Transplant-Associated Thrombotic Microangiopathy (TA-TMA) MedDRA version: 20.0 Level: PT Classification code 10043645 Term: Thrombotic microangiopathy System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Product Name: Pegcetacoplan
Product Code: [APL-2]
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: pegcetacoplan
CAS Number: 2019171-69-6
Current Sponsor code: APL-2
Concentra
Sponsors
SWEDISH ORPHAN BIOVITRUM AB (PUBL)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female patients aged = or older than 18 years at the time of informed consent form (ICF) signature. 2. Received allogeneic HSCT from a related or unrelated, human leukocyte antigen-matched or mismatched donor. Patients having received any of the following stem cell sources are eligible: granulocyte colony stimulating factor mobilized peripheral blood stem cells, bone marrow, umbilical cord blood. 3. Diagnosis of TA-TMA established by histologic evidence of microangiopathy in any biopsied organ OR, as per the laboratory markers below, indicating TMA: a. De novo or progressing thrombocytopenia (platelet count 50 % decrease in platelet count from the highest value achieved after transplantation). AND b. Elevated LDH (> 1.5 x ULN). AND at least 1 additional laboratory criteria among the following: c. Schistocytes on the peripheral blood smear (= or higher than 2 per hpf). OR d. De novo anemia (hemoglobin 2 medications (excluding diuretics). d. Serositis: clinically significant pleural effusion or pericardial effusion requiring surgical therapy (e.g., pericardiocentesis/ thoracocentesis). e. CNS: seizures attributable to posterior reversible encephalopathy syndrome. f. GI tract: presence of biopsy-proven GI TA-TMA. Patients with GI bleeding (hematemesis or hematochezia) will be excluded. 6. Women of childbearing potential, defined as any women who have experienced menarche and who are NOT permanently sterile or postmenopausal, must have a negative serum pregnancy test at screening and agree to use protocol-defined methods of contraception for the duration of the study and 8 weeks after their last IMP dose. Note: Postmenopausal is defined as having had 12 consecutive months with no menses without an alternative medical cause. 7. Men must agree to the following for the duration of the study and 8 weeks after their last dose of IMP: a. Avoid fathering a child. b. Use protocol-defined methods of contraception. c. Refrain from donating sperm. 8. Patient and/or legally authorized representative must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 7 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2
Exclusion criteria
Exclusion criteria: 1. Positive direct Coombs test. 2. Known familial or acquired ADAMTS13 deficiency. 3. Known Shiga toxin-related hemolytic uremic syndrome. 4. Known bone marrow or graft failure. 5. Diagnosis of disseminated intravascular coagulation. 6. Diagnosis of veno-occlusive disease (VOD). 7. Active GI bleeding (hematemesis or hematochezia) at baseline. 8. Body weight 100 kg. 9. Uncontrolled systemic bacterial or fungal infection, presence or suspicion of sepsis. 10. Previously or currently treated with a complement inhibitor (approved or investigational). 11. Pregnancy or breastfeeding. 12. Positive human immunodeficiency virus antibody at screening or documented in pre-HSCT medical record. 13. Hepatitis C virus detectable by polymerase chain reaction at screening or documented in pre-HSCT medical record. 14. Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (>5000 copies/mL) at screening or documented in pre-HSCT medical record. Eligible patients who are chronic active carriers (= ot lower than 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine) according to local country guidelines. 15. Inability to cooperate with study procedures or any condition that, in the opinion of the investigator, could increase the patient's risk by participating in the study or confound the outcome of the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the pharmacokinetics (PK), safety and tolerability of pegcetacoplan in patients with TA-TMA.;Secondary Objective: • To evaluate the pharmacodynamics (PD) of pegcetacoplan in patients with TA-TMA. • To evaluate the clinical response of pegcetacoplan in patients with TA TMA. • To evaluate the overall survival with pegcetacoplan in patients with TA TMA.;Primary end point(s): • Pegcetacoplan PK parameters: o AUC0-tau, Cmax, Tmax and Ctrough.;Timepoint(s) of evaluation of this end point: Days 1, 3 and 5, from Week 2 onwards, at all other visits | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PD endpoints: o Absolute levels, change from baseline, and % change from baseline to Week 24 in biomarkers of complement activation: sC5b-9, C3a, C3, Bb, C4a, functional assays for classical and alternative complement pathways. • Clinical response at Week 24 from treatment start, defined as improvement in laboratory markers and improvement in clinical status as follows: Laboratory markers: o Lactate dehydrogenase (LDH) less than 1.5 x upper limit of normal (ULN) and o Platelet count = or above 50 000/ mm3 without transfusion support during the prior 7 days. Clinical status: at least 1 of the following (without deterioration in other organs attributable to TA-TMA): o Renal response – requires > 40 % reduction in creatinine, or normalization of creatinine, or discontinuation of renal replacement therapy, or reduction of proteinuria < 30 mg/dL or random urine protein/creatinine ratio (rUPCR) < 2 mg/mg. o Pulmonary response – requires extubation and discontinuation of positive pressure ventilation. o Gastrointestinal (GI) response – applicable only to patients with biopsy proven GI TA-TMA and requires improvement in GI function as determined by the Mount Sinai Acute Graft-versus-host disease International Consortium (MAGIC) criteria (no or intermittent nausea, vomiting or anorexia attributed to TA-TMA for upper GI; stool output/day for lower GI as follows: < 500 mL/day or < 3 episodes/day. o Neurological response – requires improvement in reversible neurological conditions (e.g., cessation of seizures or controlled under medication, resolution of mental alteration; residual radiologic signs are acceptable without clinical symptomatology), or stabilization of irreversible. neurological conditions (e.g., stability of neurological deficits following stroke without further deterioration or subsequent strokes). o Freedom from transfusion – requires absence of platelet or packed red blood cells (PRBC) transfusions attributed to TA TMA during the prior | — |
Countries
France, Greece, Italy, Spain, United States
Contacts
Public ContactRegulatory Affairs
Swedish Orphan Biovitrum AB
Outcome results
None listed