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Phase 3 study of mitapivat for effectiveness and safety in children with non‑transfusion‑dependent alpha or beta thalassemia

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What is this trial about?

A plain-language summary of the goals, design and what participants do

A rare blood disorder called Non-Transfusion-Dependent Alpha- or Beta-Thalassemia causes the body to produce abnormal hemoglobin, leading to low red‑blood‑cell levels (anemia) that usually does not require regular blood transfusions. Symptoms may include fatigue, shortness of breath, and slower growth in children.

The study’s purpose is to compare the effect of an oral medicine, mitapivat, with a dummy pill (placebo) on raising hemoglobin levels and to assess its safety in children with this condition.

Children who join will take either the study medicine or the dummy pill once a day for about six months. They will visit the clinic several times, starting with an initial screening, followed by check‑ups at a few weeks and then regularly through week 24. During these visits, blood samples will be taken to measure hemoglobin, iron levels, and other markers, and growth measurements such as height and weight will be recorded. Any side effects or health changes will be monitored throughout the study period.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Initial screening and baseline assessments

    After joining the study, you will undergo a series of baseline measurements. these include a blood test to determine your hemoglobin level, other laboratory values such as bilirubin and lactate dehydrogenase, and a physical exam that records height, weight, and bone density. the purpose is to establish your health status before any medication is taken.

  2. Step 2

    Randomization to study medication

    Based on a computer‑generated random assignment, you will receive either mitapivat or a matching placebo. the assignment is double‑blind, meaning that neither you nor the study staff will know which product you receive.

  3. Step 3

    Start of study medication

    You will begin taking the study medication once a day by mouth. two formulations are used in the trial:

    - mitapivat tablet 200 mg taken daily, or the matching placebo tablet of identical appearance.

    - mitapivat granules 150 mg taken daily, or the matching placebo granules of identical appearance.

    The specific form (tablet or granules) will be assigned by the study protocol. each dose is taken with water and can be taken with or without food.

  4. Step 4

    Daily dosing period (week 1–week 24)

    You will continue the daily dose for a total of 24 weeks. adherence to the dosing schedule is important for the evaluation of efficacy and safety.

  5. Step 5

    Clinic visit at week 4

    A study visit will be scheduled at week 4. during this visit, blood will be drawn to measure the concentration of mitapivat in your plasma (pharmacokinetic assessment) and to monitor safety laboratory values.

  6. Step 6

    Clinic visits at week 12 and week 24

    At week 12 and again at week 24, you will attend clinic visits that include:

    - measurement of average hemoglobin level to determine the primary response (an increase of at least 1.0 g/dL from baseline).

    - repeat laboratory tests for bilirubin, lactate dehydrogenase, haptoglobin, reticulocytes, erythropoietin, iron metabolism markers, and iron‑overload indicators.

    - assessment of growth parameters (height‑for‑age, weight‑for‑age, body‑mass‑index‑for‑age).

    - bone mineral density scan.

    - for female participants, evaluation of sex hormones, sexual maturity rating (tanner stage), and ovarian cyst monitoring.

    - completion of fatigue and quality‑of‑life questionnaires (pedsql multidimensional fatigue scale and pedsql 4.0 generic core scales).

  7. Step 7

    End of treatment evaluation

    At the week 24 visit, the study will collect final efficacy and safety data. this includes the primary hemoglobin response, all secondary laboratory and growth assessments, and a summary of any adverse events that occurred during the 24‑week treatment period.

  8. Step 8

    Post‑treatment safety follow‑up

    After the week 24 evaluation, a short safety follow‑up may be performed to ensure that any late‑onset side effects are documented. no further study medication is taken after week 24.

Who can join the trial?

7 criteria

  • Written informed consent (or assent for children) must be signed by the patient or their legal guardian, and the patient must agree to follow all study procedures.
  • Patient must be between 1 and 17 years old and weigh at least 7 kilograms at the time of signing the consent.
  • Patient must have a confirmed diagnosis of alpha‑ or beta‑thalassemia (a genetic blood disorder) as shown by lab tests such as hemoglobin electrophoresis, high‑performance liquid chromatography, or DNA analysis.
  • Patient’s hemoglobin (Hb) level must be 10.0 g/dL or lower, based on the average of at least two blood tests taken at least 7 days apart during screening.
  • Patient must be non‑transfusion dependent, meaning they have had five or fewer blood transfusion episodes in the 24 weeks before randomization, no transfusions in the 8 weeks before consent, and no transfusions during the screening period.
  • If the patient is taking hydroxyurea (a medication used for some blood disorders), the dose must have been stable for at least 16 weeks before randomization.
  • Female patients who have started their periods (menarche) must either avoid sexual activity that could lead to pregnancy or agree to use two forms of birth control, one of which must be highly effective, from consent until 28 days after the last study dose.

Who cannot join the trial?

24 criteria

  • Pregnant or breastfeeding: you are currently carrying a baby or feeding a baby with breast milk.
  • Kidney problems defined by an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m². eGFR is a test that shows how well the kidneys filter waste.
  • High blood fat (triglycerides) when not fasting, greater than 215 mg/dL (5 mmol/L). Triglycerides are a type of fat measured in blood.
  • Active infection that needs systemic (whole‑body) antibiotics or other antimicrobial medicines. You cannot be on these medicines during screening, and the last dose must be at least 7 days before randomization.
  • Known active infection with hepatitis B or hepatitis C viruses. These are viruses that affect the liver.
  • Known infection with HIV. HIV is a virus that attacks the immune system.
  • History of major surgery (including removal of the spleen, called splenectomy) within the past 16 weeks, or any major surgery planned during the study.
  • Current enrollment in another clinical study, or participation in another study within the past 12 weeks (or long enough for the other drug to leave the body, whichever is longer).
  • Use of strong CYP3A4/5 inhibitors that have not been stopped for at least 5 days (or enough time for the drug to clear), or use of strong CYP3A4/5 inducers that have not been stopped for at least 4 weeks. CYP3A4/5 are enzymes that change how medicines are processed in the body.
  • Use of anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement is allowed if the dose has been stable for at least 12 weeks.
  • Known allergy or other reason to avoid the study drug mitapivat or any of its inactive ingredients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and the Opadry film coating containing hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2).
  • Documented history of sickle‑cell trait or disease (HbS) or hemoglobin C (HbC) in either one or both gene copies.
  • Prior exposure to gene therapy or prior bone‑marrow or stem‑cell transplantation, including any previous high‑dose chemotherapy used to destroy the marrow (myeloablative chemotherapy).
  • Any condition other than thalassemia that could affect normal sexual development (sexual maturation).
  • Currently receiving the drug luspatercept; the last dose must have been given at least 18 weeks before randomization.
  • Currently receiving hematopoietic stimulating agents (drugs that encourage blood‑cell production); the last dose must have been given at least 18 weeks before randomization.
  • History of cancer (malignancy) that is active or was treated within the past 5 years, except for very early skin, cervical, or breast cancers that have not invaded deeper tissue (in situ).
  • History of active or uncontrolled heart or lung disease, or a heart rhythm problem called QT prolongation, within the past 6 months.
  • Significant liver or bile‑duct problems (hepatobiliary disorders), such as:
    • Severe liver scarring (cirrhosis) or advanced fibrosis.
    • Symptomatic gallstones or gallbladder infection (cholelithiasis or cholecystitis).
    • Drug‑induced cholestatic hepatitis (liver inflammation caused by medication).
    • Elevated liver enzymes (aspartate aminotransferase or alanine aminotransferase) more than 2.5 times the normal upper limit (ULN), unless the rise is due to blood‑cell breakdown or iron buildup in the liver.
    • Any other medical, blood‑related, mental‑health, or behavioral condition, or any current or past therapy, that the investigator believes makes participation unsafe or could confuse the study results. This also includes people who are:
      • Institutionalized by court or regulatory order.
      • In prison, involuntary psychiatric confinement, or having a financial/familial relationship that could create undue influence on the study.
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Investigated drugs

  • Mitapivat

    is an oral medication taken as a tablet. In this study, it is being tested to see if it can improve the low red blood cell count (anemia) that occurs in children with α‑ or β‑non‑transfusion‑dependent thalassemia. The drug works by helping red blood cells produce more energy, which may allow them to survive longer and function better.

  • Mitapivat

    is also being tested in a granule form that can be taken by mouth. The granules are another way to deliver the same medicine, and the study will evaluate whether this form is safe and effective for improving anemia in pediatric thalassemia patients, just like the tablet version.

What is already known about the treatment

  • MITAPIVAT

    This medication is taken by mouth as a tablet, with each dose containing 200 mg of the active ingredient. It is an approved orphan drug for pyruvate kinase deficiency and is currently being studied for use in non‑transfusion‑dependent alpha‑ or beta‑thalassemia. The drug works by activating the enzyme pyruvate kinase in red blood cells, which helps improve the cells’ energy supply and reduces anemia. It belongs to the class of oral enzyme activators, specifically pyruvate kinase activators.

  • MITAPIVAT

    This form of the medication is administered orally as granules, providing a dose of 150 mg of the active substance. It shares the same approved orphan‑drug status for pyruvate kinase deficiency and is under clinical investigation for treating non‑transfusion‑dependent alpha‑ or beta‑thalassemia. The granules also activate pyruvate kinase in red blood cells, enhancing energy production and helping to correct low hemoglobin levels. It is classified as an oral small‑molecule enzyme activator, specifically a pyruvate kinase activator.

Investigated diseases

Non‑transfusion‑dependent alpha or beta thalassemia - It is a hereditary blood disorder that reduces the production of normal hemoglobin, leading to mild to moderate anemia that does not require regular blood transfusions. Over time, the body’s ability to make enough healthy red blood cells remains limited, causing persistent fatigue and sometimes slower growth in children. The condition can become more noticeable during illness, stress, or pregnancy, when hemoglobin levels may drop further. Typical features include small, pale red cells and occasional enlargement of the spleen. The disease follows a chronic course and may be accompanied by gradual iron buildup due to increased intestinal absorption.
Trial detailsLast updated 7 Oct 2026
Age0-17PhasePhase IIITrial ID2025-524706-15-00Protocol codeAG348-C-028Estimated enrolment45 patientsSponsorAgios Pharmaceuticals Inc.

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