Evaluation of safety and efficacy of mitapivat sulfate in adult patients with sickle cell disease.

Completed

Conditions: sickle cell disease, sickle cell anemia, hemoglobinopathy, congenital hemolytic anemia(sikkelcelziekte, sikkelcelanemie, haemoglobinopathie, congenitale hemolytische anemie)HbSS, HbS/beta(0)-thalassemia, sickle beta zero thalassemia

Registration Number: NL-OMON22508

Lead Sponsor: Julius Clinical Research B.V.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 10

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.Had at least 1 (but no more than 10) VOC in the past 12 months prior to the first day of study treatment, or sickle-cell related complications, or any sickle cell related hospital admission in the past 12 months prior to the first day of study treatment, or any history of sickle cell related complications, or presence of any clinical biomarkers associated with increased mortality in SCD prior to the first day of study treatment.
4.Age =16 years, inclusive; subjects age 16 or 17 years must be documented Tanner Stage 5 (
5.Hemoglobin (Hb) =6.9 mmol/L (approx. 11.1 g/dL) and >3.8 mmol/L (approx. 6.0 g/dL) during screening.
6.For subjects taking hydroxyurea (HU), the dose of HU (mg/kg) must have been stable for at least 3 months prior to the first 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, as defined by:
a. 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.
b. 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.
c. Serum creatinine =1.25 × ULN. If serum creatinine is >1.25 × ULN, then glomerular filtration rate, estimated by 24-hour measured or calculated (Cockcroft-Gault) creatinine clearance, must be =60 mL/min.
d. Absolute neutrophil count =1.0 × 109/L during screening.
e. Platelet count =100 × 109/L during screening.
f. Activated partial thromboplastin time and international normalized ratio =1.25 × ULN, unless the subject is receiving therapeutic anticoagulants.
9.Be willing and able to give written informed consent and to comply to all study procedures for the duration of the study.
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 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 ligation.
12.Agree to use double anticonception during the trial period plus 90 days (for male subjects) or 28 days (for female subjects) after the last dose of AG-348.

Exclusion Criteria

1.More than 10 VOCs within the past 12 months that required a hospital, emergency or health care provider visit.
2.Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior the first day of study treatment. Subjects who may get hospitalized during the Screening Period are allowed to be rescreened 14 days after discharge.
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
5.Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic or preventive transfusion), defined as more than 4 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.
6.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.
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 prior to 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: unwillingness to use double anticonception during the trial period.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
- 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. <br>- 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 Outcome Measures

Name	Time	Method
-To evaluate the effect of AG-348 on changes in hemoglobin (Hb), lactate dehydrogenase (LDH), bilirubin, carboxy hemoglobin (HbCO), red cell 2,3-DPG and ATP levels.<br>-To evaluate the effect of AG-348 on changes of surrogate markers of mortality and organ damage in SCD.<br>-To evaluate the effect of AG-348 on RBC deformability using the Osmoscan (osmotic gradient ektacytometry).<br>-To evaluate the effect of AG-348 on clinical characteristics.