Study of rADAMTS-13 (SHP655) in the Treatment of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

Phase 2

Completed

Conditions: Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

Interventions: Drug: SHP655
Other: Placebo
Other: Standard of Care

Registration Number: NCT03922308

Lead Sponsor: Shire

Brief Summary: The purpose of this study is to evaluate the pharmacokinetics, safety, and efficacy of rADAMTS-13 (SHP655) administered in addition to standard of care (SoC) treatment of acquired thrombotic thrombocytopenic purpura (aTTP) participants.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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 >=50% or platelet count <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) >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 <=200 cells/mm^3 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SoC + SHP655	SHP655	Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
Standard of Care (SoC) + Placebo	Placebo	Participants received SoC daily PEX followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
Standard of Care (SoC) + Placebo	Standard of Care	Participants received SoC daily PEX followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
SoC + SHP655 + Placebo	Placebo	Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
SoC + SHP655 + Placebo	SHP655	Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
SoC + SHP655 + Placebo	Standard of Care	Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
SoC + SHP655	Standard of Care	Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

Primary Outcome Measures

Name	Time	Method
ADAMTS-13 Activity Levels	Up to Days 11 or 12	ADAMTS-13 Activity Levels was assessed by fluorescence resonance energy transfer (FRETS) ADAMTS13 activity, 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). Data is reported for multiple timepoints as Within 15 minutes pre-PEX and post-PEX; Within 15 minutes, 0.5-3 hours, 4-6 hours post end of investigational product (IP) infusion 1; Within 15 minutes, 0.5-3 hours post end IP infusion 2; 30 minutes pre-IP infusion 2 of Schedule A and Schedule B (up to Day 11 or 12).
Platelet Count	Baseline and end of study (EOS) (up to approximately 15 months)	The platelet counts are reported in units of 10\^9 per liter blood.
Lactate Dehydrogenase (LDH) Levels	Baseline and EOS (up to approximately 15 months)	The lactate dehydrogenase levels are reported.

Secondary Outcome Measures

Name	Time	Method
Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13	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 was assessed.
PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity	Up to 6 months	Parameters included platelet and LDH counts.
Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS	Pre-PEX and post-PEX at multiple timepoints at Days 1, 2, 3, 4 or 5, 6 or 7, 8 or 9, and 11 or 12
Relationship Between ADAMTS-13 Activity and End-organ Disease Status	Up to 6 months	End-organ disease status were evaluated for renal, cardiac and neurological diseases.
Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio	Pre-PEX and post-PEX at multiple timepoints at Days 1, 2, 3, 4 or 5, 6 or 7, 8 or 9, and 11 or 12
Time to First Exacerbation	From start of study drug administration up to EOS (up to approximately 15 months)	Exacerbation was defined as recurrent thrombocytopenia following a response and requiring a reinitiation of daily plasma exchange treatment after ≥1 day but ≤30 days of no plasma exchange treatment. Data is reported based on Kaplan-Meier estimates. Data was reported for time to first exacerbation in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS).
Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655	Up to 6 months	Percentages are based on the total number of participants per treatment group that have at least one ADA sample analyzed.
Number of Participants With Clinically Relevant Changes in Vital Signs	From first dose of study drug until the EOS (up to approximately 15 months)	Vital signs were assessed based on blood pressure, pulse rate, respiratory rate and body temperature.
Number of Participants With Clinically Relevant Changes in Clinical Chemistry	From first dose of study drug until the EOS (up to approximately 15 months)	Clinical chemistry assessed alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.
Number of Participants With ADAMTS-13 Binding Antibodies Per Titer	Baseline and EOS (up to approximately 15 months)	Antibody titer indicates the level of the antibodies in a blood sample, defined as the greatest dilution (or lowest concentration) of the blood sample at which an antibody assay (such as ELISA for e.g.), still produces a detectable positive result. Data is presented per titer for ADA positive participants only.
ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS	At Days 3, 7, 10, 21, 28, 42, 56 and 84	ADAMTS-13 activity levels in participants receiving additional SHP655 for up to 30 days after the resolution of the thrombotic thrombocytopenic purpura (TTP) episode were assessed. Resolution was defined as a normal platelet count and LDH \<2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).
AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS	Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 1, 2, 3, 4 or 5 and 6 or 7
Inhibitory Autoantibodies (Nab) Titer Levels	Baseline and EOS (up to approximately 15 months)	NAb titers were summarized (median, minimum and maximum) at baseline and EOS per treatment arms, in those subjects with NAb positive results (NAb positive is defined as titer value \>=0.6 BU/mL).
Number of Participants Who Achieved Remission Following Normalization of Platelet Count	From the start of study drug administration up to 6 months post remission	Remission was defined as the time taken to achieve platelet count ≥150,000/μL, which was confirmed by a second normal platelet count ≥150,000/μL and LDH \<2 ULN 48 hours following initial normalization.
Percentage of Participants With Exacerbation	From start of study drug administration up to EOS (up to approximately 15 months)	Exacerbation was determined by platelet count or the occurrence after remission of a major clinical event (e.g., myocardial infarction (MI), stroke, death) deemed by the investigator to be related to aTTP. Data was reported for percentage of participants with exacerbation in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS).
Systemic and Antibody Induced Clearance	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)
Percentage of Participants Achieving Remission	From the start of study drug administration up to 6 months post remission	Remission was defined as a normal platelet count and LDH \<2 upper limit of normal (ULN) for at least 48 hours following initial normalization of platelet count (acute episode period). Normalization of platelet count was defined ≥150,000/μL, which was confirmed by a second normal platelet count ≥150,000/μL and LDH \<2 ULN.
Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)	From start of study drug administration up to EOS (up to approximately 15 months)	Major clinical events related to TTP included Death, Stroke, MI and organ dysfunction not normalized within the 90-day observation period which consisted of chronic renal insufficiency, neurologic impairment and neurocognitive deficits.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs	From first dose of study drug until the EOS (up to approximately 15 months)	AE=any untoward medical occurrence in a participants administered IP that does not necessarily have a causal relationship with the treatment. TEAE=an adverse event with an onset that occurs after receiving study drug. SAE=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.
Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS	Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 2, 3, 4 or 5 and 6 or 7
Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%	Pre-dose at Days 2, 3 4 or 5, 6 or 7, 8 or 9, and 11 or 12
Time to Relapse	From start of study drug administration up to EOS (up to approximately 15 months)	Relapse was 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. Data was reported for time to relapse in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS).
Percentage of Participants With Relapse	From start of study drug administration up to EOS (up to approximately 15 months)	Relapse was 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. Data was reported for percentage of participants with exacerbation in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS).
Number of Participants With Major Clinical Events Related to PEX	Up to 6 months	Major clinical events included clinically relevant bleeding (modified ITP score) or thrombosis at the site of line insertion, adverse reactions to plasma, including citrate reactions, allergic reactions, and transfusion-related acute lung injury (TRALI). Data is reported by summarizing the data for all parameters.
Number of Participants With Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline	Baseline and EOS (at approximately Month 15)
Number of Participants With Inhibitory Antibodies Relative to Baseline	Baseline and EOS (at approximately Month 15)
Number of Participants With Clinically Relevant Changes in Hematology	From first dose of study drug until the EOS (up to approximately 15 months)	Hematology consisted 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.
Percentage of Participants Receiving Rescue Therapy	From first dose of study drug until the EOS (up to approximately 15 months)	Rescue therapy was 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 was initiated, the administration of IP (SHP655 or placebo) was suspended for the duration of the study. Number of participants experiencing occurrence of receiving rescue therapy was assessed.
Percentage of Participants Meeting Rescue Criteria	From first dose of study drug until the EOS (up to approximately 15 months)	Rescue therapy was defined as any product with a known interruption to the PK/PD relationship between ADAMTS-13 activity, VWF activity, and platelet count. If rescue therapy was initiated, the administration of IP (SHP655 or placebo) was suspended for the duration of the study. Number of participants experiencing occurrence in meeting rescue therapy criteria was assessed. Percentage of participants with rescue therapy initiated are based on laboratory criteria and adverse events.

Trial Locations

Locations (24): University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
London Health Sciences Centre (LHSC) - University Hospital
🇨🇦
London, Ontario, Canada
The Ohio State University Wexner Medical Center
🇺🇸
Columbus, Ohio, United States
Hopital Conception
🇫🇷
Marseille, France
Stephenson Cancer Center
🇺🇸
Oklahoma City, Oklahoma, United States
University Hospitals Cleveland Medical Center
🇺🇸
Cleveland, Ohio, United States
Chu Saint-Antoine
🇫🇷
Paris, France
CHU de Rouen
🇫🇷
Seine Maritime, France
Hospital General Universitario de Alicante
🇪🇸
Alicante, Spain
Hamatologie, Onkologie, Hämostaseologie
🇩🇪
Frankfurt, Germany
St. Michael's Hospital
🇨🇦
Toronto, Ontario, Canada
The University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
CHU de Reims - Hôpital Maison Blanche
🇫🇷
Reims, Marne, France
Hospital Universitario Virgen del Rocio
🇪🇸
Sevilla, Spain
Hospital Dr. Peset
🇪🇸
Valencia, Spain
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
🇮🇹
Milan, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹
Rome, Italy
1st Floor, UCLH-Haematology
🇬🇧
London, United Kingdom
Hospital Universitari i Politècnic la Fe
🇪🇸
Valencia, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Medical University of South Carolina (MUSC)
🇺🇸
Charleston, South Carolina, United States
University Hospital of Wales
🇬🇧
Cardiff, West Glamorgan, United Kingdom
Royal Liverpool University Hospital
🇬🇧
Liverpool, United Kingdom