Study to evaluate Pegcetacoplan in patients with TA-TMA after hematopoietic stem cell transplantation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Swedish Orphan Biovitrum AB (publ)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

26 Jan 2022 → 9 Dec 2024

Decision date (initial)

2024-05-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-510443-37-00

EudraCT number

2021-003157-27

ClinicalTrials.gov

NCT05148299

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

To evaluate the pharmacokinetics (PK), safety and tolerability of pegcetacoplan in patients with TA-TMA.

Secondary objectives 2

1. To evaluate the PD of pegcetacoplan in patients with TA-TMA.
2. To evaluate the efficacy of pegcetacoplan in patients with TA-TMA

Conditions and MedDRA coding

Transplant-associated Thrombotic Microangiopathy (TA TMA)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male and female patients aged ≥ 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 as per the laboratory markers below, indicating TMA: a. De novo or progressing thrombocytopenia (platelet count < 50 x 109 /L or > 50 % decrease in platelet count from the highest value achieved after transplantation). AND b. Elevated LDH (> 1.5 x ULN). AND at least 2 additional laboratory/clinical criteria among the following: c. Presence of schistocytes on the peripheral blood smear (≥ 2 per hpf) or histologic evidence of microangiopathy in any biopsied organ. OR d. De novo anemia (hemoglobin < LLN or anemia requiring PRBC transfusion support as per local institutional standard). OR e. Proteinuria (random urinalysis protein concentration ≥ 30 mg/dL). OR f. Elevated plasma concentration of sC5b-9 above ULN. OR g. Arterial hypertension, defined by systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg.
4. Have a diagnosis of TA-TMA that persists despite initial management of any triggering condition.
5. Have rUPCR ≥ 1 mg/mg
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.

Exclusion criteria 17

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 < 30 kg and > 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 (≤ 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine) according to local country guidelines
15. Known or suspected hereditary fructose intolerance.
16. Hypersensitivity to pegcetacoplan or any of its excipients.
17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pegcetacoplan PK parameters: AUC0-tau, Cmax, Tmax and Ctrough.

Secondary endpoints 12

1. 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.
2. Clinical response at Week 24, defined as improvement in laboratory markers and in clinical status (renal, pulmonary, GI, Neurological responses, freedom from transfusion, cardiovascular and serositis responses). Patients meeting intercurrent events, including use of prohibited medication or study withdrawal before Week 24, will be considered as failures/nonresponders.
3. TMA response at Week 24, defined as improvement in laboratory markers as follows: o LDH < 1.5 x ULN and o Platelet count ≥ 50 000/mm3 without transfusion support during the prior 7 days and o ≥ 50 % reduction from baseline in rUPCR.
4. Overall survival at Day 100 from date of TA-TMA diagnosis.
5. Overall survival at Week 24 from treatment start.
6. Time to clinical response.
7. Time to TMA response.
8. Duration of clinical response.
9. Duration of TMA response
10. TA-TMA relapse at Week 24.
11. Clinical response at Week 12.
12. TMA response at Week 12.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Swedish Orphan Biovitrum AB (publ)

Sponsor organisation

Swedish Orphan Biovitrum AB (publ)

Address

-

City

Stockholm

Postcode

112 76

Country

Sweden

Scientific contact point

Organisation

Swedish Orphan Biovitrum AB (publ)

Contact name

Contact Point

Public contact point

Organisation

Swedish Orphan Biovitrum AB (publ)

Contact name

Contact Point

Third parties 12

Locations

4 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications