A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)
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
2 other identifiers
interventional
286
16 countries
91
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Feb 2022
Longer than P75 for phase_2
91 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 29, 2021
CompletedFirst Posted
Study publicly available on registry
September 2, 2021
CompletedStudy Start
First participant enrolled
February 11, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 30, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
February 1, 2030
ExpectedMay 29, 2026
May 1, 2026
3.7 years
July 29, 2021
May 28, 2026
Conditions
Outcome Measures
Primary Outcomes (4)
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 Outcomes (36)
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
- +31 more secondary outcomes
Study Arms (7)
Phase 2: Mitapivat 50 mg BID
EXPERIMENTALDouble-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks.
Phase 2: Mitapivat 100 mg BID
EXPERIMENTALDouble-blind Period: Mitapivat 100 mg BID for 12 weeks.
Phase 2: Placebo
PLACEBO COMPARATORDouble-blind Period: Mitapivat-matching placebo for 12 weeks.
Phase 2: Open-Label Extension Period
EXPERIMENTALParticipants 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: Mitapivat 100 mg BID
EXPERIMENTALDouble-blind Period: Mitapivat 100 mg BID for 52 weeks.
Phase 3: Placebo
PLACEBO COMPARATORDouble-blind Period: Mitapivat-matching placebo for 52 weeks.
Phase 3: Open-Label Extension Period
EXPERIMENTALParticipants 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.
Interventions
Mitapivat tablets
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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).
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (91)
University of California San Diego
La Jolla, California, 92037-1337, United States
UCLA Health
Los Angeles, California, 90095-1678, United States
Children's Hospital Oakland
Oakland, California, 94609, United States
University of Connecticut Health Center
Farmington, Connecticut, 06030-0001, United States
Children's National Hospital
Washington D.C., District of Columbia, 20010-2916, United States
MedStar Washington Hospital Center
Washington D.C., District of Columbia, 20010, United States
Sylvester Comprehensive Cancer Center-Miami
Miami, Florida, 33101, United States
University of Chicago Medical Center
Chicago, Illinois, 60637-1443, United States
Riley Hospital For Children
Indianapolis, Indiana, 46202-5109, United States
LSU Health Sciences Center - Shreveport
Shreveport, Louisiana, 71103-4228, United States
National Heart Lung and Blood Institute
Bethesda, Maryland, 20814, United States
Kaiser Permanente - Largo Medical Center
Largo, Maryland, 20774-5374, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114-2621, United States
Boston Children's Hospital
Boston, Massachusetts, 02115-5724, United States
Boston Medical Center & Boston University School of Medicine
Boston, Massachusetts, 02118, United States
University of Michigan
Ann Arbor, Michigan, 48109-5000, United States
Children's Hospital of Michigan
Detroit, Michigan, 48201, United States
Southern Specialty Clinic
Flowood, Mississippi, 39232, United States
Mississippi Center for Advanced Medicine
Madison, Mississippi, 39110-6115, United States
Cure 4 The Kids Foundation, A Division of Roseman University of Health Sciences
Las Vegas, Nevada, 89106, United States
East Carolina University - Brody School of Medicine
Greenville, North Carolina, 27834, United States
Penn Medicine - University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104-5127, United States
St. Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134-1011, United States
Lifespan at Rhode Island Hospital
Providence, Rhode Island, 02903, United States
University of Texas Health Science Center of Houston
Houston, Texas, 77030-1501, United States
Texas Children's Hospital
Houston, Texas, 77030, United States
Virginia Commonwealth University
Richmond, Virginia, 23298-5058, United States
Seattle Cancer Care Alliance, University of Washington
Seattle, Washington, 98195, United States
Hôpital Erasme
Anderlecht, Brussels Capital, 1070, Belgium
Universitair Ziekenhuis Antwerpen
Edegem, Brussels Capital, 2650, Belgium
ZAS Cadix
Antwerp, 2030, Belgium
CHR de la Citadelle
Liège, 4000, Belgium
Clinique CHC MontLégia
Liège, 4000, Belgium
Multihemo Servicos Medicos S/A
Recife, Pernambuco, 50070-460, Brazil
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
Porto Alegre, Rio Grande do Sul, 90035-903, Brazil
Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
Porto Alegre, Rio Grande do Sul, 90619-900, Brazil
Hospital de Clínicas da Unicamp
Campinas, São Paulo, 13083-878, Brazil
Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
Ribeirão Preto, São Paulo, 14051-140, Brazil
Praxis Pesquisa Medica
Santo André, São Paulo, Brazil
HEMORIO Instituto Nacional de Hematologia
Rio de Janeiro, 20211-030, Brazil
Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
São Paulo, 05403-010, Brazil
McMaster University - St. Joseph's Healthcare Hamilton
Hamilton, Ontario, L8N 3Z5, Canada
University Health Network
Toronto, Ontario, M5G2C4, Canada
CHU Montreal
Montreal, Quebec, H2X 3E4, Canada
McGill University Health Center
Montreal, Quebec, H4A 3J1, Canada
Hopitaux de La Timone
Marseille, Bouches-du-Rhône, 13005, France
Hôpital Pellegrin, CHU de Bordeaux
Bordeaux, Gironde, 33000, France
CHU Guadeloupe
Pointe à Pitre, Guadeloupe, 97139, France
Institut Universitaire du Cancer de Toulouse - Oncopole
Toulouse, Haute-Garonne, 31059, France
CHU Hôpital Henri Mondor
Créteil, Val-de-Marne, 94000, France
Hôpital Européen Georges Pompidou
Paris, Île-de-France Region, 75015, France
Universitätsklinikum Essen
Essen, 45147, Germany
Universitätsklinikum Regensburg
Regensburg, 93053, Germany
HaEmek Medical Center
Afula, 18101, Israel
Rambam Medical Center
Haifa, Ḥeifā, 31096, Israel
Ziv Medical Center
Safed, Ḥeifā, 13100, Israel
A.O.R.N. "A. Cardarelli"
Naples, Campania, 80131, Italy
AOU dell'Università degli Studi della Campania Luigi Vanvitelli
Naples, Campania, 80138, Italy
Azienda Ospedaliero Universitaria Di Modena Policlinico
Modena, Emilia-Romagna, 41100, Italy
IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
Rome, Lazio, 00165, Italy
Ente Ospedaliero Ospedali Galliera
Genoa, Liguria, 16128, Italy
Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
Palermo, Sicily, 90146, Italy
Kemri Usamru
Kisumu, Western, 40100, Kenya
Kondele Children's Hospital
Kisumu, 40100, Kenya
Victoria Biomedical Research Institute (VIBRI)
Kisumu, 40100, Kenya
KEMRI CRDR Clinical Research Clinic Nairobi
Nairobi, 00100, Kenya
KEMRI/CRDR Siaya Clinical Research Annex
Nairobi, 00200, Kenya
Strathmore University
Nairobi, 00200, Kenya
Gertrude's Children's Hospital
Nairobi, 42325- 00100, Kenya
American University of Beirut Medical Center
Beirut, Beirut, 11-0236, Lebanon
Nini Hospital
Tarablus, North Lebanon, 1434, Lebanon
American University of Beirut Medical Center
Beirut, 4407-2020, Lebanon
Hammoud Hospital University Medical Center
Sidon, H96G+247, Lebanon
Erasmus MC
Rotterdam, South Holland, 3015 GD, Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX, Netherlands
National Hospital Abuja
Abuja, Federal Capital Territory, 900271, Nigeria
University of Abuja Teaching Hospital
Abuja, Federal Capital Territory, 900271, Nigeria
Lagos University Teaching Hospital
Surulere, Lagos, 101014, Nigeria
Sultan Qaboos University Hospital, Hematology Department, COM&HS
Muscat, Musqal, H5QC+36M, Oman
King Khalid University Hospital
Riyadh, Ar Riya, 11472, Saudi Arabia
King Abdullah International Medical Research Center
Riyadh, 1515 (KAIMRC), Saudi Arabia
Hacettepe Universitesi Tip Fakultesi Hastanesi
Ankara, Adana, 06200, Turkey (Türkiye)
Hacettepe University
Ankara, Adana, Turkey (Türkiye)
Acibadem Adana Hospital
Seyhan, Adana, 01130, Turkey (Türkiye)
Evelina Children's Hospital
London, City of London, SE1 7EH, United Kingdom
Cambridge University Hospitals NHS Foundation Trust
Cambridge, CB2 0QQ, United Kingdom
Guy's and St Thomas' NHS Foundation Trust
London, SE1 7EH, United Kingdom
King's College Hospital NHS Foundation Trust
London, SE5 9RS, United Kingdom
Hammersmith Hospital
London, W12 0HS, United Kingdom
University College London Hospitals (UCLH)
London, WC1E 6BT, United Kingdom
Manchester Royal Infirmary, Manchester University NHS Foundation Trust
Manchester, M13 9WL, United Kingdom
Related Publications (4)
Conrey A, Asomaning N, Frey I, Charles RP, Lovins D, Xu JZ, Mendez-Marti S, Le K, Kruah B, Li Q, Dunkelberger E, Cellmer T, Yates A, Wind-Rotolo M, Huston C, Jeffries N, Eaton WA, Thein SL. Long-term mitapivat treatment is safe and efficacious in patients with sickle cell disease. Blood Red Cells Iron. 2025 Sep;1(2):100014. doi: 10.1016/j.brci.2025.100014. Epub 2025 Sep 11.
PMID: 41809202DERIVEDIdowu M, Otieno L, Dumitriu B, Lobo CLC, Thein SL, Andemariam B, Nnodu OE, Inati A, Glaros AK, Bartolucci P, Colombatti R, Taher AT, Abboud MR, Darbari D, Ataga KI, Antmen AB, Kuo KHM, de Souza Medina S, Oluyadi A, Iyer V, Morris S, Yates AM, Shao H, Patil S, Urbstonaitis R, Zaidi AU, Gheuens S, Smith WR. Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial. Lancet Haematol. 2025 Jan;12(1):e35-e44. doi: 10.1016/S2352-3026(24)00319-3. Epub 2024 Dec 4.
PMID: 39644907DERIVEDvan Dijk MJ, Rab MAE, van Oirschot BA, Bos J, Derichs C, Rijneveld AW, Cnossen MH, Nur E, Biemond BJ, Bartels M, Jans JJM, van Solinge WW, Schutgens REG, van Wijk R, van Beers EJ. One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. Blood Adv. 2023 Dec 26;7(24):7539-7550. doi: 10.1182/bloodadvances.2023011477.
PMID: 37934880DERIVEDObadina M, Wilson S, Derebail VK, Little J. Emerging Therapies and Advances in Sickle Cell Disease with a Focus on Renal Manifestations. Kidney360. 2023 Jul 1;4(7):997-1005. doi: 10.34067/KID.0000000000000162. Epub 2023 May 31.
PMID: 37254256DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 29, 2021
First Posted
September 2, 2021
Study Start
February 11, 2022
Primary Completion
October 30, 2025
Study Completion (Estimated)
February 1, 2030
Last Updated
May 29, 2026
Record last verified: 2026-05
Data Sharing
- IPD Sharing
- Will not share