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

Sickle Cell Disease Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05031780
• Other study ID #: AG348-C-020
• Secondary ID: 2021-001674-34
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 11, 2022
• Est. completion date: February 2030

Study information

• Verified date: April 2024
• Source: Agios Pharmaceuticals, Inc.
• Contact: Agios Medical Affairs
• Phone: 833-228-8474
• Email: medinfo[@]agios.com
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 267
• Est. completion date: February 2030
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Mitapivat
Mitapivat tablets

Other:
• Mitapivat-matching placebo
Placebo to match 50 mg or 100 mg tablets
• Mitapivat-matching placebo
Placebo to match 100 mg tablets

Locations

Country	Name	City	State
Belgium	Hôpital Erasme	Anderlecht	Brussels
Belgium	ZNA Stuivenberg	Antwerpen	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem	Brussels
Belgium	CHR de la Citadelle	Liège
Belgium	Clinique CHC MontLégia	Liège
Brazil	Hospital de Clínicas da Unicamp	Campinas	São Paulo
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	Multihemo Servicos Medicos S/A	Recife	Pernambuco
Brazil	Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP	Ribeirão Preto	São Paulo
Brazil	HEMORIO Instituto Nacional de Hematologia	Rio De Janeiro
Brazil	Praxis Pesquisa Medica	Santo Andre	São Paulo
Brazil	Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo	São Paulo
Canada	McMaster University - St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Canada	CHU Montreal	Montreal	Quebec
Canada	McGill University Health Center	Montreal	Quebec
Canada	University Health Network	Toronto	Ontario
France	Hôpital Pellegrin, CHU de Bordeaux	Bordeaux	Gironde
France	CHU Hôpital Henri Mondor	Créteil	Val-de-Marne
France	Hopitaux de La Timone	Marseille	Bouches-du-Rhône
France	Hôpital Européen Georges Pompidou	Paris	Ile De France
France	CHU Guadeloupe	Pointe-à-Pitre	Guadeloupe
France	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse	Haute-Garonne
Germany	Universitätsklinikum Essen	Essen
Germany	Universitätsklinikum Regensburg	Regensburg
Ghana	Korle-Bu Teaching Hospital	Accra
Ghana	Komfo Anokye Teaching Hospital	Kumasi
Israel	HaEmek Medical Center	Afula
Israel	Rambam Medical Center	Haifa	?eifa
Israel	Ziv Medical Center	Safed	?eifa
Italy	Ente Ospedaliero Ospedali Galliera	Genova	Liguria
Italy	Azienda Ospedaliero Universitaria Di Modena Policlinico	Modena	Emilia-Romagna
Italy	A.O.R.N. "A. Cardarelli"	Napoli	Campania
Italy	AORN A Cardarelli	Napoli	Campania
Italy	AOU dell'Università degli Studi della Campania Luigi Vanvitelli	Napoli	Campania
Italy	Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello	Palermo	Sicilia
Italy	IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN	Roma	Lazio
Kenya	Kemri Usamru	Kisumu	Western
Kenya	Kondele Children's Hospital	Kisumu
Kenya	Victoria Biomedical Research Institute (VIBRI)	Kisumu
Kenya	Gertrude's Children's Hospital	Nairobi
Kenya	KEMRI CRDR Clinical Research Clinic Nairobi	Nairobi
Kenya	KEMRI/CRDR Siaya Clinical Research Annex	Nairobi
Kenya	Strathmore University	Nairobi
Lebanon	American University of Beirut Medical Center	Beirut	Beyrouth
Lebanon	Hammoud Hospital University Medical Center	Sidon
Lebanon	Nini Hospital	Tarablus	Liban Nord
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Nigeria	National Hospital Abuja	Abuja	Abuja Capital Territory
Nigeria	University of Abuja Teaching Hospital	Abuja	Abuja Capital Territory
Nigeria	University of Calabar Teaching Hospital	Calabar
Nigeria	The University of Nigeria Teaching Hospiatal	Enugu
Nigeria	Barau Dikko Teaching Hospital (BDTH), Kaduna	Kaduna
Nigeria	Lagos University Teaching Hospital	Suru-Lere	Lagos
Oman	Sultan Qaboos University Hospital, Hematology Department, COM&HS	Muscat	Musqal
Saudi Arabia	King Abdullah International Medical Research Center	Riyadh
Turkey	Hacettepe University	Ankara	Adana
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi	Istanbul
Turkey	Ege Universitesi Tip Fakultesi Hastanesi	Izmir
Turkey	Acibadem Adana Hospital	Seyhan	Adana
Turkey	Mersin University Medical Faculty	Yenisehir	Içel
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Evelina Children's Hospital	London	City Of London
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Hammersmith Hospital	London
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	University College London Hospitals (UCLH)	London
United Kingdom	Manchester Royal Infirmary, Manchester University NHS Foundation Trust	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	National Heart Lung and Blood Institute	Bethesda	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Boston Medical Center & Boston University School of Medicine	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago Medical Center	Chicago	Illinois
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	University of Connecticut Health Center	Farmington	Connecticut
United States	East Carolina University - Brody School of Medicine	Greenville	North Carolina
United States	Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Children's Hospital	Houston	Texas
United States	University of Texas Health Science Center of Houston	Houston	Texas
United States	Riley Hospital For Children	Indianapolis	Indiana
United States	University of California San Diego	La Jolla	California
United States	Kaiser Permanente - Largo Medical Center	Largo	Maryland
United States	Cure 4 The Kids Foundation, A Division of Roseman University of Health Sciences	Las Vegas	Nevada
United States	UCLA Health	Los Angeles	California
United States	Mississippi Center for Advanced Medicine	Madison	Mississippi
United States	Sylvester Comprehensive Cancer Center-Miami	Miami	Florida
United States	Yale University	New Haven	Connecticut
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Children's Hospital Oakland	Oakland	California
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	Virginia Commonwealth University	Richmond	Virginia
United States	Seattle Cancer Care Alliance, University of Washington	Seattle	Washington
United States	LSU Health Sciences Center - Shreveport	Shreveport	Louisiana
United States	Children's National Hospital	Washington	District of Columbia
United States	MedStar Washington Hospital Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Agios Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  France,  Germany,  Ghana,  Israel,  Italy,  Kenya,  Lebanon,  Netherlands,  Nigeria,  Oman,  Saudi Arabia,  Turkey,  United Kingdom, 

Outcome

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