The Effect of Mitapivat on Cerebral Perfusion and Oxygen Metabolism in Sickle Cell Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amsterdam UMC Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Decision date (initial)

2025-06-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Amsterdam UMC, University of Amsterdam

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To assess the effect of mitapivat on the cerebral oxygen metabolism (CBF)

Secondary objectives 9

1. To determine the effect of mitapivat on cerebral blood flow (CBF) and cerebrovascular reactivity (CVR)
2. To determine the effect of mitapivat on cardiac stress biomarker (NTproBNP) and tricuspid regurgitation flow velocity determined by echocardiography
3. To determine the effect of mitapivat on biomarkers of endothelial and coagulation activation (VWFag, sVCAM-1, uPAR,F1+2, TAT complexes, and D-dimer).
4. To determine the effect of mitapivat on P-selectin mediated neutrophil-platelet adhesion as measure of neutrophil adhesiveness
5. To determine the effect of mitapivat on ischemic inflammation (inflammatory protein panel) and neutrophil phenotype (adhesion, activation, ageing and oxidative burst capacity).
6. To determine the effect of mitapivat on the metabolomic profile of neutrophils
7. To determine the effect of mitapivat on erythrocyte deformability and point of sickling
8. Effect of mitapivat on diastolic function, left atrial dilatation, LVEF + global longitudinal strain (GLS )and left ventricular end diastolic diameter (LVED) volume
9. To determine the effect of mitapivat on neurocognitive function (processing speed) as measured by the Wechsler Adult Intelligence scale IV (WAIS-IV)

Conditions and MedDRA coding

Sickle cell anaemia

Regulatory references

Plan to share IPD

No

IPD plan description

Data will not be shared

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Documented SCD genotype (HbSS, HbSβ0-thalassemia) which may be based on history of laboratory testing or must be confirmed by laboratory testing during screening
2. Age 18 and above
3. Hemoglobin (Hb) ≤10.5 g/dL.
4. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 90 days prior to participation and with no anticipated need for dose adjustments
5. Female participants of childbearing potential should agree to be abstinent as part of their usual lifestyle or use a highly effective method of contraception. Furthermore, due to the potential for mitapivat to reduce the effectiveness of hormonal contraceptives, women using hormonal contraception must also use an acceptable barrier method while enrolled in the study and for at least 28 days after their last dose. Women using non-hormonal methods of contraception as a highly effective method do not need to use an additional barrier method.
6. Participant has provided documented informed consent or assent (the informed consent form [ICF] must be reviewed and signed by each participant; the participant’s legal representative or legal guardian, and the participant’s assent must be obtained).

Exclusion criteria 17

1. No informed consent has been given.
2. Contra-indication for MRI or acetazolamide
3. Female who is breast feeding or pregnant
4. Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 90 days before participation.
5. Patients with history of overt stroke
6. Patients receiving with voxelotor or inhibitors of CYP3A4
7. Patients allergic to mitapivat or sulphonamide-based drugs
8. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior participation.
9. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >2.5 × ULN
10. Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy: • Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. • Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive.
11. Severe renal dysfunction (estimated glomerular filtration rate <30mL/min).
12. History of malignancy within the past 2 years prior to participation requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy).
13. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent, including but not limited to the following: • Unstable angina pectoris or myocardial infarction or elective coronary intervention. • Congestive heart failure requiring hospitalization. • Uncontrolled clinically significant arrhythmias.
14. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
15. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device).
16. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent.
17. Receipt of erythropoietin or other hematopoietic growth factors within 28 days of signing ICF or anticipated need for such agents during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess the effect of mitapivat on the cerebral oxygen metabolism (CBF) as measured per MRI at 3 and 12 months

Secondary endpoints 4

1. CBF will be measured by PCASL in SCD at 3 and 12 months
2. CVR will be assessed by the administration of acetazolamide which is a carbonic anhydrase inhibitor that produces a powerful cerebral vasodilatory effect comparable to 5% inhaled CO2 at 3 and 12 months
3. Cerebral metabolic rate of oxygen (CMRO2) is measured by MRI technique by T2 relaxation under spin tagging (TRUST) at 3 and 12 months
4. TRV, left atrial dilatation and LVEF + global longitudinal strain (GLS) and left ventricular end diastolic diamterer (LVED) hyperdynamic circulation as assed by trans-thoracic echocardiography after 3 and 12 months

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amsterdam UMC Stichting

Sponsor organisation

Amsterdam UMC Stichting

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Amsterdam UMC Stichting

Contact name

S. R. Thakoerdin

Public contact point

Organisation

Amsterdam UMC Stichting

Contact name

S. R. Thakoerdin

Sponsor responsibilities

Article 77 compliance

Amsterdam UMC Stichting

Contact point sponsor

Amsterdam UMC Stichting

Article 77 implementation

Amsterdam UMC Stichting

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

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

Documents 6 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