• ADAMTS-13 Activity Levels [ Time Frame: Up to 6 months ]
  ADAMTS-13 Activity Levels will be assessed by daily Plasma Exchange (PEX), Immunosuppressant therapy, with or without SHP655 Supplementation. Schedule A (Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter) or Schedule B (Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter).
• Platelet Count [ Time Frame: Up to 6 months ]
  Platelet count will be assessed.
• Lactate Dehydrogenase (LDH) levels [ Time Frame: Up to 6 months ]
  LDH levels will be assessed.

• ADAMTS-13 Activity Levels [ Time Frame: Up to 6 months ]
  ADAMTS-13 Activity Levels will be assessed by daily Plasma Exchange (PEX), Immunosuppressant therapy, with or without SHP655 Supplementation. Schedule A (Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter) or Schedule B (Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter)
• Lactate Dehydrogenase (LDH) levels [ Time Frame: Up to 6 months ]
  LDH levels will be assessed.
• Platelet Count [ Time Frame: Up to 6 months ]
  Platelet count will be assessed.

• Change from Baseline in the Titers of Binding and Inhibitory Antibodies to ADAMTS-13 [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Change from baseline in levels of ADAMTS-13 binding and inhibitory auto antibodies in response to daily Plasma Exchange (PEX), with or without SHP655 supplementation, during the acute episode and up to 30 days after the resolution of the acute aTTP episode will be assessed.
• Occurrence of Antibodies to SHP655 [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Occurrence of Antibodies to SHP655 will be assessed.
• Incidence of Incremental Recovery [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Incremental recovery of ADAMTS-13 will be assessed.
• Area Under the Curve [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  AUC of ADAMTS-13 will be assessed.
• Systemic and Antibody Induced Clearance [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Systemic and antibody induced clearance of ADAMTS-13 will be assessed.
• Trough Levels of ADAMTS-13 prior PEX [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Trough levels of ADAMTS-13 will be assessed.
• ADAMTS-13 Binding and Inhibitory Autoantibody Levels in Response to Daily PEX, With or Without SHP655 Supplementation During the Acute TTP Episode and up to 30 Days After Resolution [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  ADAMTS-13 binding and inhibitory autoantibody levels in response to daily PEX, with or without SHP655 supplementation, during the acute TTP episode and up to 30 days after resolution will be assessed. Resolution is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).
• ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution [ Time Frame: Once weekly for 4 weeks ]
  ADAMTS-13 activity levels in participants receiving additional SHP655 for up to 30 days after the resolution of the TTP episode will be assessed. Resolution is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).
• Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13 in Order to Support Induction of Remission and to Reduce the Number of PEX Procedures Needed for the Treatment of Acute aTTP Episodes [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of rADAMTS-13 in order to support induction of remission and to reduce the number of PEX procedures needed for the treatment of acute aTTP episodes will be assessed.
• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) and Specifically Product-Related AEs and SAEs [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  An AE is defined as any untoward medical occurrence in a participants administered IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is an AE with any untoward clinical manifestation of signs, symptoms or outcomes which results in death, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, results in a congenital abnormality/birth defect, important medical event, bronchospasm associated with anaphylaxis, reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V). A product related AE is any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsens.
• Number of Participants with Clinically Relevant Changes in Vital Signs [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Vital signs will be assessed based on blood pressure, pulse rate, respiratory rate and body temperature.
• Number of Participants with Clinically Relevant Changes in Clinical Chemistry [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Clinical chemistry wiil be assessed Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.
• Number of Participants with Clinically Relevant Changes in Hematology [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Hematology consists of complete blood count and leukocytes with differential (basophils, eosinophils, lymphocytes,monocytes, neutrophils), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC) and platelet count.
• Time to Normalization of Platelet Count [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Time to normalization of platelet count, defined as platelet count greater than or equal to (>=) 150,000/μL, which must be confirmed by a second normal platelet count >= 150,000/μL and LDH lesser than (<)2 ULN 48 hours following initial normalization.
• Occurrence of Remission [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Remission is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period). Normalization of platelet count is defined as greater than or equal to (>=) 150,000/μL, which must be confirmed by a second normal platelet count >= 150,000/μL and LDH lesser than (<)2 upper limit of normal (ULN).
• Occurrence of Participants Receiving Rescue Therapy [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Rescue therapy will be defined as any product with a known interruption to the pharmacokinetic/pharmacodynamic (PK/PD) relationship between ADAMTS-13 activity, von Willebrand factor (VWF) activity, and platelet count. If rescue therapy is initiated, the administration of IP (SHP655 or placebo) will be suspended for the duration of the study. Number of participants experiencing occurrence of receiving rescue therapy will be assessed.
• Occurrence of Participants Meeting Rescue Criteria [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Rescue therapy will be defined as any product with a known interruption to the pharmacokinetic/pharmacodynamic (PK/PD) relationship between ADAMTS-13 activity, VWF activity, and platelet count. If rescue therapy is initiated, the administration of IP (SHP655 or placebo) will be suspended for the duration of the study. Number of participants experiencing occurrence in meeting rescue therapy criteria will be assessed.
• Occurrence of Exacerbation [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Occurrence of exacerbation will be determined by platelet count or the occurrence after remission of a major clinical event (e.g. MI, stroke, death) deemed by the investigator to be related to aTTP.
• Occurrence of Relapse [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Occurrence of relapse will be determined by platelet count or the occurrence after remission of a major clinical event (e.g. Myocardial Infraction (MI), stroke, death) deemed by the investigator to be related to aTTP.
• Occurrence of Major Clinical Events Related to TTP [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Major clinical events related to TTP including (Death, Stroke, MI, organ dysfunction not normalized within the 90-day observation period).
• Time to First Exacerbation [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
  Exacerbation is defined as recurrent thrombocytopenia following a response and requiring a reinitiation of daily plasma exchange treatment after greater than or equal to (>=) 1 day but less than or equal to (<= 30) days of no plasma exchange treatment.

• Changes in the Titer of Binding and Inhibitory Antibodies to ADAMTS-13 [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Changes in levels of ADAMTS-13 binding and inhibitory autoantibodies in response to daily Plasma Exchange (PEX), with or without SHP655 supplementation, during the acute episode and up to 30 days after the resolution of the TTP episode will be assessed.
• Occurrence of Antibodies to SHP655 [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Occurrence of Antibodies to SHP655 will be assessed.
• Incidence of Incremental Recovery [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Incremental recovery of ADAMTS-13 will be assessed.
• Area Under the Curve [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  AUC of ADAMTS-13 will be assessed.
• Systemic and Antibody Induced Clearance [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Systemic and antibody induced clearance of ADAMTS-13 will be assessed.
• Trough Levels of ADAMTS-13 prior PEX [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  Trough levels of ADAMTS-13 will be assessed.
• ADAMTS-13 Binding and Inhibitory Autoantibody Levels in Response to Daily PEX, With or Without SHP655 Supplementation During the Acute TTP Episode and up to 30 Days After Resolution [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2,15 minutes, 0.5-3 hours post-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
  ADAMTS-13 binding and inhibitory autoantibody levels in response to daily PEX, with or without SHP655 supplementation, during the acute TTP episode and up to 30 days after resolution will be assessed. Resolution is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).
• ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution [ Time Frame: Once weekly for 4 weeks ]
  ADAMTS-13 activity levels in participants receiving additional SHP655 for up to 30 days after the resolution of the TTP episode will be assessed. Resolution is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).
• Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13 in Order to Support Induction of Remission and to Reduce the Number of PEX Procedures Needed for the Treatment of Acute aTTP Episodes [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of rADAMTS-13 in order to support induction of remission and to reduce the number of PEX procedures needed for the treatment of acute aTTP episodes will be assessed
• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) and Specifically Product-Related AEs and SAEs [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  An AE is defined as any untoward medical occurrence in a participants administered IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is an AE with any untoward clinical manifestation of signs, symptoms or outcomes which results in death, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, results in a congenital abnormality/birth defect, important medical event, bronchospasm associated with anaphylaxis, reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V). A product related AE is any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsens.
• Number of Participants with Clinically Relevant Changes in Vital Signs [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Vital signs will be assessed based on blood pressure, pulse rate, respiratory rate and body temperature.
• Number of Participants with Clinically Relevant Changes in Clinical Chemistry [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Clinical chemistry wiil be assessed Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.
• Number of Participants with Clinically Relevant Changes in Hematology [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Hematology consists of complete blood count and leukocytes with differential (basophils, eosinophils, lymphocytes,monocytes, neutrophils), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC) and platelet count.
• Time to Normalization of Platelet Count [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Time to normalization of platelet count, defined as platelet count greater than or equal to (>=) 150,000/μL, which must be confirmed by a second normal platelet count >= 150,000/μL and LDH lesser than (<)2 ULN 48 hours following initial normalization.
• Occurrence of Remission [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Remission is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period). Normalization of platelet count is defined as greater than or equal to (>=) 150,000/μL, which must be confirmed by a second normal platelet count >= 150,000/μL and LDH lesser than (<)2 upper limit of normal (ULN).
• Time to First Exacerbation [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Exacerbation is defined as recurrent thrombocytopenia following a response and requiring a reinitiation of daily plasma exchange treatment after greater than or equal to (>=) 1 day but less than or equal to (<= 30) days of no plasma exchange treatment.
• Occurrence of Relapse [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Occurrence of relapse will be determined by platelet count or the occurrence after remission of a major clinical event (e.g. Myocardial Infraction (MI), stroke, death) deemed by the investigator to be related to aTTP.
• Occurrence of Exacerbation [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Occurrence of exacerbation will be determined by platelet count or the occurrence after remission of a major clinical event (e.g. MI, stroke, death) deemed by the investigator to be related to aTTP.
• Occurrence of Major Clinical Events Related to TTP [ Time Frame: From start of study drug administration up to 37 days post last dose (up to 6 months) ]
  Major clinical events related to TTP including (Death, Stroke, MI, organ dysfunction not normalized within the 90-day observation period).

• Other: Placebo
  Participants will receive injection of placebo matched to SHP655.
• Drug: SHP655
  Participants will receive injection of SHP655.
  Other Name: rADAMTS-13
• Other: Standard of Care
  Participants will receive PEX as Standard of Care (SOC).
  Other Name: PEX

• Placebo Comparator: Standard of Care (SoC) + Placebo Twice Daily
  Participants will receive SoC daily plasma exchange (PEX) immediately followed by placebo (0.9% saline) and after 12 +/- 1 hours until remission is achieved.
  Interventions:

  • Other: Placebo
  • Other: Standard of Care
• Experimental: SoC + SHP655 Once Daily + Placebo 12 Hours Later
  Participants will receive SoC daily PEX and intravenous (i.v.) injection of 40 +/- 4 International units per kilogram (IU/kg) of SHP655 once daily immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission is achieved.
  Interventions:

  • Other: Placebo
  • Drug: SHP655
  • Other: Standard of Care
• Experimental: SoC + SHP655 Twice Daily
  Participants will receive SoC daily plasma exchange and i.v. injection of 40 +/- 4 IU/kg of SHP655 twice daily (BID) immediately after PEX and 12 +/- 1 hours after completion of PEX until remission is achieved.
  Interventions:

  • Drug: SHP655
  • Other: Standard of Care

Inclusion Criteria:

• Participant or legally authorized representative voluntarily signs informed consent. For participants unable to provide consent, a fully recognized medical proxy may be used according to local laws.
• Participant is 18 to 75 years old at the time of screening.

• Participant has been diagnosed with primary or secondary autoimmune acquired thrombotic thrombocytopenic purpura (aTTP) based on the following criteria:

  a) Thrombocytopenia [drop in platelet count greater than or equal to (>=) 50% or platelet count lesser than (<) 100,000/microlitre (μL)] i) No more than 3 participants per arm may be enrolled with a screening platelet count >= 50,000/μL.

  b) Microangiopathic hemolytic anemia [elevation of lactate dehydrogenase (LDH) greater than (>) 2-fold or by presence or increase of schistocytes in peripheral blood smear].

• Willingness to fully comply with study procedures and requirements, and intention to initiate plasma exchange (PEX). Participants may be provisionally entered into the trial and undergo randomization pending the results of the ADAMTS-13 activity, anti-ADAMTS-13 antibody, and genetic testing for congenital thrombotic thrombocytopenic purpura (cTTP).
• If female of childbearing potential, participant presents with a negative pregnancy test and agrees to employ adequate birth control measures for the duration of the study. Sexually active males must use an accepted and effective method of contraception during the treatment and until a minimum of 16 days after the last dose administered.

Exclusion Criteria:

• Participant has been diagnosed with congenital TTP.
• Participant has plasma ADAMTS-13 activity > 10% of normal at the central lab; if screening samples are not taken until after the first PEX, ADAMTS-13 activity from the local lab is permitted to determine eligibility.
• Participant has been diagnosed with another cause of thrombotic microangiopathy (TMA) including: DIC, disseminated malignancy, malignant hypertension, hematopoietic stem cell transplantation, shiga toxin related and atypical HUS, drug toxicity (e.g. gemcitabine, mitomycin C, clopidogrel) and pregnancy-related thrombocytopenia syndromes (e.g. HELLP, eclampsia).
• Participant has been exposed to another IP within 30 days prior to enrollment or is scheduled to participate in another clinical study involving IP or investigational device during the course of the study.
• Participant has received caplacizumab within 1 month prior to study enrollment.
• Participant is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+ count lesser than or equal to (<=) 200 cells/mm3 within 3 months screening.
• Participants with conditions of severe immunodeficiency.
• Participant has had a previous aTTP event in the past 30 days.
• Participant has another underlying progressive fatal disease and/or life expectancy of less than 3 months.
• Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures
• Participant suffers from a mental condition rendering him/her unable to understand the nature, scope, and possible consequences of the study and/or evidence of an uncooperative attitude. However, a fully recognized medical proxy will be permitted to provide consent.
• If female, participant is pregnant or lactating.
• Participant is a family member or employee of the Sponsor or investigator.
• Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing information.
• Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADAMTS-13, hamster protein, or other constituents of SHP655.