Trial Outcomes & Findings for A Study of SHP655 (rADAMTS13) in Sickle Cell Disease (NCT NCT03997760)

Results Overview

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product (IP) or medicinal product. TEAEs were defined as AEs that started or worsened in severity on or after the infusion of IP. A serious TEAEs was any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose) which resulted in death, was life-threatening, required inpatient hospitalization, prolongation of hospitalization, was an important medical event. TEAEs included both serious and non-serious AEs.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

19 participants

Primary outcome timeframe

From date of signing informed consent up to end of study visit (Day 28)

Results posted on

2024-04-23

Participant Flow

This study was conducted at 9 active sites in the United States from 21 October 2019 to 26 October 2022.

A total of 19 participants were enrolled and treated in this study.

Participant milestones

Participant milestones
Measure	Placebo Participants with Sickle Cell Disease (SCD) at their baseline health received a single intravenous (IV) infusion of placebo matched to TAK-755 at 3 dose levels of 40 International units per kilogram (IU/kg), 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Overall Study STARTED	5	4	6	4
Overall Study COMPLETED	5	3	6	4
Overall Study NOT COMPLETED	0	1	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants with Sickle Cell Disease (SCD) at their baseline health received a single intravenous (IV) infusion of placebo matched to TAK-755 at 3 dose levels of 40 International units per kilogram (IU/kg), 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Overall Study Protocol Deviation	0	1	0	0

Baseline Characteristics

A Study of SHP655 (rADAMTS13) in Sickle Cell Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=5 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.	Total n=19 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=39 Participants	4 Participants n=41 Participants	6 Participants n=35 Participants	4 Participants n=31 Participants	19 Participants n=146 Participants
Age, Categorical >=65 years	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Sex: Female, Male Female	3 Participants n=39 Participants	1 Participants n=41 Participants	3 Participants n=35 Participants	1 Participants n=31 Participants	8 Participants n=146 Participants
Sex: Female, Male Male	2 Participants n=39 Participants	3 Participants n=41 Participants	3 Participants n=35 Participants	3 Participants n=31 Participants	11 Participants n=146 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants n=39 Participants	4 Participants n=41 Participants	6 Participants n=35 Participants	4 Participants n=31 Participants	19 Participants n=146 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Race (NIH/OMB) Asian	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Race (NIH/OMB) Black or African American	5 Participants n=39 Participants	4 Participants n=41 Participants	6 Participants n=35 Participants	4 Participants n=31 Participants	19 Participants n=146 Participants
Race (NIH/OMB) White	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Race (NIH/OMB) More than one race	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants

PRIMARY outcome

Timeframe: From date of signing informed consent up to end of study visit (Day 28)

Population: SAS included all participants randomized and who received any dose of IP.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product (IP) or medicinal product. TEAEs were defined as AEs that started or worsened in severity on or after the infusion of IP. A serious TEAEs was any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose) which resulted in death, was life-threatening, required inpatient hospitalization, prolongation of hospitalization, was an important medical event. TEAEs included both serious and non-serious AEs.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious (TEAEs) Participants with TEAEs	2 Participants	2 Participants	4 Participants	2 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious (TEAEs) Participants with Serious TEAEs	0 Participants	1 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From date of signing informed consent up to end of study visit (Day 28)

Population: The SAS included all participants randomized and who received any dose of IP.

Measurement of Anti-ADAMTS13 antibodies can be used to assess whether the body's immune system has been stimulated to react to TAK-755. Binding Anti-ADAMTS13 antibodies measure antibodies that are able to bind to ADAMTS13, whether or not the antibodies have an effect on how well ADAMTS13 works. An inhibitory Anti-ADAMTS13 antibody is antibody that both binds to ADAMTS13 and able to affect how well ADAMTS13 works. Binding and Inhibitory anti-ADAMTS13 antibodies were categorized as pre-existing, treatment-induced, and treatment-boosted. Pre-existing: anti-ADAMTS13 antibodies were detected in the baseline sample prior to infusion with TAK-755. Treatment-induced: no anti-ADAMTS13 antibodies were detected in baseline sample but were detected in any sample drawn after TAK-755 infusion. Treatment-boosted: anti-ADAMTS13 antibodies were pre-existing and were detected at any time after TAK-755 infusion at titers that were at least 4 steps higher than the titers detected before TAK-755 infusion.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755 Pre-Existing Inhibitory Anti-ADAMTS13 Antibodies	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755 Treatment-Induced Inhibitory Anti-ADAMTS13 Antibodies	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755 Treatment-Boosted Inhibitory Anti-ADAMTS13 Antibodies	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755 Pre-Existing Binding Anti-ADAMTS13 Antibodies	1 Participants	1 Participants	2 Participants	2 Participants
Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755 Treatment-Induced Binding Anti-ADAMTS13 Antibodies	1 Participants	1 Participants	1 Participants	0 Participants
Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755 Treatment-Boosted Binding Anti-ADAMTS13 Antibodies	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The Pharmacokinetic (PK) Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

IR was defined as the ratio of maximum increase in plasma ADAMTS13 antigen or activity level to TAK-755 dose per body weight. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall. Here "IU/mL/IU/kg" refers to "International units per milliliter per international units per kilogram".

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Incremental Recovery (IR) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	0.022440 IU/mL/IU/kg Standard Deviation 32.3	0.025227 IU/mL/IU/kg Standard Deviation 33.4	0.018423 IU/mL/IU/kg Standard Deviation 33.6	—
Incremental Recovery (IR) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	0.021809 IU/mL/IU/kg Standard Deviation 25.8	0.021925 IU/mL/IU/kg Standard Deviation 30.1	0.022012 IU/mL/IU/kg Standard Deviation 22.2	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

Cmax was a measure of the maximum amount of drug in the plasma after the dose was given. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Observed Maximum Concentration (Cmax) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	0.90202 international units per milliliter Geometric Coefficient of Variation 33.5	2.0080 international units per milliliter Geometric Coefficient of Variation 33.2	2.9539 international units per milliliter Geometric Coefficient of Variation 33.6	—
Observed Maximum Concentration (Cmax) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	0.49848 international units per milliliter Geometric Coefficient of Variation 27.9	1.0382 international units per milliliter Geometric Coefficient of Variation 30.3	2.0392 international units per milliliter Geometric Coefficient of Variation 22.2	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

Tmax was a measure of the time to reach the maximum concentration in the plasma after the drug dose. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Time to Reach Cmax (Tmax) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	2.16 hour Interval 0.32 to 3.03	1.08 hour Interval 0.25 to 74.45	0.45 hour Interval 0.32 to 1.18	—
Time to Reach Cmax (Tmax) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	0.45 hour Interval 0.25 to 24.17	1.10 hour Interval 0.28 to 3.48	0.83 hour Interval 0.32 to 1.5	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

t1/2 was the time required for a given drug concentration in the plasma to decrease by 50%. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Terminal Half-Life (t1/2) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	NA hour Standard Deviation NA Mean and SD were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	54.56 hour Standard Deviation 28.230	42.22 hour Standard Deviation 9.7253	—
Terminal Half-Life (t1/2) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	NA hour Standard Deviation NA Mean and SD were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	65.17 hour Standard Deviation 41.728	46.88 hour Standard Deviation 16.821	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

The MRT is the average time that the study product stays in the body (or plasma). The MRT0-Inf is defined as the average time from zero (pre-dose) extrapolated to infinite time (MRT0-inf). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Mean Residence Time From Zero to Infinite (MRT0-Inf) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	NA hour Standard Deviation NA Mean and SD were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	118.6 hour Standard Deviation 46.170	87.54 hour Standard Deviation 37.734	—
Mean Residence Time From Zero to Infinite (MRT0-Inf) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	NA hour Standard Deviation NA Mean and SD were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	116.3 hour Standard Deviation 57.699	69.48 hour Standard Deviation 23.555	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, and 72 hours post-dose

Population: Since MRT0-72 was considered irrelevant to the objective of the PK, therefore data for this outcome measure was not collected and reported.

The MRT is the average time that the study product stays in the body (or plasma) and The MRT0-72 is defined as the average time from zero (predose) to 72 hours post-dose (MRT0-72). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

AUC0-Last was an area under the concentration-time curve from zero (pre-dose) to time of last quantifiable concentration. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Area Under the Curve From Zero to Time of Last Quantifiable Concentration (AUC0-Last) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	NA hour* International unit per milliliter Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	161.5 hour* International unit per milliliter Geometric Coefficient of Variation 28.1	137.2 hour* International unit per milliliter Geometric Coefficient of Variation 36.1	—
Area Under the Curve From Zero to Time of Last Quantifiable Concentration (AUC0-Last) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	25.96 hour* International unit per milliliter Geometric Coefficient of Variation 32.9	79.05 hour* International unit per milliliter Geometric Coefficient of Variation 22.0	105.7 hour* International unit per milliliter Geometric Coefficient of Variation 27.7	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, and 72 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-775 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

AUC0-72 was an area under the concentration-time curve from zero (predose) to 72 hours post-dose (AUC0-72). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Area Under the Curve Time Curve From Zero to 72 Hours Post-dose (AUC0-72) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	19.77 hour* International unit per milliliter Geometric Coefficient of Variation 122.3	78.44 hour* International unit per milliliter Geometric Coefficient of Variation 36.8	92.41 hour* International unit per milliliter Geometric Coefficient of Variation 27.1	—
Area Under the Curve Time Curve From Zero to 72 Hours Post-dose (AUC0-72) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	17.91 hour* International unit per milliliter Geometric Coefficient of Variation 22.7	42.86 hour* International unit per milliliter Geometric Coefficient of Variation 9.5	73.20 hour* International unit per milliliter Geometric Coefficient of Variation 22.0	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

AUC0-inf was area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Area Under the Curve From Zero to Infinite Time (AUC0-Inf) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	NA hour* International unit per milliliter Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	190.1 hour* International unit per milliliter Geometric Coefficient of Variation 45.3	152.5 hour* International unit per milliliter Geometric Coefficient of Variation 46.6	—
Area Under the Curve From Zero to Infinite Time (AUC0-Inf) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	NA hour* International unit per milliliter Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	88.34 hour* International unit per milliliter Geometric Coefficient of Variation 34.6	114.0 hour* International unit per milliliter Geometric Coefficient of Variation 27.5	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Systemic Clearance (CL) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	NA liters per hour (L/h) Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	37.22 liters per hour (L/h) Geometric Coefficient of Variation 64.3	74.35 liters per hour (L/h) Geometric Coefficient of Variation 46.8	—
Systemic Clearance (CL) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	NA liters per hour (L/h) Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	51.28 liters per hour (L/h) Geometric Coefficient of Variation 66.1	54.47 liters per hour (L/h) Geometric Coefficient of Variation 54.47	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: The PK Analysis Set included all participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and had no major protocol deviations or events that may affect the integrity of the PK data. Data was not analyzed for PK parameters in the placebo arm where participants did not receive TAK-755.

Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by MRT(0-inf)\*CL. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=5 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Volume of Distribution at Steady State (Vss) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Activity	NA liters Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	3993 liters Geometric Coefficient of Variation 48.2	5771 liters Geometric Coefficient of Variation 17.2	—
Volume of Distribution at Steady State (Vss) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755 Baseline-adjusted ADAMTS13 Antigen	NA liters Geometric Coefficient of Variation NA Geometric Mean and %CV were not determined because insufficient number of participants had appropriate number of positive baseline-adjusted concentration data points to determine this PK parameter.	4682 liters Geometric Coefficient of Variation 8.4	3661 liters Geometric Coefficient of Variation 21.7	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: Pharmacodynamic analysis set: All participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 valid data point post-dose of the respective infusion for at least 1 PD measurement for any of the PD outcome and had no major protocol deviations or events that may have affected the integrity of the PD data. Overall Number of Participants Analyzed refers participants evaluable for this outcome and "number analyzed" refers participants at the specified timepoints.

Von Willebrand factor (vWF or VWF) is a protein that is one of several components of the coagulation system that work together to stop bleeding within the body. VWF:Ag measures the level of von Willebrand factor protein in the blood. The change from baseline in VWF:Ag concentration was measured at different time points. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=3 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 0.25 hours	5.20 Percentage of vWF Ag Standard Deviation 23.774	-29.47 Percentage of vWF Ag Standard Deviation 17.719	-0.96 Percentage of vWF Ag Standard Deviation 32.870	-16.27 Percentage of vWF Ag Standard Deviation 9.341
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 1 hour	-9.90 Percentage of vWF Ag Standard Deviation 27.518	-19.47 Percentage of vWF Ag Standard Deviation 10.161	9.50 Percentage of vWF Ag Standard Deviation 20.168	4.00 Percentage of vWF Ag Standard Deviation 12.139
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 3 hours	-7.80 Percentage of vWF Ag Standard Deviation 12.301	-18.27 Percentage of vWF Ag Standard Deviation 4.670	-0.30 Percentage of vWF Ag Standard Deviation 22.744	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 8 hours	-8.20 Percentage of vWF Ag Standard Deviation 14.245	13.07 Percentage of vWF Ag Standard Deviation 20.433	-0.24 Percentage of vWF Ag Standard Deviation 15.028	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 24 hours	0.10 Percentage of vWF Ag Standard Deviation 17.116	16.00 Percentage of vWF Ag Standard Deviation 34.113	20.42 Percentage of vWF Ag Standard Deviation 18.756	2.93 Percentage of vWF Ag Standard Deviation 24.981
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 72 hours	-25.20 Percentage of vWF Ag Standard Deviation 27.695	8.93 Percentage of vWF Ag Standard Deviation 43.275	20.32 Percentage of vWF Ag Standard Deviation 25.345	9.47 Percentage of vWF Ag Standard Deviation 25.026
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 120 hours	-14.40 Percentage of vWF Ag Standard Deviation 37.183	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	0.67 Percentage of vWF Ag Standard Deviation 29.733	9.60 Percentage of vWF Ag Standard Deviation 47.411
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 168 hours	-46.80 Percentage of vWF Ag Standard Deviation 23.708	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	6.82 Percentage of vWF Ag Standard Deviation 29.703	-20.40 Percentage of vWF Ag Standard Deviation 24.212
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 216 hours	-44.10 Percentage of vWF Ag Standard Deviation 35.056	13.87 Percentage of vWF Ag Standard Deviation 15.597	-4.90 Percentage of vWF Ag Standard Deviation 43.425	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 288 hours	-38.40 Percentage of vWF Ag Standard Deviation 33.032	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	2.58 Percentage of vWF Ag Standard Deviation 32.591	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.
Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints Change at 648 hours	-34.30 Percentage of vWF Ag Standard Deviation 45.276	NA Percentage of vWF Ag Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	25.17 Percentage of vWF Ag Standard Deviation 30.641	-26.93 Percentage of vWF Ag Standard Deviation 45.377

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: Pharmacodynamic analysis set: All participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 valid data point post-dose of the respective infusion for at least 1 PD measurement for any of the PD outcome and had no major protocol deviations or events that may have affected the integrity of the PD data. Overall Number of Participants Analyzed refers participants evaluable for this outcome and "number analyzed" refers participants at the specified timepoints.

Von Willebrand factor (vWF or VWF) is a protein that is one of several components of the coagulation system that work together, to stop bleeding within the body. VWF:RCo assay is a test that measures the activity of the VWF in a plasma sample in terms of how well it is able to clump platelets together in the presence of the antibiotic ristocetin. Change from baseline in vWF:RCo concentration was measured at different timepoints. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=3 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 0.25 hours	-6.78 Percentage of vWF RCo Standard Deviation 8.107	-7.40 Percentage of vWF RCo Standard Deviation 10.802	-6.06 Percentage of vWF RCo Standard Deviation 14.134	-3.50 Percentage of vWF RCo Standard Deviation 13.365
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 1 hour	-10.08 Percentage of vWF RCo Standard Deviation 11.346	-7.80 Percentage of vWF RCo Standard Deviation 9.242	6.63 Percentage of vWF RCo Standard Deviation 31.637	-4.60 Percentage of vWF RCo Standard Deviation 8.285
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 3 hours	-9.75 Percentage of vWF RCo Standard Deviation 5.047	-20.80 Percentage of vWF RCo Standard Deviation 72.904	-10.10 Percentage of vWF RCo Standard Deviation 7.833	-7.00 Percentage of vWF RCo Standard Deviation 10.835
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 8 hours	0.28 Percentage of vWF RCo Standard Deviation 34.209	-34.80 Percentage of vWF RCo Standard Deviation 63.461	-17.36 Percentage of vWF RCo Standard Deviation 34.424	-8.00 Percentage of vWF RCo Standard Deviation 14.178
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 24 hours	8.30 Percentage of vWF RCo Standard Deviation 5.582	20.07 Percentage of vWF RCo Standard Deviation 36.049	9.32 Percentage of vWF RCo Standard Deviation 18.590	-1.20 Percentage of vWF RCo Standard Deviation 26.771
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 72 hours	-8.03 Percentage of vWF RCo Standard Deviation 8.176	20.17 Percentage of vWF RCo Standard Deviation 22.167	8.60 Percentage of vWF RCo Standard Deviation 9.908	-11.30 Percentage of vWF RCo Standard Deviation 11.895
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 120 hours	4.33 Percentage of vWF RCo Standard Deviation 15.284	NA Percentage of vWF RCo Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	-32.33 Percentage of vWF RCo Standard Deviation 50.707	-0.55 Percentage of vWF RCo Standard Deviation 11.301
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 168 hours	-9.87 Percentage of vWF RCo Standard Deviation 6.217	NA Percentage of vWF RCo Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	0.97 Percentage of vWF RCo Standard Deviation 7.227	15.00 Percentage of vWF RCo Standard Deviation 9.367
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 216 hours	-15.90 Percentage of vWF RCo Standard Deviation 20.132	13.20 Percentage of vWF RCo Standard Deviation 37.091	9.35 Percentage of vWF RCo Standard Deviation 8.005	7.08 Percentage of vWF RCo Standard Deviation 22.733
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 288 hours	-22.33 Percentage of vWF RCo Standard Deviation 11.712	NA Percentage of vWF RCo Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	8.58 Percentage of vWF RCo Standard Deviation 3.812	7.83 Percentage of vWF RCo Standard Deviation 36.533
Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints Change at 648 hours	-17.03 Percentage of vWF RCo Standard Deviation 10.801	NA Percentage of vWF RCo Standard Deviation NA Mean and SD were not determined because insufficient number of participants (\<=2 participants) had data and therefore, summary statistics could not be performed, as was pre-specified in the analysis plan.	9.43 Percentage of vWF RCo Standard Deviation 10.112	-12.83 Percentage of vWF RCo Standard Deviation 83.921

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: Pharmacodynamic analysis set: All participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 valid data point post-dose of the respective infusion for at least 1 PD measurement for any of the PD outcome and had no major protocol deviations or events that may have affected the integrity of the PD data. Overall Number of Participants Analyzed refers participants evaluable for this outcome and "number analyzed" refers participants at the specified timepoints.

Blood samples were collected to analyze platelet count. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Thechange from baseline was calculated by subtracting the baseline value from the post-dose value.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Change From Baseline in Platelet Count at Specified Timepoints Change at 3 hours	-39.40 10^9 cells per liter Standard Deviation 35.795	3.50 10^9 cells per liter Standard Deviation 27.111	-42.80 10^9 cells per liter Standard Deviation 27.151	-32.00 10^9 cells per liter Standard Deviation 19.511
Change From Baseline in Platelet Count at Specified Timepoints Change at 8 hours	-33.96 10^9 cells per liter Standard Deviation 29.535	11.40 10^9 cells per liter Standard Deviation 24.309	-38.42 10^9 cells per liter Standard Deviation 33.679	-23.77 10^9 cells per liter Standard Deviation 25.325
Change From Baseline in Platelet Count at Specified Timepoints Change at 24 hours	-1.60 10^9 cells per liter Standard Deviation 38.946	22.88 10^9 cells per liter Standard Deviation 36.779	-11.83 10^9 cells per liter Standard Deviation 55.654	-18.50 10^9 cells per liter Standard Deviation 25.265
Change From Baseline in Platelet Count at Specified Timepoints Change at 72 hours	-20.80 10^9 cells per liter Standard Deviation 61.378	36.35 10^9 cells per liter Standard Deviation 19.025	-7.10 10^9 cells per liter Standard Deviation 81.770	-40.75 10^9 cells per liter Standard Deviation 64.691
Change From Baseline in Platelet Count at Specified Timepoints Change at 120 hours	4.50 10^9 cells per liter Standard Deviation 100.018	40.83 10^9 cells per liter Standard Deviation 35.617	18.94 10^9 cells per liter Standard Deviation 104.933	-47.25 10^9 cells per liter Standard Deviation 61.927
Change From Baseline in Platelet Count at Specified Timepoints Change at 168 hours	-38.40 10^9 cells per liter Standard Deviation 94.648	22.33 10^9 cells per liter Standard Deviation 58.046	20.35 10^9 cells per liter Standard Deviation 122.803	-73.33 10^9 cells per liter Standard Deviation 97.007
Change From Baseline in Platelet Count at Specified Timepoints Change at 288 hours	-42.00 10^9 cells per liter Standard Deviation 97.060	17.67 10^9 cells per liter Standard Deviation 10.408	6.17 10^9 cells per liter Standard Deviation 105.447	-50.75 10^9 cells per liter Standard Deviation 70.296
Change From Baseline in Platelet Count at Specified Timepoints Change at 648 hours	-116.40 10^9 cells per liter Standard Deviation 232.119	29.00 10^9 cells per liter Standard Deviation 27.313	6.93 10^9 cells per liter Standard Deviation 77.027	3.75 10^9 cells per liter Standard Deviation 51.344

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose

Population: Pharmacodynamic analysis set: All participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 valid data point post-dose of the respective infusion for at least 1 PD measurement for any of the PD outcome and had no major protocol deviations or events that may have affected the integrity of the PD data. Overall Number of Participants Analyzed refers participants evaluable for this outcome and "number analyzed" refers participants at the specified timepoints.

The plasma free hemoglobin test measures the level of hemoglobin in the plasma (that is, not contained within the red blood cells). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=3 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 3 hours	-5.23 milligrams per deciliter (mg/dL) Standard Deviation 21.732	-8.98 milligrams per deciliter (mg/dL) Standard Deviation 23.930	NA milligrams per deciliter (mg/dL) Standard Deviation NA Mean and SD was not determined as the sample size (\<= 2 observed values) were not sufficient to determine the Plasma Free Hemoglobin parameter.	-106.15 milligrams per deciliter (mg/dL) Standard Deviation 216.380
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 8 hours	-11.28 milligrams per deciliter (mg/dL) Standard Deviation 18.671	-30.58 milligrams per deciliter (mg/dL) Standard Deviation 34.219	NA milligrams per deciliter (mg/dL) Standard Deviation NA Mean and SD was not determined as the sample size (\<= 2 observed values) were not sufficient to determine the Plasma Free Hemoglobin parameter.	-147.80 milligrams per deciliter (mg/dL) Standard Deviation 251.263
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 24 hours	-3.88 milligrams per deciliter (mg/dL) Standard Deviation 21.390	-34.28 milligrams per deciliter (mg/dL) Standard Deviation 36.621	-44.77 milligrams per deciliter (mg/dL) Standard Deviation 47.417	-105.95 milligrams per deciliter (mg/dL) Standard Deviation 214.072
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 72 hours	-9.23 milligrams per deciliter (mg/dL) Standard Deviation 22.105	-44.93 milligrams per deciliter (mg/dL) Standard Deviation 35.400	-49.27 milligrams per deciliter (mg/dL) Standard Deviation 47.550	-108.30 milligrams per deciliter (mg/dL) Standard Deviation 218.455
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 120 hours	-14.70 milligrams per deciliter (mg/dL) Standard Deviation 27.120	NA milligrams per deciliter (mg/dL) Standard Deviation NA Mean and SD was not determined as the sample size (\<= 2 observed values) were not sufficient to determine the Plasma Free Hemoglobin parameter.	-47.47 milligrams per deciliter (mg/dL) Standard Deviation 48.187	-98.18 milligrams per deciliter (mg/dL) Standard Deviation 226.371
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 168 hours	-10.60 milligrams per deciliter (mg/dL) Standard Deviation 23.047	-44.37 milligrams per deciliter (mg/dL) Standard Deviation 50.024	-41.37 milligrams per deciliter (mg/dL) Standard Deviation 47.933	-123.83 milligrams per deciliter (mg/dL) Standard Deviation 274.097
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 288 hours	-8.05 milligrams per deciliter (mg/dL) Standard Deviation 25.683	-46.47 milligrams per deciliter (mg/dL) Standard Deviation 43.714	-46.67 milligrams per deciliter (mg/dL) Standard Deviation 47.013	5.17 milligrams per deciliter (mg/dL) Standard Deviation 4.319
Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints Change at 648 hours	13.30 milligrams per deciliter (mg/dL) Standard Deviation 53.656	-26.43 milligrams per deciliter (mg/dL) Standard Deviation 45.465	-43.83 milligrams per deciliter (mg/dL) Standard Deviation 50.519	-130.87 milligrams per deciliter (mg/dL) Standard Deviation 265.316

SECONDARY outcome

Timeframe: Baseline (Pre-dose), 3, 8, 24, 72, 120, 168, 288, and 648 hours post-dose

Population: Pharmacodynamic analysis set: All participants who received at least 1 complete dose of TAK-755 or placebo and provided at least 1 valid data point post-dose of the respective infusion for at least 1 PD measurement for any of the PD outcome and had no major protocol deviations or events that may have affected the integrity of the PD data. Overall Number of Participants Analyzed refers participants evaluable for this outcome and "number analyzed" refers participants at the specified timepoints.

Change from baseline in plasma thrombospondin levels over time was reported. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 40 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 Participants Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 24 hours	-934.0 nanograms per milliliter (ng/mL) Standard Deviation 1815.42	-408.0 nanograms per milliliter (ng/mL) Standard Deviation 1140.98	-1077.0 nanograms per milliliter (ng/mL) Standard Deviation 1699.60	-1567.8 nanograms per milliliter (ng/mL) Standard Deviation 957.61
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 3 hours	840.4 nanograms per milliliter (ng/mL) Standard Deviation 3979.24	-628.5 nanograms per milliliter (ng/mL) Standard Deviation 1420.49	-1177.2 nanograms per milliliter (ng/mL) Standard Deviation 1730.05	-736.3 nanograms per milliliter (ng/mL) Standard Deviation 860.29
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 8 hours	-1892.8 nanograms per milliliter (ng/mL) Standard Deviation 3500.43	-604.5 nanograms per milliliter (ng/mL) Standard Deviation 1763.64	-1471.8 nanograms per milliliter (ng/mL) Standard Deviation 1274.07	-1290.0 nanograms per milliliter (ng/mL) Standard Deviation 1060.98
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 72 hours	-701.4 nanograms per milliliter (ng/mL) Standard Deviation 2560.18	-651.8 nanograms per milliliter (ng/mL) Standard Deviation 1208.59	-1080.0 nanograms per milliliter (ng/mL) Standard Deviation 1945.58	-1406.0 nanograms per milliliter (ng/mL) Standard Deviation 843.31
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 120 hours	-1075.0 nanograms per milliliter (ng/mL) Standard Deviation 1357.88	-1428.7 nanograms per milliliter (ng/mL) Standard Deviation 1892.45	-331.8 nanograms per milliliter (ng/mL) Standard Deviation 3735.24	1351.8 nanograms per milliliter (ng/mL) Standard Deviation 5880.93
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 168 hours	-3886.0 nanograms per milliliter (ng/mL) Standard Deviation 3999.22	-847.0 nanograms per milliliter (ng/mL) Standard Deviation 1728.41	-1623.7 nanograms per milliliter (ng/mL) Standard Deviation 1569.60	-687.5 nanograms per milliliter (ng/mL) Standard Deviation 1373.36
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 288 hours	-103.0 nanograms per milliliter (ng/mL) Standard Deviation 1974.37	-482.0 nanograms per milliliter (ng/mL) Standard Deviation 1150.09	-1290.7 nanograms per milliliter (ng/mL) Standard Deviation 1723.60	-903.5 nanograms per milliliter (ng/mL) Standard Deviation 1232.02
Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints Change at 648 hours	-2857.0 nanograms per milliliter (ng/mL) Standard Deviation 4236.96	-766.0 nanograms per milliliter (ng/mL) Standard Deviation 1948.34	-909.7 nanograms per milliliter (ng/mL) Standard Deviation 1082.66	525.5 nanograms per milliliter (ng/mL) Standard Deviation 3358.11

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

TAK-755: 40 IU/kg

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

TAK-755: 80 IU/kg

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

TAK-755: 160 IU/kg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=5 participants at risk Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed up for to 28 days.	TAK-755: 40 IU/kg n=4 participants at risk Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 participants at risk Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 participants at risk Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Blood and lymphatic system disorders Sickle cell anaemia with crisis	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.

Other adverse events

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=5 participants at risk Participants with SCD at their baseline health received a single IV infusion of placebo matched to TAK-755 at 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg on Day 1 and followed up for to 28 days.	TAK-755: 40 IU/kg n=4 participants at risk Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 40 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 80 IU/kg n=6 participants at risk Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 80 IU/kg on Day 1 and followed for up to 28 days.	TAK-755: 160 IU/kg n=4 participants at risk Participants with SCD at their baseline health received a single IV infusion of TAK-755 at a dose level of 160 IU/kg on Day 1 and followed for up to 28 days.
Investigations Alanine aminotransferase increased	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	16.7% 1/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Investigations Aspartate aminotransferase increased	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Gastrointestinal disorders Abdominal pain	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	33.3% 2/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Investigations Blood lactate dehydrogenase increased	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Nervous system disorders Dizziness	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Investigations Fibrin D dimer increased	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Injury, poisoning and procedural complications Foot fracture	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Nervous system disorders Headache	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	33.3% 2/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Infections and infestations Laryngitis	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	16.7% 1/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	16.7% 1/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	16.7% 1/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Gastrointestinal disorders Nausea	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
General disorders Pain	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Musculoskeletal and connective tissue disorders Pain in extremity	20.0% 1/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
General disorders Pyrexia	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	16.7% 1/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Blood and lymphatic system disorders Sickle cell anaemia with crisis	20.0% 1/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Infections and infestations Upper respiratory tract infection	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	16.7% 1/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.
Gastrointestinal disorders Vomiting	0.00% 0/5 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	25.0% 1/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/6 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.	0.00% 0/4 • From date of signing informed consent up to end of study visit (Day 28) SAS included all participants randomized and who received any dose of IP.