Trial Outcomes & Findings for Study to Assess Efficacy and Safety of Anti-von Willebrand Factor (vWF) Nanobody in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) (NCT NCT01151423)

NCT ID: NCT01151423

Last Updated: 2023-04-04

Results Overview

Time-to-response, defined by the achievement of platelet count response, confirmed at 48 hours after the initial reporting of this response. Platelet response was defined as recovery of platelets ≥ 150,000/µL. This response had to be confirmed at 48 hours after the initial reporting of platelet recovery ≥ 150,000/µL by a de novo measure of platelets ≥ 150,000/µL and lactate dehydrogenase (LDH) ≤ 2x upper limit of normal (ULN) (i.e., 'confirmed platelet response').

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 75 participants
• Primary outcome timeframe: From the day of first study drug administration up to 30 days after first study drug administration
• Results posted on: 2023-04-04

Participant Flow

Subjects with aTTP were recruited from 11 countries in Europe, Australia, Asia and United States (US). Only adults were recruited; no adolescent patients were enrolled, although the trial was open for adolescent patients. A total of 75 patients were included in the trial.

76 subjects were screened, 75 subjects were randomized (= Intent-to-treat [ITT] population): 36 in the ALX-0081 group, 39 in the placebo group.

Participant milestones

Measure	Caplacizumab Caplacizumab: * Subjects received a first i.v. bolus of 10 mg (filled at 5 mg/mL) caplacizumab via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of 10 mg study drug within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received caplacizumab up to 30 days after the last PE session.	Placebo Placebo: * Subjects received a first i.v. bolus of placebo via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of placebo within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received placebo up to 30 days after the last PE session.
Overall Study STARTED	36	39
Overall Study Received Study Drug	35	37
Overall Study COMPLETED	20	21
Overall Study NOT COMPLETED	16	18

Reasons for withdrawal

Measure	Caplacizumab Caplacizumab: * Subjects received a first i.v. bolus of 10 mg (filled at 5 mg/mL) caplacizumab via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of 10 mg study drug within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received caplacizumab up to 30 days after the last PE session.	Placebo Placebo: * Subjects received a first i.v. bolus of placebo via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of placebo within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received placebo up to 30 days after the last PE session.
Overall Study Study terminated by Sponsor	9	10
Overall Study Protocol Violation	0	1
Overall Study Physician Decision	1	1
Overall Study Pregnancy	0	1
Overall Study Death	0	1
Overall Study Adverse Event	3	0
Overall Study Withdrawal by Subject	1	3
Overall Study Lost to Follow-up	1	0
Overall Study Diagnosed as non-TTP patient	0	1
Overall Study Participated in other clinical trial	1	0

Baseline Characteristics

Study to Assess Efficacy and Safety of Anti-von Willebrand Factor (vWF) Nanobody in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

Baseline characteristics by cohort

Measure	Caplacizumab n=36 Participants Caplacizumab: * Subjects received a first i.v. bolus of 10 mg (filled at 5 mg/mL) caplacizumab via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of 10 mg study drug within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received caplacizumab up to 30 days after the last PE session.	Placebo n=39 Participants Placebo: * Subjects received a first i.v. bolus of placebo via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of placebo within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received placebo up to 30 days after the last PE session.	Total n=75 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	35 Participants n=5 Participants	38 Participants n=7 Participants	73 Participants n=5 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Age, Continuous	40.6 years STANDARD_DEVIATION 12.7 • n=5 Participants	42.5 years STANDARD_DEVIATION 13.18 • n=7 Participants	41.6 years STANDARD_DEVIATION 12.9 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	20 Participants n=7 Participants	44 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	19 Participants n=7 Participants	31 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Caucasian	32 Participants n=5 Participants	34 Participants n=7 Participants	66 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Black	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the day of first study drug administration up to 30 days after first study drug administration

Population: ITT Population

Time-to-response, defined by the achievement of platelet count response, confirmed at 48 hours after the initial reporting of this response. Platelet response was defined as recovery of platelets ≥ 150,000/µL.

This response had to be confirmed at 48 hours after the initial reporting of platelet recovery ≥ 150,000/µL by a de novo measure of platelets ≥ 150,000/µL and lactate dehydrogenase (LDH) ≤ 2x upper limit of normal (ULN) (i.e., 'confirmed platelet response').

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Time-to-response of Treatment Defined by a Confirmed Recovery of Platelets ≥ 150,000/µL YES - One PE session prior to randomization	2.4 days Interval 1.9 to 3.0	4.3 days Interval 2.9 to 5.7
Time-to-response of Treatment Defined by a Confirmed Recovery of Platelets ≥ 150,000/µL NO - No PE session prior to randomization	3 days Interval 2.7 to 3.9	4.9 days Interval 3.2 to 6.6

SECONDARY outcome

Timeframe: From the day of first study drug administration up to 30 days after first study drug administration

Population: ITT Population

Number and percentage of subjects with complete remission (defined as confirmed platelet count response and absence of exacerbation) following initial daily PE.

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Number and Percentage of Subjects With Complete Remission Following Initial Daily Plasma Exchange (PE)	29 Participants	18 Participants

SECONDARY outcome

Timeframe: Within 30 days of last day of initial daily PE

Population: ITT Population

Number and percentage of subjects with exacerbations of TTP (defined as recurrent thrombocytopenia following a confirmed platelet count response and requiring a re-initiation of daily PE treatment after ≥ 1 day but ≤ 30 days of end of daily PE treatment.

Time to first exacerbation of TTP was also examined as part of this end point analysis; the median time to first exacerbation could not be determined because of the small number of events.

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Number and Percentage of Subjects With Exacerbations of TTP	3 Participants	11 Participants

SECONDARY outcome

Timeframe: Later than 30 days after the last daily PE

Population: ITT Population

Number and percentage of subjects with relapse of TTP (defined as de novo TTP event that occurred later than 30 days after the last daily PE) was evaluated.

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Number and Percentage of Subjects With Relapse of TTP	11 Participants	3 Participants

SECONDARY outcome

Timeframe: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days

Population: Number of subjects from the ITT Population with data available

Number of daily PE sessions during the initial daily PE period which could include more than 1 PE per day was evaluated.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Number of Daily PE Sessions During the Initial Daily PE Period	6.7 PE sessions Standard Deviation 3.69	8.4 PE sessions Standard Deviation 6.74

SECONDARY outcome

Timeframe: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days

Population: Number of subjects from the ITT Population with data available

The total volume of plasma administered during the initial daily PE period was measured.

Outcome measures

Measure	Caplacizumab n=34 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Total Volume of Plasma Administered During the Initial Daily PE Period	22481.8 mL Standard Deviation 15914.85	28358.4 mL Standard Deviation 21344.16

SECONDARY outcome

Timeframe: During the total course of the study (from Screening till the 12-month follow-up [FU] visit)

Population: Number of subjects from the ITT Population with data available

Number of days for PE was evaluated. This implies the number of days with at least one PE administration during the total course of the study.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Number of Days With at Least One PE Administration During the Total Course of the Study	11.8 days Standard Deviation 7.43	12.6 days Standard Deviation 9.15

SECONDARY outcome

Timeframe: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days

Population: Number of subjects from the ITT Population with data available

The maximum number of consecutive days per subject where there was no interruption of PE during the initial daily PE period.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
The Maximum Number of Consecutive Days Per Subject Where There Was no Interruption of PE During the Initial Daily PE Period	6.6 days Standard Deviation 3.35	8.1 days Standard Deviation 6.46

SECONDARY outcome

Timeframe: From Baseline till the 12-month FU visit

Population: The Computerized Neuropsychological Test Battery (CNTB) was completed by a low proportion of subjects with baseline data available for only 3 subjects in the caplacizumab and 4 subjects in the placebo group and 12 month post-discharge data available for 10 and 6 subjects, respectively.

Resolution of non-focal neurological symptoms as defined by neurocognitive function at complete remission, measured by a Computerised Neuropsychological Test Battery(CNTB) (adults only). The CNTB included 6 modules: word list learning and selective reminding (WLL/SR), choice reaction time (CRT), visual memory (VMEM), simple reaction time (SRT), working memory (WMEM), and word list learning and delayed recall (WLL/DR). The 6 tasks are rated as a percentage correct (for CRT and SRT, the percentage correct corresponds to the percentage hits) and the mean score from these provides the CNTB summary score (range: 0-100). A higher CNTB summary score indicates better neuropsychological functioning.

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Resolution of Non-focal Neurological Symptoms Baseline	66.76 score on a scale Standard Deviation 11.88	49.62 score on a scale Standard Deviation 12.91
Resolution of Non-focal Neurological Symptoms 12 months post discharge	62.10 score on a scale Standard Deviation 12.06	58.36 score on a scale Standard Deviation 10.23

SECONDARY outcome

Timeframe: End of daily PE treatment period (median [min, max] duration of exposure to study drug of 6 [2, 36] days), end of study treatment period (median [min, max] duration of exposure to study drug of 36.5 [2, 90] days) and at 1 month follow-up

Population: ITT Population

Resolution or improvement (improvement of ≥ 1 grade in the Common Terminology Criteria for Adverse Events [CTCAE] v4.0 scale) of TTP-related signs and symptoms as captured on physical examination and as adverse events. This endpoint was only evaluated for "resolution".

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Number of Participants With Resolution of TTP-related Signs or Symptoms End of daily PE treatment period	29 Participants	29 Participants
Number of Participants With Resolution of TTP-related Signs or Symptoms End of study treatment period	30 Participants	33 Participants
Number of Participants With Resolution of TTP-related Signs or Symptoms At 1 month follow-up	31 Participants	27 Participants

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up

Population: ITT Population

Total mortality up to 1 month follow-up.

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Mortality	0 Participants	2 Participants

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up

Population: ITT Population

Number of PE treatment-related adverse events (AEs).

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Number of PE Related Adverse Events	72 adverse events	44 adverse events

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up

Population: ITT Population

Number and percentage of subjects with PE related AEs.

Outcome measures

Measure	Caplacizumab n=36 Participants Caplacizumab 10 mg once daily	Placebo n=39 Participants Placebo once daily
Number and Percentage of Subjects With PE Related AEs	20 Participants	20 Participants

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up

Population: Safety Population

Number and severity of TEAEs were evaluated. The severity grades of AEs were defined as: mild, moderate, and severe. Note: the numbers listed do not include the TEAEs with missing severity.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Number of Treatment-emergent Adverse Events (TEAEs) by Severity Mild	348 adverse events	299 adverse events
Number of Treatment-emergent Adverse Events (TEAEs) by Severity Moderate	154 adverse events	173 adverse events
Number of Treatment-emergent Adverse Events (TEAEs) by Severity Severe	37 adverse events	23 adverse events

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up

Population: Safety Population

Number and percentage of subjects with TEAEs by severity. The severity grades of AEs were defined as: mild, moderate, and severe.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Number and Percentage of Subjects With TEAEs by Severity Mild	31 Participants	36 Participants
Number and Percentage of Subjects With TEAEs by Severity Moderate	27 Participants	31 Participants
Number and Percentage of Subjects With TEAEs by Severity Severe	18 Participants	14 Participants

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up

Population: Safety Population

Number of TEAEs and their relationship to study drug were evaluated. Relationship of AEs to study drug was: related, possibly related, and unlikely/not related.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Number of TEAEs and Their Relationship to Study Drug Related	12 adverse events	6 adverse events
Number of TEAEs and Their Relationship to Study Drug Possibly related	59 adverse events	9 adverse events
Number of TEAEs and Their Relationship to Study Drug Unlikely/not related	486 adverse events	524 adverse events

SECONDARY outcome

Timeframe: From the start of the study until last follow-up visit

Population: Number of subjects from the Safety Population with data available

The development of anti-drug antibodies (ADA) was monitored from the start of the study until last follow-up visit.

Outcome measures

Measure	Caplacizumab n=32 Participants Caplacizumab 10 mg once daily	Placebo n=30 Participants Placebo once daily
Number of Participants Who Developed Treatment-emergent Anti-Drug Antibodies (ADA)	3 Participants	0 Participants

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).

Population: PK Population, no PK data were generated for the subjects in the placebo group

The concentration of caplacizumab in plasma was determined at different time points. pharmacokinetics (PK) Population: the PK Population consisted of all subjects who received the study drug and for whom the primary PK data are considered to be sufficient and interpretable.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo Placebo once daily
Plasma Concentrations of Caplacizumab Baseline	100 ng/mL Standard Error 0	—
Plasma Concentrations of Caplacizumab Day 1 of daily PE, 5 - 10 min postdose	1765.9 ng/mL Standard Error 185.04	—
Plasma Concentrations of Caplacizumab Day 1 of daily PE, 3 - 6 hours postdose	450.4 ng/mL Standard Error 36.15	—
Plasma Concentrations of Caplacizumab Day 1 of daily PE, 8 - 24 hours postdose	562 ng/mL Standard Error 36.8	—
Plasma Concentrations of Caplacizumab Day 2 of daily PE, predose	288 ng/mL Standard Error 24.05	—
Plasma Concentrations of Caplacizumab Day 2 of daily PE, 1 - 6 hours postdose	415.8 ng/mL Standard Error 24.75	—
Plasma Concentrations of Caplacizumab Day 2 of daily PE, 6 - 12 hours postdose	570.7 ng/mL Standard Error 52.22	—
Plasma Concentrations of Caplacizumab Day 2 of daily PE, 18 - 24 hours postdose	489.3 ng/mL Standard Error 32.54	—
Plasma Concentrations of Caplacizumab Last day of daily PE, predose	348.4 ng/mL Standard Error 38.32	—
Plasma Concentrations of Caplacizumab Day 1 after daily PE	521.9 ng/mL Standard Error 31.52	—
Plasma Concentrations of Caplacizumab Week 1 after daily PE	490.6 ng/mL Standard Error 36.11	—
Plasma Concentrations of Caplacizumab Week 2 after daily PE	524.9 ng/mL Standard Error 39.37	—
Plasma Concentrations of Caplacizumab Week 3 after daily PE	499.6 ng/mL Standard Error 35.1	—
Plasma Concentrations of Caplacizumab Week 4 after daily PE	503.4 ng/mL Standard Error 31.21	—
Plasma Concentrations of Caplacizumab Day 3 of follow-up period	346.7 ng/mL Standard Error 25.43	—
Plasma Concentrations of Caplacizumab Day 7 of follow-up period	162.3 ng/mL Standard Error 20.2	—
Plasma Concentrations of Caplacizumab 1 month follow-up	100 ng/mL Standard Error 0	—

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).

Population: Safety Population

The change from baseline in RICO activity was measured at different time points.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Baseline	76.2 percentage of RICO activity Standard Deviation 4.95	82.1 percentage of RICO activity Standard Deviation 3.76
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Day 1 of daily PE, post dose	16.2 percentage of RICO activity Standard Deviation 0.72	84.4 percentage of RICO activity Standard Deviation 6.09
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Day 2 of daily PE, post dose	21.4 percentage of RICO activity Standard Deviation 3.64	94.4 percentage of RICO activity Standard Deviation 3.69
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Last day of daily PE, post dose	15.4 percentage of RICO activity Standard Deviation 0.39	118.2 percentage of RICO activity Standard Deviation 1.78
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Day 1 after daily PE	19.2 percentage of RICO activity Standard Deviation 3.94	105.2 percentage of RICO activity Standard Deviation 4.31
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Week 1 after daily PE	15 percentage of RICO activity Standard Deviation 0	107.3 percentage of RICO activity Standard Deviation 3.05
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Week 2 after daily PE	18.9 percentage of RICO activity Standard Deviation 2.87	109.2 percentage of RICO activity Standard Deviation 2.8
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Week 3 after daily PE	17.4 percentage of RICO activity Standard Deviation 2.34	104 percentage of RICO activity Standard Deviation 3.46
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Week 4 after daily PE	15.1 percentage of RICO activity Standard Deviation 0.07	105.5 percentage of RICO activity Standard Deviation 3.59
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Day 3 of follow-up period	42.3 percentage of RICO activity Standard Deviation 6.33	99.1 percentage of RICO activity Standard Deviation 4.56
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time Day 7 of follow-up period	88.3 percentage of RICO activity Standard Deviation 4.99	99.7 percentage of RICO activity Standard Deviation 4.06
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time 1 month follow-up	94.6 percentage of RICO activity Standard Deviation 3.78	94.7 percentage of RICO activity Standard Deviation 5.35

SECONDARY outcome

Timeframe: From the start of the study drug up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).

Population: Safety Population

The change from baseline in vWF:Ag concentration was measured at different time points.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Baseline	185.1 Percentage of vWF:Ag Standard Deviation 15.09	204.4 Percentage of vWF:Ag Standard Deviation 14.52
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Day 1 of daily PE, post dose	120.6 Percentage of vWF:Ag Standard Deviation 7.98	166.6 Percentage of vWF:Ag Standard Deviation 9.24
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Day 2 of daily PE, post dose	94.6 Percentage of vWF:Ag Standard Deviation 4.83	140.2 Percentage of vWF:Ag Standard Deviation 6.16
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Last day of daily PE, post dose	93.6 Percentage of vWF:Ag Standard Deviation 6.01	151.2 Percentage of vWF:Ag Standard Deviation 14.25
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Day 1 after daily PE	86.2 Percentage of vWF:Ag Standard Deviation 6.15	166 Percentage of vWF:Ag Standard Deviation 10.05
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Week 1 after daily PE	93.4 Percentage of vWF:Ag Standard Deviation 6.4	234.9 Percentage of vWF:Ag Standard Deviation 20.91
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Week 2 after daily PE	115.9 Percentage of vWF:Ag Standard Deviation 12.42	242.6 Percentage of vWF:Ag Standard Deviation 19.43
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Week 3 after daily PE	102.4 Percentage of vWF:Ag Standard Deviation 6.45	224.2 Percentage of vWF:Ag Standard Deviation 18.62
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Week 4 after daily PE	100.1 Percentage of vWF:Ag Standard Deviation 5	204.3 Percentage of vWF:Ag Standard Deviation 17.08
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Day 3 of follow-up period	137.8 Percentage of vWF:Ag Standard Deviation 9.32	184.1 Percentage of vWF:Ag Standard Deviation 13.89
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time Day 7 of follow-up period	190.2 Percentage of vWF:Ag Standard Deviation 12.9	190.3 Percentage of vWF:Ag Standard Deviation 14.81
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time 1 month follow-up	176.3 Percentage of vWF:Ag Standard Deviation 15.63	167.2 Percentage of vWF:Ag Standard Deviation 15.46

SECONDARY outcome

Timeframe: From the start of the study up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).

Population: Safety Population

The change from baseline in FVIII:C concentration was measured at different ime points.

Outcome measures

Measure	Caplacizumab n=35 Participants Caplacizumab 10 mg once daily	Placebo n=37 Participants Placebo once daily
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Baseline	144.18 Percentage of FVIII:C activity Standard Deviation 11.14	156.8 Percentage of FVIII:C activity Standard Deviation 12.54
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Day 1 of daily PE, post dose	104 Percentage of FVIII:C activity Standard Deviation 6.95	149 Percentage of FVIII:C activity Standard Deviation 9.16
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Day 2 of daily PE, post dose	90.7 Percentage of FVIII:C activity Standard Deviation 5.49	152.9 Percentage of FVIII:C activity Standard Deviation 9.41
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Last day of daily PE, post dose	102.4 Percentage of FVIII:C activity Standard Deviation 10.91	169.5 Percentage of FVIII:C activity Standard Deviation 17.79
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Day 1 after daily PE	116.3 Percentage of FVIII:C activity Standard Deviation 13.33	234.2 Percentage of FVIII:C activity Standard Deviation 16.05
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Week 1 after daily PE	116.4 Percentage of FVIII:C activity Standard Deviation 11.73	296.8 Percentage of FVIII:C activity Standard Deviation 26.07
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Week 2 after daily PE	125.2 Percentage of FVIII:C activity Standard Deviation 16.88	291.1 Percentage of FVIII:C activity Standard Deviation 18.25
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Week 3 after daily PE	106.3 Percentage of FVIII:C activity Standard Deviation 9.7	273.1 Percentage of FVIII:C activity Standard Deviation 20.35
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Week 4 after daily PE	95.8 Percentage of FVIII:C activity Standard Deviation 6.09	249.1 Percentage of FVIII:C activity Standard Deviation 18.27
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Day 3 of follow-up period	146.3 Percentage of FVIII:C activity Standard Deviation 12.59	227.7 Percentage of FVIII:C activity Standard Deviation 17.32
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time Day 7 of follow-up period	208.6 Percentage of FVIII:C activity Standard Deviation 15.54	237.5 Percentage of FVIII:C activity Standard Deviation 15.65
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time 1 month follow-up	212.2 Percentage of FVIII:C activity Standard Deviation 17.33	200.1 Percentage of FVIII:C activity Standard Deviation 17.11

Adverse Events

Caplacizumab

Serious events: 20 serious events

Other events: 33 other events

Deaths: 0 deaths

Placebo

Serious events: 19 serious events

Other events: 37 other events

Deaths: 2 deaths

Serious adverse events

Measure	Caplacizumab n=35 participants at risk Caplacizumab 10 mg once daily	Placebo n=37 participants at risk Placebo once daily
Blood and lymphatic system disorders Thrombotic thrombocytopenic purpura	37.1% 13/35 • Number of events 16 • From time of the first study drug administration up to the last follow-up visit (12 months)	35.1% 13/37 • Number of events 17 • From time of the first study drug administration up to the last follow-up visit (12 months)
Blood and lymphatic system disorders Anemia	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Cardiac disorders Atrial fibrillation	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Cardiac disorders Atrial flutter	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Eye disorders Retinal hemorrhage	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Abdominal pain	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Abdominal pain upper	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Dysphagia	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Nausea	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Vomiting	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Hepatobiliary disorders Hypertransaminasemia	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Bacterial infection	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Muscle abscess	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Sepsis	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Urinary tract infection	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Device related sepsis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Injury, poisoning and procedural complications Traumatic fracture	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Alanine aminotransferase increased	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Aspartate aminotransferase increased	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Autoantibody test	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Transaminases increased	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Liver function test abnormal	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Muscle spasms	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Dizziness	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Headache	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Transient ischemic attack	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Dysarthria	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Paresthesia	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Subarachnoid hemorrhage	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Cerebral hemorrhage	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Facial paresis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Mental status changes	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Substance-induced psychotic disorder	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Renal and urinary disorders Hematuria	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Reproductive system and breast disorders Metrorrhagia	2.9% 1/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Reproductive system and breast disorders Prostatitis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Dyspnea	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Dermatitis allergic	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Hyperhidrosis	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Vascular disorders Deep vein thrombosis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)

Other adverse events

Measure	Caplacizumab n=35 participants at risk Caplacizumab 10 mg once daily	Placebo n=37 participants at risk Placebo once daily
Psychiatric disorders Insomnia	14.3% 5/35 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)	13.5% 5/37 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Restlessness	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Sleep disorder	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Urticaria	11.4% 4/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)
Vascular disorders Deep vein thrombosis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Vascular disorders Hematoma	11.4% 4/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	10.8% 4/37 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)
Vascular disorders Hypertension	14.3% 5/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	16.2% 6/37 • Number of events 7 • From time of the first study drug administration up to the last follow-up visit (12 months)
Vascular disorders Hypotension	11.4% 4/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Vascular disorders Phlebitis	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Productive cough	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Alopecia	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Ecchymosis	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Erythema	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Hyperhidrosis	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Petechiae	11.4% 4/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Pruritus	11.4% 4/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)
Skin and subcutaneous tissue disorders Rash	8.6% 3/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	10.8% 4/37 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Agitation	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	13.5% 5/37 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Anxiety	11.4% 4/35 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)	13.5% 5/37 • Number of events 7 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Confusional state	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Depression	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Psychiatric disorders Disorientation	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Blood and lymphatic system disorders Anemia	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	21.6% 8/37 • Number of events 34 • From time of the first study drug administration up to the last follow-up visit (12 months)
Blood and lymphatic system disorders Leukocytosis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Blood and lymphatic system disorders Neutrophilia	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Cardiac disorders Acute myocardial infarction	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Cardiac disorders Cardiac disorder	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Cardiac disorders Palpitations	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Cardiac disorders Tachycardia	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Eye disorders Diplopia	2.9% 1/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Eye disorders Vision blurred	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Abdominal discomfort	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Abdominal pain	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	10.8% 4/37 • Number of events 27 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Abdominal pain upper	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Constipation	20.0% 7/35 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)	27.0% 10/37 • Number of events 10 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Diarrhea	17.1% 6/35 • Number of events 10 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Dyspepsia	8.6% 3/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Gingival bleeding	14.3% 5/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Nausea	28.6% 10/35 • Number of events 20 • From time of the first study drug administration up to the last follow-up visit (12 months)	27.0% 10/37 • Number of events 12 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Paraesthesia oral	11.4% 4/35 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Gastrointestinal disorders Vomiting	20.0% 7/35 • Number of events 11 • From time of the first study drug administration up to the last follow-up visit (12 months)	18.9% 7/37 • Number of events 9 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Asthenia	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	16.2% 6/37 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Catheter site pain	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Chest pain	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Chills	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Fatigue	17.1% 6/35 • Number of events 10 • From time of the first study drug administration up to the last follow-up visit (12 months)	13.5% 5/37 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Injection site bruising	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Injection site hemorrhage	8.6% 3/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Local swelling	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Malaise	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Non-cardiac chest pain	11.4% 4/35 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Edema peripheral	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Pain	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
General disorders Pyrexia	17.1% 6/35 • Number of events 7 • From time of the first study drug administration up to the last follow-up visit (12 months)	16.2% 6/37 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Bronchitis	0.00% 0/35 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Influenza	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Nasopharyngitis	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Infections and infestations Urinary tract infection	14.3% 5/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Injury, poisoning and procedural complications Contusion	11.4% 4/35 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Injury, poisoning and procedural complications Transfusion reaction	11.4% 4/35 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Activated partial thromboplastin time prolonged	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Alanine aminotransferase increased	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Aspartate aminotransferase increased	2.9% 1/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Blood lactate dehydrogenase increased	8.6% 3/35 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Blood potassium decreased	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Brain natriuretic peptide increased	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations C-reactive protein increased	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Hemoglobin decreased	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Haptoglobin decreased	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Neutrophil count increased	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations Platelet count decreased	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 11 • From time of the first study drug administration up to the last follow-up visit (12 months)
Investigations White blood cell count increased	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Metabolism and nutrition disorders Decreased appetite	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Metabolism and nutrition disorders Fluid retention	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Metabolism and nutrition disorders Hyperglycemia	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	13.5% 5/37 • Number of events 11 • From time of the first study drug administration up to the last follow-up visit (12 months)
Metabolism and nutrition disorders Hypocalcemia	2.9% 1/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Metabolism and nutrition disorders Hypokalemia	25.7% 9/35 • Number of events 18 • From time of the first study drug administration up to the last follow-up visit (12 months)	21.6% 8/37 • Number of events 12 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Arthralgia	8.6% 3/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	21.6% 8/37 • Number of events 11 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Back pain	11.4% 4/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Muscle spasms	8.6% 3/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	13.5% 5/37 • Number of events 7 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Pain in extremity	14.3% 5/35 • Number of events 7 • From time of the first study drug administration up to the last follow-up visit (12 months)	18.9% 7/37 • Number of events 11 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Myalgia	20.0% 7/35 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Disturbance in attention	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Dizziness	17.1% 6/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Headache	31.4% 11/35 • Number of events 19 • From time of the first study drug administration up to the last follow-up visit (12 months)	27.0% 10/37 • Number of events 26 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Migraine	5.7% 2/35 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Paraesthesia	20.0% 7/35 • Number of events 13 • From time of the first study drug administration up to the last follow-up visit (12 months)	21.6% 8/37 • Number of events 14 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Syncope	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Transient ischemic attack	5.7% 2/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	2.7% 1/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Nervous system disorders Tremor	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Reproductive system and breast disorders Menorrhagia	5.7% 2/35 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)	0.00% 0/37 • From time of the first study drug administration up to the last follow-up visit (12 months)
Reproductive system and breast disorders Metrorrhagia	2.9% 1/35 • Number of events 1 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Cough	14.3% 5/35 • Number of events 6 • From time of the first study drug administration up to the last follow-up visit (12 months)	5.4% 2/37 • Number of events 2 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Dyspnea	11.4% 4/35 • Number of events 5 • From time of the first study drug administration up to the last follow-up visit (12 months)	10.8% 4/37 • Number of events 4 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Epistaxis	31.4% 11/35 • Number of events 16 • From time of the first study drug administration up to the last follow-up visit (12 months)	10.8% 4/37 • Number of events 8 • From time of the first study drug administration up to the last follow-up visit (12 months)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	8.6% 3/35 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)	8.1% 3/37 • Number of events 3 • From time of the first study drug administration up to the last follow-up visit (12 months)

Additional Information

Medical Monitor

Ablynx

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Email: clinicaltrials@ablynx.com

Results disclosure agreements

• Principal investigator is a sponsor employee Publication of any results from this study will be according to the principles of the Declaration of Helsinki, in particular point 30, and will require prior review and written agreement of the Sponsor.
• Publication restrictions are in place

Restriction type: OTHER