Sickle Cell DiseasePhase 2/3NCT05031780
A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)
A Phase 2/3 study testing Mitapivat in people with Sickle Cell Disease, run by Agios Pharmaceuticals, Inc. at 91 sites in 16 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Sickle Cell Disease
- What is being tested?
- Mitapivat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 286 participants
- Where
- 91 sitesin 16 countries
- Study dates
- 11 Feb 2022to Feb 2030
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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).
Trial locations and contacts
91 sites in 16 countries.
91 sites in 16 countries
United States28 sites
University of Michigan
Ann Arbor, Michigan, 48109-5000
National Heart Lung and Blood Institute
Bethesda, Maryland, 20814
Massachusetts General Hospital
Boston, Massachusetts, 02114-2621
Boston Children's Hospital
Boston, Massachusetts, 02115-5724
Boston Medical Center & Boston University School of Medicine
Boston, Massachusetts, 02118
University of Chicago Medical Center
Chicago, Illinois, 60637-1443
Children's Hospital of Michigan
Detroit, Michigan, 48201
University of Connecticut Health Center
Farmington, Connecticut, 06030-0001
Southern Specialty Clinic
Flowood, Mississippi, 39232
East Carolina University - Brody School of Medicine
Greenville, North Carolina, 27834
University of Texas Health Science Center of Houston
Houston, Texas, 77030-1501
Texas Children's Hospital
Houston, Texas, 77030
Riley Hospital For Children
Indianapolis, Indiana, 46202-5109
University of California San Diego
La Jolla, California, 92037-1337
Kaiser Permanente - Largo Medical Center
Largo, Maryland, 20774-5374
Cure 4 The Kids Foundation, A Division of Roseman University of Health Sciences
Las Vegas, Nevada, 89106
UCLA Health
Los Angeles, California, 90095-1678
Mississippi Center for Advanced Medicine
Madison, Mississippi, 39110-6115
Sylvester Comprehensive Cancer Center-Miami
Miami, Florida, 33101
Children's Hospital Oakland
Oakland, California, 94609
Penn Medicine - University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104-5127
St. Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134-1011
Lifespan at Rhode Island Hospital
Providence, Rhode Island, 02903
Virginia Commonwealth University
Richmond, Virginia, 23298-5058
Seattle Cancer Care Alliance, University of Washington
Seattle, Washington, 98195
LSU Health Sciences Center - Shreveport
Shreveport, Louisiana, 71103-4228
Children's National Hospital
Washington D.C., District of Columbia, 20010-2916
MedStar Washington Hospital Center
Washington D.C., District of Columbia, 20010
Brazil8 sites
Hospital de Clínicas da Unicamp
Campinas, São Paulo, 13083-878
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
Porto Alegre, Rio Grande do Sul, 90035-903
Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
Porto Alegre, Rio Grande do Sul, 90619-900
Multihemo Servicos Medicos S/A
Recife, Pernambuco, 50070-460
Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
Ribeirão Preto, São Paulo, 14051-140
HEMORIO Instituto Nacional de Hematologia
Rio de Janeiro, 20211-030
Praxis Pesquisa Medica
Santo André, São Paulo
Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
São Paulo, 05403-010
Kenya7 sites
Kemri Usamru
Kisumu, Western, 40100
Kondele Children's Hospital
Kisumu, 40100
Victoria Biomedical Research Institute (VIBRI)
Kisumu, 40100
KEMRI CRDR Clinical Research Clinic Nairobi
Nairobi, 00100
KEMRI/CRDR Siaya Clinical Research Annex
Nairobi, 00200
Strathmore University
Nairobi, 00200
Gertrude's Children's Hospital
Nairobi, 42325- 00100
United Kingdom7 sites
Cambridge University Hospitals NHS Foundation Trust
Cambridge, CB2 0QQ
Evelina Children's Hospital
London, City of London, SE1 7EH
Guy's and St Thomas' NHS Foundation Trust
London, SE1 7EH
King's College Hospital NHS Foundation Trust
London, SE5 9RS
Hammersmith Hospital
London, W12 0HS
University College London Hospitals (UCLH)
London, WC1E 6BT
Manchester Royal Infirmary, Manchester University NHS Foundation Trust
Manchester, M13 9WL
France6 sites
Hôpital Pellegrin, CHU de Bordeaux
Bordeaux, Gironde, 33000
CHU Hôpital Henri Mondor
Créteil, Val-de-Marne, 94000
Hopitaux de La Timone
Marseille, Bouches-du-Rhône, 13005
Hôpital Européen Georges Pompidou
Paris, Île-de-France Region, 75015
CHU Guadeloupe
Pointe à Pitre, Guadeloupe, 97139
Institut Universitaire du Cancer de Toulouse - Oncopole
Toulouse, Haute-Garonne, 31059
Italy6 sites
Ente Ospedaliero Ospedali Galliera
Genoa, Liguria, 16128
Azienda Ospedaliero Universitaria Di Modena Policlinico
Modena, Emilia-Romagna, 41100
A.O.R.N. "A. Cardarelli"
Naples, Campania, 80131
AOU dell'Università degli Studi della Campania Luigi Vanvitelli
Naples, Campania, 80138
Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
Palermo, Sicily, 90146
IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
Rome, Lazio, 00165
Belgium5 sites
Hôpital Erasme
Anderlecht, Brussels Capital, 1070
ZAS Cadix
Antwerp, 2030
Universitair Ziekenhuis Antwerpen
Edegem, Brussels Capital, 2650
CHR de la Citadelle
Liège, 4000
Clinique CHC MontLégia
Liège, 4000
Canada4 sites
McMaster University - St. Joseph's Healthcare Hamilton
Hamilton, Ontario, L8N 3Z5
CHU Montreal
Montreal, Quebec, H2X 3E4
McGill University Health Center
Montreal, Quebec, H4A 3J1
University Health Network
Toronto, Ontario, M5G2C4
Lebanon4 sites
American University of Beirut Medical Center
Beirut, Beirut, 11-0236
American University of Beirut Medical Center
Beirut, 4407-2020
Hammoud Hospital University Medical Center
Sidon, H96G+247
Nini Hospital
Tarablus, North Lebanon, 1434
Israel3 sites
HaEmek Medical Center
Afula, 18101
Rambam Medical Center
Haifa, Ḥeifā, 31096
Ziv Medical Center
Safed, Ḥeifā, 13100
Nigeria3 sites
National Hospital Abuja
Abuja, Federal Capital Territory, 900271
University of Abuja Teaching Hospital
Abuja, Federal Capital Territory, 900271
Lagos University Teaching Hospital
Surulere, Lagos, 101014
Turkey (Türkiye)3 sites
Hacettepe Universitesi Tip Fakultesi Hastanesi
Ankara, Adana, 06200
Hacettepe University
Ankara, Adana
Acibadem Adana Hospital
Seyhan, Adana, 01130
Germany2 sites
Universitätsklinikum Essen
Essen, 45147
Universitätsklinikum Regensburg
Regensburg, 93053
Netherlands2 sites
Erasmus MC
Rotterdam, South Holland, 3015 GD
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX
Saudi Arabia2 sites
King Khalid University Hospital
Riyadh, Ar Riya, 11472
King Abdullah International Medical Research Center
Riyadh, 1515 (KAIMRC)
Oman1 site
Sultan Qaboos University Hospital, Hematology Department, COM&HS
Muscat, Musqal, H5QC+36M
About this study
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
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.
Read the 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.
- Conditions
- Sickle Cell Disease
- Being tested
- Mitapivat, Mitapivat-matching placebo
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MitapivatDrug
Also called AG-348, Mitapivat Sulfate
Mitapivat tablets
Mitapivat-matching placeboOther
Placebo to match 50 mg or 100 mg tablets
Mitapivat-matching placeboOther
Placebo to match 100 mg tablets
| Study group | Role | What they receive |
|---|---|---|
| Phase 2: Mitapivat 50 mg BID | Experimental | Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks. Receives: Drug: Mitapivat |
| Phase 2: Mitapivat 100 mg BID | Experimental | Double-blind Period: Mitapivat 100 mg BID for 12 weeks. Receives: Drug: Mitapivat |
| Phase 2: Placebo | Placebo comparator | Double-blind Period: Mitapivat-matching placebo for 12 weeks. Receives: Other: Mitapivat-matching placebo |
| Phase 2: Open-Label Extension Period | Experimental | 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. Receives: Drug: Mitapivat |
| Phase 3: Mitapivat 100 mg BID | Experimental | Double-blind Period: Mitapivat 100 mg BID for 52 weeks. Receives: Drug: Mitapivat |
| Phase 3: Placebo | Placebo comparator | Double-blind Period: Mitapivat-matching placebo for 52 weeks. Receives: Other: Mitapivat-matching placebo |
| Phase 3: Open-Label Extension Period | Experimental | 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. Receives: Drug: Mitapivat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 2: Percentage of Participants With Hemoglobin (Hb) Response
Measured: Week 12
Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)
Measured: Up to Week 12
Phase 3: Percentage of Participants With Hb Response
Measured: Week 52
Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs)
Measured: Up to Week 52
Secondary outcomes (36)
Phase 2: Change From Baseline in Hb Concentration
Measured: Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Indirect Bilirubin
Measured: Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH)
Measured: Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Absolute Reticulocytes Count
Measured: Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Percent Reticulocytes
Measured: Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Erythropoietin
Measured: 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
Measured: Baseline, Week 10 up to Week 12
Phase 2: Annualized Rate of SCPCs
Measured: 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)
Measured: Day 1 up to Week 8
Phase 2: Mitapivat Concentration Over Time
Measured: Day 1 up to Week 8
Phase 2: Mitapivat Area Under the Concentration
Measured: Day 1 up to Week 8
Phase 2: Mitapivat Maximum (Peak) Concentration
Measured: Day 1 up to Week 8
Phase 3: Change From Baseline in Hb Concentration
Measured: Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Indirect Bilirubin
Measured: Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Percent Reticulocytes
Measured: Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores
Measured: Baseline, Week 24 up to Week 52
Phase 3: Annualized Frequency of Hospitalizations for SCPC
Measured: Up to Week 52
Phase 3: Change From Baseline in LDH Concentration
Measured: Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Absolute Reticulocytes
Measured: Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Erythropoietin
Measured: Baseline, Week 24 up to Week 52
Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue
Measured: Baseline, Weeks 24, 28, 40, and 52
Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue
Measured: Baseline, Weeks 24, 28, 40, and 52
Phase 3: Time to First SCPC
Measured: Up to Week 52
Phase 3: Time to Second SCPC
Measured: Up to Week 52
Phase 3: Annualized Rate of Hospitalization Days for SCPC
Measured: Up to Week 52
Phase 3: Annualized Rate of Emergency Room Visits for SCPC
Measured: Up to Week 52
Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT)
Measured: Baseline, Week 52
Phase 3: Change From Baseline in PROMIS Pain Intensity
Measured: Baseline, Week 24 and 52
Phase 3: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact
Measured: Baseline, Week 24 and 52
Phase 3: PGIC of Pain
Measured: Baseline, Week 52
Phase 3: Change From Baseline in PGIS of Pain
Measured: Baseline, Week 52
Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)
Measured: Up to 56 weeks
Phase 3: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels
Measured: Day 1 up to Week 40
Phase 3: Mitapivat Concentration Over Time
Measured: Day 1 up to Week 40
Phase 3: Mitapivat Area Under the Concentration Curve
Measured: Day 1 up to Week 40
Phase 3: Mitapivat Maximum (Peak) Concentration
Measured: Day 1 up to Week 40
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Sep 2021
- Study start11 Feb 2022
- Primary completion30 Oct 2025
- Study completionFeb 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by Agios Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 286 participants (actual)
Sponsor and investigators
- Lead sponsor
- Agios Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05031780
- Sponsor's protocol ID
- AG348-C-020
- Other IDs
- 2021-001674-34
- Status last verified
- Oct 2026
- First submitted
- 29 Jul 2021
- Last updated
- 26 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Andemariam B, Kuo KHM, Algahtani FH, Al Kindi S, Ataga KI, Bartolucci P, Campbell A, Colombatti R, Glaros AK, Hafraoui K, Idowu M, Jacob SA, Lobo CLC, Nnodu OE, Otieno L, Smith WR, Thein SL, van Beers EJ, Gheuens S, Hensley B, Oluyadi A, Osman K, Pathan A, Patil S, Song T, Yates AM, Zaidi AU, Minniti C, Abboud MR; RISE UP Investigators. Efficacy and safety of mitapivat in patients with sickle cell disease (RISE UP): a phase 3, double-blind, global, randomised, placebo-controlled trial. Lancet. 2026 Oct 24;408(10565):1705-1716. doi: 10.1016/S0140-6736(26)01480-7.
PubMed 42913682Conrey 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.
PubMed 41809202Idowu 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.
PubMed 39644907van 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.
PubMed 37934880Obadina 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.
PubMed 37254256
Study at a glance
From the registry record, last updated by the sponsor on 26 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05031780
- Acronym / sponsor ID
- AG348-C-020
- Conditions
- Sickle Cell Disease
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 286 participants (actual)
- Lead sponsor
- Agios Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 11 Feb 2022 (actual)
- Primary completion
- 30 Oct 2025 (actual)
- Study completion
- Feb 2030 (estimated)
- First posted
- 2 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Phase 2: Mitapivat 50 mg BID | Experimental | Drug: MitapivatDouble-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks. |
| Phase 2: Mitapivat 100 mg BID | Experimental | Drug: MitapivatDouble-blind Period: Mitapivat 100 mg BID for 12 weeks. |
| Phase 2: Placebo | Placebo comparator | Other: Mitapivat-matching placeboDouble-blind Period: Mitapivat-matching placebo for 12 weeks. |
| Phase 2: Open-Label Extension Period | Experimental | Drug: MitapivatParticipants 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 | Experimental | Drug: MitapivatDouble-blind Period: Mitapivat 100 mg BID for 52 weeks. |
| Phase 3: Placebo | Placebo comparator | Other: Mitapivat-matching placeboDouble-blind Period: Mitapivat-matching placebo for 52 weeks. |
| Phase 3: Open-Label Extension Period | Experimental | Drug: MitapivatParticipants 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. |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- 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;
Key exclusion criteria (9 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MitapivatAlso: AG-348, Mitapivat SulfateMitapivat tablets | Drug | Phase 2: Mitapivat 100 mg BID, Phase 2: Mitapivat 50 mg BID, Phase 2: Open-Label Extension Period, Phase 3: Mitapivat 100 mg BID, Phase 3: Open-Label Extension Period |
| Mitapivat-matching placeboPlacebo to match 50 mg or 100 mg tablets | Other | Phase 2: Placebo |
| Mitapivat-matching placeboPlacebo to match 100 mg tablets | Other | Phase 3: Placebo |
Primary outcome
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
36 secondary outcomes
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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Oct 2026.
- Derived from this study: PubMed 42913682Andemariam B, Kuo KHM, Algahtani FH, Al Kindi S, Ataga KI, Bartolucci P, Campbell A, Colombatti R, Glaros AK, Hafraoui K, Idowu M, Jacob SA, Lobo CLC, Nnodu OE, Otieno L, Smith WR, Thein SL, van Beers EJ, Gheuens S, Hensley B, Oluyadi A, Osman K, Pathan A, Patil S, Song T, Yates AM, Zaidi AU, Minniti C, Abboud MR; RISE UP Investigators. Efficacy and safety of mitapivat in patients with sickle cell disease (RISE UP): a phase 3, double-blind, global, randomised, placebo-controlled trial. Lancet. 2026 Oct 24;408(10565):1705-1716. doi: 10.1016/S0140-6736(26)01480-7.
- Derived from this study: PubMed 41809202Conrey 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.
- Derived from this study: PubMed 39644907Idowu 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.
- Derived from this study: PubMed 37934880van 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.
- Derived from this study: PubMed 37254256Obadina 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
91 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Mitapivat in people with Sickle Cell Disease, run by Agios Pharmaceuticals, Inc. at 91 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 26 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 91 sites in United States, Brazil, Kenya, United Kingdom, France and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 2: Percentage of Participants With Hemoglobin (Hb) Response (time frame: Week 12). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05031780, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2026.