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

Phase 2

Recruiting

Conditions: sickle cell anemia
Sickle cell disease
10038158

Registration Number: NL-OMON54689

Lead Sponsor: Julius Clinical

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 10

Inclusion Criteria

1. Male or female with homozygous sickle cell anemia (HbSS) or HbS/beta(0 or
+)-thallassemia). 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,
billirubin, 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 urine and serum pregnancy test
at screening. 12. For (fertile men of) women of reproductive potential: 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.

Exclusion Criteria

1. More than 10 VOCs 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 ty

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>- To assess (maximum) efficacy of treatment with mitapivat on sickling as<br /><br>evaluated by change in Point of Sicking (PoS, expressed in mmHg), as quantified<br /><br>by the Oxygenscan. During the Dose Finding Period the maximum efficacy is<br /><br>defined as the lowest PoS measured during the treatment period relative (%) to<br /><br>the mean PoS during the Screening Period (Day -50 to Day -1) and D0. During the<br /><br>Fixed Dose Extension Period, the efficacy of treatment with mitapivat is<br /><br>evaluated by mean PoS during this treatment period relative (%) to the mean PoS<br /><br>during the Screening Period (Day -50 to Day -1) and D0.<br /><br><br /><br>- To evaluate safety of AG-348 (including the type, incidence, severity and<br /><br>relationship of AG-348 to AE and SAE; number of medication discontinuations due<br /><br>to AE; physical examination findings, vital signs and 12-lead electrocardiogram<br /><br>(ECG) data).</p><br>

Secondary Outcome Measures