Prospective Follow-up Study for Patients who Completed Study ALX0681-C301 (HERCULES) to Evaluate Long-term Safety and Efficacy of Caplacizumab (Post-HERCULES)

Caplacizumab (Sponsor code: ALX-0081) is intended to inhibit the interaction
between von Willebrand factor (vWF) and platelets, by targeting the A1 domain
of vWF. Caplacizumab selectively prevents thrombus formation in high-shear
blood vessels, blocks ultra-large (UL) vWF mediated platelet interactions, and
is expected not to interact with hemostasis in normal, healthy blood vessels.

This is a follow-up (FU) study for subjects who completed Study ALX0681-C301
(HERCULES) according to the protocol (i.e., completed the Final [28 day] FU
visit).

Subjects who completed Study ALX0681-C301 will be given the option to
participate in this FU study and attend twice yearly (Q6M) visits for 3 years
starting with a baseline visit coinciding with or scheduled to take place
within 1 month after the Final [28 day] FU visit in Study ALX0681 C301 .
Assessments at these Q6M visits will include patient reported outcome measures,
clinical assessments (including adverse events [AEs], safety laboratory
parameters, vital signs and physical examination), and determination of
anti-drug antibodies (ADA), vWF antigen (vWF:Ag; pharmacodynamic [PD]
parameter), and disease-related markers (a disintegrin-like and malloprotease
with thrombospondin repeats 13 [ADAMTS13] activity and Troponin I [TnI]).

• To evaluate long-term safety and efficacy of caplacizumab
• To evaluate safety and efficacy of repeated use of caplacizumab
• To characterize long term impact of TTP

Screening/Baseline and Q6M visits:
• Medical history (including general and TTP-related medical history) and
demographics
• Cognitive assessment: Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS)
• Adverse events
• Concomitant medication
• Physical examination, vital signs
• Quality of life assessment: short form 36 (SF36) questionnaire
• Headache Impact Test (HIT-6*)
• Laboratory assessments:
- Hematology (hemoglobin [Hb], hematocrit [Hct], red blood cells [RBC], white
blood cells [WBC], platelets)
- Chemistry (aspartate aminotransferase [AST], alanine aminotransferase [ALT],
lactate dehydrogenase [LDH], creatinine, protein, C-reactive protein [CRP],
cholesterol)
- Organ damage marker: troponin (TnI)
- ADAMTS13 activity
- PD parameter: vWF:Ag
- Immunogenicity: ADA panel
• Urine:
- Albumin (to calculate albumin creatinine ratio)

At TTP recurrence:
• Review of caplacizumab treatment criteria
• TTP recurrence information
• Concomitant medication
• Study drug administration
• PE information
• Quality of life assessment: SF36 questionnaire
• Adverse events
• Physical examination, vital signs
• Laboratory assessments:
- Hematology (Hb, Hct, RBC, WBC, platelets)
- Chemistry (AST, ALT, LDH, creatinine, protein, cholesterol and CRP)
- Organ damage marker: troponin (TnI)
- ADAMTS13 activity
- Immunogenicity: ADA panel
- Pharmacokinetics (not assessed if treatment with caplacizumab has not been
initiated)
- PD parameters: vWF:Ag and RICO (the latter will not be assessed if treatment
with caplacizumab has not been initiated).
• Urine:
- Albumin
• Pregnancy test (blood or urine) for female subjects of childbearing potential
(Note: pregnancy is an exclusion criterion for treatment with caplacizumab)

The following items are not part of the standard of care for this condition and
are an additional burden for the study subjects associated with participation
in the study: urine pregnancy test, 30 days follow up after the end of the
plasma exchange with daily subcutaneous injections and weekly visits to the
hospital & 1 follow-up visit after last dosing or 6-monthly visits in case
there is no TTP episode.