A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients with Pyruvate Kinase Deficiency
- Conditions
- Pyruvate Kinase DeficiencyMedDRA version: 18.0Level: PTClassification code 10037682Term: Pyruvate kinase deficiency anaemiaSystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
- Registration Number
- EUCTR2015-000484-13-NL
- Lead Sponsor
- Agios Pharmaceuticals Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 75
1.Signed written informed consent obtained prior to performing any study procedure, including screening procedures.
2.Male or female, aged 18 years and older.
3.Known medical history of PK deficiency.
4.All patients must have documented clinical laboratory confirmation of PK deficiency by RBC pyruvate kinase enzymatic assay performed at Screening by a designated central laboratory. Patients with prior documentation of PK deficiency by RBC enzymatic assay will have a reconfirmation of this result during Screening as a condition of enrollment.
a.In the event that a patient’s screening pyruvate kinase enzymatic assay is negative (i.e., shows normal pyruvate kinase activity), the patient will be eligible for enrollment if the genotyping shows a mutant genotype that has been previously documented in the literature to be associated with pyruvate kinase deficiency. If the genotyping shows a previously undescribed mutation in the PKR gene, then the eligibility for enrollment will be determined on a case-by-case basis by the Coordinating Investigator and Medical Monitor in discussion with the Investigator. If no mutation is defined, then the patient will not be eligible.
5.All patients must have genotypic characterization of the mutant PKR gene performed by a designated central laboratory at Screening, unless genotype is available from the patient's participation in the Pyruvate Kinase Deficiency Natural History Study (NCT02053480).
6.All patients must have genotypic characterization of the UGT1A1 gene performed by a designated central laboratory to document whether they may have underlying Gilbert's Disease. Patients with Gilbert’s Disease are eligible to enroll.
7.Males must have Hb = 12.0 g/dL; females must have Hb = 11.0 g/dL.
8.All patients must be considered transfusion independent as defined by: no greater than 3 units of RBCs transfused in the 12-month period up to the first day of study dosing and no transfusions within 4 months of first day of study dosing. Patients who have received more transfusion support than described above will evaluated for eligibility on a case-by-case basis by the Medical Monitor.
9.Eligible patients may still have their spleens in place, or may have undergone prior splenectomy For splenectomized patients:
a.Must have undergone their procedure at least 6 months prior to Screening.
b.Must be current in their vaccinations for Pneumococcal Conjugate (PCV13), Pneumococcal Polysaccharide (PPSV23), Quadrivalent Meningococcal vaccine, and Haemophilus influenzae type b (Hib) as recommended by Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) or immunization advisory groups in Canada and the European Union (for patients enrolled in Canada and the EU). [http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf] [Any missing vaccinations may be administered during the screening period.]
10.Eastern Cooperative Oncology Group (ECOG) Performance Status = 2.
11.Patients must be taking at least 1 mg of folic acid daily for at least 21 days prior to first dose and continued daily during study participation.
12.Adequate organ function, defined as:
a.Serum AST and ALT = 1.5 × upper limit of normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis).
b.Normal or elevated levels of serum bilirubin. In patients with serum bilirubin > ULN, the elevation must be attributed to hemolysis with or without Gilbert's synd
1.Hemoglobin level > 12.0 g/dL if male; Hb > 11.0 g/dL if female.
2.Additional diagnosis of any other congenital or acquired blood disorder, including glucose-6-phosphate-dehydrogenase (G6PD) deficiency, or any other hemolytic anemia process except for mild allo-immunization as a consequence of transfusion therapy.
3.Iron overload (hemosiderosis or concurrent hemochromatosis) sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac, hepatic, or pancreatic insufficiency.
4.Prior bone marrow or stem cell transplant.
5.Clinically symptomatic cholelithiasis or cholecystitis. (Prior cholecystectomy is not exclusionary. Patients with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.)
6.Currently enrolled in another therapeutic clinical trial involving on-going therapy with any investigational or marketed product or placebo. Concurrent participation in the Pyruvate Kinase Deficiency Natural History Study (NCT02053480) is permitted.
7.Exposure to any investigational drug, device, or procedure within 28 days prior to Screening.
8.Concurrent medical condition that could compromise participation in the study such as:
a.Poorly controlled hypertension (defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg) refractory to medical management.
b.History of recent (within < 6 months from Screening date) congestive heart failure; myocardial infarction or unstable angina pectoris; or hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
c.Currently active infection requiring the use of parenteral anti-microbial agents or that is = Grade 3 (CTCAEv4.03) within 6 months of first dose.
d.A pattern or frequency of post-splenectomy sepsis that in the assessment of the Investigator could reasonably be expected to interfere with the ability of the patient to complete the 24 week study participation.
e.Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody with signs of active Hepatitis B or C virus infection.
f.Positive test for human immunodeficiency virus (HIV) 1 or 2 antibody.
g.Diabetes mellitus judged to be in poor control by the Investigator or requiring > 3 anti-diabetic agents counting insulin; use of insulin per se is not exclusionary.
h.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 and no known active disease present and no treatment administered during the last 3 years.
9.Undergone major surgery within 6 months of first dose.
10.Current or recent history of psychiatric disorder that in the opinion of the Investigator or Medical Monitor could compromise the ability of the patient to cooperate with study visits and procedures.
11.Use of any of the restricted list of products known to strongly inhibit CYP3A4 metabolism (Appendix 15.3, Table 7) within 5 days prior to Day 1 dosing; or to strongly induce CYP3A4 metabolism (Appendix 15.3, Table 8) within 28 days prior to Day 1 dosing; or to strongly inhibit P-gp transporter (Appendix 15.3, Table 9) within 5 days prior to Day 1 dosing; or digoxin within 5 days prior to Day 1 dosing. For patients who require chronic inhaled glucocorticoid therapy, Investigators should confer with the Medical Monitor for add
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method