A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)

Phase 3Active Not RecruitingNCT05031780

Agios Pharmaceuticals, Inc.286 enrolled

Overview

This clinical trial is a Phase 2/3 study that will determine the recommended dose of mitapivat and evaluate the efficacy and safety of mitapivat in sickle cell disease by testing how well mitapivat works compared to placebo to increase the amount of hemoglobin in the blood and to reduce or prevent the occurrence of sickle cell pain crises. In addition, the long-term effect of mitapivat on efficacy and safety will be explored in an open-label extension portion.

Mitapivat is a small molecule, oral activator of pyruvate kinase R (PKR). PKR is involved with maintaining health, energy, and longevity of red blood cells (RBCs). The study aims to evaluate the efficacy and safety of treatment with mitapivat in participants with sickle cell disease. The study is a Phase 2/3 study in which the recommended dose of mitapivat will be selected and further evaluated. The Phase 2 portion includes a 12-week randomized, placebo-controlled period in which participants will be randomized in a 1:1:1 ratio to receive 2 dose levels of mitapivat or placebo. The Phase 3 portion includes a 52-week randomized, placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive the recommended mitapivat dose level or placebo. Participants who complete either the Phase 2 or Phase 3 portion will have the option to move into a 216-week open label extension period to receive mitapivat.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

286

Conditions

Sickle Cell Disease

Interventions

MitapivatDRUG

Mitapivat tablets

Mitapivat-matching placeboOTHER

Placebo to match 50 mg or 100 mg tablets

Mitapivat-matching placeboOTHER

Placebo to match 100 mg tablets

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 16 years or older (18 years or older \[France and Germany\]); participants age 16 or 17 years must physically have completed puberty; * Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC \[combined heterozygosity for hemoglobins S and C\], HbS/beta 0- thalassemia, HbS/ beta plus thalassemia, or other sickle cell syndrome variants); * At least 2 SCPCs and no more than 10 SCPCs in the past 12 months; * Hemoglobin at least 5.5 and 10.5 gram per deciliter (g/dL) at the most. 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 before starting study drug. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent; * Women capable of becoming pregnant must agree to use 2 forms of contraception. Exclusion Criteria: * Pregnant, breastfeeding, or parturient; * Receiving regularly scheduled transfusions; * Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease; * Severe kidney disease; * Prior exposure to gene therapy or prior bone marrow or stem cell transplantation; * Currently receiving treatment with a disease-modifying therapy 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 randomization; * 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).

Locations (91)

Outcomes

Primary Outcomes

Phase 2: Percentage of Participants With Hemoglobin (Hb) Response

Time frame: Week 12

Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)

Time frame: Up to Week 12

Phase 3: Percentage of Participants With Hb Response

Time frame: Week 52

Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs)

Time frame: Up to Week 52

Secondary Outcomes

Phase 2: Change From Baseline in Hb Concentration

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Change From Baseline in Indirect Bilirubin

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH)

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Change From Baseline in Absolute Reticulocytes Count

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Change From Baseline in Percent Reticulocytes

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Change From Baseline in Erythropoietin

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Change From Baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

University of California San Diego

La Jolla, California, United States

UCLA Health

Los Angeles, California, United States

Children's Hospital Oakland

Oakland, California, United States

University of Connecticut Health Center

Farmington, Connecticut, United States

Children's National Hospital

Washington D.C., District of Columbia, United States

MedStar Washington Hospital Center

Washington D.C., District of Columbia, United States

Sylvester Comprehensive Cancer Center-Miami

Miami, Florida, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Riley Hospital For Children

Indianapolis, Indiana, United States

LSU Health Sciences Center - Shreveport

Shreveport, Louisiana, United States

...and 81 more locations

Time frame: Baseline, Week 10 up to Week 12

Phase 2: Annualized Rate of SCPCs

Time frame: Up to Week 12

Phase 2: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG)

Time frame: Day 1 up to Week 8

Phase 2: Mitapivat Concentration Over Time

Time frame: Day 1 up to Week 8

Phase 2: Mitapivat Area Under the Concentration

Time frame: Day 1 up to Week 8

Phase 2: Mitapivat Maximum (Peak) Concentration

Time frame: Day 1 up to Week 8

Phase 3: Change From Baseline in Hb Concentration

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Change From Baseline in Indirect Bilirubin

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Change From Baseline in Percent Reticulocytes

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Annualized Frequency of Hospitalizations for SCPC

Time frame: Up to Week 52

Phase 3: Change From Baseline in LDH Concentration

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Change From Baseline in Absolute Reticulocytes

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Change From Baseline in Erythropoietin

Time frame: Baseline, Week 24 up to Week 52

Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue

Time frame: Baseline, Weeks 24, 28, 40, and 52

Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue

Time frame: Baseline, Weeks 24, 28, 40, and 52

Phase 3: Time to First SCPC

Time frame: Up to Week 52

Phase 3: Time to Second SCPC

Time frame: Up to Week 52

Phase 3: Annualized Rate of Hospitalization Days for SCPC

Time frame: Up to Week 52

Phase 3: Annualized Rate of Emergency Room Visits for SCPC

Time frame: Up to Week 52

Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT)

Time frame: Baseline, Week 52

Phase 3: Change From Baseline in PROMIS Pain Intensity

Time frame: Baseline, Week 24 and 52

Phase 3: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact

Time frame: Baseline, Week 24 and 52

Phase 3: PGIC of Pain

Time frame: Baseline, Week 52

Phase 3: Change From Baseline in PGIS of Pain

Time frame: Baseline, Week 52

Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)

Time frame: Up to 56 weeks

Phase 3: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels

Time frame: Day 1 up to Week 40

Phase 3: Mitapivat Concentration Over Time

Time frame: Day 1 up to Week 40

Phase 3: Mitapivat Area Under the Concentration Curve

Time frame: Day 1 up to Week 40

Phase 3: Mitapivat Maximum (Peak) Concentration

Time frame: Day 1 up to Week 40