Clinical trial NCT05031780: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Sickle Cell Disease
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-09-02
Enrollment: 286
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Phase 2: Percentage of Participants With Hemoglobin (Hb) Response
timeFrame: Week 12
measure: Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)
timeFrame: Up to Week 12
measure: Phase 3: Percentage of Participants With Hb Response
timeFrame: Week 52
measure: Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs)
timeFrame: Up to Week 52
Secondary outcomes:
measure: Phase 2: Change From Baseline in Hb Concentration
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Change From Baseline in Indirect Bilirubin
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH)
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Change From Baseline in Absolute Reticulocytes Count
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Change From Baseline in Percent Reticulocytes
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Change From Baseline in Erythropoietin
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Change From Baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score
timeFrame: Baseline, Week 10 up to Week 12
measure: Phase 2: Annualized Rate of SCPCs
timeFrame: Up to Week 12
measure: Phase 2: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG)
timeFrame: Day 1 up to Week 8
measure: Phase 2: Mitapivat Concentration Over Time
timeFrame: Day 1 up to Week 8
measure: Phase 2: Mitapivat Area Under the Concentration
timeFrame: Day 1 up to Week 8
measure: Phase 2: Mitapivat Maximum (Peak) Concentration
timeFrame: Day 1 up to Week 8
measure: Phase 3: Change From Baseline in Hb Concentration
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Change From Baseline in Indirect Bilirubin
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Change From Baseline in Percent Reticulocytes
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Annualized Frequency of Hospitalizations for SCPC
timeFrame: Up to Week 52
measure: Phase 3: Change From Baseline in LDH Concentration
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Change From Baseline in Absolute Reticulocytes
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Change From Baseline in Erythropoietin
timeFrame: Baseline, Week 24 up to Week 52
measure: Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue
timeFrame: Baseline, Weeks 24, 28, 40, and 52
measure: Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue
timeFrame: Baseline, Weeks 24, 28, 40, and 52
measure: Phase 3: Time to First SCPC
timeFrame: Up to Week 52
measure: Phase 3: Time to Second SCPC
timeFrame: Up to Week 52
measure: Phase 3: Annualized Rate of Hospitalization Days for SCPC
timeFrame: Up to Week 52
measure: Phase 3: Annualized Rate of Emergency Room Visits for SCPC
timeFrame: Up to Week 52
measure: Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT)
timeFrame: Baseline, Week 52
measure: Phase 3: Change From Baseline in PROMIS Pain Intensity
timeFrame: Baseline, Week 24 and 52
measure: Phase 3: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact
timeFrame: Baseline, Week 24 and 52
measure: Phase 3: PGIC of Pain
timeFrame: Baseline, Week 52
measure: Phase 3: Change From Baseline in PGIS of Pain
timeFrame: Baseline, Week 52
measure: Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)
timeFrame: Up to 56 weeks
measure: Phase 3: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels
timeFrame: Day 1 up to Week 40
measure: Phase 3: Mitapivat Concentration Over Time
timeFrame: Day 1 up to Week 40
measure: Phase 3: Mitapivat Area Under the Concentration Curve
timeFrame: Day 1 up to Week 40
measure: Phase 3: Mitapivat Maximum (Peak) Concentration
timeFrame: Day 1 up to Week 40
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: UCLA Health
state: California
city: Oakland
country: United States
facility: Children's Hospital Oakland
state: California
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
city: Washington
country: United States
facility: Children's National Hospital
state: District of Columbia
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center-Miami
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital For Children
state: Indiana
city: Shreveport
country: United States
facility: LSU Health Sciences Center - Shreveport
state: Louisiana
city: Bethesda
country: United States
facility: National Heart Lung and Blood Institute
state: Maryland
city: Largo
country: United States
facility: Kaiser Permanente - Largo Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center & Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Flowood
country: United States
facility: Southern Specialty Clinic
state: Mississippi
city: Madison
country: United States
facility: Mississippi Center for Advanced Medicine
state: Mississippi
city: Las Vegas
country: United States
facility: Cure 4 The Kids Foundation, A Division of Roseman University of Health Sciences
state: Nevada
city: Greenville
country: United States
facility: East Carolina University - Brody School of Medicine
state: North Carolina
city: Philadelphia
country: United States
facility: Penn Medicine - University of Pennsylvania Health System
state: Pennsylvania
city: Philadelphia
country: United States
facility: St. Christopher's Hospital for Children
state: Pennsylvania
city: Providence
country: United States
facility: Lifespan at Rhode Island Hospital
state: Rhode Island
city: Houston
country: United States
facility: University of Texas Health Science Center of Houston
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance, University of Washington
state: Washington
city: Anderlecht
country: Belgium
facility: Hôpital Erasme
state: Brussels
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
state: Brussels
city: Antwerpen
country: Belgium
facility: ZAS Cadix
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Liège
country: Belgium
facility: Clinique CHC MontLégia
city: Recife
country: Brazil
facility: Multihemo Servicos Medicos S/A
state: Pernambuco
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
state: Rio Grande Do Sul
city: Campinas
country: Brazil
facility: Hospital de Clínicas da Unicamp
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
state: São Paulo
city: Santo Andre
country: Brazil
facility: Praxis Pesquisa Medica
state: São Paulo
city: Rio De Janeiro
country: Brazil
facility: HEMORIO Instituto Nacional de Hematologia
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
city: Hamilton
country: Canada
facility: McMaster University - St. Joseph's Healthcare Hamilton
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montreal
country: Canada
facility: CHU Montreal
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Marseille
country: France
facility: Hopitaux de La Timone
state: Bouches-du-Rhône
city: Bordeaux
country: France
facility: Hôpital Pellegrin, CHU de Bordeaux
state: Gironde
city: Pointe-à-Pitre
country: France
facility: CHU Guadeloupe
state: Guadeloupe
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse - Oncopole
state: Haute-Garonne
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
state: Ile De France
city: Créteil
country: France
facility: CHU Hôpital Henri Mondor
state: Val-de-Marne
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Afula
country: Israel
facility: HaEmek Medical Center
city: Haifa
country: Israel
facility: Rambam Medical Center
state: Ḥeifā
city: Safed
country: Israel
facility: Ziv Medical Center
state: Ḥeifā
city: Napoli
country: Italy
facility: A.O.R.N. "A. Cardarelli"
state: Campania
city: Napoli
country: Italy
facility: AOU dell'Università degli Studi della Campania Luigi Vanvitelli
state: Campania
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria Di Modena Policlinico
state: Emilia-Romagna
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
state: Lazio
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera
state: Liguria
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
state: Sicilia
city: Kisumu
country: Kenya
facility: Kemri Usamru
state: Western
city: Kisumu
country: Kenya
facility: Kondele Children's Hospital
city: Kisumu
country: Kenya
facility: Victoria Biomedical Research Institute (VIBRI)
city: Nairobi
country: Kenya
facility: KEMRI CRDR Clinical Research Clinic Nairobi
city: Nairobi
country: Kenya
facility: KEMRI/CRDR Siaya Clinical Research Annex
city: Nairobi
country: Kenya
facility: Strathmore University
city: Nairobi
country: Kenya
facility: Gertrude's Children's Hospital
city: Beirut
country: Lebanon
facility: American University of Beirut Medical Center
state: Beyrouth
city: Tarablus
country: Lebanon
facility: Nini Hospital
state: Liban Nord
city: Beirut
country: Lebanon
facility: American University of Beirut Medical Center
city: Sidon
country: Lebanon
facility: Hammoud Hospital University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid-Holland
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Abuja
country: Nigeria
facility: National Hospital Abuja
state: Abuja Capital Territory
city: Abuja
country: Nigeria
facility: University of Abuja Teaching Hospital
state: Abuja Capital Territory
city: Suru-Lere
country: Nigeria
facility: Lagos University Teaching Hospital
state: Lagos
city: Muscat
country: Oman
facility: Sultan Qaboos University Hospital, Hematology Department, COM&HS
state: Musqal
city: Riyadh
country: Saudi Arabia
facility: King Khalid University Hospital
state: Ar Riya
city: Riyadh
country: Saudi Arabia
facility: King Abdullah International Medical Research Center
city: Ankara
country: Turkey
facility: Hacettepe University
state: Adana
city: Seyhan
country: Turkey
facility: Acibadem Adana Hospital
state: Adana
city: London
country: United Kingdom
facility: Evelina Children's Hospital
state: City Of London
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London Hospitals (UCLH)
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary, Manchester University NHS Foundation Trust
Study officials:
References: