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

NCT07347990 | Not Yet Recruiting

• 1 other identifier: IPTA-TMA-001
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Thrombotic Microangiopathy; Hematopoietic Stem Cell Transplantation (HSCT)

Keywords

hematopoietic stem cell transplantation; transplantation-associated thrombotic microangiopathy; Iptacopan

Outcome Measures

Primary Outcomes (1)

• Six-month Overall Survival Rate Following TA-TMA Diagnosis

  The primary endpoint is defined as the proportion of patients who remain alive at 6 months after the initial diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA). Survival status will be systematically assessed through follow-up visits, medical record review, or direct patient contact at the 6-month timepoint.

  From the date of TA-TMA diagnosis until 6 months post-diagnosis.

Secondary Outcomes (11)

• TA-TMA Complete Response Rate by Week 12 (Jodele Criteria)

  12 weeks from start of treatment.

• TA-TMA Partial Response Rate by Week 12 (Jodele Criteria)

  12 weeks from start of treatment.

• Overall Survival (OS)

  Up to 24 months from diagnosis.

• Non-Relapse Mortality (NRM)

  Up to 24 months from diagnosis.

• Cumulative Incidence of Relapse (CIR)

  Up to 24 months from diagnosis.

Study Arms (1)

Iptacopan group

EXPERIMENTAL

This experimental arm includes patients diagnosed with transplantation-associated thrombotic microangiopathy (TA-TMA) who have failed first-line therapy; all participants will receive Iptacopan as second-line treatment.

Drug: iptacopan

Interventions

iptacopan DRUG

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.

Iptacopan group

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• \. 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.
• \. For subjects unable to receive meningococcal vaccines, antibiotic prophylaxis must be continued throughout treatment and for 8 months post-last dose.
• \. For subjects of reproductive potential: agreement to use effective contraception and, for females, a negative pregnancy test at screening.
• \. Provision of signed informed consent and compliance with study procedures.

You may not qualify if:

• 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).

Sponsors & Collaborators

• First Affiliated Hospital of Zhejiang University: lead
• Ruijin Hospital: collaborator
• The First Affiliated Hospital of Zhengzhou University: collaborator
• Tongji Hospital: collaborator
• The Children's Hospital of Zhejiang University School of Medicine: collaborator
• First Affiliated Hospital of Ningbo University: collaborator
• Nanfang Hospital, Southern Medical University: collaborator
• Peking University People's Hospital: collaborator
• Fujian Medical University Union Hospital: collaborator
• Hebei Yanda Ludaopei Hospital: collaborator
• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology: collaborator

Study Sites (1)

The First Affiliated Hospital of Zhejiang University School of Medicine

Hangzhou, China, 310003, China

Location

Related Publications (10)

• 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 Fontbrune FS, Gandhi S, Trikha R, Alashkar F, Yang C, Liu H, Kelly RJ, Hochsmann B, Lawniczek T, Mahajan N, Solar-Yohay S, Kerloeguen C, Ferber P, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, de Latour RP. Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors. Lancet Haematol. 2025 Jun;12(6):e414-e430. doi: 10.1016/S2352-3026(25)00081-X.

  PMID: 40447351 BACKGROUND

• 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 Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Hochsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. doi: 10.1056/NEJMoa2308695.

  PMID: 38477987 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014 Jul 24;124(4):645-53. doi: 10.1182/blood-2014-03-564997. Epub 2014 May 29.

  PMID: 24876561 BACKGROUND

• Jodele S, Dandoy CE, Lane A, Laskin BL, Teusink-Cross A, Myers KC, Wallace G, Nelson A, Bleesing J, Chima RS, Hirsch R, Ryan TD, Benoit S, Mizuno K, Warren M, Davies SM. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020 Mar 26;135(13):1049-1057. doi: 10.1182/blood.2019004218.

  PMID: 31932840 BACKGROUND

MeSH Terms

Conditions

Thrombotic Microangiopathies

Interventions

iptacopan

Condition Hierarchy (Ancestors)

Thrombocytopenia; Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Central Study Contacts

Fei Gao, Attending, MD

CONTACT

+86 19857035073; gf0906@zju.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice Director, Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University

Study Record Dates

• First Submitted: December 27, 2025
• First Posted: January 16, 2026
• Study Start: January 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2029
• Last Updated: January 16, 2026

Record last verified: 2026-01

Locations

CN (1)