A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)
- Conditions
- Sickle Cell Disease
- Interventions
- Other: Mitapivat-matching placebo
- Registration Number
- NCT05031780
- Lead Sponsor
- Agios Pharmaceuticals, Inc.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 286
- 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.
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 2: Mitapivat 50 mg BID Mitapivat Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks. Phase 2: Mitapivat 100 mg BID Mitapivat Double-blind Period: Mitapivat 100 mg BID for 12 weeks. Phase 2: Placebo Mitapivat-matching placebo Double-blind Period: Mitapivat-matching placebo for 12 weeks. Phase 2: Open-Label Extension Period Mitapivat 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. Phase 3: Placebo Mitapivat-matching placebo Double-blind Period: Mitapivat-matching placebo for 52 weeks. Phase 3: Mitapivat 100 mg BID Mitapivat Double-blind Period: Mitapivat 100 mg BID for 52 weeks. Phase 3: Open-Label Extension Period Mitapivat 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.
- Primary Outcome Measures
Name Time Method Phase 3: Percentage of Participants With Hb Response Week 52 Phase 2: Percentage of Participants With Hemoglobin (Hb) Response Week 12 Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs) Up to Week 52 Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs) Up to Week 12
- Secondary Outcome Measures
Name Time Method Phase 2: Mitapivat Area Under the Concentration Day 1 up to Week 8 Phase 3: Mitapivat Area Under the Concentration Curve Day 1 up to Week 40 Phase 2: Change From Baseline in Erythropoietin Baseline, Week 10 up to Week 12 Phase 2: Mitapivat Concentration Over Time Day 1 up to Week 8 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 3: Change From Baseline in Absolute Reticulocytes Baseline, Week 24 up to Week 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: Annualized Rate of Emergency Room Visits for SCPC Up to Week 52 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: 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: Change From Baseline in Hb Concentration 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: Annualized Rate of SCPCs Up to Week 12 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: Time to Second SCPC Up to Week 52 Phase 3: Change From Baseline in LDH Concentration Baseline, Week 24 up to Week 52 Phase 3: Time to First SCPC Up to 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: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact Baseline, Week 24 and 52 Phase 2: Mitapivat Maximum (Peak) Concentration Day 1 up to Week 8 Phase 3: Change From Baseline in Erythropoietin Baseline, Week 24 up to Week 52 Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT) Baseline, Week 52 Phase 3: Change From Baseline in Hb Concentration Baseline, Week 24 up to Week 52 Phase 3: Annualized Frequency of Hospitalizations for SCPC 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: Annualized Rate of Hospitalization Days for SCPC Up to Week 52 Phase 3: PGIC of Pain Baseline, Week 52 Phase 3: Change From Baseline in PGIS of Pain Baseline, Week 52 Phase 3: Change From Baseline in PROMIS Pain Intensity Baseline, Week 24 and 52 Phase 3: Mitapivat Maximum (Peak) Concentration Day 1 up to Week 40
Trial Locations
- Locations (89)
University of California San Diego
🇺🇸La Jolla, California, United States
KEMRI CRDR Clinical Research Clinic Nairobi
🇰🇪Nairobi, Kenya
Nini Hospital
🇱🇧Tarablus, Liban Nord, Lebanon
Hammoud Hospital University Medical Center
🇱🇧Sidon, Lebanon
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, District of Columbia, United States
MedStar Washington Hospital Center
🇺🇸Washington, 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
National Heart Lung and Blood Institute
🇺🇸Bethesda, Maryland, United States
Kaiser Permanente - Largo Medical Center
🇺🇸Largo, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Boston Medical Center & Boston University School of Medicine
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Southern Specialty Clinic
🇺🇸Flowood, Mississippi, United States
Mississippi Center for Advanced Medicine
🇺🇸Madison, Mississippi, United States
Cure 4 The Kids Foundation, A Division of Roseman University of Health Sciences
🇺🇸Las Vegas, Nevada, United States
East Carolina University - Brody School of Medicine
🇺🇸Greenville, North Carolina, United States
Penn Medicine - University of Pennsylvania Health System
🇺🇸Philadelphia, Pennsylvania, United States
St. Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Lifespan at Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
University of Texas Health Science Center of Houston
🇺🇸Houston, Texas, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
Seattle Cancer Care Alliance, University of Washington
🇺🇸Seattle, Washington, United States
Hôpital Erasme
🇧🇪Anderlecht, Brussels, Belgium
Universitair Ziekenhuis Antwerpen
🇧🇪Edegem, Brussels, Belgium
ZAS Cadix
🇧🇪Antwerpen, Belgium
CHR de la Citadelle
🇧🇪Liège, Belgium
Clinique CHC MontLégia
🇧🇪Liège, Belgium
Multihemo Servicos Medicos S/A
🇧🇷Recife, Pernambuco, Brazil
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital de Clínicas da Unicamp
🇧🇷Campinas, São Paulo, Brazil
Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
🇧🇷Ribeirão Preto, São Paulo, Brazil
Praxis Pesquisa Medica
🇧🇷Santo Andre, São Paulo, Brazil
HEMORIO Instituto Nacional de Hematologia
🇧🇷Rio De Janeiro, Brazil
Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
🇧🇷São Paulo, Brazil
McMaster University - St. Joseph's Healthcare Hamilton
🇨🇦Hamilton, Ontario, Canada
University Health Network
🇨🇦Toronto, Ontario, Canada
CHU Montreal
🇨🇦Montreal, Quebec, Canada
McGill University Health Center
🇨🇦Montreal, Quebec, Canada
Hopitaux de La Timone
🇫🇷Marseille, Bouches-du-Rhône, France
Hôpital Pellegrin, CHU de Bordeaux
🇫🇷Bordeaux, Gironde, France
CHU Guadeloupe
🇫🇷Pointe-à-Pitre, Guadeloupe, France
Institut Universitaire du Cancer de Toulouse - Oncopole
🇫🇷Toulouse, Haute-Garonne, France
Hôpital Européen Georges Pompidou
🇫🇷Paris, Ile De France, France
CHU Hôpital Henri Mondor
🇫🇷Créteil, Val-de-Marne, France
Universitätsklinikum Essen
🇩🇪Essen, Germany
Universitätsklinikum Regensburg
🇩🇪Regensburg, Germany
HaEmek Medical Center
🇮🇱Afula, Israel
Rambam Medical Center
🇮🇱Haifa, Ḥeifā, Israel
Ziv Medical Center
🇮🇱Safed, Ḥeifā, Israel
A.O.R.N. "A. Cardarelli"
🇮🇹Napoli, Campania, Italy
AOU dell'Università degli Studi della Campania Luigi Vanvitelli
🇮🇹Napoli, Campania, Italy
Azienda Ospedaliero Universitaria Di Modena Policlinico
🇮🇹Modena, Emilia-Romagna, Italy
IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
🇮🇹Roma, Lazio, Italy
Ente Ospedaliero Ospedali Galliera
🇮🇹Genova, Liguria, Italy
Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
🇮🇹Palermo, Sicilia, Italy
Kemri Usamru
🇰🇪Kisumu, Western, Kenya
Kondele Children's Hospital
🇰🇪Kisumu, Kenya
Victoria Biomedical Research Institute (VIBRI)
🇰🇪Kisumu, Kenya
KEMRI/CRDR Siaya Clinical Research Annex
🇰🇪Nairobi, Kenya
Strathmore University
🇰🇪Nairobi, Kenya
Gertrude's Children's Hospital
🇰🇪Nairobi, Kenya
American University of Beirut Medical Center
🇱🇧Beirut, Lebanon
Erasmus MC
🇳🇱Rotterdam, Zuid-Holland, Netherlands
Universitair Medisch Centrum Utrecht
🇳🇱Utrecht, Netherlands
National Hospital Abuja
🇳🇬Abuja, Abuja Capital Territory, Nigeria
University of Abuja Teaching Hospital
🇳🇬Abuja, Abuja Capital Territory, Nigeria
Lagos University Teaching Hospital
🇳🇬Suru-Lere, Lagos, Nigeria
Sultan Qaboos University Hospital, Hematology Department, COM&HS
🇴🇲Muscat, Musqal, Oman
King Khalid University Hospital
🇸🇦Riyadh, Ar Riya, Saudi Arabia
King Abdullah International Medical Research Center
🇸🇦Riyadh, Saudi Arabia
Hacettepe University
🇹🇷Ankara, Adana, Turkey
Acibadem Adana Hospital
🇹🇷Seyhan, Adana, Turkey
Evelina Children's Hospital
🇬🇧London, City Of London, United Kingdom
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
Guy's and St Thomas' NHS Foundation Trust
🇬🇧London, United Kingdom
King's College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
Hammersmith Hospital
🇬🇧London, United Kingdom
University College London Hospitals (UCLH)
🇬🇧London, United Kingdom
Manchester Royal Infirmary, Manchester University NHS Foundation Trust
🇬🇧Manchester, United Kingdom