Trial Outcomes & Findings for Efficacy and Safety of 4-aminopyridine on Cognitive Performance and Motor Function of Patients With Multiple Sclerosis (NCT NCT02280096)

Results Overview

Neuropsychological tests to assess: verbal fluency. Participants have to say as many words as possible from a category in a given time 60 Sec (F, A, S) Max score 72 and min score 19 words. Higher scores indicate a better cognitive performance.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

24 participants

Primary outcome timeframe

10-15 minutes

Results posted on

2019-09-12

Participant Flow

Twenty-four patients were recruited, of whom 21 completed the study

Three patients were excluded: one because of lack of adherence to the treatment; another presented an anxiety crisis and third one due to pregnancy. In the end, 11 patients were included in the treatment group and 10 in the placebo (control) group.

Participant milestones

Participant milestones
Measure	4-aminopyridine Treatment 4-aminopyridine is given as gelatin capsules containing 4-aminopyridine 10 mg and microcrystalline cellulose as the excipient. Each patient will take two capsules every 6 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study. 4-aminopyridine: Each patient will take two capsules every 6 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study.	Placebo Patients randomized to the placebo sequence will receive placebo for 20 weeks after the run-in period. They will be blinded to the fact that they are taking placebo, and capsules will be identical in appearance to the intervention capsules. Placebo: The placebo arm will include Microcrystalline Cellulose placebo
Overall Study STARTED	13	11
Overall Study COMPLETED	11	10
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	4-aminopyridine Treatment 4-aminopyridine is given as gelatin capsules containing 4-aminopyridine 10 mg and microcrystalline cellulose as the excipient. Each patient will take two capsules every 6 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study. 4-aminopyridine: Each patient will take two capsules every 6 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study.	Placebo Patients randomized to the placebo sequence will receive placebo for 20 weeks after the run-in period. They will be blinded to the fact that they are taking placebo, and capsules will be identical in appearance to the intervention capsules. Placebo: The placebo arm will include Microcrystalline Cellulose placebo
Overall Study Pregnancy	1	0
Overall Study Functional neurological disorder	1	0
Overall Study Lack of attachment	0	1

Baseline Characteristics

Efficacy and Safety of 4-aminopyridine on Cognitive Performance and Motor Function of Patients With Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	4-aminopyridine Treatment (20 Weeks) n=11 Participants 4-aminopyridine is given as gelatin capsules containing 4-aminopyridine 10 mg and microcrystalline cellulose as the excipient. Each patient will take two capsules every 8 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study.	Placebo (20 Weeks) n=10 Participants Patients randomized to the placebo sequence will receive placebo for 20 weeks after the run-in period. They will be blinded to the fact that they are taking placebo, and capsules will be identical in appearance to the intervention capsules. Placebo: The placebo arm will include Microcrystalline Cellulose placebo	Total n=21 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	11 Participants n=5 Participants	10 Participants n=7 Participants	21 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	39.5 years STANDARD_DEVIATION 8 • n=5 Participants	34.3 years STANDARD_DEVIATION 9.8 • n=7 Participants	36.9 years STANDARD_DEVIATION 8.9 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants
Weight	66.1 kg STANDARD_DEVIATION 18.3 • n=5 Participants	76.1 kg STANDARD_DEVIATION 18.1 • n=7 Participants	71.1 kg STANDARD_DEVIATION 18.2 • n=5 Participants
Disease duration	8.55 years n=5 Participants	9.4 years n=7 Participants	8.97 years n=5 Participants
Education	15.9 years n=5 Participants	16.9 years n=7 Participants	16.4 years n=5 Participants
Mini Mental State Examination (MMSE)	27.1 units on a scale STANDARD_DEVIATION 1.4 • n=5 Participants	27 units on a scale STANDARD_DEVIATION 1.6 • n=7 Participants	27.05 units on a scale STANDARD_DEVIATION 1.5 • n=5 Participants
Interferon beta 1a	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Interferon beta 1b	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Interferon beta 1a subcutaneous	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Glatiramer acetate	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: 10-15 minutes

Population: Word List Generation (3 trials/60 sec)

Neuropsychological tests to assess: verbal fluency. Participants have to say as many words as possible from a category in a given time 60 Sec (F, A, S) Max score 72 and min score 19 words. Higher scores indicate a better cognitive performance.

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
The Brief Repeatable Battery of Rao	42.09 Correct words Standard Deviation 14.5	35.5 Correct words Standard Deviation 6.6

PRIMARY outcome

Timeframe: 7-10 min

Population: Attention spam.

Integrated Program of Neuropsychological Exploration Test Barcelona: Digit Span Forward (DSF), (attention spam and improved scoring metrics significantly enhance the precision of DSF assessments of short-term verbal memory). Digit sequences are presented beginning with a length of two digits and two trials are presented at each increasing list length. Max score 8 and min score 0 digits. Higher scores indicate a better cognitive performance.

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Integrated Program of Neuropsychological Exploration Test Barcelona	6.1 correct numbers recalled Standard Deviation 1.5	5 correct numbers recalled Standard Deviation 0.8

PRIMARY outcome

Timeframe: 10-15 minutes

The purpose of this test is to assess visual-spatial constructional ability and visual memory. The time required to copy the drawing is recorded. Less time indicates a better performance and more time indicates a worse outcome (min score 60 and max score 300 seconds).

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Rey-Osterrieth Complex Figure Test (ROCF)	208.6 units on a scale (seconds) Standard Deviation 121.2	231.2 units on a scale (seconds) Standard Deviation 114.8

PRIMARY outcome

Timeframe: 8-10 min

Processing speed information (which includes reading, count, and alternation speed). Cards with a different number of stimuli are shown to the patient, who has to read, count, and respond to a change of instructions (alternation). Reading speed (min 12, max 31+ seconds), counting speed (min 14, max 28+ seconds), and alternation speed (min 26, max 56+ seconds) are recorded. Less speed corresponds to a better outcome.

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Five Digit Test (FDT). Processing Speed Alternation speed	60.3 seconds Standard Deviation 25.7	58.8 seconds Standard Deviation 17.7
Five Digit Test (FDT). Processing Speed Reading speed	28 seconds Standard Deviation 9	29.6 seconds Standard Deviation 4.2
Five Digit Test (FDT). Processing Speed Count speed	30.5 seconds Standard Deviation 9.2	34.2 seconds Standard Deviation 12

PRIMARY outcome

Timeframe: 10-15 minutes

Is used primarily to assess perseveration and abstract thinking, allows the clinician to assess the following 'frontal' lobe functions: strategic planning, organised searching, utilising environmental feedback to shift cognitive sets, directing behaviour toward achieving a goal. WCST measures abstract reasoning and ability to alter problem solving strategies. Patients are given 128 response cards and 4 stimulus cards and asked to match each stimulus card to 1 pile of response cards. The patient is not told how to match the cards, only "right" or "wrong" to each placement. The examiner may change matching rules during the test. Perseveration errors occur when subject repeats the same error no matter how many times they are told the placement is wrong. Higher scores indicate a worse cognitive performance (min=0-3, max=58-126)

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Wisconsin Card Sorting Test (WCST)	19.8 score on a scale Standard Deviation 35.6	22.8 score on a scale Standard Deviation 32.2

PRIMARY outcome

Timeframe: 5-8 minutes

Population: Color Trails Test 1. Execution time

Measure sustained attention. The CTT uses numbered coloured circles and universal sign language symbols. The circles are printed with vivid pink or yellow backgrounds that are perceptible to colourblind individuals. For the Colour Trails 1 trial, the respondent uses a pencil to rapidly connect circles numbered 1 through 25 in sequence. Less time indicates better performance (min=10, max= 240).

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Color Trails Test (CTT)	68.91 units on a scale (seconds) Standard Deviation 40.7	67.3 units on a scale (seconds) Standard Deviation 37.4

PRIMARY outcome

Timeframe: 25-30 minutes

Measures higher order problem-solving ability. The information it provides is not only useful when assessing frontal lobe damage, but also when evaluating attention disorders and executive functioning difficulties. The administrator arranges red, green, and blue beads on a peg board to match the configuration in the diagram. The patient is asked to replicate the configuration on a second peg board. Scores are calculated for Total Correct Moves and Total Moves. Total moves: higher scores indicate a worse cognitive performance (min= 0, max=58+); Total correct higher scores indicate a better cognitive performance (min=0, max=10).

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Tower Of London (TOL). Total Moves and Total Correct Moves Total moves	42.7 score on a scale Standard Deviation 19.7	50.8 score on a scale Standard Deviation 23.9
Tower Of London (TOL). Total Moves and Total Correct Moves Correct moves	4 score on a scale Standard Deviation 2.7	3 score on a scale Standard Deviation 1.9

PRIMARY outcome

Timeframe: 25-30 minutes

Measures higher-order problem-solving ability. The information it provides is not only useful when assessing frontal lobe damage, but also when evaluating attention disorders and executive functioning difficulties. The administrator arranges red, green, and blue beads on a peg board to match the configuration in the diagram. The patient is asked to replicate the configuration on a second peg board. Scores are calculated for Total Execution Time (since the patient performs the first move until he ends the test), Total Problem-Solving Time (the sum of planning and execution times). Total execution time higher scores indicate a worse outcome (min= 0-78, max=564+ seconds), Total problem-solving time higher scores indicate a worse outcome (min= 0-56, max=500+ seconds).

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Tower Of London (TOL). Execution Time and Problem-solving Time Total execution time	296.2 seconds Standard Deviation 109.3	367.9 seconds Standard Deviation 265.4
Tower Of London (TOL). Execution Time and Problem-solving Time Total problem-solving time	363.3 seconds Standard Deviation 130	426.8 seconds Standard Deviation 278.9

SECONDARY outcome

Timeframe: 15-20 minutes

The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. It is widely used in clinical trials and in the assessment of people with MS. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist. The first levels 1.0 to 4.5 refers to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refers to the loss of ambulatory ability. It also provides eight subscale measurements called Functional System (FS) scores. The levels of function within each category refer to the eight FS affected by MS: The FS are scored on a scale of 0 (low level of problems) to 5 (high level of problems) to best reflect the level of disability observed clinically.

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Improved Physical Capacity	4.6 score on a scale Standard Deviation 1.55	4.04 score on a scale Standard Deviation 1.27

SECONDARY outcome

Timeframe: 10 minutes

The Fatigue Severity Scale (FSS) is one of the most frequently used inventories for measuring fatigue in people with chronic illnesses. The FSS questionnaire is comprised of nine statements inquiring about the examinee's sleep habits over the preceding week. Ratings are on a 7-point Likert scale, where higher scores indicate how strongly the patient agrees with the nine statements.Scale. Scoring using a bimodal response system or a Likert score with weights assigned to each response choice. Likert or bimodal rating scales with 4 response options. For the Likert Scale: better than usual= 0, no more than usual= 1, worse than usual= 2, much worse than usual= 3. For the bimodal scale: better than usual= 0, no more than usual= 0, worse than usual= 1, much worse than usual= 1. Sum all items for a total score. Score range. Range is 0 -11 for bimodal response format. Interpretation of scores. Higher score indicates more fatigue. Self report scale

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Fatigue	4.3 score on a scale Standard Deviation 1.4	3.3 score on a scale Standard Deviation 1.8

SECONDARY outcome

Timeframe: 5-10 minutes

Timed 25 Foot Walk Test (T25-FW). The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. TIME LIMIT PER TRIAL (2) 3 minutes (180 seconds) per trial.

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Walk	15.2 seconds Standard Deviation 13.3	10.4 seconds Standard Deviation 5.7

SECONDARY outcome

Timeframe: 22 weeks

Safety surveillance will be done every two weeks from the beginning of the study, intentionally searching for adverse events (AE). EEG (Diffuse or focal cerebral dysfunction through demonstration of background slowing or presence of epileptiform activity assessed by a neurophysiologist) and laboratory tests (Presence of values higher of the normal value established by local laboratory and related to the administration of treatments), blood and urine samples: creatinine, blood urea nitrogen, total cholesterol, triglycerides, total direct, and indirect bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine kinase, lactic acid dehydrogenase, amylase and lipase. A complete blood cell count with differentials and a routine urinalysis and urine culture also obtained at each visit, will be done before the patients take 40, 50 and 60 mg/day. The number of participants with abnormal studies were reported.

Outcome measures

Outcome measures
Measure	4-aminopyridine n=11 Participants The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 Participants Identical placebo capsules administered for 22 weeks.
Number of Participants With Abnormal Studies Number of participants with abnormal lab results	1 Participants	0 Participants
Number of Participants With Abnormal Studies Number of participants with abnormal EEG	0 Participants	0 Participants

Adverse Events

4-aminopyridine

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Israel Grijalva

Instituto Mexicano del Seguro Social. Unidad de Investigación Médica en Enfermedades Neurológicas.

Phone: (01152) 5555780240

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	4-aminopyridine n=11 participants at risk 22 weeks administration of 4-aminopyridine. The mean dose provided to the patients was 0.63 ± 0.05 mg per kg of body weight.	Placebo n=10 participants at risk Identical placebo tablet administered bid for 20 weeks
Psychiatric disorders Insominia	63.6% 7/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	80.0% 8/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Headache	54.5% 6/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	70.0% 7/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Gastrointestinal disorders Nausea	54.5% 6/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	30.0% 3/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Vertigo	54.5% 6/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	30.0% 3/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Tremor in hands	36.4% 4/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	10.0% 1/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Mouth/tongue paresthesias	36.4% 4/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	20.0% 2/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Hand/feet paresthesias	27.3% 3/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	0.00% 0/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Gastrointestinal disorders Gastritis	27.3% 3/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	10.0% 1/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Eye disorders Blurred vision	18.2% 2/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	0.00% 0/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Global muscle tremor	18.2% 2/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	0.00% 0/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Psychiatric disorders Irritability	18.2% 2/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	40.0% 4/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Eye disorders Eye pain	18.2% 2/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	10.0% 1/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Tingling in feet	9.1% 1/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	20.0% 2/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Nervous system disorders Abnormal taste in mouth	9.1% 1/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	0.00% 0/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
Psychiatric disorders Hypersomnia	9.1% 1/11 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.	20.0% 2/10 • 22 weeks An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.