This study has been transitioned to CTIS with ID 2024-515202-84-00 check the CTIS register for the current data. Phase 2:Primary ObjectivesTo determine the recommended Phase3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 2:
• Hemoglobin (Hb) response, defined as a >=1.0 g/dL increase in average Hb
concentration from Week 10through Week 12 compared with baseline
• Type, severity, and relationship to study drug of adverse events (AEs) and
serious (SAEs)
Phase 3:
• Hemoglobin (Hb) response, defined as a >=1.0 g/dL increase in average Hb
concentration from Week 24 through Week 52 compared with baseline
• Annualized rate of SCPCs (as defined in Section 8.5.2.1)
Secondary outcome
Phase 2:
• Average change from baseline in Hb concentration from Week 10 through Week 12
• Average change from baseline in markers of hemolysis, including indirect
bilirubin and lactate dehydrogenase (LDH), from Week 10 through Week 12
• Average change from baseline in markers of percent reticulocyte, and
erythropoietin, from Week 10 through Week 12
• Average change from baseline in Patient-Reported Outcomes Measurement
Information System® (PROMIS) Fatigue 13a Short Form (SF) score from Week 10
through Week 12
• Annualized rate of SCPCs (as defined in Section 8.5.2.1)
• Exposure response (or pharmacokinetic/pharmacodynamic) relationship between
relevant pharmacokinetic parameters and endpoints that are indicators of
clinical activity and safety
• Change in mitapivat concentration over time and derived mitapivat
pharmacokinetic parameters (including area under the concentration × time curve
and maximum [peak] concentration)
Phase 3:
• Average Change from baseline in average Hb concentration from Week 24 through
Week 52
• Average Change from baseline in average indirect bilirubin from Week 24
through Week 52
• Average Change from baseline in average percent reticulocyte from Week 24
through Week 52
• Average Change from baseline in average Patient-Reported Outcomes Measurement
Information System® (PROMIS) Fatigue 13a Short Form (SF) scores from Week 24
through Week 52
• Annualized frequency of hospitalizations for SCPC
• Average Change from baseline in average LDH concentration from Week 24
through Week 52
• Average Change from baseline in average absolute reticulocytes and
erythropoietin from Week 24 through Week 52.
• Improvement on the Patient Global Impression of Severity (PGIS) of fatigue by
at least 1 category at Weeks 24, 28, 40, and 52 compared to baseline, or remain
stable if none or mild fatigue at baseline
• Improvement on the Patient Global Impression of Change (PGIC) of fatigue at
Weeks 24, 28, 40, and 52, or "no change" if none or mild fatigue at baseline
• Time to first SCPC
• Time to second SCPC
• Annualized rate of hospitalization days for SCPC
• Annualized rate of Emergency Room visits for SCPC
• Change from baseline in 6-minute walk test at Week 52
• Change from baseline in PROMIS Pain Intensity 1a and Adult Sickle Cell
Quality of Life Measurement Information System (ASCQ-Me) Pain Impact average
scores at Week 24 and at Week 52
• PGIC of pain and change from baseline in PGIS of pain at Week 52
• Type, severity, and relationship to study drug of adverse events (AEs) and
serious AEs (SAEs)
• Exposure response (or pharmacokinetic/pharmacodynamic) relationship between
relevant pharmacokinetic parameters and endpoints that are indicators of
clinical activity and safety
• Change in mitapivat concentration over time and derived mitapivat
pharmacokinetic parameters (including area under the concentration × time curve
and maximum [peak] concentration)
Background summary
The double-blind design of the Phase 2 and Phase 3 portions minimizes
assessment bias and the
use of placebo as a comparator allows an objective evaluation of the efficacy
and safety of
mitapivat. Although new treatment options have emerged for the treatment of SCD
in recent
years (Section 2.1.2), these agents are not approved in all regions and thus
are not appropriate to
serve as comparators in this global study. Additionally, none of these
therapies have been shown
to improve both hemolytic anemia and VOCs, the 2 primary objectives of the
Phase 3 portion of
the study. Therefore, it is appropriate to use a placebo control, rather than
an active comparator,
to evaluate the efficacy of mitapivat.
The randomization ratios selected for the Phase 2 and Phase 3 portions ensure
that subjects have
a greater likelihood of being randomized to receive mitapivat than placebo, and
the Open-label
Extension Period provides an opportunity for subjects who were randomized to
placebo to
receive mitapivat.
The proposed study populations for the Phase 2 and Phase 3 portions will
include subjects 16
years and older (subjects who are 16 or 17 years old must be documented Tanner
Stage 5) with a
diagnosis of SCD, including HbSS, HbC, HbS β-thalassemia, or other sickle cell
syndrome
variants. Eligible subjects will include individuals with anemia and recurrent
VOCs. The criteria
for anemia, defined as a Hb concentration of >=5.5 g/dL and <=10.5 g/dL, and
recurrent VOCs,
defined based on the occurrence of >=2 and <=10 SCPCs in the past 12 months, will
identify a
study population with an unmet need for effective treatment. Subjects who are
regularly
transfused (defined as receiving regular RBC transfusion therapy or planning to
undergo an
exchange transfusion in the next 12 months) will be excluded given the
potentially confounding
effect of transfusions on Hb assessments and other laboratory measurements,
such as the
percentage of sickle Hb.
During the study, subjects will continue to receive appropriate supportive care
to manage
symptoms and prevent secondary complications. An Independent Data Monitoring
Committee
(IDMC; Section 10.6) will be responsible for ongoing monitoring of the safety
of subjects.
Additional study design elements specific to the Phase 2, Phase 3, and
Open-label Extension
Periods are described in the following sections.
Study objective
This study has been transitioned to CTIS with ID 2024-515202-84-00 check the CTIS register for the current data.
Phase 2:
Primary Objectives
To determine the recommended Phase
3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat
versus placebo on:
• Anemia in subjects with sickle cell disease (SCD)
• Safety
Secondary Objectives
To evaluate the effect of 2 doses of mitapivat versus placebo on:
• Anemia
• Markers of hemolysis and erythropoiesis
• Patient-reported fatigue
• Sickle cell pain crises (SCPCs)
To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat
Phase 3:
Primary Objectives
To determine the effect of mitapivat versus placebo on:
• Anemia in subjects with sickle cell disease (SCD)
• Sickle cell pain crises (SCPCs) in subjects with SCD
Secondary Objectives
To evaluate the effect of mitapivatversus placebo on:
• Anemia in subjects with SCD
• Markers of hemolysis
• Markers of erythropoiesis
• Patient-reported fatigue
• Additional clinical efficacy measures related to SCPC
To evaluate the effect of mitapivat versus placebo on:
• Additional markers of hemolysis
• Additional markers of erythropoiesis
• Additional measures of patient-reported fatigue
• Additional clinical efficacy measures related to SCPC
• Physical activity
• Patient-reported pain
• Safety
To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat
Study design
Study AG348-C-018 is a Phase 2/3, double-blind, randomized, placebo-controlled,
global,
multicenter study evaluating the efficacy and safety of mitapivat versus
placebo in subjects with
SCD using an operationally seamless design.
The Phase 2 portion is a double-blind, randomized, placebo-controlled,
dose-finding study
evaluating 2 dose levels of mitapivat (50 mg BID and 100 mg BID) versus placebo
to select the
dose of mitapivat to be evaluated in the Phase 3 portion. The Phase 3 portion
is a double-blind,
randomized, placebo-controlled study evaluating the efficacy and safety of
mitapivat at the
selected Phase 3 dose versus placebo. Subjects who complete the Double-blind
Period in either
the Phase 2 or Phase 3 portion will have the option to receive mitapivat in the
Open-label
Extension Period. The initiation of the Phase 3 portion will be based on
prespecified go/no-go
criteria and dose selection criteria. Subjects who participate in the Phase 2
portion of the study
are not eligible to participate in the Phase 3 portion of the study.
Intervention
In the Phase 2 portion of the study, eligible subjects will be randomized 1:1:1
to receive 50 mg BID mitapivat, 100 mg BID mitapivat, or matched placebo. In
the Phase 3 portion of the study, eligible subjects will be randomized 2:1 to
receive mitapivat or matched placebo. Randomization will be stratified by the
number of SCPCs in the prior year (<5, >=5) and concomitant hydroxyurea use
(yes, no). Subjects who have completed the Phase 2 portion of the study and had
been receiving active treatment will be eligible to continue receiving the same
dose in the Open-label Extension Period. Subjects who had been receiving
placebo will be randomized 1:1 to receive either 50 mg BID mitapivat or 100 mg
BID mitapivat in the Open-label Extension Period. Study subjects,
Investigators, clinical study center personnel, pharmacists, and the Sponsor
will be blinded to the subject*s treatment assignment. After completing the
Double-blind Period, subjects will be provided the opportunity to receive
mitapivat in the Open-label Extension Period. At the last study visit of the
Double-blind Period, subjects who continue in the Open-label Extension Period
will be provided with active mitapivat; however, study subjects, Investigators,
clinical study center personnel, and the Sponsor will continue to remain
blinded to the randomized treatment assignment during the previous Double-blind
Period until the study is unblinded for the analysis of the primary endpoint in
the corresponding Phase 2 or Phase 3 portion of the study.
Study burden and risks
Mitapivat may cause side effects. The following side effects are common:
• Headache
• Nausea
• Swelling of nose and throat, often seen in common colds
• Fatigue (feeling tired)
• Insomnia (trouble sleeping)
• Initial insomnia (trouble falling asleep)
• Back pain
• Fever
• Joint pain
• Diarrhea (loose stool)
• Liver enzyme increased
• Dizziness
• Sore throat
• Cough
• Vomiting (throwing up)
• Indigestion/heartburn
• Pain in extremity
The study doctor or site staff may give the subject medicines to help lessen
side effects. The study doctor may reduce or delay study drug dosing for a
short period of time based on side effects that the subject may have. Many side
effects go away soon after the subject stops taking an experimental drug.
The following side effects are rare and can be serious:
• Bone mineral density decrease (bones become weaker)
• Withdrawal hemolysis (destruction of red blood cells when the subject stops
taking the study drug too quick)
Mitapivat can also have side effects that we do not know about at the moment.
You can read more about the side effects in appendix D of the ICF.
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Listed location countries
Age
Inclusion criteria
1. Age >=16 years; subjects age 16 or 17 years must be documented Tanner Stage 5
(see Appendix 3)
2. Documented diagnosis of SCD (HbSS, HbSC [combined heterozygosity for
hemoglobins S and C], HbS/β0-thalassemia, HbS/β+-thalassemia, or other sickle
cell syndrome variants)
3. At least 2 SCPCs (defined in Section 8.5.2.1) and no more than 10 SCPCs in
the 12 months prior to providing informed assent/consent.
4. 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.
5. If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90
days prior to randomization. Discontinuation of hydroxyurea requires a 90-day
washout prior to informed assent/consent.
Exclusion criteria
1. Pregnant, breastfeeding or parturient 2. Receiving regularly scheduled RBC
transfusion therapy (also termed chronic, prophylactic, or preventative
transfusion); episodic transfusion in response to worsened anemia or VOC is
permitted. Additionally, subjects may not have received a transfusion within 60
days before providing informed assent/consent or during the Screening Period.
3. Hospitalized for an SCPC and/or other vaso-occlusive event within 14 days
prior to providing informed assent/consent or during the Screening Period. A
hospitalization is defined as an in-patient admission to a hospital that may or
may not be preceded by an emergency room or out patient clinic visit. A visit
to an emergency room that does not result in an in-patient admission does not
meet the definition of hospitalization. 4. 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. 5. 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. 6. History of active and/or
uncontrolled cardiac or pulmonary disease within 6 months before providing
informed assent/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 of >=470 milliseconds
for female subjects and >=450 milliseconds for male subjects, 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 heart failure, and oxygen indicated 7.
Hepatobiliary disorders including but not limited to: a. Liver disease with
histopathological evidence of cirrhosis or severe fibrosis b. Clinically
symptomatic cholelithiasis or cholecystitis (subjects with prior
cholecystectomy are eligible) c. History of drug-induced cholestatic hepatitis
d. Aspartate aminotransferase >2.5× the upper limit of normal (ULN) (unless due
to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×
the ULN (unless due to hepatic iron deposition) 8. Renal dysfunction as defined
by an estimated glomerular filtration rate <30 mL/min/1.73 m2 by the Chronic
Kidney Disease Epidemiology Collaboration creatinine equation 9. Nonfasting
triglycerides >440 mg/dL (5 mmol/L) 10. Active uncontrolled infection requiring
systemic antimicrobial therapy 11. Positive test for hepatitis C virus antibody
with evidence of active hepatitis C virus infection, or positive test for
hepatitis B surface antigen 12. Positive test for HIV-1 antibody or HIV-2
antibody 13. 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 14. 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 15.
Prior exposure to gene therapy or prior bone marrow or stem cell
transplantation. 16. Currently receiving treatment with hematopoietic
stimulating agents; the last dose must have been administered at least 90 days
before randomization. 17. 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 18. 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. 19. 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, tr iacetin, and FD&C Blue #2]) 20. 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 21. Phase 3 only: Participated in the Phase 2 portion of Study
AG348-C-020.
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 | CTIS2024-515202-84-00 |
| EudraCT | EUCTR2021-001674-34-NL |
| ClinicalTrials.gov | NCT05031780 |
| CCMO | NL78134.078.21 |