This study has been transitioned to CTIS with ID 2024-512747-23-00 check the CTIS register for the current data. Study AG348-C-018 is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study designed to demonstrate the clinical…
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is to compare the effect of mitapivat versus placebo on
anemia in subjects with α- or β-transfusion-dependent thalassemia. The primary
endpoint is transfusion reduction response (TRR), defined as a >=50% reduction
in transfused red blood cell (RBC) units with a reduction of >=2 units of
transfused RBCs in any consecutive 12-week period through Week 48 compared with
baseline.
Secondary outcome
The key secondary objective is to compare the durability of the effect of
mitapivat versus placebo on transfusion burden.
Other secondary objectives are to evaluate the effect of mitapivat versus
placebo on additional measures of transfusion burden, to evaluate the effect of
mitapivat versus placebo on iron metabolism, to evaluate the safety of
mitapivat and to evaluate the pharmacokinetic and pharmacodynamic effects of
mitapivat
Background summary
In thalassemia, the imbalance in globin chain synthesis imposes metabolic
stress on the RBCs, specifically in the form of excess generation of reactive
oxygen species and an increased demand on adenosine triphosphate
(ATP)-dependent proteolytic mechanisms to clear excess globin chains. In
thalassemic RBCs, ATP supply appears to be insufficient to maintain RBC
membrane fitness and clearance of globin precipitates, leading to early and
increased death of RBC precursors in the bone marrow and in extramedullary
sites.
These pathophysiological changes lead to the hallmarks of the disease:
ineffective erythropoiesis, peripheral hemolysis, and subsequent anemia.
Clinical implications of the α- and β-globin imbalance include lack of
sufficient RBCs and Hb for effective oxygen transport, and ineffective
erythropoiesis and hemolysis, which can lead to splenomegaly, bone marrow
expansion (extramedullary hematopoiesis), concomitant bone deformities, and
iron overload.
Alpha- and β-thalassemias are genetically heterogeneous and vary by phenotype
and severity.
Clinical management with RBC transfusions is an essential factor in classifying
thalassemias as either transfusion-dependent thalassemia (TDT) or non-
transfusion dependent thalassemia (NTDT). Patients with TDT need life-long
regular transfusions for survival. Patients with NTDT do not need life-long
regular transfusions for survival; however, they may require transfusions
during times of erythroid stress such as infection, pregnancy, surgery, or
aplastic crisis, and may transition to requiring regular transfusions and
becoming transfusion-dependent later in life.
The investigational drug mitapivat (also known as mitapivat sulfate and AG-348)
is a first in class, orally bioavailable, potent, allosteric activator of
wild-type RBC-specific form of pyruvate kinase (PKR) and a range of PKR mutant
enzymes. The RBC specific form of pyruvate kinase is 1 of 4 pyruvate kinase
isoenzymes expressed in human tissues from 2 separate genes, liver specific
form of pyruvate kinase (PKL) and pyruvate kinase muscle isozyme (PKM). Both
PKR and PKL are splice isoforms of the PKLR gene, while PKM1 and PKM2 are both
expressed from the PKM gene. Mitapivat is an allosteric activator of the PKR,
PKL, and PKM2 isoenzymes, with similar potency against each.
Mitapivat acts by allosterically binding to the PKR tetramer and enhancing its
affinity for phosphoenolpyruvate (PEP), thereby increasing the conversion of
PEP + adenosine diphosphate to pyruvate + ATP.
Study objective
This study has been transitioned to CTIS with ID 2024-512747-23-00 check the CTIS register for the current data.
Study AG348-C-018 is a Phase 3, double-blind, randomized, placebo-controlled,
multicenter study designed to demonstrate the clinical efficacy and safety of
mitapivat in subjects with α- or β-TDT. The primary objective of the study is
to compare the effect of mitapivat versus placebo on transfusion burden.
Secondary objectives include the evaluation of markers of iron overload as well
as safety and pharmacokinetic and pharmacodynamic parameters.
Study design
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter
study evaluating the efficacy and safety of mitapivat versus placebo in adult
subjects with α- or β-TDT followed by an Open-label Extension Period.
Approximately 240 subjects are planned to be randomized in this study. This
multicenter study will be conducted internationally.
Intervention
Subjects will receive 100 mg BID (twice daily) mitapivat or matched-placebo for
oral administration. Tablets are to be swallowed whole with water and may be
taken with or without food.
Subjects who discontinue study drug should undergo the recommended dose taper
and be monitored as clinically indicated for signs and symptoms of acute
hemolysis and worsening anemia. If immediate or abrupt study drug
discontinuation is required for an AE or medical emergency, subjects should be
monitored as clinically indicated for signs of acute hemolysis or worsening
anemia.
Study burden and risks
Mitapivat has been generally well tolerated in both healthy adult subjects and
adult subjects with hemolytic anemias, although aromatase inhibition and
transaminase increases have been observed. The doses of mitapivat planned for
future clinical studies will not exceed a 200 mg total daily dose, which is
expected to reduce the risks associated with potential liver toxicity.
Liver function tests will be monitored in clinical studies of mitapivat, and
transaminase increased of more than 2.5× patient individual baseline or to
Grade 2 will be reported as an AESI. Moreover, data available at this time also
indicate that mitapivat does not have a significant QT/QTc prolongation effect.
Based on currently available data, reported benefits of treatment with
mitapivat outweigh the observed risks of treatment.
88 Sidney Street 88 Sidney Street
Cambridge MA 02139-4169
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88 Sidney Street 88 Sidney Street
Cambridge MA 02139-4169
US
Listed location countries
Age
Inclusion criteria
1. >=18 years of age at the time of providing informed consent.
2. Documented diagnosis of thalassemia (β-thalassemia with or without α-globin
gene
mutations, HbE/β-thalassemia, or α-thalassemia/HbH disease) based on DNA
analysis
from the subject*s medical record. If this information is not available from
the subject*s
medical record, DNA analysis can be performed by a local laboratory during the
Screening Period. If a local laboratory is unable to perform the test, results
from the
comprehensive α- and β-globin genotyping performed by the study central
laboratory can
be used.
3. Transfusion dependent, defined as 6 to 20 RBC units transfused and a <=6-week
transfusion-free period during the 24-week period before randomization.
4. If taking hydroxyurea, the hydroxyurea dose must be stable for >=16 weeks
before
randomization.
5. Women of childbearing potential (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, 1 of which must be
considered highly
effective, from the time of providing informed consent, throughout the study,
and for
28 days after the last dose of study drug. The second form of contraception can
be an acceptable barrier
method.
6. Written informed consent before any study-related procedures are conducted
and willing
to comply with all study procedures for the duration of the study.
Exclusion criteria
1. Pregnant, breastfeeding or parturient.
2. Documented history of homozygous or heterozygous HbS or HbC.
3. Prior exposure to gene therapy or prior bone marrow or stem cell
transplantation.
4. Currently receiving treatment with luspatercept; the last dose must have
been administered >=36 weeks before randomization.
5. Currently receiving treatment with hematopoietic stimulating agents; the
last dose must have been administered >=36 weeks before randomization.
6. History of malignancy (active or treated) <=5 years before providing informed
consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in
situ, or breast carcinoma in situ.
7. History of active and/or uncontrolled cardiac or pulmonary disease <=6 months
before providing informed consent, including but not limited to:
a. New York Heart Association Class III or IV heart failure or clinically
significant dysrhythmia
b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or
thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
c. Heart rate-corrected QT interval using Fridericia*s method >=450 milliseconds
(males) or >=470 milliseconds (females), except for right or left bundle branch
block
d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of
right-sided heart failure, and radiographic pulmonary fibrosis >50%
e. Severe pulmonary hypertension as defined by severe symptoms associated with
hypoxia, right-sided heart failure, and oxygen indicated
8. Hepatobiliary disorders, including but not limited to:
a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis
b. Clinically symptomatic cholelithiasis or cholecystitis (prior
cholecystectomy is not exclusionary)
c. History of drug-induced cholestatic hepatitis
d. Aspartate aminotransferase >2.5 × upper limit of normal (ULN); unless due to
hemolysis and hepatic iron deposition) and alanine aminotransferase >2.5 × ULN
(unless due to hepatic iron deposition)
9. Estimated glomerular filtration rate <45 mL/min/1.73 m2 by Chronic Kidney
Disease Epidemiology Collaboration creatinine equation.
10. Nonfasting triglycerides >440 mg/dL (5 mmol/L).
11. Active infection requiring systemic antimicrobial therapy at the time of
providing informed consent. If antimicrobial therapy is required during the
Screening Period, screening procedures should not be performed while
antimicrobial therapy is being administered, and the last dose of antimicrobial
therapy must be administered >=7 days before randomization.
12. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of
active HCV infection, or positive test for hepatitis B surface antigen.
13. Positive test for HIV-1 Ab or HIV-2 Ab.
14. History of major surgery (including splenectomy) <=6 months before providing
informed consent and/or a major surgical procedure planned during the study.
15. Current enrollment or past participation (<=12 weeks before administration
of the first dose of study drug or a time frame equivalent to 5 half-lives of
the investigational treatment, whichever is longer) in any other clinical study
involving an investigational treatment or device.
16. Receiving strong cytochrome P450 (CYP)3A4/5 inhibitors that have not been
stopped for >=5 days or a time frame equivalent to 5 half-lives (whichever is
longer), or strong CYP3A4 inducers that have not been stopped for >=4 weeks or a
time frame equivalent to 5 half-lives (whichever is longer), before
randomization.
17. 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 >=12 weeks before randomization.
18. Known allergy, or other contraindication, to mitapivat or its excipients
(microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate,
mannitol, and magnesium stearate), Opadry® II Blue [hypromellose, titanium
dioxide, lactose monohydrate, triacetin, and FD&C Blue #2]).
19. 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 who are institutionalized by regulatory or court order
-Subjects with any condition(s) that could create undue influence (including
but not limited to incarceration, involuntary psychiatric confinement, and
financial or familial affiliation with the Investigator or Sponsor)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512747-23-00 |
| EudraCT | EUCTR2021-000212-34-NL |
| CCMO | NL77086.041.21 |