Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Clinical Trial
— SOAR-HIOfficial 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
| Verified date | November 2022 |
| Source | Takeda |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 28 |
| Est. completion date | August 5, 2021 |
| Est. primary completion date | August 5, 2021 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 75 Years |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| Canada | London Health Sciences Centre (LHSC) - University Hospital | London | Ontario |
| Canada | St. Michael's Hospital | Toronto | Ontario |
| France | Hopital Conception | Marseille | |
| France | Chu Saint-Antoine | Paris | |
| France | CHU de Reims - Hôpital Maison Blanche | Reims | Marne |
| France | CHU de Rouen | Seine Maritime | |
| Germany | Hamatologie, Onkologie, Hämostaseologie | Frankfurt | |
| Italy | Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico | Milan | |
| Italy | Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Rome | |
| Spain | Hospital General Universitario de Alicante | Alicante | |
| Spain | Hospital General Universitario Gregorio Maranon | Madrid | |
| Spain | Hospital Universitario Virgen del Rocio | Sevilla | |
| Spain | Hospital Dr. Peset | Valencia | |
| Spain | Hospital Universitari i Politècnic la Fe | Valencia | |
| United Kingdom | University Hospital of Wales | Cardiff | West Glamorgan |
| United Kingdom | Royal Liverpool University Hospital | Liverpool | |
| United Kingdom | 1st Floor, UCLH-Haematology | London | |
| United States | The University of Alabama at Birmingham | Birmingham | Alabama |
| United States | Brigham and Women's Hospital | Boston | Massachusetts |
| United States | Medical University of South Carolina (MUSC) | Charleston | South Carolina |
| United States | University Hospitals Cleveland Medical Center | Cleveland | Ohio |
| United States | The Ohio State University Wexner Medical Center | Columbus | Ohio |
| United States | University of Minnesota | Minneapolis | Minnesota |
| United States | Stephenson Cancer Center | Oklahoma City | Oklahoma |
| Lead Sponsor | Collaborator |
|---|---|
| Shire | Takeda Development Center Americas, Inc. |
United States, Canada, France, Germany, Italy, Spain, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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). | Up to Days 11 or 12 | |
| Primary | Platelet Count | The platelet counts are reported in units of 10^9 per liter blood. | Baseline and end of study (EOS) (up to approximately 15 months) | |
| Primary | Lactate Dehydrogenase (LDH) Levels | The lactate dehydrogenase levels are reported. | Baseline and EOS (up to approximately 15 months) | |
| Secondary | 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. | From start of study drug administration up to 13 weeks (following remission up to 6 months) | |
| Secondary | PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity | Parameters included platelet and LDH counts. | Up to 6 months | |
| Secondary | 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. | Baseline and EOS (up to approximately 15 months) | |
| Secondary | 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). | Baseline and EOS (up to approximately 15 months) | |
| Secondary | 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). | At Days 3, 7, 10, 21, 28, 42, 56 and 84 | |
| Secondary | Relationship Between ADAMTS-13 Activity and End-organ Disease Status | End-organ disease status were evaluated for renal, cardiac and neurological diseases. | Up to 6 months | |
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | 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) | ||
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | 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. | From the start of study drug administration up to 6 months post remission | |
| Secondary | 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. | From the start of study drug administration up to 6 months post remission | |
| Secondary | 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). | From start of study drug administration up to EOS (up to approximately 15 months) | |
| Secondary | 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). | From start of study drug administration up to EOS (up to approximately 15 months) | |
| Secondary | 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). | From start of study drug administration up to EOS (up to approximately 15 months) | |
| Secondary | 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). | From start of study drug administration up to EOS (up to approximately 15 months) | |
| Secondary | 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. | From start of study drug administration up to EOS (up to approximately 15 months) | |
| Secondary | 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. | Up to 6 months | |
| Secondary | Number of Participants With Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline | Baseline and EOS (at approximately Month 15) | ||
| Secondary | Number of Participants With Inhibitory Antibodies Relative to Baseline | Baseline and EOS (at approximately Month 15) | ||
| Secondary | 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. | Up to 6 months | |
| Secondary | 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. | From first dose of study drug until the EOS (up to approximately 15 months) | |
| Secondary | 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. | From first dose of study drug until the EOS (up to approximately 15 months) | |
| Secondary | 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. | From first dose of study drug until the EOS (up to approximately 15 months) | |
| Secondary | 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. | From first dose of study drug until the EOS (up to approximately 15 months) | |
| Secondary | 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. | From first dose of study drug until the EOS (up to approximately 15 months) | |
| Secondary | 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. | From first dose of study drug until the EOS (up to approximately 15 months) |