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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Mitapivat
* Other: Mitapivat-matching placebo
* Other: Mitapivat-matching placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2: Mitapivat 50 mg BID<br>Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks. | Drug: Mitapivat<br>* Mitapivat tablets<br>* Other names: Mitapivat Sulfate;|
| Experimental: Phase 2: Mitapivat 100 mg BID<br>Double-blind Period: Mitapivat 100 mg BID for 12 weeks. | Drug: Mitapivat<br>* Mitapivat tablets<br>* Other names: Mitapivat Sulfate;|
| Placebo Comparator: Phase 2: Placebo<br>Double-blind Period: Mitapivat-matching placebo for 12 weeks. | Other: Mitapivat-matching placebo<br>* Placebo to match 50 mg or 100 mg tablets<br>|
| Experimental: Phase 2: Open-Label Extension Period<br>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<br>* Mitapivat tablets<br>* Other names: Mitapivat Sulfate;|
| Experimental: Phase 3: Mitapivat selected Phase 3 dose<br>Double-blind Period: Mitapivat selected Phase 3 dose (50 mg or 100 mg BID) for 52 weeks. | Drug: Mitapivat<br>* Mitapivat tablets<br>* Other names: Mitapivat Sulfate;|
| Placebo Comparator: Phase 3: Placebo<br>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<br>* Placebo to match selected Phase 3 dose tablets<br>|
| Experimental: Phase 3: Open-Label Extension Period<br>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<br>* Mitapivat tablets<br>* Other names: Mitapivat Sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Percentage of Participants With Hemoglobin (Hb) Response |  | Week 12 | 
| Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs) |  | Up to Week 12 | 
| Phase 3: Percentage of Participants With Hb Response |  | Week 52 | 
| Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs) |  | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Change From Baseline in Hb Concentration |  | Baseline, Week 10 up to Week 12 | 
| Phase 2: Change From Baseline in Indirect Bilirubin |  | Baseline, Week 10 up to Week 12 | 
| Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH) |  | Baseline, Week 10 up to Week 12 | 
| Phase 2: Change From Baseline in Absolute Reticulocytes Count |  | Baseline, Week 10 up to Week 12 | 
| Phase 2: Change From Baseline in Percent Reticulocytes |  | Baseline, Week 10 up to Week 12 | 
| Phase 2: Change From Baseline in Erythropoietin |  | 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 |  | Baseline, Week 10 up to Week 12 | 
| Phase 2: Annualized Rate of SCPCs |  | 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) |  | Day 1 up to Week 8 | 
| Phase 2: Mitapivat Concentration Over Time |  | Day 1 up to Week 8 | 
| Phase 2: Mitapivat Area Under the Concentration |  | Day 1 up to Week 8 | 
| Phase 2: Mitapivat Maximum (Peak) Concentration |  | Day 1 up to Week 8 | 
| Phase 3: Change From Baseline in Hb Concentration |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Change From Baseline in Indirect Bilirubin |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Change From Baseline in Percent Reticulocytes |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Annualized Frequency of Hospitalizations for SCPC |  | Up to Week 52 | 
| Phase 3: Change From Baseline in LDH Concentration |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Change From Baseline in Absolute Reticulocytes |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Change From Baseline in Erythropoietin |  | Baseline, Week 24 up to Week 52 | 
| Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue |  | Baseline, Weeks 24, 28, 40, and 52 | 
| Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue |  | Baseline, Weeks 24, 28, 40, and 52 | 
| Phase 3: Time to First SCPC |  | Up to Week 52 | 
| Phase 3: Time to Second SCPC |  | Up to Week 52 | 
| Phase 3: Annualized Rate of Hospitalization Days for SCPC |  | Up to Week 52 | 
| Phase 3: Annualized Rate of Emergency Room Visits for SCPC |  | Up to Week 52 | 
| Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT) |  | Baseline, Week 52 | 
| Phase 3: Change From Baseline in PROMIS Pain Intensity |  | Baseline, Week 24 and 52 | 
| Phase 3: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact |  | Baseline, Week 24 and 52 | 
| Phase 3: PGIC of Pain |  | Baseline, Week 52 | 
| Phase 3: Change From Baseline in PGIS of Pain |  | Baseline, Week 52 | 
| Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs) |  | Up to 56 weeks | 
| Phase 3: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels |  | Day 1 up to Week 40 | 
| Phase 3: Mitapivat Concentration Over Time |  | Day 1 up to Week 40 | 
| Phase 3: Mitapivat Area Under the Concentration Curve |  | Day 1 up to Week 40 | 
| Phase 3: Mitapivat Maximum (Peak) Concentration |  | Day 1 up to Week 40 |