Trial Outcomes & Findings for Study of OTO-104 in Subjects With Unilateral Meniere's Disease (NCT NCT02612337)

Last Updated: 2023-01-12

Results Overview

The number of DVDs at Week 12 (defined as the 4-week \[28 days\] interval from Week 9 through Week 12) was compared between OTO-104 and placebo. Week 12 = 12 weeks after dosing at the Baseline visit. Baseline occurred at the end of lead-in and no intervention was administered during lead-in.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

166 participants

Primary outcome timeframe

Week 12 (3 months)

Results posted on

2023-01-12

Participant Flow

166 subjects were randomized and 165 subjects received study drug. The most common reason for screen failure was that there was not a sufficient number of definitive vertigo days in the 28-day lead-in period. The first subject enrolled on October 27, 2015, and the last subject completed the study on July 18, 2017. A total of 47 centers in the US enrolled subjects.

In addition to meeting all screening visit inclusion criteria, potential subjects had to experience and record at least 4 and a maximum of 22 definitive vertigo day (DVD) during the 4 week lead-in period. In addition, the subject needed to complete at least 22 of 28 diary entries during the 4-week lead-in period. A DVD was defined each day the subject recorded a vertigo episode lasting at least 20 minutes corresponding to a vertigo score of 2 or more.

Participant milestones

Participant milestones
Measure	OTO-104 12 mg dexamethasone OTO-104: Single intratympanic injection of 12 mg OTO-104	Placebo Placebo: Single intratympanic injection of placebo
Overall Study STARTED	83	83
Overall Study Received Study Drug	83	82
Overall Study COMPLETED	80	80
Overall Study NOT COMPLETED	3	3

Reasons for withdrawal

Reasons for withdrawal
Measure	OTO-104 12 mg dexamethasone OTO-104: Single intratympanic injection of 12 mg OTO-104	Placebo Placebo: Single intratympanic injection of placebo
Overall Study Lack of Efficacy	1	0
Overall Study Withdrawal by Subject	2	2
Overall Study Did not receive study drug	0	1

Baseline Characteristics

Study of OTO-104 in Subjects With Unilateral Meniere's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	OTO-104 (Full Analysis Set) n=83 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=82 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Total n=165 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	65 Participants n=5 Participants	61 Participants n=7 Participants	126 Participants n=5 Participants
Age, Categorical >=65 years	18 Participants n=5 Participants	21 Participants n=7 Participants	39 Participants n=5 Participants
Age, Continuous	54.0 years n=5 Participants	58.0 years n=7 Participants	55.7 years n=5 Participants
Sex: Female, Male Female	48 Participants n=5 Participants	46 Participants n=7 Participants	94 Participants n=5 Participants
Sex: Female, Male Male	35 Participants n=5 Participants	36 Participants n=7 Participants	71 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	73 Participants n=5 Participants	75 Participants n=7 Participants	148 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	0 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	74 Participants n=5 Participants	80 Participants n=7 Participants	154 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	83 participants n=5 Participants	82 participants n=7 Participants	165 participants n=5 Participants
Previous IT Steroid Injection	20 Participants n=5 Participants	30 Participants n=7 Participants	50 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 12 (3 months)

Population: The full analysis set subjects who were randomized, received study drug, had a baseline definitive vertigo measurement for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline, i.e., at least 1 post-baseline daily diary entry.

Outcome measures

Outcome measures
Measure	OTO-104 (Full Analysis Set) n=83 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=82 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).
The Number of DVD at Week 12 (Defined as the 4-week [28 Days] Interval From Week 9 Through Week 12).	2.191 Definitive Vertigo Day Interval 1.644 to 2.919	2.415 Definitive Vertigo Day Interval 1.823 to 3.198

SECONDARY outcome

Timeframe: 3 months

Questionnaire - subjects were instructed to record the effect on their daily activities of their total vertigo experienced that day using a 5-point scoring system: 0 = normal activity 1. = slight limitation 2. = moderate limitation 3. = sick at home 4. = bed ridden

Outcome measures

Outcome measures
Measure	OTO-104 (Full Analysis Set) n=83 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=82 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).
Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3)	1.287 days Standard Deviation 2.8797	1.058 days Standard Deviation 2.077

SECONDARY outcome

Timeframe: 3 months

Otoscopic examinations were conducted at each visit. It was considered important to understand if the tympanic perforation that resulted from the IT injection at the Baseline visit persisted at the end of study visit (Week 12 \[Month 3\]).

Outcome measures

Outcome measures
Measure	OTO-104 (Full Analysis Set) n=82 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=83 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).
Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3)	4 participants	0 participants

SECONDARY outcome

Timeframe: 3 months

Population: Subjects that had no impairment at the Baseline visit (air-bone gap \<=10 dB)

The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 500 Hz.

Outcome measures

Outcome measures
Measure	OTO-104 (Full Analysis Set) n=62 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=70 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).
Audiometry - Shift in Air-Bone Gap at 500 Hz From Baseline to Week 12 (Month 3)	2 Participants	7 Participants

SECONDARY outcome

Timeframe: Week 12 (Month 3)

Population: Subjects that had no impairment at the Baseline visit (air-bone gap \<=10 dB

The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 1000 Hz.

Outcome measures

Outcome measures
Measure	OTO-104 (Full Analysis Set) n=70 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=68 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).
Audiometry - Shift in Air-Bone Gap at 1000 Hz From Baseline to Week 12 (Month 3)	3 Participants	3 Participants

SECONDARY outcome

Timeframe: Week 12 (Month 3)

Population: Subjects that had no impairment at the Baseline visit (air-bone gap \<=10 dB)

The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 2000 Hz.

Outcome measures

Outcome measures
Measure	OTO-104 (Full Analysis Set) n=74 Participants Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).	Placebo (Full Analysis Set) n=78 Participants Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry).
Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3)	4 Participants	1 Participants

Adverse Events

OTO-104 (Safety Analysis Set)

Serious events: 2 serious events

Other events: 34 other events

Deaths: 0 deaths

Placebo (Safety Analysis Set)

Serious events: 2 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	OTO-104 (Safety Analysis Set) n=82 participants at risk All subjects who received OTO-104. Subjects were included in this treatment group according to the actual treatment received regardless of their randomized assignment.	Placebo (Safety Analysis Set) n=83 participants at risk All subjects who received Placebo. Subjects were included in this treatment group according to the actual treatment received regardless of their randomized assignment.
Immune system disorders Kidney transplant rejection	1.2% 1/82 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Musculoskeletal and connective tissue disorders Muscular weakness	1.2% 1/82 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Renal and urinary disorders Acute kidney injury	1.2% 1/82 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Psychiatric disorders Suicidal ideation	0.00% 0/82 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	1.2% 1/83 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Psychiatric disorders Suicide attempt	0.00% 0/82 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	1.2% 1/83 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).

Other adverse events

Additional Information

Otonomy Medical Information Center

Otonomy, Inc.

Phone: 1-844-686-4636

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	OTO-104 (Safety Analysis Set) n=82 participants at risk All subjects who received OTO-104. Subjects were included in this treatment group according to the actual treatment received regardless of their randomized assignment.	Placebo (Safety Analysis Set) n=83 participants at risk All subjects who received Placebo. Subjects were included in this treatment group according to the actual treatment received regardless of their randomized assignment.
Infections and infestations Nasopharyngitis	3.7% 3/82 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	10.8% 9/83 • Number of events 9 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Infections and infestations Upper respiratory tract infection	3.7% 3/82 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	2.4% 2/83 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Infections and infestations Bronchitis	2.4% 2/82 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Infections and infestations Sinusitis	2.4% 2/82 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Infections and infestations Influenza	0.00% 0/82 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	3.6% 3/83 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Infections and infestations Pharyngitis streptococcal	0.00% 0/82 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	2.4% 2/83 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Ear and labyrinth disorders Ear pain	4.9% 4/82 • Number of events 4 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	4.8% 4/83 • Number of events 4 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Ear and labyrinth disorders Meniere's disease	2.4% 2/82 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	1.2% 1/83 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Ear and labyrinth disorders Tinnitus	2.4% 2/82 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Gastrointestinal disorders Diarrhea	3.7% 3/82 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Nervous system disorders Headache	3.7% 3/82 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	3.6% 3/83 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Nervous system disorders Hypoesthesia	3.7% 3/82 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Musculoskeletal and connective tissue disorders Muscle spasms	2.4% 2/82 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
General disorders Non-cardiac chest pain	2.4% 2/82 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	0.00% 0/83 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Vascular disorders Hypertension	3.7% 3/82 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	1.2% 1/83 • Number of events 1 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Investigations White blood cell count increased	0.00% 0/82 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	2.4% 2/83 • Number of events 2 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).
Psychiatric disorders Suicidal ideation	0.00% 0/82 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).	3.6% 3/83 • Number of events 3 • Reported or observed during or after dosing with the study drug at the Baseline visit up to the Week 12 (Month 3) end of study visit. The Baseline visit occurred after the Lead-in period when no intervention was administered. Therefore, collection of adverse events started during dosing at the Baseline visit and lasted to the end of the study (Week 12 (Month 3).