Safety and Efficacy of Iptacopan in Patients With High-Risk Transplantation-Associated Thrombotic Microangiopathy

Official title

A Prospective, Multicenter, Single-Arm Study: Safety and Efficacy of Iptacopan in the Treatment of High-Risk Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy (TA-TMA)

Overview

The goal of this clinical trial is to evaluate the efficacy and safety of Iptacopan as a second-line treatment for high-risk hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA). Iptacopan is a selective oral small-molecule complement factor B inhibitor. It acts by inhibiting factor B, blocking the formation of C3 convertase, reducing C3b deposition, thereby suppressing C5 convertase (C3bBbC3b) and ultimately decreasing the formation of the membrane attack complex (MAC), which is expected to mitigate endothelial damage in TA-TMA pathology. The main questions this study aims to answer are: * Does Iptacopan improve 6-month overall survival in high-risk TA-TMA patients? * What adverse events do participants experience while taking Iptacopan? * Does Iptacopan provide hematological response and organ function recovery in TA-TMA patients? In this prospective, multicenter, open-label, single-arm Phase II study, all participants will receive Iptacopan treatment. The primary endpoint of this study is the 6-month overall survival rate from TA-TMA diagnosis. Secondary endpoints include safety evaluation, hematological response, and organ function recovery. During the study, participants will: * Receive Iptacopan treatment according to protocol * Undergo regular assessments for safety and efficacy monitoring * Be followed for up to 24 months post-treatment initiation

Interventions

• Drug iptacopan
  Iptacopan will be administered under the supervision of hospital staff during inpatient stays or self-managed by patients in an outpatient setting. The induction phase lasts 4 weeks at a dosage of 200 mg twice daily (BID). Starting from Day 29, patients will enter the maintenance phase at a dosage of 200 mg once daily (QD), continuing until treatment completion at Week 12.

Primary outcome measures

• Six-month Overall Survival Rate Following TA-TMA Diagnosis [Time frame: From the date of TA-TMA diagnosis until 6 months post-diagnosis.]

Secondary outcome measures (11)

• TA-TMA Complete Response Rate by Week 12 (Jodele Criteria) [Time frame: 12 weeks from start of treatment.]
• TA-TMA Partial Response Rate by Week 12 (Jodele Criteria) [Time frame: 12 weeks from start of treatment.]
• Overall Survival (OS) [Time frame: Up to 24 months from diagnosis.]
• Non-Relapse Mortality (NRM) [Time frame: Up to 24 months from diagnosis.]
• Cumulative Incidence of Relapse (CIR) [Time frame: Up to 24 months from diagnosis.]
• Mean Hemoglobin Change from Baseline [Time frame: Baseline to 12 weeks.]
• Exploratory Biomarker Analysis [Time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks after treatment .]
• Failure-Free Survival (FFS) [Time frame: Up to 12 weeks from treatment initiation.]
• Incidence of Acute and Chronic GVHD [Time frame: Up to 24 months from treatment initiation.]
• Multiple Organ Dysfunction Syndrome (MODS) Involvement and Resolution [Time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after treatment; thereafter, every three months until study completion]
• Safety and Tolerability Assessment [Time frame: From treatment initiation to 30 days after last dose.]

Eligibility criteria

Inclusion criteria

• Age ≥12 years at the time of ICF signature.
• Previous recipient of autologous or allogeneic HSCT.
• Persistent TA-TMA despite initial management of potential triggers (e.g., CNI/mTOR inhibitor reduction, infection or GVHD treatment), with TMA activity sustained for ≥72 hours post-intervention.
• TA-TMA diagnosis, confirmed ≤14 days prior to or during screening by either biopsy-proven microthrombi or ≥4 of the following:

(1) LDH > ULN (2) Proteinuria (rUPCR ≥1 mg/mg) (3) Hypertension (age-adjusted) (4) New-onset thrombocytopenia (platelet decrease ≥50%, count ≤50,000/mm³, or transfusion-refractory) (5) New-onset anemia or increased transfusion need (6) Microangiopathy on blood smear (schistocytes ≥1%) or biopsy (7) Elevated terminal complement complex (C5b-9) 5. High-risk TMA features (per 2023 consensus), meeting ≥1 criterion:

• LDH ≥2× ULN
• Elevated sC5b-9
• Proteinuria (rUPCR ≥1 mg/mg)
• Multi-organ dysfunction syndrome (MODS)
• Concurrent Grade II-IV acute GVHD
• Active systemic infection 6. Able to receive oral medication. 7. Failure of first-line therapy (e.g., CNI/mTOR inhibitor adjustment, plasma exchange, rituximab, defibrotide), excluding prior complement inhibitors.

8\. Life expectancy >8 weeks. 9. Required vaccination against encapsulated bacteria (meningococcal, pneumococcal) per local guidelines, administered ≥2 weeks prior to first dose. If vaccination is delayed, antimicrobial prophylaxis is required.

10\. For subjects unable to receive meningococcal vaccines, antibiotic prophylaxis must be continued throughout treatment and for 8 months post-last dose.

11\. For subjects of reproductive potential: agreement to use effective contraception and, for females, a negative pregnancy test at screening.

12\. Provision of signed informed consent and compliance with study procedures.

Exclusion criteria

• Known familial or acquired ADAMTS13 deficiency (activity <5%).
• Known Shiga toxin-associated HUS (positive Shiga toxin assay or culture).
• Positive direct Coombs test with clinically significant immune-mediated hemolysis per investigator.
• Clinically overt disseminated intravascular coagulation (DIC) according to ISTH criteria.
• Bone marrow/graft failure.
• Known HIV infection (confirmed by testing within 6 months prior to screening).
• Active meningococcal disease.
• Septic shock requiring vasopressor support within 7 days prior to enrollment.
• Pregnant or breastfeeding.
• Any concurrent or prior medical condition unrelated to TA-TMA that, in the opinion of the investigator or sponsor, could increase risk or confound study outcomes (e.g., significant cardiac, pulmonary, renal, endocrine, or hepatic disease).
• All-cause respiratory failure requiring mechanical ventilation within 72 hours prior to enrollment.
• Acute/chronic heart failure with left ventricular ejection fraction ≤40%.
• Prior treatment with iptacopan, eculizumab, or other complement inhibitors within 60 days before first study dose.
• Use of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to screening.
• Recurrent primary malignancy or post-transplant lymphoproliferative disorder (PTLD).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital of Zhejiang University School of Medicine — Hangzhou

Publications

• Risitano AM, Kulasekararaj AG, Scheinberg P, Roth A, Han B, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Lee LWL, Yap ES, Frieri C, Marano L, de Fo PMID 40447351
• Peffault de Latour R, Roth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de PMID 38477987
• Ardissino G, Capone V, Tedeschi S, Porcaro L, Cugno M. Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy. Pharmaceuticals (Basel). 2022 Jul 9;15(7):845. doi: 10.3390/ph15070845. PMID 35890144
• Sartain S, Shubert S, Wu MF, Wang T, Martinez C. The alternative complement pathway activation product Ba as a marker for transplant-associated thrombotic microangiopathy. Pediatr Blood Cancer. 2020 Mar;67(3):e28070. doi: 10.1002/pbc.28070. Epub 2019 Nov 27. PMID 31774252
• Okamura H, Nakamae H, Shindo T, Ohtani K, Hidaka Y, Ohtsuka Y, Makuuchi Y, Kuno M, Takakuwa T, Harada N, Nishimoto M, Nakashima Y, Koh H, Hirose A, Nakamae M, Wakamiya N, Hino M, Inoue N. Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy. Front Immunol. 2021 Jul 13;12:695037. doi: 10.3389/fimmu.2021.695037. eCollection 2021. PMID 34326846
• Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA, Davies SM, Pluthero FG, Lu L, Laskin BL. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood. 2013 Sep 19;122(12):2003-7. doi: 10.1182/blood-2013-05-501445. Epub 2013 Jun 27. PMID 23814021
• Rotz SJ, Luebbering N, Dixon BP, Gavriilaki E, Brodsky RA, Dandoy CE, Jodele S, Davies SM. In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy. Blood Adv. 2017 Aug 23;1(20):1632-1634. doi: 10.1182/bloodadvances.2017008250. eCollection 2017 Sep 12. PMID 29296809
• Han W, Han Y, Chen J, Ma X, Chen F, Wu XJ, Qi JQ, Qiu HY, Sun AN, Wu DP. [Allogeneic hematopoietic stem cell transplantation associated thrombotic microangiopathy: 16 cases report and literature review]. Zhonghua Xue Ye Xue Za Zhi. 2016 Aug 14;37(8):666-70. doi: 10.3760/cma.j.issn.0253-2727.2016.08.007. Chinese. PMID 27587247

Identifiers

NCT: NCT07347990 · IPTA-TMA-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗