Trial Outcomes & Findings for A MAD Study of TT301/MW189 in Healthy Volunteers (NCT NCT02942771)

NCT ID: NCT02942771

Last Updated: 2020-06-16

Results Overview

The number of participants who experienced serious adverse events.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 35 participants
• Primary outcome timeframe: 4 weeks
• Results posted on: 2020-06-16

Participant Flow

Participant milestones

Measure	Placebo No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5	Cohort 4- TT301/MW189 TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5
Overall Study STARTED	9	6	6	6	8
Overall Study COMPLETED	6	6	6	6	4
Overall Study NOT COMPLETED	3	0	0	0	4

Reasons for withdrawal

Measure	Placebo No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5	Cohort 4- TT301/MW189 TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5
Overall Study Adverse Event	1	0	0	0	2
Overall Study Lost to Follow-up	1	0	0	0	0
Overall Study Withdrawal by Subject	1	0	0	0	2

Baseline Characteristics

A MAD Study of TT301/MW189 in Healthy Volunteers

Baseline characteristics by cohort

Measure	Placebo n=8 Participants No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5	Cohort 4- TT301/MW189 n=8 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Total n=34 Participants Total of all reporting groups
Sex: Female, Male Female	5 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants	15 Participants n=8 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants	4 Participants n=21 Participants	19 Participants n=8 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	3 Participants n=8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	6 Participants n=4 Participants	7 Participants n=21 Participants	31 Participants n=8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	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	0 Participants n=8 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	0 Participants n=8 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=8 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	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants	5 Participants n=21 Participants	17 Participants n=8 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants	11 Participants n=8 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	5 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	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	0 Participants n=8 Participants
Region of Enrollment United States	8 participants n=5 Participants	6 participants n=7 Participants	6 participants n=5 Participants	6 participants n=4 Participants	8 participants n=21 Participants	34 participants n=8 Participants
Height	165.8 cm STANDARD_DEVIATION 6.7 • n=5 Participants	171.6 cm STANDARD_DEVIATION 8.7 • n=7 Participants	164.0 cm STANDARD_DEVIATION 11.1 • n=5 Participants	170.9 cm STANDARD_DEVIATION 10.5 • n=4 Participants	173.1 cm STANDARD_DEVIATION 8.4 • n=21 Participants	169.1 cm STANDARD_DEVIATION 9.7 • n=8 Participants
Weight	74.5 kg STANDARD_DEVIATION 6.1 • n=5 Participants	70.5 kg STANDARD_DEVIATION 9.1 • n=7 Participants	75.2 kg STANDARD_DEVIATION 6.3 • n=5 Participants	85.5 kg STANDARD_DEVIATION 20.5 • n=4 Participants	86.4 kg STANDARD_DEVIATION 12.7 • n=21 Participants	78.6 kg STANDARD_DEVIATION 12.8 • n=8 Participants
BMI	27.1 kg/m^2 STANDARD_DEVIATION 1.9 • n=5 Participants	24.1 kg/m^2 STANDARD_DEVIATION 3.8 • n=7 Participants	28.1 kg/m^2 STANDARD_DEVIATION 2.7 • n=5 Participants	29.1 kg/m^2 STANDARD_DEVIATION 5.7 • n=4 Participants	28.8 kg/m^2 STANDARD_DEVIATION 3.8 • n=21 Participants	27.5 kg/m^2 STANDARD_DEVIATION 3.9 • n=8 Participants
Age, Continuous	34.7 years STANDARD_DEVIATION 6.7 • n=5 Participants	32.4 years STANDARD_DEVIATION 5.9 • n=7 Participants	31.6 years STANDARD_DEVIATION 6.2 • n=5 Participants	34.5 years STANDARD_DEVIATION 7.4 • n=4 Participants	30.5 years STANDARD_DEVIATION 10.9 • n=21 Participants	33.3 years STANDARD_DEVIATION 7.7 • n=8 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: One subject randomized to the Placebo Group was withdrawn prior to receiving the study drug. Consequently, this subject is excluded from this safety analysis. As the remaining 8 subjects in the Placebo Group and all 8 subjects in Cohort 4 received an intervention they are included in safety outcomes.

The number of participants who experienced serious adverse events.

Outcome measures

Measure	Cohort 4- TT301/MW189 n=8 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Placebo n=8 Participants No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5
Serious Adverse Events	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: One subject randomized to the Placebo Group was withdrawn prior to receiving the study drug. Consequently, this subject is excluded from this safety analysis. As the remaining 8 subjects in the Placebo Group and all 8 subjects in Cohort 4 received an intervention they are included in safety outcomes.

The number of participants who experienced treatment-emergent adverse events (TEAEs). A TEAE is defined as an adverse event that started during the treatment period.

Outcome measures

Measure	Cohort 4- TT301/MW189 n=8 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Placebo n=8 Participants No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5
Treatment-Emergent Adverse Events	6 Participants	5 Participants	6 Participants	4 Participants	6 Participants

SECONDARY outcome

Timeframe: 5 days

Population: Pharmacokinetic parameters for TT301/MW189 can not be analyzed in the placebo group, as they did not receive the study drug. Although 8 subjects were enrolled in Cohort 4 and are included in the safety analyses, only 4 completed sampling for PK parameters at all timepoints.

Maximum observed concentration in plasma.

Outcome measures

Measure	Cohort 4- TT301/MW189 n=4 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Placebo No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5
Pharmacokinetics - Cmax	750 ng/ml Standard Deviation 235	—	227 ng/ml Standard Deviation 80.5	347 ng/ml Standard Deviation 86.8	609 ng/ml Standard Deviation 180

SECONDARY outcome

Timeframe: 5 days

Population: Tmax was not measured for any group.

Time to maximum concentration

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 5 days

Population: Pharmacokinetic parameters for TT301/MW189 can not be analyzed in the placebo group, as they did not receive the study drug. Although 8 subjects were enrolled in Cohort 4 and are included in the safety analyses, only 4 completed sampling for PK parameters at all timepoints.

Area under the concentration-time curve

Outcome measures

Measure	Cohort 4- TT301/MW189 n=4 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Placebo No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5
Pharmacokinetics - AUC	1525 ng*h/ml Standard Deviation 458	—	362 ng*h/ml Standard Deviation 123	639 ng*h/ml Standard Deviation 220	1225 ng*h/ml Standard Deviation 474

SECONDARY outcome

Timeframe: 5 days

Population: Pharmacokinetic parameters for TT301/MW189 can not be analyzed in the placebo group, as they did not receive the study drug. Although 8 subjects were enrolled in Cohort 4 and are included in the safety analyses, only 4 completed sampling for PK parameters at all timepoints.

Terminal half-life (T1/2)

Outcome measures

Measure	Cohort 4- TT301/MW189 n=4 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Placebo No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5
Pharmacokinetics - T1/2	9.1 hours Standard Deviation 2.8	—	8.5 hours Standard Deviation 3.4	8.5 hours Standard Deviation 3.7	8.8 hours Standard Deviation 2.8

SECONDARY outcome

Timeframe: 5 days

Population: Pharmacokinetic parameters for TT301/MW189 can not be analyzed in the placebo group, as they did not receive the study drug. Although 8 subjects were enrolled in Cohort 4 and are included in the safety analyses, only 4 completed sampling for PK parameters at all timepoints.

Elimination rate constant

Outcome measures

Measure	Cohort 4- TT301/MW189 n=4 Participants TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5	Placebo No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 Participants TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 Participants TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 Participants TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5
Pharmacokinetics - Kel	0.081 h^-1 Standard Deviation 0.022	—	0.090 h^-1 Standard Deviation 0.029	0.093 h^-1 Standard Deviation 0.034	0.085 h^-1 Standard Deviation 0.028

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Cohort 1 - TT301/MW189

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 2 -TT301/MW189

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Cohort 3- TT301/MW189

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 4- TT301/MW189

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Placebo n=8 participants at risk No drug intervention. Placebo: 0.9% sodium chloride	Cohort 1 - TT301/MW189 n=6 participants at risk TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 1 - TT301/MW189: 0.075 mg/kg IV twice daily on Days 1 through 5	Cohort 2 -TT301/MW189 n=6 participants at risk TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 2- TT301MW189: 0.15 mg/kg IV twice daily on Days 1 through 5	Cohort 3- TT301/MW189 n=6 participants at risk TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 3 - TT301/MW189: 0.25 mg/kg IV twice daily on Days 1 through 5	Cohort 4- TT301/MW189 n=8 participants at risk TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive Cohort 4 - TT301/MW189: 0.30 mg/kg IV twice daily on Days 1 through 5
Gastrointestinal disorders Sensitivity of Teeth	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Vascular disorders Phlebitis	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	50.0% 3/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	33.3% 2/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	66.7% 4/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	25.0% 2/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Vascular disorders Diastolic Hypertension	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Musculoskeletal and connective tissue disorders Pain in Extremety	37.5% 3/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	50.0% 3/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	37.5% 3/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Musculoskeletal and connective tissue disorders Back Pain	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Skin and subcutaneous tissue disorders Contact Dermatitits	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	66.7% 4/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	25.0% 2/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	33.3% 2/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
General disorders Fatigue	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	25.0% 2/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
General disorders Infusion-Site Pain	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
General disorders Infusion-Site Erythema	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
General disorders Nodule	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
General disorders Peripheral Swelling	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
General disorders Infusion-Site Phlebitis	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Nervous system disorders Headache	50.0% 4/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	33.3% 2/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	37.5% 3/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Nervous system disorders Dizziness	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	25.0% 2/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Nervous system disorders Parasthesia	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Nervous system disorders Somnolence	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Gastrointestinal disorders Nausea	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	25.0% 2/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Gastrointestinal disorders Abdominal Pain, Lower	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Gastrointestinal disorders Toothache	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Investigations ECG T-Wave Inversion	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Investigations Increased Blood Creatine Phosphokinase	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Investigations Decreased Hemoglobin	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Blood and lymphatic system disorders Anemia	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Ear and labyrinth disorders Ear Pain	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Infections and infestations Upper Respiratory Tract Infection	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	16.7% 1/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Infections and infestations Pharyngitis	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Injury, poisoning and procedural complications Road Traffic Accident	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Injury, poisoning and procedural complications Contusion	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Psychiatric disorders Anxiety	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.
Metabolism and nutrition disorders Hypokalemia	12.5% 1/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/6 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.	0.00% 0/8 • 4 weeks Assessment was systematic. Safety and tolerability were assessed by clinical observation, lab tests and spontaneous reporting by subjects. Placebo group: 9 subjects were randomized,1 subject withdrew prior to starting the intervention. As this subject did not receive intervention, safety data are reported only for the remaining 8 subjects. Cohort 4: 8 subjects were randomized, only 4 completed all timepoints. As all 8 subjects received study drug, safety data are reported for all 8.

Additional Information

Dr. Linda Van Eldik

University of Kentucky

Phone: (859) 257-5566

Email: linda.vaneldik@uky.edu

Results disclosure agreements

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