This study has been transitioned to CTIS with ID 2024-515569-32-00 check the CTIS register for the current data. To study the safety and efficacy of mitapivat in the treatment of adult subjects with sickle cell disease.
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To assess (maximum) efficacy of treatment with mitapivat 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, the efficacy of treatment with mitapivat 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 outcome
Secondary:
- To evaluate the effect of mitapivat on changes in hemoglobin (Hb) an other
hematological parameters, lactate dehydrogenase (LDH), bilirubin, carboxy
hemoglobin (HbCO), red cell 2,3-DPG and ATP levels.
- To evaluate the effect of mitapivat on changes of surrogate markers of
mortality and organ damage in SCD (NT-proBNP, Urinary albumin to creatinine
ratio (ACR), C-reactive protein (CRP), LDH/HbCO).
- To evaluate the effect of mitapivat on RBC deformability using the Osmoscan
(osmotic gradient ektacytometry).
- To evaluate the effect of mitapivat on clinical characteristics quality of
life (questionnaires EQ-5D-5L and SF-12), fatigue (questionnaire PROMIS fatigue
short form), questionnaire dyspnea (MRC dyspnea) and movement behaviour
(accelerometer Activ8).
Exploratory:
- To evaluate the number of VOCs (per 365 days) during study drug compliant
period.
- To evaluate the number of days admitted in hospital for acute sickle cell
related complications (per 365 days) during study drug compliant period.
- To evaluate PK activity and -thermostability in relation to PoS, red cell ATP
and 2,3-DPG levels and the effect of AG-348 on the relation between these
parameters.
- To evaluate changes in metabolomics
- To evaluate changes in additional urinary parameters and markers of sickle
cell nephropathy
Background summary
The number one cause of years lost to disability by anemia in Western Europe
and North America is Sickle Cell Disease (SCD). Patients with SCD have severe
anemia and experience extremely painful events called vaso-occlusive crises
(VOC). The intracellular level of 2,3-diphosphoglycerate (2,3-DPG, a glycolytic
metabolite) is high in sickled red blood cells and associated with high Point
of Sickling (PoS) and disease severity. Preliminary results from our laboratory
suggest that high 2,3-DPG levels in SCD patients may result from decreased
pyruvate kinase (PK) (thermo-)stability.
Mitapivat sulfate (AG-348, mitapivat) is a drug currently in clinical
development for the treatment of hereditary PK deficiency (PKD). PKD, like SCD,
is associated with high 2,3-DPG levels. Mitapivat has been shown to lower
2,3-DPG levels in healthy subjects and ex-vivo treated red blood cells of PKD
patients. Therefore mitapivat represents an investigational agent that may
offer clinical benefit for SCD patients as well.
Based on the results of mitapivat in healthy subjects and PKD patients, there
is reason to believe that treatment of SCD patients with mitapivat may result
in the same improvement in PoS as ex vivo treatment has shown. Subsequently,
this may also result in associated improvement of erythrocyte parameters
(erythrocyte count, Hb, hematocrit, mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH), red cell distribution width (RDW), reticulocyte
parameters (reticulocyte count, immature reticulocyte fraction (IRF),
reticulocyte hemoglobin concentration (CHCr) and surrogate markers of mortality
risk in SCD such as C-reactive protein (CRP) and N-terminal prohormone
brain-type natriuretic peptide (NT-proBNP)).
Study objective
This study has been transitioned to CTIS with ID 2024-515569-32-00 check the CTIS register for the current data.
To study the safety and efficacy of mitapivat in the treatment of adult
subjects with sickle cell disease.
Study design
Prospective exploratory monocenter pilot study.
Intervention
During the 8-week Dose Finding Period, subjects will be treated with an initial
dose of 20 mg mitapivat twice daily (BID). Depending on safety and Hb changes,
dosing may be increased in two steps, i.e. from 20 mg BID to 50 mg BID at week
2, and subsequently from 50 mg BID to 100 mg BID for week 4 through 8. Subjects
who remain on 20 mg BID through week 4 may be increased to 50 mg BID (but not
100 mg BID) for week 4 through 8. Subjects who safely tolerate mitapivat and
show evidence of clinical activity, may be eligible to continue a 52-week
follow-up period (Fixed Dose Extension Period), allowing patients to remain on
their optimal dose of mitapivat. During the Fixed Dose Extension Period, the
dose may not exceed the maximum doses that was used during Dose Finding Period.
Hereafter, subjects may continue in the Prolonged Fixed Dose Extension for a
period of 24 months.
After this period, patients will be given the opportunity to participate in the
'extended period' which will take 36 months. Long-term safety and efficacy data
will be collected in this period.
Study burden and risks
Besides anemia, SCD patients are confronted with extremely painful events
called vaso-occlusive crises, chronic pain and a shortened life expectancy;
half of the SCD patients in high income western society will have died before
reaching the age of sixty. The safety profile of mitapivat established in
clinical trials to date is favorable. Mitapivat AG-348 has been generally well
tolerated in both healthy adult subjects at single doses up to 2500 mg and
multiple doses up to 70 mg BID and adult subjects with PK deficiency, although
aromatase inhibition has been observed in both subject populations. Adverse
drug reactions also included decreased bone mineral density, withdrawal
hemolysis, insomnia, gastrointestinal disturbances, triglyceride increase and
hot flushes. Taken together the risk benefit ratio for mitapivat in SCD is
positive.
Broederplein 41-43
Zeist 3703CD
NL
Broederplein 41-43
Zeist 3703CD
NL
Listed location countries
Age
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 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.
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 | CTIS2024-515569-32-00 |
| EudraCT | EUCTR2019-003438-18-NL |
| CCMO | NL71253.041.20 |
| Other | NL8517 (NTR) |