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

• Sponsor: Otsuka Pharmaceutical Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03303079
• Collaborator: (none)
• Enrollment: 571
• Location: 1
• Arms: 3
• Actual Duration (Months): 23.4
• Patients Per Site Per Month: 24.4

Study Details

Study Description

Brief 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

Condition or Disease	Intervention/Treatment	Phase
Migraine	Drug: TEV-48125; Drug: TEV-48125 or placebo; Drug: Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 571 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Chronic Migraine
• Actual Study Start Date: Dec 19, 2017
• Actual Primary Completion Date: Nov 30, 2019
• Actual Study Completion Date: Nov 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
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; TEV-48125 will be subcutaneously administered once monthly for 3 months.
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; TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months.
Placebo Comparator: Placebo group Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).	Drug: Placebo; Placebo will be subcutaneously administered once monthly for 3 months.

Outcome Measures

Primary Outcome Measures

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) [Baseline, 12 weeks]

   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.

Secondary Outcome Measures

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

   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.

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 [12 weeks]

   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.

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 [Baseline, 12 weeks]

   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).

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 [Baseline, 12 weeks]

   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."

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 [Baseline, 4 weeks]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: 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:

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Saitama Medical University Hospital	Iruma		Japan

Sponsors and Collaborators

• Otsuka Pharmaceutical Co., Ltd.

Investigators

• Study Director: Takehisa Matsumaru, Otsuka Pharmaceutical Co., Ltd.

Study Documents (Full-Text)

• Study Protocol - Jul 8, 2019
• Statistical Analysis Plan - Dec 12, 2019

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Co., Ltd.
• ClinicalTrials.gov Identifier: NCT03303079
• Other Study ID Numbers: 406-102-00001; JapicCTI-173723
• First Posted: Oct 5, 2017
• Last Update Posted: Jun 15, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Migraine Disorders; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Period Title: Overall Study
STARTED	189	191	191
COMPLETED	182	180	179
NOT COMPLETED	7	11	12

Baseline Characteristics

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group	Total
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).	Total of all reporting groups
Overall Participants	189	191	191	571
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	187 98.9%	184 96.3%	190 99.5%	561 98.2%
>=65 years	2 1.1%	7 3.7%	1 0.5%	10 1.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.7 (10.2)	43.5 (10.2)	42.1 (10.2)	42.8 (10.2)
Sex: Female, Male (Count of Participants)
Female	163 86.2%	165 86.4%	163 85.3%	491 86%
Male	26 13.8%	26 13.6%	28 14.7%	80 14%
Race/Ethnicity, Customized (Count of Participants)
Asian	189 100%	191 100%	191 100%	571 100%
Region of Enrollment (participants) [Number]
Japan	159 84.1%	159 83.2%	161 84.3%	479 83.9%
South Korea	30 15.9%	32 16.8%	30 15.7%	92 16.1%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of headache days of at least moderate severity

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Measure Participants	187	189	190
Mean (Standard Error) [days/month]	-4.12 (0.43)	-4.14 (0.43)	-2.45 (0.43)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of headache days of at least moderate severity

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Measure Participants	187	189	190
Mean (Standard Error) [days/month]	-4.90 (0.50)	-4.07 (0.49)	-2.79 (0.49)

3. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of headache days of at least moderate severity "Overall Number of Participants Analyzed" = the number of subjects meeting responder criteria

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Measure Participants	54	55	25
Number [percentage of participants]	29.0 15.3%	29.1 15.2%	13.2 6.9%

4. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of headache days of at least moderate severity

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Measure Participants	187	189	190
Mean (Standard Error) [days/month]	-3.74 (0.44)	-3.87 (0.43)	-2.44 (0.43)

5. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of headache days of at least moderate severity

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Measure Participants	149	149	149
Mean (Standard Error) [days/month]	-3.74 (0.44)	-3.87 (0.43)	-2.44 (0.43)

6. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of headache days of at least moderate severity

Arm/Group Title	TEV-48125 (675/225/225 mg) Group	TEV-48125 (675 mg/Placebo/Placebo) Group	Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).	TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).	Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Measure Participants	182	180	179
Mean (Standard Error) [score on a scale]	-8.06 (0.70)	-8.03 (0.68)	-6.49 (0.68)

Adverse Events

Time Frame	Double-blind treatment period (12 weeks)
Adverse Event Reporting Description	Safety set (SS):Subjects who received the IMP at least once
Arm/Group Title	TEV-48125 (675/225/225 mg) Group		TEV-48125 (675 mg/Placebo/Placebo) Group		Placebo Group
Arm/Group Description	TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg).		TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo).		Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
All Cause Mortality
	TEV-48125 (675/225/225 mg) Group		TEV-48125 (675 mg/Placebo/Placebo) Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/188 (0%)		0/190 (0%)		0/191 (0%)
Serious Adverse Events
	TEV-48125 (675/225/225 mg) Group		TEV-48125 (675 mg/Placebo/Placebo) Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/188 (1.6%)		1/190 (0.5%)		1/191 (0.5%)
Gastrointestinal disorders
Intestinal haemorrhage	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Infections and infestations
Influenza	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Injury, poisoning and procedural complications
Brain contusion	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Other (Not Including Serious) Adverse Events
	TEV-48125 (675/225/225 mg) Group		TEV-48125 (675 mg/Placebo/Placebo) Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	115/188 (61.2%)		116/190 (61.1%)		117/191 (61.3%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Anaemia	0/188 (0%)		1/190 (0.5%)		2/191 (1%)
Lymphadenitis	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Cardiac disorders
Palpitations	2/188 (1.1%)		0/190 (0%)		1/191 (0.5%)
Prinzmetal angina	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Bundle branch block right	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Left ventricular hypertrophy	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Ear and labyrinth disorders
Deafness neurosensory	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Vertigo	1/188 (0.5%)		1/190 (0.5%)		0/191 (0%)
Meniere's disease	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Tinnitus	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Eye disorders
Dry eye	2/188 (1.1%)		0/190 (0%)		0/191 (0%)
Astigmatism	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Conjunctival cyst	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Conjunctivitis allergic	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Ocular discomfort	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Asthenopia	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Blepharospasm	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Chalazion	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Retinopathy solar	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Gastrointestinal disorders
Chronic gastritis	3/188 (1.6%)		2/190 (1.1%)		1/191 (0.5%)
Diarrhoea	3/188 (1.6%)		4/190 (2.1%)		0/191 (0%)
Constipation	2/188 (1.1%)		1/190 (0.5%)		2/191 (1%)
Gastrooesophageal reflux disease	2/188 (1.1%)		3/190 (1.6%)		2/191 (1%)
Nausea	2/188 (1.1%)		5/190 (2.6%)		2/191 (1%)
Tooth loss	2/188 (1.1%)		0/190 (0%)		0/191 (0%)
Abdominal discomfort	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Abdominal pain	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Abdominal pain upper	1/188 (0.5%)		2/190 (1.1%)		1/191 (0.5%)
Cheilitis	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Dyspepsia	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Enterocolitis	1/188 (0.5%)		1/190 (0.5%)		0/191 (0%)
Gastritis	1/188 (0.5%)		1/190 (0.5%)		1/191 (0.5%)
Toothache	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Anal fissure	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Colitis ischaemic	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Dental caries	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Epigastric discomfort	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Gastric polyps	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Haemorrhoids	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Irritable bowel syndrome	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Lumbar hernia	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Periodontal inflammation	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Salivary gland mass	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Stomatitis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Vomiting	0/188 (0%)		2/190 (1.1%)		0/191 (0%)
General disorders
Injection site induration	33/188 (17.6%)		23/190 (12.1%)		24/191 (12.6%)
Injection site erythema	29/188 (15.4%)		23/190 (12.1%)		21/191 (11%)
Injection site pain	14/188 (7.4%)		24/190 (12.6%)		17/191 (8.9%)
Injection site pruritus	10/188 (5.3%)		3/190 (1.6%)		5/191 (2.6%)
Injection site swelling	3/188 (1.6%)		2/190 (1.1%)		0/191 (0%)
Injection site haemorrhage	1/188 (0.5%)		3/190 (1.6%)		0/191 (0%)
Injection site rash	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Malaise	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Pyrexia	1/188 (0.5%)		1/190 (0.5%)		2/191 (1%)
Chest pain	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Generalised oedema	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Injection site bruising	0/188 (0%)		0/190 (0%)		2/191 (1%)
Injection site dermatitis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Injection site inflammation	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Non-cardiac chest pain	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Thirst	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Immune system disorders
Seasonal allergy	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Infections and infestations
Nasopharyngitis	30/188 (16%)		40/190 (21.1%)		36/191 (18.8%)
Influenza	4/188 (2.1%)		1/190 (0.5%)		3/191 (1.6%)
Upper respiratory tract infection	3/188 (1.6%)		0/190 (0%)		0/191 (0%)
Gastroenteritis	2/188 (1.1%)		3/190 (1.6%)		1/191 (0.5%)
Herpes virus infection	2/188 (1.1%)		0/190 (0%)		0/191 (0%)
Bronchitis	1/188 (0.5%)		2/190 (1.1%)		0/191 (0%)
Conjunctivitis	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Gingivitis	1/188 (0.5%)		1/190 (0.5%)		2/191 (1%)
Kaposi's varicelliform eruption	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Oral herpes	1/188 (0.5%)		1/190 (0.5%)		0/191 (0%)
Sinusitis	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Tonsillitis	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Vulvitis	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Cystitis	0/188 (0%)		4/190 (2.1%)		1/191 (0.5%)
Helicobacter infection	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Herpes simplex	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Hordeolum	0/188 (0%)		1/190 (0.5%)		1/191 (0.5%)
Parotitis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Pharyngitis	0/188 (0%)		1/190 (0.5%)		1/191 (0.5%)
Pharyngotonsillitis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Pneumonia	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Pulpitis dental	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Streptococcal infection	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Urinary tract infection	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Injury, poisoning and procedural complications
Contusion	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Fracture	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Stab wound	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Wound	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Arthropod sting	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Dental restoration failure	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Ligament sprain	0/188 (0%)		2/190 (1.1%)		0/191 (0%)
Muscle contusion	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Post-traumatic neck syndrome	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Procedural pain	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Investigations
Urine leukocyte esterase positive	2/188 (1.1%)		1/190 (0.5%)		0/191 (0%)
Weight decreased	2/188 (1.1%)		2/190 (1.1%)		2/191 (1%)
Alanine aminotransferase increased	1/188 (0.5%)		2/190 (1.1%)		1/191 (0.5%)
Aspartate aminotransferase increased	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Blood urine present	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Gamma-glutamyltransferase increased	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Blood bilirubin increased	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Blood creatine phosphokinase increased	0/188 (0%)		2/190 (1.1%)		0/191 (0%)
Blood glucose increased	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Blood potassium increased	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Blood pressure increased	0/188 (0%)		2/190 (1.1%)		1/191 (0.5%)
Eosinophil count increased	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Weight increased	0/188 (0%)		1/190 (0.5%)		1/191 (0.5%)
White blood cell count increased	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Decreased appetite	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Metabolism and nutrition disorders
Hyperglycaemia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Vitamin D deficiency	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Diabetic complication	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Musculoskeletal and connective tissue disorders
Back pain	5/188 (2.7%)		1/190 (0.5%)		1/191 (0.5%)
Musculoskeletal pain	3/188 (1.6%)		0/190 (0%)		0/191 (0%)
Pain in extremity	3/188 (1.6%)		0/190 (0%)		0/191 (0%)
Myalgia	2/188 (1.1%)		1/190 (0.5%)		0/191 (0%)
Neck pain	2/188 (1.1%)		1/190 (0.5%)		1/191 (0.5%)
Muscle spasms	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Musculoskeletal stiffness	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Temporomandibular joint syndrome	1/188 (0.5%)		1/190 (0.5%)		0/191 (0%)
Tenosynovitis	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Arthralgia	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Limb discomfort	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Osteoarthritis	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Osteopenia	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Spinal deformity	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Spondylolisthesis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Nervous system disorders
Dizziness	3/188 (1.6%)		2/190 (1.1%)		3/191 (1.6%)
Headache	3/188 (1.6%)		1/190 (0.5%)		1/191 (0.5%)
Syncope	2/188 (1.1%)		0/190 (0%)		0/191 (0%)
Cognitive disorder	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Hypersomnia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Hypoaesthesia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Migraine	1/188 (0.5%)		3/190 (1.6%)		2/191 (1%)
Monoplegia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Paraesthesia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Presyncope	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Amnestic disorder	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Dizziness postural	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Intercostal neuralgia	0/188 (0%)		1/190 (0.5%)		1/191 (0.5%)
Memory impairment	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Neuralgia	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Somnolence	0/188 (0%)		0/190 (0%)		2/191 (1%)
Psychiatric disorders
Depression	2/188 (1.1%)		0/190 (0%)		0/191 (0%)
Alcoholic hangover	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Insomnia	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Mental fatigue	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Panic disorder	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Sleep disorder	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Suicidal ideation	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Renal and urinary disorders
Haematuria	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Proteinuria	0/188 (0%)		1/190 (0.5%)		1/191 (0.5%)
Reproductive system and breast disorders
Dysmenorrhoea	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Menorrhagia	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Vaginal haemorrhage	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Premenstrual syndrome	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/188 (0.5%)		4/190 (2.1%)		0/191 (0%)
Cough	1/188 (0.5%)		2/190 (1.1%)		1/191 (0.5%)
Oropharyngeal pain	1/188 (0.5%)		0/190 (0%)		3/191 (1.6%)
Rhinitis allergic	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Reflux laryngitis	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Throat tightness	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Upper respiratory tract inflammation	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Skin and subcutaneous tissue disorders
Eczema	2/188 (1.1%)		1/190 (0.5%)		2/191 (1%)
Dermatitis contact	1/188 (0.5%)		0/190 (0%)		2/191 (1%)
Drug eruption	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Dry skin	1/188 (0.5%)		0/190 (0%)		1/191 (0.5%)
Miliaria	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Pruritus	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Urticaria	1/188 (0.5%)		1/190 (0.5%)		0/191 (0%)
Erythema	0/188 (0%)		0/190 (0%)		1/191 (0.5%)
Onycholysis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Rash	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Seborrhoeic dermatitis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Solar dermatitis	0/188 (0%)		1/190 (0.5%)		0/191 (0%)
Vascular disorders
Peripheral coldness	1/188 (0.5%)		0/190 (0%)		0/191 (0%)
Neurogenic shock	0/188 (0%)		1/190 (0.5%)		0/191 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.