Evaluation of Mitapivat on Cerebral Perfusion and Oxygen Metabolism in Patients with Sickle Cell Anemia

Trial ID: 2024-513528-41-02
Sponsor: Amsterdam UMC Stichting

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Diseases & Conditions

Sickle cell anaemia

Objectives

The primary objective of this study is to assess the effect of **mitapivat** on cerebral oxygen metabolism, specifically focusing on cerebral blood flow (CBF) in patients with **sickle cell anaemia**. This is clinically relevant as sickle cell anaemia is associated with impaired cerebral perfusion, which can lead to neurological complications. Understanding the impact of mitapivat on cerebral oxygen metabolism could provide insights into potential therapeutic benefits for improving cerebral perfusion in these patients.

Secondary objectives include evaluating the effect of mitapivat on various physiological and biochemical parameters:

Cerebral blood flow (CBF) and cerebrovascular reactivity (CVR).
Cardiac stress biomarkers (NTproBNP) and tricuspid regurgitation flow velocity via echocardiography.
Biomarkers of endothelial and coagulation activation, including VWFag, sVCAM-1, uPAR, F1+2, TAT complexes, and D-dimer.
P-selectin mediated neutrophil-platelet adhesion as a measure of neutrophil adhesiveness.
Ischemic inflammation and neutrophil phenotype, including adhesion, activation, ageing, and oxidative burst capacity.
Metabolomic profile of neutrophils.
Erythrocyte deformability and point of sickling.
Diastolic function, left atrial dilatation, left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and left ventricular end diastolic diameter (LVED) volume.
Neurocognitive function, specifically processing speed, as measured by the Wechsler Adult Intelligence Scale IV (WAIS-IV).

Participants

The clinical trial focuses on individuals diagnosed with **sickle cell anaemia**, specifically those with documented SCD genotype (HbSS, HbSβ0-thalassemia). The study population includes both male and female participants aged 18 and above, with a hemoglobin level of ≤10.5 g/dL. Participants may be on a stable dose of hydroxyurea for at least 90 days prior to the trial. The trial does not involve a vulnerable population. Lifestyle considerations include the requirement for female participants of childbearing potential to use a highly effective method of contraception, with additional barrier methods if using hormonal contraceptives, due to potential interactions with mitapivat. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the effect of **mitapivat** on cerebral perfusion and oxygen metabolism in individuals with **sickle cell anaemia**. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know who is receiving the treatment or placebo, thus minimizing bias. The trial is expected to last approximately 12 months, with participant involvement spanning the same duration. The primary objective is to assess the impact of mitapivat on cerebral oxygen metabolism, specifically cerebral blood flow (CBF), as measured by MRI at 3 and 12 months. Secondary endpoints include measurements of CBF using PCASL, cerebral vasoreactivity (CVR) assessed with acetazolamide, and cerebral metabolic rate of oxygen (CMRO2) using MRI techniques.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented sickle cell disease genotype, age, hemoglobin levels, and stable hydroxyurea dosage if applicable. Following the screening, participants will attend follow-up visits at 3 and 12 months, where primary and secondary endpoints will be evaluated. The end-of-study visit will conclude the trial, ensuring all data is collected and any necessary follow-up care is arranged. Participants are expected to adhere to the study protocol, and any deviation, such as non-compliance with medication or withdrawal of consent, may lead to early termination from the study. The trial aims to provide valuable insights into the secondary effects of mitapivat, contributing to the understanding of its role in managing sickle cell anaemia.

Treatment

The clinical trial involves the administration of **MITAPIVAT**, a chemical compound developed by AGIOS PHARMACEUTICALS. MITAPIVAT is formulated as a **TABLET** and is classified as a pyruvate kinase activator. The active substance, also known by its chemical name N-(4-((4-(cyclopropylmethyl)-1-piperazinyl)carbonyl)phenyl)-8-quinolinesulfonamide, is administered orally. The dosing regimen for MITAPIVAT involves a maximum daily dose of 200 mg, with a total maximum dose of 73,000 mg over a treatment period of up to 12 months. The trial aims to evaluate the effect of MITAPIVAT on cerebral oxygen metabolism in individuals with sickle cell disease.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the available data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve a pediatric formulation, and MITAPIVAT is not classified as an orphan drug for this study. The pharmaceutical form and administration route are consistent with standard practices for oral medications, ensuring ease of use and patient compliance.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the effect of **mitapivat** on cerebral oxygen metabolism in patients with Sickle Cell Disease (SCD). The primary endpoint is the assessment of cerebral blood flow (CBF) as measured by magnetic resonance imaging (MRI) at 3 and 12 months. Secondary endpoints include the measurement of CBF using pseudo-continuous arterial spin labeling (PCASL) at the same timepoints, and the assessment of cerebrovascular reactivity (CVR) through the administration of acetazolamide, a carbonic anhydrase inhibitor, which induces cerebral vasodilation comparable to 5% inhaled CO2.

Additionally, the cerebral metabolic rate of oxygen (CMRO2) will be measured using the MRI technique T2 relaxation under spin tagging (TRUST) at 3 and 12 months. Other secondary endpoints involve the evaluation of tricuspid regurgitant velocity (TRV), left atrial dilatation, left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and left ventricular end-diastolic diameter (LVED) hyperdynamic circulation, all assessed by trans-thoracic echocardiography after 3 and 12 months. These assessments will provide comprehensive data on the efficacy of mitapivat in improving cerebral perfusion and oxygen metabolism in SCD patients.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Documented SCD genotype (HbSS, HbSβ0-thalassemia) which may be based on history of laboratory testing or must be confirmed by laboratory testing during screening
Age 18 and above
Hemoglobin (Hb) ≤10.5 g/dL.
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
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.
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).

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Exclusion Criteria

No informed consent has been given.
Contra-indication for MRI or acetazolamide
Female who is breast feeding or pregnant
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.
Patients with history of overt stroke
Patients receiving with voxelotor or inhibitors of CYP3A4
Patients allergic to mitapivat or sulphonamide-based drugs
Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior participation.
Hepatic dysfunction characterized by alanine aminotransferase (ALT) >2.5 × ULN
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.
Severe renal dysfunction (estimated glomerular filtration rate <30mL/min).
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).
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.
Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
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).
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.
Receipt of erythropoietin or other hematopoietic growth factors within 28 days of signing ICF or anticipated need for such agents during the study.