Trial Outcomes & Findings for Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis (NCT NCT03185065)

NCT ID: NCT03185065

Last Updated: 2020-10-20

Results Overview

MFIS score during the fifth week of treatment period. The total score of the MFIS ranges from 0 to 84. Higher scores denote more severe fatigue.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 141 participants
• Primary outcome timeframe: Week 5 of each treatment period
• Results posted on: 2020-10-20

Participant Flow

Participant milestones

Measure	Arm A amantadine, placebo, modafinil, methylphenidate Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Arm B placebo, methylphenidate, amantadine, modafinil Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Arm C modafinil, amantadine, methylphenidate, placebo Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Arm D methylphenidate, modafinil, placebo and amantadine Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily
Period 1 (6 Weeks) STARTED	35	34	35	37
Period 1 (6 Weeks) COMPLETED	32	33	32	36
Period 1 (6 Weeks) NOT COMPLETED	3	1	3	1
Washout (2 Weeks) STARTED	31	29	29	32
Washout (2 Weeks) COMPLETED	31	28	27	32
Washout (2 Weeks) NOT COMPLETED	0	1	2	0
Period 2 (6 Weeks) STARTED	32	31	32	35
Period 2 (6 Weeks) COMPLETED	32	31	32	34
Period 2 (6 Weeks) NOT COMPLETED	0	0	0	1
Period 3 (6 Weeks) STARTED	31	29	31	32
Period 3 (6 Weeks) COMPLETED	31	29	29	32
Period 3 (6 Weeks) NOT COMPLETED	0	0	2	0
Period 4 (6 Weeks) STARTED	31	28	27	32
Period 4 (6 Weeks) COMPLETED	31	27	26	31
Period 4 (6 Weeks) NOT COMPLETED	0	1	1	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis

Baseline characteristics by cohort

Measure	Arm A n=35 Participants amantadine, placebo, modafinil, methylphenidate Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Arm B n=34 Participants placebo, methylphenidate, amantadine, modafinil Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Arm C n=35 Participants modafinil, amantadine, methylphenidate, placebo Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Arm D n=37 Participants methylphenidate, modafinil, placebo and amantadine Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated Placebos: 1 placebo capsule increased to max of 2 capsules twice daily	Total n=141 Participants Total of all reporting groups
Age, Continuous	48.3 years STANDARD_DEVIATION 9.9 • n=5 Participants	46.9 years STANDARD_DEVIATION 12.4 • n=7 Participants	46.1 years STANDARD_DEVIATION 10.3 • n=5 Participants	45.8 years STANDARD_DEVIATION 10.2 • n=4 Participants	46.8 years STANDARD_DEVIATION 10.7 • n=21 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	26 Participants n=7 Participants	27 Participants n=5 Participants	29 Participants n=4 Participants	109 Participants n=21 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	8 Participants n=7 Participants	8 Participants n=5 Participants	8 Participants n=4 Participants	32 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 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	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	4 Participants n=4 Participants	19 Participants n=21 Participants
Race (NIH/OMB) White	27 Participants n=5 Participants	25 Participants n=7 Participants	26 Participants n=5 Participants	29 Participants n=4 Participants	107 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	15 Participants n=21 Participants

PRIMARY outcome

Timeframe: Week 5 of each treatment period

MFIS score during the fifth week of treatment period. The total score of the MFIS ranges from 0 to 84. Higher scores denote more severe fatigue.

Outcome measures

Measure	Placebo n=123 Participants 1 placebo capsule increased to max of 2 capsules twice daily	Amantadine n=124 Participants 100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	Modafinil n=124 Participants 100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	Methylphenidate n=127 Participants 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Modified Fatigue Impact Scale (MFIS) Score	40.6 score on a scale Interval 38.2 to 43.1	41.3 score on a scale Interval 38.8 to 43.7	39.0 score on a scale Interval 36.6 to 41.4	38.6 score on a scale Interval 36.2 to 41.0

SECONDARY outcome

Timeframe: Week 5 of each treatment period

Neuro-QoL Item Bank - Fatigue T score during the fifth week of treatment period. T-score distributions rescale raw scores into standardized scores with a mean of 50 and a standard deviation (SD) of 10. Higher T-scores denote more severe fatigue.

Outcome measures

Measure	Placebo n=123 Participants 1 placebo capsule increased to max of 2 capsules twice daily	Amantadine n=124 Participants 100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	Modafinil n=124 Participants 100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	Methylphenidate n=127 Participants 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score	53.1 score on a scale Interval 51.9 to 54.3	53.0 score on a scale Interval 51.7 to 54.2	52.5 score on a scale Interval 51.3 to 53.8	52.0 score on a scale Interval 50.8 to 53.2

SECONDARY outcome

Timeframe: Week 5 of each treatment period

ESS score during the fifth week of treatment period. The ESS score can range from 0 to 24. The higher the score, the higher that person's average sleep propensity in daily life, or their 'daytime sleepiness'.

Outcome measures

Measure	Placebo n=123 Participants 1 placebo capsule increased to max of 2 capsules twice daily	Amantadine n=124 Participants 100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	Modafinil n=124 Participants 100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	Methylphenidate n=127 Participants 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Epworth Sleepiness Scale (ESS) Score	9.4 score on a scale Interval 8.7 to 10.1	9.3 score on a scale Interval 8.6 to 10.1	8.3 score on a scale Interval 7.6 to 9.1	8.8 score on a scale Interval 8.1 to 9.6

POST_HOC outcome

Timeframe: Week 5 of each treatment period

Participants will answer yes or no to this question: "Taken into consideration the possible benefits and/or disadvantages of this medication, would you choose it, going forward to treat your MS fatigue?". The number of participants who answered "Yes" to this question is reported here.

Outcome measures

Measure	Placebo n=123 Participants 1 placebo capsule increased to max of 2 capsules twice daily	Amantadine n=124 Participants 100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	Modafinil n=124 Participants 100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	Methylphenidate n=127 Participants 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Acceptability of Treatment as Assessed by a Single Question Questionnaire	39 Participants	41 Participants	55 Participants	55 Participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 38 other events

Deaths: 0 deaths

Amantadine

Serious events: 2 serious events

Other events: 49 other events

Deaths: 0 deaths

Modafinil

Serious events: 1 serious events

Other events: 50 other events

Deaths: 0 deaths

Methylphenidate

Serious events: 0 serious events

Other events: 51 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=124 participants at risk 1 placebo capsule increased to max of 2 capsules twice daily.	Amantadine n=127 participants at risk 100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	Modafinil n=125 participants at risk 100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	Methylphenidate n=129 participants at risk 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Vascular disorders Pulmonary embolism	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Cardiac disorders Myocardiitis	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Nervous system disorders MS exacerbation	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.80% 1/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).

Other adverse events

Measure	Placebo n=124 participants at risk 1 placebo capsule increased to max of 2 capsules twice daily.	Amantadine n=127 participants at risk 100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	Modafinil n=125 participants at risk 100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	Methylphenidate n=129 participants at risk 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Cardiac disorders Cardiac disorders	2.4% 3/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	2.4% 3/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	3.1% 4/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Ear and labyrinth disorders Ear and labyrinth disorders	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Eye disorders Eye disorders	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.78% 1/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Gastrointestinal disorders Gastrointestinal disorders	8.1% 10/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	11.0% 14/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	15.2% 19/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	10.1% 13/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
General disorders General disorders	1.6% 2/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	3.1% 4/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	4.0% 5/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	3.1% 4/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Immune system disorders Immune system disorders	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.80% 1/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Infections and infestations Infections and infestations	2.4% 3/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.78% 1/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Injury, poisoning and procedural complications Injury, poisoning, and procedural complications	0.81% 1/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	3.1% 4/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Metabolism and nutrition disorders Metabolism and nutrition disorders	1.6% 2/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	2.4% 3/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	3.2% 4/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.78% 1/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Nervous system disorders Nervous system disorders	10.5% 13/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	18.9% 24/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	17.6% 22/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	15.5% 20/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Psychiatric disorders Psychiatric disorders	8.1% 10/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	15.7% 20/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	14.4% 18/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	17.8% 23/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Renal and urinary disorders Renal and urinary disorders	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.80% 1/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Reproductive system and breast disorders Reproductive system	0.81% 1/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.79% 1/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Respiratory, thoracic and mediastinal disorders Respiratory disorders	0.00% 0/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	1.6% 2/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	1.6% 2/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	4.0% 5/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.00% 0/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).
Vascular disorders Vascular disorders	0.81% 1/124 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	2.4% 3/127 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	2.4% 3/125 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).	0.78% 1/129 • Adverse events were collected during each six-week medication period. The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).

Additional Information

Dr. Bardia Nourbakhsh

Johns Hopkins University

Phone: 4106141522

Email: bnourba1@jhmi.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place