Back to results

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

Primary Purpose

Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Placebo

SHP655

Standard of Care

About this trial

This is an interventional treatment trial for Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Arm Label

Standard of Care (SoC) + Placebo

SoC + SHP655 + Placebo

SoC + SHP655

Arm Description

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).

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).

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).

Outcomes

Primary Outcome Measures

ADAMTS-13 Activity Levels

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

The platelet counts are reported in units of 10^9 per liter blood.

Lactate Dehydrogenase (LDH) Levels

The lactate dehydrogenase levels are reported.

Secondary Outcome Measures

Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13

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

Parameters included platelet and LDH counts.

Number of Participants With ADAMTS-13 Binding Antibodies Per Titer

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.

Inhibitory Autoantibodies (Nab) Titer Levels

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).

ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS

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).

Relationship Between ADAMTS-13 Activity and End-organ Disease Status

End-organ disease status were evaluated for renal, cardiac and neurological diseases.

Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio

AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS

Systemic and Antibody Induced Clearance

Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS

Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS

Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%

Number of Participants Who Achieved Remission Following Normalization of Platelet Count

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 Achieving 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.

Time to First Exacerbation

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).

Time to Relapse

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 Exacerbation

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).

Percentage of Participants With Relapse

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).

Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)

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 Major Clinical Events Related to PEX

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

Number of Participants With Inhibitory Antibodies Relative to Baseline

Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655

Percentages are based on the total number of participants per treatment group that have at least one ADA sample analyzed.

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs

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.

Number of Participants With Clinically Relevant Changes in Vital Signs

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

Clinical chemistry 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

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

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

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.

Full Information

NCT ID

NCT03922308

First Posted

April 5, 2019

Last Updated

November 11, 2022

Sponsor

Shire

Collaborators

Takeda Development Center Americas, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03922308

Brief Title

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

Acronym

SOAR-HI

Official Title

A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-blind Study in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) to Evaluate the Pharmacokinetics, Safety and Efficacy of rADAMTS-13 (SHP655) Administered in Addition to Standard Of Care (SoC) Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

October 9, 2019 (Actual)

Primary Completion Date

August 5, 2021 (Actual)

Study Completion Date

August 5, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Shire

Collaborators

Takeda Development Center Americas, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard of Care (SoC) + Placebo

Arm Type

Placebo Comparator

Arm Description

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).

Arm Title

SoC + SHP655 + Placebo

Arm Type

Experimental

Arm Description

Arm Title

SoC + SHP655

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Participants will receive injection of placebo matched to SHP655.

Intervention Type

Drug

Intervention Name(s)

SHP655

Other Intervention Name(s)

rADAMTS-13

Intervention Description

Participants will receive injection of SHP655.

Intervention Type

Other

Intervention Name(s)

Standard of Care

Other Intervention Name(s)

PEX

Intervention Description

Participants will receive PEX as Standard of Care (SOC).

Primary Outcome Measure Information:

Title

ADAMTS-13 Activity Levels

Description

Time Frame

Up to Days 11 or 12

Title

Platelet Count

Description

The platelet counts are reported in units of 10^9 per liter blood.

Time Frame

Baseline and end of study (EOS) (up to approximately 15 months)

Title

Lactate Dehydrogenase (LDH) Levels

Description

The lactate dehydrogenase levels are reported.

Time Frame

Baseline and EOS (up to approximately 15 months)

Secondary Outcome Measure Information:

Title

Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13

Description

Time Frame

From start of study drug administration up to 13 weeks (following remission up to 6 months)

Title

PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity

Description

Parameters included platelet and LDH counts.

Time Frame

Up to 6 months

Title

Number of Participants With ADAMTS-13 Binding Antibodies Per Titer

Description

Time Frame

Baseline and EOS (up to approximately 15 months)

Title

Inhibitory Autoantibodies (Nab) Titer Levels

Description

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).

Time Frame

Baseline and EOS (up to approximately 15 months)

Title

ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS

Description

Time Frame

At Days 3, 7, 10, 21, 28, 42, 56 and 84

Title

Relationship Between ADAMTS-13 Activity and End-organ Disease Status

Description

End-organ disease status were evaluated for renal, cardiac and neurological diseases.

Time Frame

Up to 6 months

Title

Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio

Time Frame

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

Title

AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS

Time Frame

Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 1, 2, 3, 4 or 5 and 6 or 7

Title

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)

Title

Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS

Time Frame

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

Title

Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS

Time Frame

Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 2, 3, 4 or 5 and 6 or 7

Title

Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%

Time Frame

Pre-dose at Days 2, 3 4 or 5, 6 or 7, 8 or 9, and 11 or 12

Title

Number of Participants Who Achieved Remission Following Normalization of Platelet Count

Description

Time Frame

From the start of study drug administration up to 6 months post remission

Title

Percentage of Participants Achieving Remission

Description

Time Frame

From the start of study drug administration up to 6 months post remission

Title

Time to First Exacerbation

Description

Time Frame

From start of study drug administration up to EOS (up to approximately 15 months)

Title

Time to Relapse

Description

Time Frame

From start of study drug administration up to EOS (up to approximately 15 months)

Title

Percentage of Participants With Exacerbation

Description

Time Frame

From start of study drug administration up to EOS (up to approximately 15 months)

Title

Percentage of Participants With Relapse

Description

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).

Time Frame

From start of study drug administration up to EOS (up to approximately 15 months)

Title

Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)

Description

Time Frame

From start of study drug administration up to EOS (up to approximately 15 months)

Title

Number of Participants With Major Clinical Events Related to PEX

Description

Time Frame

Up to 6 months

Title

Number of Participants With Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline

Time Frame

Baseline and EOS (at approximately Month 15)

Title

Number of Participants With Inhibitory Antibodies Relative to Baseline

Time Frame

Baseline and EOS (at approximately Month 15)

Title

Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655

Description

Percentages are based on the total number of participants per treatment group that have at least one ADA sample analyzed.

Time Frame

Up to 6 months

Title

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs

Description

Time Frame