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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05031780
Recruitment Status : Active, not recruiting
First Posted : September 2, 2021
Last Update Posted : May 26, 2023
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Mitapivat Other: Mitapivat-matching placebo Phase 2 Phase 3

Detailed Description:
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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 267 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 19, 2022
Estimated Primary Completion Date : September 2025
Estimated Study Completion Date : November 2029

Resource links provided by the National Library of Medicine

Drug Information available for: Mitapivat

Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase 2: Mitapivat 50 mg BID
Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks.
 Drug: Mitapivat
Mitapivat tablets
Other Names:
  • AG-348
  • Mitapivat Sulfate
Experimental: Phase 2: Mitapivat 100 mg BID
Double-blind Period: Mitapivat 100 mg BID for 12 weeks.
 Drug: Mitapivat
Mitapivat tablets
Other Names:
  • AG-348
  • Mitapivat Sulfate
Placebo Comparator: Phase 2: Placebo
Double-blind Period: Mitapivat-matching placebo for 12 weeks.
 Other: Mitapivat-matching placebo
Placebo to match 50 mg or 100 mg tablets
Experimental: Phase 2: Open-Label Extension Period

Participants who received mitapivat 50mg BID in the double-blind period may choose to receive mitapivat 50mg BID for 216 weeks after.

Participants who received mitapivat 100mg BID in the double-blind period may choose to receive mitapivat 100 mg BID for 216 weeks after.

Participants who received mitapivat-matching placebo in the double-blind period, may be randomized to receive either mitapivat 50 mg or 100 mg BID for 216 weeks after.

 Drug: Mitapivat
Mitapivat tablets
Other Names:
  • AG-348
  • Mitapivat Sulfate
Experimental: Phase 3: Mitapivat selected Phase 3 dose
Double-blind Period: Mitapivat selected Phase 3 dose (50 mg or 100 mg BID) for 52 weeks.
 Drug: Mitapivat
Mitapivat tablets
Other Names:
  • AG-348
  • Mitapivat Sulfate
Placebo Comparator: Phase 3: Placebo
Double-blind Period: Mitapivat-matching placebo selected Phase 3 dose (which can be either 50 mg or 100 mg BID based on the phase 2 results) for 52 weeks.
 Other: Mitapivat-matching placebo
Placebo to match selected Phase 3 dose tablets
Experimental: Phase 3: Open-Label Extension Period
Participants may choose to receive the selected Phase 3 mitapivat dose (which can be either 50 mg or 100 mg BID based on the phase 2 results) for 216 weeks after the Double-blind Period.
 Drug: Mitapivat
Mitapivat tablets
Other Names:
  • AG-348
  • Mitapivat Sulfate


Outcome Measures
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Primary Outcome Measures :
  1. Phase 2: Percentage of Participants With Hemoglobin (Hb) Response [ Time Frame: Week 12 ]
  2. Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs) [ Time Frame: Up to Week 12 ]
  3. Phase 3: Percentage of Participants With Hb Response [ Time Frame: Week 52 ]
  4. Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs) [ Time Frame: Up to Week 52 ]

Secondary Outcome Measures :
  1. Phase 2: Change From Baseline in Hb Concentration [ Time Frame: Baseline, Week 10 up to Week 12 ]
  2. Phase 2: Change From Baseline in Indirect Bilirubin [ Time Frame: Baseline, Week 10 up to Week 12 ]
  3. Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH) [ Time Frame: Baseline, Week 10 up to Week 12 ]
  4. Phase 2: Change From Baseline in Absolute Reticulocytes Count [ Time Frame: Baseline, Week 10 up to Week 12 ]
  5. Phase 2: Change From Baseline in Percent Reticulocytes [ Time Frame: Baseline, Week 10 up to Week 12 ]
  6. Phase 2: Change From Baseline in Erythropoietin [ Time Frame: Baseline, Week 10 up to Week 12 ]
  7. Phase 2: Change From Baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score [ Time Frame: Baseline, Week 10 up to Week 12 ]
  8. Phase 2: Annualized Rate of SCPCs [ Time Frame: Up to Week 12 ]
  9. 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 ]
  10. Phase 2: Mitapivat Concentration Over Time [ Time Frame: Day 1 up to Week 8 ]
  11. Phase 2: Mitapivat Area Under the Concentration [ Time Frame: Day 1 up to Week 8 ]
  12. Phase 2: Mitapivat Maximum (Peak) Concentration [ Time Frame: Day 1 up to Week 8 ]
  13. Phase 3: Change From Baseline in Hb Concentration [ Time Frame: Baseline, Week 24 up to Week 52 ]
  14. Phase 3: Change From Baseline in Indirect Bilirubin [ Time Frame: Baseline, Week 24 up to Week 52 ]
  15. Phase 3: Change From Baseline in Percent Reticulocytes [ Time Frame: Baseline, Week 24 up to Week 52 ]
  16. Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores [ Time Frame: Baseline, Week 24 up to Week 52 ]
  17. Phase 3: Annualized Frequency of Hospitalizations for SCPC [ Time Frame: Up to Week 52 ]
  18. Phase 3: Change From Baseline in LDH Concentration [ Time Frame: Baseline, Week 24 up to Week 52 ]
  19. Phase 3: Change From Baseline in Absolute Reticulocytes [ Time Frame: Baseline, Week 24 up to Week 52 ]
  20. Phase 3: Change From Baseline in Erythropoietin [ Time Frame: Baseline, Week 24 up to Week 52 ]
  21. 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 ]
  22. 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 ]
  23. Phase 3: Time to First SCPC [ Time Frame: Up to Week 52 ]
  24. Phase 3: Time to Second SCPC [ Time Frame: Up to Week 52 ]
  25. Phase 3: Annualized Rate of Hospitalization Days for SCPC [ Time Frame: Up to Week 52 ]
  26. Phase 3: Annualized Rate of Emergency Room Visits for SCPC [ Time Frame: Up to Week 52 ]
  27. Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT) [ Time Frame: Baseline, Week 52 ]
  28. Phase 3: Change From Baseline in PROMIS Pain Intensity [ Time Frame: Baseline, Week 24 and 52 ]
  29. 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 ]
  30. Phase 3: PGIC of Pain [ Time Frame: Baseline, Week 52 ]
  31. Phase 3: Change From Baseline in PGIS of Pain [ Time Frame: Baseline, Week 52 ]
  32. Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs) [ Time Frame: Up to 56 weeks ]
  33. 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 ]
  34. Phase 3: Mitapivat Concentration Over Time [ Time Frame: Day 1 up to Week 40 ]
  35. Phase 3: Mitapivat Area Under the Concentration Curve [ Time Frame: Day 1 up to Week 40 ]
  36. Phase 3: Mitapivat Maximum (Peak) Concentration [ Time Frame: Day 1 up to Week 40 ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 sickle cell pain crises (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;
  • Women capable of becoming pregnant and men with partners who are women that are 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 for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of such therapies 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).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05031780


Locations
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Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
More Information
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Responsible Party: Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT05031780    
Other Study ID Numbers: AG348-C-020
2021-001674-34 ( EudraCT Number )
First Posted: September 2, 2021    Key Record Dates
Last Update Posted: May 26, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
 Hemoglobinopathies
Genetic Diseases, Inborn
Mitapivat
Enzyme Activators
Molecular Mechanisms of Pharmacological Action