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

• ClinicalTrials.gov Identifier: NCT05031780
• Recruitment Status: Recruiting
• First Posted: September 2, 2021
• Last Update Posted: May 14, 2024
• Sponsor: Agios Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Agios Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: July 29, 2021
• First Posted Date: September 2, 2021
• Last Update Posted Date: May 14, 2024
• Actual Study Start Date: February 11, 2022
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 30, 2021)

• 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 ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 30, 2021)

• 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 [ 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 ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)
• 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
• 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.
• 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 Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sickle Cell Disease

Intervention

• Drug: Mitapivat
  Mitapivat tablets
  Other Names:

  • AG-348
  • Mitapivat Sulfate
• Other: Mitapivat-matching placebo
  Placebo to match 50 mg or 100 mg tablets
• Other: Mitapivat-matching placebo
  Placebo to match 100 mg tablets

Study Arms

• Experimental: Phase 2: Mitapivat 50 mg BID
  Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks.
  Intervention: Drug: Mitapivat
• Experimental: Phase 2: Mitapivat 100 mg BID
  Double-blind Period: Mitapivat 100 mg BID for 12 weeks.
  Intervention: Drug: Mitapivat
• Placebo Comparator: Phase 2: Placebo
  Double-blind Period: Mitapivat-matching placebo for 12 weeks.
  Intervention: Other: Mitapivat-matching placebo
• 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.

  Intervention: Drug: Mitapivat
• Experimental: Phase 3: Mitapivat 100 mg BID
  Double-blind Period: Mitapivat 100 mg BID for 52 weeks.
  Intervention: Drug: Mitapivat
• Placebo Comparator: Phase 3: Placebo
  Double-blind Period: Mitapivat-matching placebo for 52 weeks.
  Intervention: Other: Mitapivat-matching placebo
• Experimental: Phase 3: Open-Label Extension Period

  Participants may choose to receive mitapivat 100 mg BID for 216 weeks after the Double-blind Period.

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

  Intervention: Drug: Mitapivat

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 30, 2021): 267
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2030
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility 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 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Agios Medical Affairs; 833-228-8474; medinfo@agios.com

• Listed Location Countries: Belgium, Brazil, Canada, France, Germany, Ghana, Israel, Italy, Kenya, Lebanon, Netherlands, Nigeria, Oman, Saudi Arabia, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05031780
• Other Study ID Numbers: AG348-C-020; 2021-001674-34 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Agios Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Agios Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Agios Pharmaceuticals, Inc.
• Verification Date: May 2024