E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pyruvate Kinase Deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Lack of Pyruvate Kinase enzyme |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037682 |
E.1.2 | Term | Pyruvate kinase deficiency anaemia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the efficacy of treatment with AG-348, as assessed by the reduction in transfusion burden. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to evaluate the safety of treatment with AG-348.
Exploratory objectives are: • To determine the effect of AG-348 on liver iron status, as measured by: − Liver iron concentration (LIC) − Use of iron chelation therapy • To evaluate health-related quality of life (HRQoL), as determined using patient-reported outcomes • To evaluate the pharmacokinetics of AG-348 following oral administration • To evaluate the change in the levels of red blood cell-specific form of pyruvate kinase (PKR) protein in whole blood |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have provided signed written informed consent prior to performing any study procedure, including screening procedures. 2. Be male or female, aged 18 years and older. 3. Have documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory. 4. Have a history of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent as documented in the transfusion history of the subject. 5. Have complete records of transfusion history, defined as having the following available for the 52 weeks prior to the date of informed consent: (1) all the transfusion dates, (2) the number of blood units transfused for all the transfusions, and (3) Hb levels within 1 week prior to transfusion for at least 80% of the transfusions. 6. Received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation. 7. Have adequate organ function, as defined by: a. Serum AST ≤2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and ALT ≤2.5 × ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition) 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 hepatocellular or biliary disease. c. Serum creatinine ≤1.25 × ULN. If serum creatinine is >1.25 × ULN, then 24-hour measured or calculated (Cockcroft-Gault) glomerular filtration rate (GFR) must be ≥60 mL/min. d. Absolute neutrophil count (ANC) ≥1.0 × 109/L e. Platelet count ≥100 × 109/L f. Activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤1.25 × ULN, unless the subject is receiving therapeutic anticoagulants 8. For women of reproductive potential— defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (ie, who have not menstruated at all for at least the preceding 12 months and have an elevated follicle-stimulating hormone (FSH) level indicative of menopause at screening): a. Have a negative serum pregnancy test during Screening. b. For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential: − Be abstinent as part of their usual life style, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 30 days (both men and women) following the last dose of AG-348. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization. 9. Be willing to comply with all study procedures, in particular the Individual TT (calculated based on 52 weeks of transfusion history), for the duration of the study.
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E.4 | Principal exclusion criteria |
1. Be homozygous for the R479H mutation or have 2 non-missense mutations in the PKLR gene, as determined per the genotyping performed by the study central genotyping laboratory. 2. Have a significant medical condition that confers an unacceptable risk to participate in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following: 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 prior to providing informed consent) congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism. c. Cardiac dysrhythmias judged as clinically significant by the Investigator. d. Heart-rate corrected QT interval-Fridericia’s method (QTcF) >450 msec with the exception of subjects with right or left bundle branch block. e. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved. f. History of drug-induced cholestatic hepatitis. g. Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (eg, clinically significant impaired left ventricular ejection fraction), hepatic (eg, fibrosis, cirrhosis), or pancreatic (eg, diabetes) dysfunction. h. Have a diagnosis of any other congenital or acquired blood disorder, or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy. i. Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody (Ab) with signs of active hepatitis B or C virus infection. If the subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be re-screened after receiving appropriate hepatitis C treatment. j. Positive test for human immunodeficiency virus (HIV)-1 or -2 Ab. k. Active infection requiring the use of parenteral antimicrobial agents or ≥Grade 3 in severity (per NCI CTCAE) within 2 months prior to first dose of study drug. l. Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary. m. History of any primary malignancy, with the exception of: curatively treated nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years. n. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise. o. Current or recent history of psychiatric disorder that, in the opinion of the Investigator or the Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures. 3. Have a history of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to signing the ICF. 4. Have a splenectomy scheduled during the study treatment period or have undergone splenectomy within 60 days prior to the Screening Visit. 5. Be currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior participation in the PK Deficiency NHS (NCT02053480) or PK Deficiency Registry is permitted; subjects enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry. 6. Have exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug. 7. Have a prior bone marrow or stem cell transplant. 8. Be currently pregnant or breastfeeding. 9. Have a history of major surgery within 6 months of providing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context. 10. Is currently receiving medications that are strong inhibitors of CYP3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 times their half-life prior to start of study drug dosing (Day 1 of Part 1). 11. Have a history of allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, or rash of erythema multiforme type or Stevens-Johnson syndrome, or other serious clinical manifestations. 12. Have a history of hypersensitivity to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is the proportion of subjects who achieve a reduction in transfusion burden, defined as a ≥33% reduction in the number of RBC units transfused during the 24 weeks of Part 2 compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
All through the study: for each transfusion administered at any time during the study, the date of transfusion, number of RBC units transfused, HCT, and volume of RBC units will be recorded. |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints The secondary endpoints of the study are the following: • Annualized total number of RBC units transfused during the study (both Part 1 and Part 2) compared with the historical transfusion burden • Number of transfusion episodes during Part 2 compared to the Standardized Control Period • Proportion of subjects who become transfusion-free, defined as 0 transfusions administered during Part 2 • Proportion of subjects who achieve Hb levels in the normal range at least once, 8 weeks or more after a transfusion in Part 2 • The type, incidence, severity, and relationship to treatment of adverse events (AEs) and serious adverse events (SAEs); AEs leading to treatment dose reduction, treatment interruption, and treatment discontinuation • Clinical laboratory tests over time (serum chemistry/liver function tests/lactate dehydrogenase, hematology, coagulation, lipids, sex steroids, urinalysis), physical examination findings, dual energy x-ray absorptiometry (DXA) scans (hip and lumbar spine), vital signs, and 12-lead electrocardiograms (ECGs) Exploratory Endpoints
The exploratory endpoints of the study are the following: • Change from baseline over time in LIC as assessed by magnetic resonance imaging • Change from baseline over time in usage of iron chelation therapy • Changes from baseline over time in HRQoL scores (eg, Pyruvate Kinase Deficiency Impact Assessment, Pyruvate Kinase Deficiency Diary, EuroQol-5D-5L, Patient Global Impression of Severity) • Characterization of pharmacokinetic profile (drug concentrations over time) and determination of pharmacokinetic parameters of AG-348 (eg, area under the plasma concentration × time curve, maximum (peak) concentration, and others as applicable) in Part 2 • Changes in total PKR protein levels. Changes in pyruvate kinase muscle isozyme protein levels and levels of intermediates in the metabolic pathways affected by PKR may also be assessed to further elucidate the mechanism and effects of PKR activation by AG-348 (only in subjects who have agreed to have this optional test performed).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary: Transfusion & AE: all through the study Physical exa: Scr, part 1 d1, wk12, part 2 d1, wk12, 24 + FU (ED) Vital sign, Hematology, Liver function: all visits ECG: Scr, part 1 d1, part 2 d1, FU DXA scan: Scr, part 2 d1, wk24, FU (ED) Serum chem.: Scr, part 1 d1, wk12, part 2 d1, wk12, 24, FU Coagulation & Urinalysis: Scr, part 1 d1, wk12, part 2 d1, wk12, 24, FU Lipid: part 1 d1, wk6, 12, 18, part 2 d1, wk4, 8, 12, 18, 24, FU Sex steroids: part 1 d1, wk4, 8, 12, 16, 20, 24, part 2 d1, wk4, 8, 12, 18, 24, FU
Exploratory: MRI: Scr, part 2 d1, wk24, FU (ED) Iron panel: Scr, part 1 d1, wk12, part 2 d1, wk24, FU (ED) HRQoL assess.: Scr, part 1 d1, wk4, 8, 12, 16, 20, 24, part 2 d1, wk 4, 8, 12, 18, 24, FU PK profile: part 2 wk 24 PKR prot.: Scr, part 1 d1, part 2 wk 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part 1 individualized dose optimization followed by a part 2 fixed-dose period |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Denmark |
France |
Ireland |
Italy |
Japan |
Netherlands |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 27 |