This study is currently recruiting participants.
Number
001565-H
Sponsoring Institute
National Heart, Lung and Blood Institute (NHLBI)
Recruitment Detail
Type: Enrolling by Invitation Gender: Male & Female Min Age: 16 Years Max Age: 100 Years
Referral Letter Required
No
Population Exclusion(s)
Fetuses;Pregnant Women;Neonates;Adults who are or may become unable to consent
Keywords
Sickle Cell Disease; mitapivat; AG-348; Sickle Cell Anemia; SCD
Recruitment Keyword(s)
None
Condition(s)
Sickle Cell Disease; Sickle Cell Anemia; SCD
Investigational Drug(s)
AG-348
Investigational Device(s)
Intervention(s)
Drug: mitapivat Other: Placebo Drug: mitapivat (AG-348)
Supporting Site
National Heart, Lung, and Blood Institute
Sickle cell disease (SCD) is an inherited blood disorder. The disease affects the ability of red blood cells to carry oxygen. This in turn can injure organs, including the heart, lungs, and kidneys. Current treatments for SCD are not always effective.
Objective:
To test a drug (mitapivat) in people with SCD.
Eligibility:
People aged 16 years and older with SCD.
Design:
Participants will have 12 clinic visits in 52 weeks.
Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of their heart function and a bone scan. They will complete questionnaires about their quality of life.
Mitapivat is a tablet taken by mouth. All participants will take a tablet 2 times a day for 1 year. Some participants will take the study drug. Others will take a placebo. The placebo looks like the study drug but does not contain any medicine. Neither participants nor health providers will know which tablet they are taking. They will record their doses in an electronic diary.
Bone scans, blood tests, and other tests will be repeated during study visits. Study visits will also include a 6-minute walk test: Participants will walk as far as they can on a hard, flat surface for 6 minutes.
Participants may choose to remain in the study for 4 more years after the end of 1 year. Those who had been taking the placebo will switch to mitapivat during this period. The frequency of study visits will be reduced.
Participants will have a safety follow-up visit about 28 days after their last dose of the study drug.
--Back to Top--
INCLUSION CRITERIA: -Age >=16 years; subjects age 16 or 17 years must be documented Tanner Stage 5 -Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/(Beta)+-thalassemia, HbS/Beta+-thalassemia, or other sickle cell syndrome variants) -At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the 12 months prior to providing informed assent/consent. -Hemoglobin >=5.5 and <=10.5 g/dL. 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 prior to randomization. -Women of childbearing potential (WOCBP) and men with partners who are WOCBP must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed assent/consent, throughout the study, and for 28 days after the last dose of study drug for women and 90 days after the last dose of study drug for men. The second form of contraception can include an acceptable barrier method. -Written informed assent/consent (for subjects under 18 years of age, or prior to the age at which a subject is considered legally an adult per local regulations, parental permission and child assent will be obtained) must be obtained before any study-related procedures are conducted and subjects must be willing to comply with all study procedures for the duration of the study EXCLUSION CRITERIA: -Pregnant, breastfeeding, or parturient -Receiving regularly scheduled red blood cell (RBC) transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or vaso-occlusive crisis (VOC) is permitted. Additionally, subjects may not have received a transfusion within 60 days before providing informed assent/consent or during the Screening Period. -Hospitalized for an SCPC or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period -Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of such therapies must have been administered at least 90 days before randomization. -History of any malignancy except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Subjects must not have active disease or received anticancer treatment <=5 years before providing informed assent/consent. -History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed assent/consent, including but not limited to: --New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia --Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism --Heart rate-corrected QT interval using Fridericia s method of >=470 milliseconds for female subjects and >=450 milliseconds for male subjects, except for right or left bundle branch block --Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% --Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right heart failure, and oxygen indicated -Hepatobiliary disorders including but not limited to: --Liver disease with histopathological evidence of cirrhosis or severe fibrosis --Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible) --History of drug-induced cholestatic hepatitis --Aspartate aminotransferase >2.5x the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5x the ULN (unless due to hepatic iron deposition) -Renal dysfunction as defined by an estimated glomerular filtration rate <30 mL/min/1.73 m^2 by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation -Nonfasting triglycerides >440 mg/dL (5 mmol/L) -Active uncontrolled infection requiring systemic antimicrobial therapy -Positive test for hepatitis C virus antibody with evidence of active hepatitis C virus infection, or positive test for hepatitis B surface antigen -Positive test for HIV-1 antibody or HIV-2 antibody -History of major surgery (including splenectomy) <=16 weeks before providing informed assent/consent and/or planning on undergoing a major surgical procedure during the study -Current enrollment or past participation (within 90 days before randomization or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device -Prior exposure to gene therapy or prior bone marrow or stem cell transplantation. -Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before randomization. -Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for >=5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for >=28 days or a time frame equivalent to 5 half-lives (whichever is longer), prior to randomization -Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for >=10 weeks before randomization. -Known allergy to mitapivat or tablet excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and the Opadry Blue II film-coat [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD and C Blue number 2]). -Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are: --Subjects deprived of liberty by court or administrative decision (eg, subjects accommodated in an institution by order of an authority or court) --Subjects undergoing psychiatric care without their consent --Subjects admitted to a health or social establishment for purposes other than research --Adult subjects subject to a legal protection measure (guardian, curatorship, legal protection) --Subjects unable to express their consent -Phase 3 only: Participated in the Phase 2 portion of Study AG348-C-020.
-Age >=16 years; subjects age 16 or 17 years must be documented Tanner Stage 5
-Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/(Beta)+-thalassemia, HbS/Beta+-thalassemia, or other sickle cell syndrome variants)
-At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the 12 months prior to providing informed assent/consent.
-Hemoglobin >=5.5 and <=10.5 g/dL. 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 prior to randomization.
-Women of childbearing potential (WOCBP) and men with partners who are WOCBP must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed assent/consent, throughout the study, and for 28 days after the last dose of study drug for women and 90 days after the last dose of study drug for men. The second form of contraception can include an acceptable barrier method.
-Written informed assent/consent (for subjects under 18 years of age, or prior to the age at which a subject is considered legally an adult per local regulations, parental permission and child assent will be obtained) must be obtained before any study-related procedures are conducted and subjects must be willing to comply with all study procedures for the duration of the study
EXCLUSION CRITERIA:
-Pregnant, breastfeeding, or parturient
-Receiving regularly scheduled red blood cell (RBC) transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or vaso-occlusive crisis (VOC) is permitted. Additionally, subjects may not have received a transfusion within 60 days before providing informed assent/consent or during the Screening Period.
-Hospitalized for an SCPC or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period
-Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of such therapies must have been administered at least 90 days before randomization.
-History of any malignancy except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Subjects must not have active disease or received anticancer treatment <=5 years before providing informed assent/consent.
-History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed assent/consent, including but not limited to:
--New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia
--Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
--Heart rate-corrected QT interval using Fridericia s method of >=470 milliseconds for female subjects and >=450 milliseconds for male subjects, except for right or left bundle branch block
--Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50%
--Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right heart failure, and oxygen indicated
-Hepatobiliary disorders including but not limited to:
--Liver disease with histopathological evidence of cirrhosis or severe fibrosis
--Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible)
--History of drug-induced cholestatic hepatitis
--Aspartate aminotransferase >2.5x the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5x the ULN (unless due to hepatic iron deposition)
-Renal dysfunction as defined by an estimated glomerular filtration rate <30 mL/min/1.73 m^2 by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation
-Nonfasting triglycerides >440 mg/dL (5 mmol/L)
-Active uncontrolled infection requiring systemic antimicrobial therapy
-Positive test for hepatitis C virus antibody with evidence of active hepatitis C virus infection, or positive test for hepatitis B surface antigen
-Positive test for HIV-1 antibody or HIV-2 antibody
-History of major surgery (including splenectomy) <=16 weeks before providing informed assent/consent and/or planning on undergoing a major surgical procedure during the study
-Current enrollment or past participation (within 90 days before randomization or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device
-Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
-Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before randomization.
-Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for >=5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for >=28 days or a time frame equivalent to 5 half-lives (whichever is longer), prior to randomization
-Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for >=10 weeks before randomization.
-Known allergy to mitapivat or tablet excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and the Opadry Blue II film-coat [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD and C Blue number 2]).
-Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:
--Subjects deprived of liberty by court or administrative decision (eg, subjects accommodated in an institution by order of an authority or court)
--Subjects undergoing psychiatric care without their consent
--Subjects admitted to a health or social establishment for purposes other than research
--Adult subjects subject to a legal protection measure (guardian, curatorship, legal protection)
--Subjects unable to express their consent
-Phase 3 only: Participated in the Phase 2 portion of Study AG348-C-020.
Principal Investigator
Referral Contact
For more information: