A Dose-Finding Study of AG-348 in Sickle Cell Disease
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ClinicalTrials.gov Identifier: NCT04000165 |
Recruitment Status :
Completed
First Posted : June 27, 2019
Results First Posted : July 12, 2022
Last Update Posted : July 12, 2022
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Tracking Information | |||||||||||||
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First Submitted Date ICMJE | June 22, 2019 | ||||||||||||
First Posted Date ICMJE | June 27, 2019 | ||||||||||||
Results First Submitted Date ICMJE | May 6, 2022 | ||||||||||||
Results First Posted Date ICMJE | July 12, 2022 | ||||||||||||
Last Update Posted Date | July 12, 2022 | ||||||||||||
Actual Study Start Date ICMJE | July 11, 2019 | ||||||||||||
Actual Primary Completion Date | June 21, 2021 (Final data collection date for primary outcome measure) | ||||||||||||
Current Primary Outcome Measures ICMJE |
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Original Primary Outcome Measures ICMJE |
safety and tolerability [ Time Frame: day 51 ] frequency and severity of AEs, and changes in laboratory parameters, including levels in hemoglobin, reticulocyte counts, bilirubin and lactate dehydrogenase
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Change History | |||||||||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE |
PK & PD [ Time Frame: day 51 ] RBC 2,3-DPG activities from baseline, 2,3-DPG, ATP levels at different doses of AG-348 and change from baseline etc.
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Current Other Pre-specified Outcome Measures | Not Provided | ||||||||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||||||||
Descriptive Information | |||||||||||||
Brief Title ICMJE | A Dose-Finding Study of AG-348 in Sickle Cell Disease | ||||||||||||
Official Title ICMJE | A Pilot Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease | ||||||||||||
Brief Summary | Background: Sickle Cell Disease (SCD) is an inherited blood disorder. People with SCD have abnormal hemoglobin in their red blood cells. Researchers are investigating the safety and efficacy of an investigational medicine called AG-348 (mitapivat sulfate) to determine if it will help people with SCD. Objective: To test the tolerability and safety of AG-348 in people with SCD. Eligibility: People ages 18 and older with SCD. Design: Participants will have 8 visits over approximately 14 weeks. At the first visit participants will be screened with a medical history, a physical exam, blood and urine testing, and an EKG. During the following 5 visits, participants will stay at the clinic for 1 night each. Participants will take study drug in increasing doses up to visit 6, after which the drug will be tapered off. All visits will include physical exam, blood, and urine tests. The last visit will occur 4 weeks after stopping the drug. Participants will provide DNA from the blood samples they provide. The DNA will be tested for an inherited gene that can cause differences in response to the study drug. Researchers may also test other genes to see if they can find any genes that interact with SCD. |
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Detailed Description | Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute clinical events and progressive organ damage. Episodic pain, triggered by micro-vasoocclusion induced by sickled red blood cells, is the most common acute complication and the leading cause of hospitalization. Management strategies for SCD have evolved very slowly, and treatment of acute pain is still limited to supportive therapy with opioid medication. Until recently in 2017, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but not universally effective. In addition to HU, transfusions with normal red blood cells are widely used to treat severe sickle crises, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). The only curative treatment is bone marrow transplantation, but this option carries significant risks and is limited by the availability of histocompatible donors. As the root cause of SCD is polymerization of deoxy-HbS, there is a strong rationale for exploring agents that could inhibit/ reduce the polymerization process itself. HbS polymerizes only when deoxygenated, its oxygenation is influenced by a few factors, one key factor being the 2,3- diphosphoglycerate (2,3-DPG) concentration in the red blood cell. 2,3-DPG decreases oxygen binding by preferentially binding to the low oxygen-affinity T conformation of HbS and also stabilizes the T form of hemoglobin S and HbS fiber. In addition, increased 2,3- DPG concentration decreases intracellular red cell pH further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of ATP production in red blood cells. Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis; PK converts phosphoenolpyruvate to pyruvate, creating 50% of the total red cell ATP that is essential for maintaining integrity of the red cell membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3- DPG, that favors polymerization of deoxy-HbS. In humans with SCD, and even in sickle carriers who are generally asymptomatic, reduced oxygen affinity will favor deoxygenation of HbS and its polymerization, and thus sickling. Indeed, the combination of PK deficiency and sickle cell trait causing an acute sickling syndrome has been previously reported in two cases. Current approaches to reduce HbS polymerization include fetal hemoglobin induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (eg. Oxbryta (TM) / Voxelotor / GBT440). Increasing red cell PK (PK-R) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. AG-348 / mitapivat is a novel, orally bioavailable, small molecule allosteric activator of PK-R, that is currently in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007). Overview of the preclinical AG-348 data and other data support dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation at all multiple ascending doses tested, supporting the potential role of AG-348 in the treatment of sickle cell disease. The overall objective of the present study is to determine the clinical safety and tolerability of AG-348 in subjects with SCD. |
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Study Type ICMJE | Interventional | ||||||||||||
Study Phase ICMJE | Early Phase 1 | ||||||||||||
Study Design ICMJE | Allocation: N/A Intervention Model: Sequential Assignment Masking: None (Open Label) Primary Purpose: Basic Science |
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Condition ICMJE | Sickle Cell Disease | ||||||||||||
Intervention ICMJE | Drug: AG-348
This is a nonrandomized, intra-patient dose escalating clinical study. AG-348 will be administered starting at 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Other Name: Mitapivat
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Study Arms ICMJE | Experimental: AG-348 in participants with Sickle Cell Disease
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Intervention: Drug: AG-348
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Publications * | Xu JZ, Conrey A, Frey I, Gwaabe E, Menapace LA, Tumburu L, Lundt M, Lequang T, Li Q, Glass K, Dunkelberger EB, Iyer V, Mangus H, Kung C, Dang L, Kosinski PA, Hawkins P, Jeffries N, Eaton WA, Lay Thein S. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403. | ||||||||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||||||||
Recruitment Status ICMJE | Completed | ||||||||||||
Actual Enrollment ICMJE |
17 | ||||||||||||
Original Estimated Enrollment ICMJE |
25 | ||||||||||||
Actual Study Completion Date ICMJE | June 21, 2021 | ||||||||||||
Actual Primary Completion Date | June 21, 2021 (Final data collection date for primary outcome measure) | ||||||||||||
Eligibility Criteria ICMJE |
For enrollment, subjects must meet all of the following criteria during the screening period:
EXCLUSION CRITERIA: Subjects who meet any of the following criteria during screening will not receive AG348 and will not be counted toward the final enrollment count for statistical purposes:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 70 Years (Adult, Older Adult) | ||||||||||||
Accepts Healthy Volunteers ICMJE | No | ||||||||||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||||||||||
Listed Location Countries ICMJE | United States | ||||||||||||
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Administrative Information | |||||||||||||
NCT Number ICMJE | NCT04000165 | ||||||||||||
Other Study ID Numbers ICMJE | 190097 19-H-0097 |
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Has Data Monitoring Committee | Not Provided | ||||||||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Current Responsible Party | Swee Lay Thein, M.D., National Institutes of Health Clinical Center (CC) | ||||||||||||
Original Responsible Party | National Heart, Lung, and Blood Institute (NHLBI) | ||||||||||||
Current Study Sponsor ICMJE | National Institutes of Health Clinical Center (CC) | ||||||||||||
Original Study Sponsor ICMJE | National Heart, Lung, and Blood Institute (NHLBI) | ||||||||||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | National Institutes of Health Clinical Center (CC) | ||||||||||||
Verification Date | June 2022 | ||||||||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |