Sickle cell disease MedDRA version: 21.0 Level: PT Classification code 10040644 Term: Sickle cell disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: AG-348 sulfate hydrate
Product Code: AG-348
Pharmaceutical Form: Tablet
INN or Proposed INN: Mitapivat
CAS Number: 2151847-10-6
Current Sponsor code: AG-348 sulfate hydrate
Other descri
Sponsors
Julius Clinical
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female with documented homozygous sickle cell anemia (HbSS) or HbS/beta(0 or +)-thalassemia). 2. Documented history of VOCs, and number of days admitted in hospital for acute sickle cell related complications during 24 months before inclusion. 3. SCD with at least one of the following conditions: I. Had at least 1 (but no more than 10) VOC in the past 12 months prior to the first day of study treatment; II. any sickle cell related hospital admission in the past 12 months prior to the first day of study treatment; III. any history of sickle cell related complications (such as osteonecrosis, osteoporosis, nephropathy, retinopathy, leg ulcer, acute chest syndrome, acute hemolytic crisis); IV. presence of any clinical biomarkers associated with increased mortality in SCD prior to the first day of study treatment (NT-proBNP >160 pg/mL, LDH/HbCO ratio >1,200, tricuspid regurgitant jet velocity =2.5 m/s). 4. Age 16 years and older, inclusive; subjects age 16 or 17 years must be documented Tanner Stage 5. 5. Hemoglobin =6.9 mmol/L (approx 11.1 g/dL) and >2.5 mmol/L (approx 4.0 g/dL). 6. For subjects on hydroxyurea: the dose must have been stable for at least 3 months prior the 1st day of study treatment. 7. Subjects must start or continue taking at least the equivalent of daily 0.7 mg oral folic acid for the duration of the study. 8. Have adequate organ function based on ALT, AST, bilirubin, creatinine, neutrophil and platelet count and INR. 9. Willing and able to give written informed consent and comply to all study procedures. 10. Patients with increased albumin to creatinine ratio are prioritized above patients with a normal albumin to creatinine ratio. Both are eligible. 11. For women of reproductive potential: have a negative serum pregnancy test at screening. 12. If fertile, agree to use double anticonception during the study plus 90 days (for males) or 28 days (for females) after the last dose of the study drug. Are the trial subjects under 18? yes Number of subjects for this age range: 2 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 8 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1. More than 10 vaso-occlusive crises within the past 12 months. 2. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior to the first day of study treatment (rescreening is allowed). 3. Have a point of sickling (PoS) =24.6 mmHg as quantified by the Oxygenscan during screening to exclude subjects with no clinical relevant detectable sickling. 4. Subjects age 16 or 17 years who are documented Tanner stage 1-4 (see Appendix II). 5. Receiving regularly scheduled (red blood cell) transfusion, defined as more than 4 transfusions in the 12 months prior 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. 6. Have a significant medical condition that confers an unacceptable risk to participation in the study, and/or that could confound interpretation of the study data (such as poorly controlled hypertension, cardiac diseases, cholelithiasis, cholecystitis, cholestatis hepatitis, iron overload that could result in cardiac/hepatic/pancreatic dysfunction, have diagnosis of other congenital or acquired blood disorder, active hepatitis B or C infection or antibodies, HIV-1 of HIV-2 antibodies, active infections, poorly controlled diabetes mellitus, history of primary malignancy (except for non-melanomatous skin cancer, curatively treated cervical or breast carcinoma in situ with 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 fibrosis/cirrhosis or NASH, current or recent history of psychiatric disorder that could compromise the ability of the subject to cooperate with study visits and procedures. 7. 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. 8. Have exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment. 9. Have had any prior treatment with a pyruvate kinase activator. 10. Have a prior bone marrow or stem cell transplant. 11. Are currently pregnant or breastfeeding, or planning to become pregnant during the course of the study. 12. Have a history of major surgery within 6 months of signing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context. 13. Are currently receiving medications that are strong inhibitors of CYP3A4 or 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. 14. 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. 15. 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. 16. For men and women of reproductive potential: unwillingne
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To assess (maximum) efficacy of treatment with AG-348 on sickling as evaluated by change in Point of Sicking (PoS, expressed in mmHg), as quantified by the Oxygenscan. During the Dose Finding Period the maximum efficacy is defined as the lowest PoS measured during the treatment period relative (%) to the mean PoS during the Screening Period (Day -50 to Day -1) and D0. During the Fixed Dose Extension Period and the Prolonged Fixed Dose Extension Period, the efficacy of treatment with AG-348 is evaluated by mean PoS during this treatment period relative (%) to the mean PoS during the Screening Period (Day -50 to Day -1) and D0. - To evaluate safety of AG-348 (including the type, incidence, severity and relationship of AG-348 to AE and SAE; number of medication discontinuations due to AE; physical examination findings, vital signs and 12-lead electrocardiogram (ECG) data). ;Secondary Objective: - To evaluate the effect of AG-348 on changes in hemoglobin (Hb) and other hematological parameters, lactate dehydrogenase (LDH), bilirubin, carboxy hemoglobin (HbCO), red cell 2,3-DPG and ATP levels. - To evaluate the effect of AG-348 on changes of surrogate markers of mortality and organ damage in SCD (NT-proBNP, urinary albumin to creatinine ratio (ACR), CRP, LDH/HbCO). - To evaluate the effect of AG-348 on RBC deformability using the Osmoscan (osmotic gradient ektacytometry) - To evaluate the effect of AG-348 on clinical characteristics: Health Related Quality of Life (HRQoL) (EQ-5D-5L, SF-36), movement behaviour (accelerometer Activ8), dyspnea (MRC dyspnea) and fatigue (PROMIS fatigue short form);Primary end point(s): - Safety of AG-348 including the type, incidence, severity and relationship of AG-348 to AE and SAE; number of medication discontinuations due to AE; physical examination findings, vital signs and 12-lead electrocardiogram (ECG) data. - Efficacy of treatment of AG-348 as evaluated by changes in sickling behaviour (Point of Sickling) as qua | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Maximum change in Hb, bilirubin, HbCO, p50 (TCS HEMOX Analyzer), 2,3-DPG and ATP levels. - Maximum change in RBC deformability, dehydration and cell membrane stability, ex vivo (Osmotic gradient ektacytometry (Osmoscan). - Changes in clinical characteristics: o Health related Quality of Life (HRQoL) (EQ-5D-5L, SF-36). o Movement behaviour (accelerometer Activ8) o Dyspnea (MRC dyspnea) o Fatigue (PROMIS fatigue short form) - Changes in surrogate markers of organ damage or biomarkers associated with mortality at D56 compared to baseline: o Urinary albumin to creatinine ratio o NT-proBNP o CRP o LDH/HbCO ratio o Endothelial activation: D-dimer, von Willebrand factor-antigen (VWF), soluble vascular cell adhesion molecule (sVCAM) o Change in number of crises compared to historical rate ;Timepoint(s) of evaluation of this end point: End of Study | — |
Countries
Netherlands
Contacts
Public ContactEduard van Beers
UMC Utrecht - Van Creveldkliniek
Outcome results
None listed