Efficacy and Safety Evaluation of Mitapivat in Patients with Sickle Cell Disease: A Phase 2/3 Double-Blind, Randomized, Placebo-Controlled Multicenter Study
- Trial ID
- 2024-515202-84-00
- Protocol
- AG348-C-020
- Sponsor
- Agios Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the effect of **mitapivat** versus placebo on anemia in subjects with **sickle cell disease** (SCD) or sickle cell pain crises (SCPCs) in subjects with SCD. This is clinically relevant as anemia and pain crises are significant complications of SCD, impacting patient quality of life and increasing healthcare utilization.
Secondary objectives include evaluating the effect of mitapivat versus placebo on:
- Anemia in subjects with SCD
- Markers of hemolysis
- Markers of erythropoiesis
- Patient-reported fatigue
- Additional clinical efficacy measures related to SCPC
Participants
The clinical trial involves a total of **210 participants** diagnosed with **sickle cell disease (SCD)**, including variants such as HbSS, HbSC, HbS/β0-thalassemia, and HbS/β+-thalassemia. The study population comprises both male and female subjects aged 16 years and older, with those aged 16 or 17 required to be at Tanner Stage 5. Participants must have experienced between 2 to 10 sickle cell pain crises in the 12 months preceding the trial. The trial includes individuals with a hemoglobin concentration between 5.5 and 10.5 g/dL, based on an average of at least two measurements taken at least seven days apart during the screening period. Those on hydroxyurea must have a stable dose for at least 90 days before randomization, or a 90-day washout period if discontinued. Women of childbearing potential are required to use two forms of contraception, one highly effective, throughout the study and for 28 days after the last dose. The trial population was selected based on these criteria, ensuring participants are willing to comply with all study procedures. The study does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **Phase 2/3**, double-blind, randomized, placebo-controlled, multicenter study to evaluate the efficacy and safety of **mitapivat** in subjects with **sickle cell disease** (SCD). The trial aims to assess the effect of mitapivat versus placebo on anemia and sickle cell pain crises (SCPCs) in subjects with SCD. The study is expected to run from December 2021 to April 2030, with a maximum treatment period of 276 days for each participant. Participants will be randomly assigned to receive either mitapivat or a placebo, both administered orally in tablet form.
The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility criteria are assessed, including age, documented diagnosis of SCD, and hemoglobin levels. Participants must have experienced at least two SCPCs in the 12 months prior to consent and meet other specific criteria, such as stable hydroxyurea dosage if applicable. Following the screening, eligible participants will be randomized and begin the treatment phase. Follow-up visits will occur regularly to monitor safety, efficacy, and any adverse events. The primary endpoints include hemoglobin response and the annualized rate of SCPCs, while secondary endpoints focus on changes in hemoglobin concentration, indirect bilirubin, reticulocyte percentage, and patient-reported outcomes related to fatigue.
The end-of-study visit marks the conclusion of the participant's involvement, where final assessments are conducted. Participants are expected to be involved for the duration of the treatment period, with conditions for early termination including withdrawal of consent, significant adverse events, or non-compliance with study procedures. The trial is conducted under strict adherence to ethical guidelines, ensuring informed consent is obtained and maintained throughout the study.
Treatment
The clinical trial involves the administration of **Mitapivat**, a chemical compound with the active substance name **Mitapivat**. The pharmaceutical form of Mitapivat is a tablet, and it is administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 386,400 mg over a treatment period of up to 276 days. The tablets are produced by Agios Pharmaceuticals and are identified by the sponsor product code AG-348. The chemical name of Mitapivat is N-(4-((4-(cyclopropylmethyl)-1-piperazinyl)carbonyl)phenyl)-8-quinolinesulfonamide. The trial aims to evaluate the efficacy and safety of Mitapivat in subjects with sickle cell disease.
The study also includes a **placebo** group to match the Mitapivat treatment. The placebo is provided in various forms to match the Mitapivat tablets and granules. The placebo tablets are film-coated, blue, and available in round forms for 5 mg and 20 mg doses, and oblong forms for 50 mg and 100 mg doses. Additionally, placebo granules are supplied as film-coated, white, round granules for oral administration. The placebo is used to ensure the double-blind nature of the study, allowing for a controlled comparison of the effects of Mitapivat versus no active treatment.
Efficacy
The efficacy of **Mitapivat** in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the **hemoglobin (Hb) response**, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline, and the annualized rate of sickle cell pain crises (SCPCs). Secondary endpoints will evaluate the average change from baseline in Hb concentration, indirect bilirubin, and percent reticulocyte from Week 24 through Week 52. Additionally, changes in Patient-Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form (SF) scores and the annualized frequency of hospitalizations for SCPC will be measured.
These efficacy parameters will be collected and analyzed at specified timepoints, including baseline, Week 24, and Week 52. The assessments will utilize validated scales and laboratory tests to ensure accuracy and reliability. The trial is designed as a Phase 2/3, double-blind, randomized, placebo-controlled study, focusing on subjects with sickle cell disease. The study aims to determine the effect of Mitapivat versus placebo on anemia and SCPCs in this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥16 years; subjects age 16 or 17 years must be documented Tanner Stage 5 (see Appendix 3).
- Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/β0-thalassemia, HbS/β+-thalassemia, or other sickle cell syndrome variants).
- At least 2 sickle cell pain crises (SCPCs) (defined in Section 8.5.2.1) and no more than 10 SCPCs in the 12 months prior to providing informed assent/consent.
- Hemoglobin ≥5.5 and ≤10.5 g/dL. Hemoglobin concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period.
- If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days prior to randomization. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent.
- Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed assent/consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can include an acceptable barrier method (see Appendix 2).
- Written informed assent/consent (for subjects under 18 years of age, or prior to the age at which a subject is considered legally an adult per local regulations, parental permission and child assent will be obtained) must be obtained before any study-related procedures are conducted and subjects must be willing to comply with all study procedures for the duration of the study.
Exclusion Criteria
- Pregnant or breastfeeding.
- Receiving regularly scheduled transfusions.
- Hospitalized for an SCPC and/or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an emergency room or out patient clinic visit. A visit to an emergency room that does not result in an in-patient admission does not meet the definition of hospitalization
- Currently receiving treatment for SCD (eg, voxelotor, crizanlizumab, L glutamine), with the exception of hydroxyurea. The last dose of voxelotor, crizanlizumab, and L-glutamine must have been administered at least 90 days before starting study drug.
- Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug.
- Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial.
- Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).
- Any medical, hematological, psychological, or behavioral condition(s), including alcohol use disorder, or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study.
- Receiving herbal or dietary supplements that have not been stable in dose and preparation for ≥8 weeks prior to randomization.
- Other protocol defined exclusion criteria may apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Dec 2021 | 6 |
 France | Not Recruiting | 01 Dec 2021 | 22 |
 Germany | Not Recruiting | 01 Dec 2021 | 20 |
 Italy | Not Recruiting | 01 Dec 2021 | 12 |
 The Netherlands | Not Recruiting | 01 Dec 2021 | — |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MITAPIVAT | Test | TABLET | ORAL | 200 | 276 | PRD11396452 |
MITAPIVAT | Test | TABLET | ORAL | 200 | 276 | PRD11396451 |
"Placebo to Match Mitapivat Tablets, 5 mg and 20 mg, are supplied as film-coated, blue, round
tablets for oral administration
Placebo to Match Mitapivat Tablets, 50 mg or 100 mg, are supplied as film-coated, blue, oblong
tablets for oral administration.
Placebo to Match Mitapivat Granules, 1 mg, are supplied as film-coated, white, round granules
for oral administration" | Placebo | N/A | — | — | — | N/A |
MITAPIVAT | Test | TABLET | ORAL | 200 | 276 | PRD11387021 |