complication	Injury, poisoning and procedural complications	MedDRA (25.1)	Systematic Assessment	EG0009 affected408 at risk EG0012 affected206 at risk EG00216 affected343 at risk EG003
Weight increased	Investigations	MedDRA (25.1)	Systematic Assessment	EG00012 affected408 at risk EG00122 affected206 at risk EG0020 affected343 at risk EG003
Dizziness	Nervous system disorders	MedDRA (25.1)	Systematic Assessment	EG0007 affected408 at risk EG00118 affected206 at risk EG0026 affected343 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (25.1)	Systematic Assessment	EG0005 affected408 at risk EG00115 affected206 at risk EG0023 affected343 at risk EG003
Somnolence	Nervous system disorders	MedDRA (25.1)	Systematic Assessment	EG0005 affected408 at risk EG00115 affected206 at risk EG0020 affected343 at risk EG003

ID	Term
D008881	Migraine Disorders
D012008	Recurrence
D006261	Headache

ID	Term
D051270	Headache Disorders, Primary
D020773	Headache Disorders
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D010146	Pain
D009461	Neurologic Manifestations
D012816	Signs and Symptoms