Hereditary Red Blood Cell Disorder (Disorder)Phase 2SATISFYNCT05935202
Safety and Efficacy of Mitapivat Sulfate in Adult Patients With Erythrocyte Membranopathies
A Phase 2 study testing Mitapivat sulfate in people with Hereditary Red Blood Cell Disorder (Disorder), run by EuroBloodNet Association at 2 sites in 2 countries.
Trial summary
This is a prospective exploratory multicentre pilot study designed to study the safety and efficacy of mitapivat in RBC membranopathies and CDAII Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Hereditary Red Blood Cell Disorder (Disorder)
- What is being tested?
- Mitapivat sulfate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 21 Dec 2023to 15 Dec 2026
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female with RBC membranopathy or congenital dyserythropoietic anemia type II(CDAII). Diagnosis must be supported genetically by a ACMG class 3 (VUS), 4 or 5 variant
- Age ≥18 years at the first screening
- Average hemoglobin (Hb) concentration (average of at least 2 Hb measurements separated by a minimum of 7 days the during screening period) must be less than 13.0 g/dL for males and 11.0 g/dL for females. Patients with average Hb >10.0 g/dL for males and females must meet at least one of the following additional criteria:
- Splenomegaly (length ≥12.5 cm)
- Fatigue attributed to hemolysis
- Active hemolysis as evaluated by one or more of the following: haptoglobin, bilirubin, LDH, reticulocytes
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- Subjects must start or continue taking at least the equivalent of daily 0.8 mg oral folic acid for the duration of the study
- Have adequate organ function, as defined by:
- Serum aspartate aminotransferase (AST) ≤2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) ≤2.5 × ULN.
- Normal or elevated levels of serum bilirubin. In subjects with serum bilirubin > ULN, the elevation must be attributed to hemolysis with or without Gilbert's syndrome and must not be associated with choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease Elevated bilirubin attributed to hemolysis with or without Gilbert's syndrome is not exclusionary.
- Estimated glomerular filtration rate ≥45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration creatinine
- Be willing and able to give written informed consent and to comply to all study procedures for the duration of the study
- For women of reproductive potential, have a negative urine or serum pregnancy test during the Screening Period (Day -50 to Day -1). Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion; or who have not been naturally postmenopausal (i.e. who have not menstruated at all for at least the preceding 12 months prior to signing informed consent), or has a known diagnosis of hypogonadotropic hypogonadism.
- For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent 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 giving informed consent, during the study, and for A highly effective form of contraception is defined as combined (estrogen and progestin containing) hormonal contraceptives (oral, intravaginal, or transdermal) associated with inhibition of ovulation; progestin-only hormonal contraceptives (oral, injectable, or implantable) associated with inhibition of ovulation; intrauterine device; intrauterine hormone releasing system; bilateral tube occlusion; or vasectomized partner. The second form of contraception can include an acceptable barrier method, which includes male or female condoms with or without spermicide, and cervical cap, diaphragm, or sponge with spermicide. Women of reproductive potential using hormonal contraception as a highly effective form of contraception must also utilize an acceptable barrier method while enrolled in the study and for at least 28 days after their last dose of study drug.
Who cannot join
- Known history of pyruvate kinase deficiency (decreased PK activity or two pathogenic PKLR alleles). PK activity and PKLR testing is not required.
- Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic or preventive transfusion), defined as more than 5 transfusion episodes in the 12-month period up to the first day of study treatment, and/or have received a transfusion within the past 3 months prior to the first day of study treatment.
- Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound interpretation of the study data. Such significant medical conditions include, but are not limited to:
- Poorly controlled hypertension (defined as systolic blood pressure >150 mm Hg or diastolic blood pressure >90 mm Hg) refractory to medical management.
- Any history of congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; or recent (< 6 months prior to signing informed consent) deep venous thrombosis; or pulmonary or arterial embolism.
- Cardiac dysrhythmias judged as clinically significant by the Investigator.
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- Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.
- History of drug-induced cholestatic hepatitis.
- Severe iron overload as evaluated by the Investigator. This includes cardiac (eg, clinically significant impaired left ventricular ejection fraction) or hepatic (eg, fibrosis, cirrhosis) dysfunction.
- Have a diagnosis of any other congenital or acquired blood disorder or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy.
- Positive test for HBsAg or HCVAb with signs of active hepatitis B or C virus infection. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment.
- Positive test for HIV-1 or -2 antibodies.
- Active infection requiring the use of parenteral antimicrobial agents or Grade ≥3 in severity (per NCI CTCAE) within 2 months prior to the first dose of study treatment.
- Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary.
- History of any primary malignancy, with the exception of: curatively treated non-melanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years.
- Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
- Severe hepatic issues such as liver fibrosis (F3 or worse), significant cirrhosis or non-alcoholic fatty liver disease (NASH).
- Current or recent history of psychiatric disorder that, in the opinion of the Investigator, could compromise the ability of the subject to cooperate with study visits and procedures.
- Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Participation in registry studies is allowed.
- Have exposure to any investigational drug, device, or procedure within 5 half-lives or 3 months (whichever is longer) to the first dose of study treatment.
- Have had any prior treatment with a pyruvate kinase activator.
- Have a prior bone marrow or stem cell transplant.
- Are currently pregnant or breastfeeding or planning to become pregnant during the course of the study.
- Have a history of major surgery within 6 months prior to signing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context.
- Are currently receiving medications that are strong inhibitors of CYP3A4 and strong inducers of CYP3A4 that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment.
- Are currently receiving hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment.
- Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) or history of acute allergic reaction to drugs characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations.
- For men and women of reproductive potential: unwillingness to be abstinent or use double anticonception during the trial period.
Trial locations and contacts
2 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
2 sites in 2 countries
Denmark1 site
Copenhagen University Hospital - Rigshospitalet
Copenhagen, 1054
Andreas B. Glenthøj, MD, PhD, +45 3545 3740, andreas.glenthoej@regionh.dk
Netherlands1 site
Department of Internal Medicine, University Medical Center Utrecht
Utrecht, 3454
Eduard J. van Beers, MD, PhD, +31 3188 75 58 45, E.J.vanBeers-3@umcutrecht.nl
About this study
This is a prospective exploratory multicentre pilot study designed to study the safety and efficacy of mitapivat in RBC membranopathies and CDAII
Read the detailed description
Patients will be recruited from centres of expertise in the European Union starting with Denmark and the Netherlands, and outside the EU in Canada. Overall, approximately 25 patients are expected to be enrolled: Approximately 16 patients at sites in the EU and approximately 9 patients in Canada.
For this purpose, two sibling studies will be conducted: One in the EU and one in Canada. The study report will be a combined analysis of all patients (EU + Canada) where some exploratory measures will only be available for EU patients. This protocol is for the EU portionof the study
This project is carried out within the framework of European Reference Network on Rare Haematological Diseases (ERN-EuroBloodNet)-Project ID No 101085717. ERN-EuroBloodNet is partly co-funded by the European Union within the framework of the Fourth EU Health Programme.
- Being tested
- Mitapivat sulfate
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Mitapivat sulfateDrug
Also called AG-348
Subjects enrolled Maximum dose: will receive Mitapivat during 56 weeks Starting dose: 50 mg BD Maximum dose: 100 mg BD
| Study group | Role | What they receive |
|---|---|---|
| Mitapivat | Experimental | subjects who enter the Dose Escalation Period will receive an initial dose of 50 mg mitapivat BID. After 4 weeks dose will be increased from 50 mg BID to 100 mg BID unless dose-limiting side effects have occurred or maximum allowed Hb levels have been reached. Subjects who safely tolerate mitapivat may be eligible to continue in two consecutive 24-week Fixed Dose Periods, allowing patients to remain on their tolerated dose of mitapivat for up to 48 weeks after dose escalation. During the Fixed Dose Periods, the dose may not exceed the maximum dose that was used during Dose Escalation Period.
8 weeks: Dose Escalation Period 24-week: Fixed Dose Period 1 24-week: Fixed Dose Period 2 Receives: Drug: Mitapivat sulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and tolerability of mitapivat in adult patients with erythrocyte membranopathies
Frequency and severity of AEs and laboratory parameters of mitapivat in adult patients with erythrocyte membranopathies
Measured: Up to 56 weeks
Percentage of Participants With AEs and SAEs, Graded by Severity
The severity of all AEs will be graded by the Investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) on a 5-point severity scale (Grade 1 through Grade 5) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening and Grade 5 is fatal.
Measured: Up to 56 weeks
Secondary outcomes (1)
Hb response (HR)
Hb response (HR) defined as a ≥1 g/dL increase in Hb concentration from baseline
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jul 2023
- Study start21 Dec 2023 (estimated)
- Primary completion15 Jul 2025 (estimated)
- Study completion15 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hereditary Red Blood Cell Disorder (Disorder)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- EuroBloodNet Association
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Andreas Glenthøj, MD/PhD, Principal investigator, Copenhagen University Hospital, RigshospitaletPierre FENAUX, MD/PhD, Study chair, Hôpital Saint Louis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05935202
- Sponsor's protocol ID
- SATISFY
- Acronym
- SATISFY
- Status last verified
- Dec 2023
- First submitted
- 11 Apr 2023
- Last updated
- 26 Dec 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Glenthoj A, van Beers EJ, van Wijk R, Rab MAE, Groot E, Vejlstrup N, Toft N, Bendtsen SK, Petersen J, Helby J, Chermat F, Fenaux P, Kuo KHM. Designing a single-arm phase 2 clinical trial of mitapivat for adult patients with erythrocyte membranopathies (SATISFY): a framework for interventional trials in rare anaemias - pilot study protocol. BMJ Open. 2024 Jul 30;14(7):e083691. doi: 10.1136/bmjopen-2023-083691.
PubMed 39079928