E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
acquired thrombotic thrombocytopenic purpura (aTTP) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043648 |
E.1.2 | Term | Thrombotic thrombocytopenic purpura |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Co-Primary:
1. Assess the PK of ADAMTS-13 in aTTP subjects treated for an acute episode by daily plasma exchange (PEX), immunosuppressant therapy, with or without SHP655 supplementation
2. Study the PK/PD relationship between ADAMTS-13 activity levels and pathophysiological biomarkers, as well as clinical efficacy parameters |
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E.2.2 | Secondary objectives of the trial |
PK/PD Objectives
1. Evaluate changes in levels of ADAMTS-13 binding and inhibitory autoantibodies from baseline in response to daily PEX, with or without SHP655 supplementation, during the acute episode and up to 30 days after the resolution of the acute aTTP episode
2. Evaluate ADAMTS-13 activity levels in subjects up to 30 days after acute aTTP episode remission
3. Specify dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of rADAMTS-13
Safety/Efficacy Objectives
1. Assess the safety and immunogenicity of two regimens of SHP655 supplementation administered during an acute TTP episode in subjects undergoing PEX treatment and immunosuppressant therapy
2. Evaluate the occurrences of aTTP related complications, aTTP relapses, exacerbations and end-organ function improvement
3. Evaluate the time to aTTP related complications, aTTP relapses, exacerbations and end-organ function improvement
4. Evaluate the occurrence of procedure related adverse events |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject or legally authorized representative voluntarily signs informed consent. For subjects unable to provide consent, a fully recognized medical proxy may be used according to local laws.
2. Subject is 18 to 75 years old at the time of screening.
3. Subject has been diagnosed with primary or secondary autoimmune aTTP based on the following criteria:
a. Thrombocytopenia [drop in platelet count ≥50% or platelet count < 100,000/μL];
No more than 3 subjects 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].
4. Willingness to fully comply with study procedures and requirements, and intention to initiate plasma exchange (PEX). Subjects 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 cTTP.
5. If female of childbearing potential, subject 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. |
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E.4 | Principal exclusion criteria |
1. Subject has been diagnosed with congenital TTP.
2. Subject 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
3. Subject 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).
4. Subject 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.
5. Subject has received caplacizumab within 1 months of study enrollment.
6. Subject is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+ count ≤200 cells/mm3 within 3 months screening.
7. Subjects with conditions of severe immunodeficiency.
8. Subject has had a previous aTTP event in the past 30 days.
9. Subject has another underlying progressive fatal disease and/or life expectancy of less than 3 months.
10. Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.
11. Subject 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.
12. If female, subject is pregnant or lactating.
13. Subject is a family member or employee of the Sponsor or investigator.
14. Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing information.
15. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent
molecule ADAMTS-13, hamster protein, or other constituents of SHP655. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. ADAMTS-13 activity levels
2. Platelet count and LDH levels |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Various time points throughout the study |
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E.5.2 | Secondary end point(s) |
PK/PD Endpoints
1. The PK/PD temporal relationship of efficacy parameters (e.g., platelet count, LDH levels), as a function of ADAMTS-13 activity
2. The 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
3. ADAMTS-13 activity levels in subjects receiving additional SHP655 for up to 30 days after the resolution of the TTP episode
4. The relationship between ADAMTS-13 activity and end-organ disease status (e.g., renal, neurologic, and cardiac)
5. PK parameters such as incremental recovery, area under the curve, systemic and antibody induced clearance, maximum ADAMTS-13 activity between PEX or SHP 655 infusions, and trough levels prior PEX
6. Occurrence of ADAMTS-13 activity trough levels >10%
Safety/Efficacy endpoints
1. Time to normalization of platelet count, defined as platelet count ≥ 150,000/μL, which must be confirmed by a second normal platelet count ≥ 150,000/μL and LDH <2 ULN 48 hours following initial normalization
2. Occurrence of remission, defined as a normal platelet count and LDH <2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period)
3. Time to first exacerbation (aTTP episode ≤30 days following remission)
4. Time to relapse (aTTP episode >30 days following remission)
5. Occurrence of exacerbation
6. Occurrence of relapse
7. Occurrence of major clinical events related to TTP including: a. Death, b. Stroke, c. MI
d. Organ dysfunction not normalized within the 90-day observation period; i. Chronic renal insufficiency, ii. Neurologic impairment, iii. Neurocognitive deficits.
8. Incidence of major clinical events related to PEX, including clinically relevant bleeding (modified ITP score) or thrombosis at the site of line insertion, adverse reactions to plasma, including citrate reactions, allergic reactions, and TRALI
9. Changes in the titer of binding and inhibitory antibodies to ADAMTS-13
10. Occurrence of antibodies to SHP655
11. Incidence of AEs and SAEs, and specifically product-related AEs and SAEs
12. Clinically relevant changes in vital signs, clinical chemistry, and hematology |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various time points throughout the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Germany |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |