| 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 |
| Pyruvate Kinase Deficiency |
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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 | 18.0 |
| 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 |
| • Evaluate the safety and tolerability of up to 24 weeks of AG 348 administration in patients with PK deficiency. |
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| E.2.2 | Secondary objectives of the trial |
• Evaluate the pharmacokinetics (PK) of AG-348 and the metabolite AGI-8702.
• Evaluate the PD response of ATP and 2,3 DPG after administration of AG-348.
• Evaluate indicators of clinical activity of AG-348 in patients with PK deficiency, including changes in hemoglobin (Hb), HCT, reticulocyte count, haptoglobin (Hp), carboxyhemoglobin (COHb), lactate dehydrogenase (LDH), total and indirect bilirubin, erythropoietin (EPO), ferritin, and transferrin saturation (serum iron/iron binding capacity).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 syndrome and must not be choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease.
c. Serum creatinine ≤ 1.25 × ULN. If serum creatinine > 1.25 × ULN, then 24 hour measured or calculated (Cockcroft-Gault) glomerular filtration rate (GFR) ≥ 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 patient is receiving therapeutic anticoagulants.
13. Women of childbearing potential (WOCBP) must agree to abstain from sexual intercourse or to use an acceptable/effective method of contraception (i.e., condom plus spermicide, condom plus oral contraceptive, condom plus intrauterine device [IUD], condom plus diaphragm with spermicide) from as soon as feasible during the Screening period until 30 days following the last dose of AG-348.
14. WOCBP must have a negative serum or urine pregnancy test within 72 hours before start of AG 348 dosing.
15. Women must not be breastfeeding.
16. Male patients, with the exception of those who have undergone vasectomy at least 6 months prior to Screening, must agree to abstain from sexual intercourse or, if sexually active, to use a condom with spermicide as contraception (regardless of their female partner's childbearing potential or their partner's use of their own contraception) from Day 1 of dosing until 30 days following the last dose of AG-348.
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| E.4 | Principal exclusion criteria |
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 additional guidance.
12. Serum bilirubin > ULN attributable to factors other than hemolysis and/or Gilbert's syndrome.
13. Male patients with heart-rate corrected QT (Fridericia's correction factor) QTcF interval > 450 msec, or female patients with QTcF interval > 470 msec with the exception of patients with a left bundle branch block (LBBB). Medical Monitor approval needed in patients with a LBBB.
14. Cardiac dysrhythmias judged as clinically significant by the Investigator or requiring therapy with drugs that are primarily substrates of CYP3A4.
15. History of allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, or rash of erythema multiforme type or Stevens-Johnson syndrome.
16. Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient’s ability to understand and sign informed consent; cooperate with study visits, tests, and procedures; or otherwise safely and reliably participate in the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for the study is the description of safety and tolerability: AEs, including determination of SAEs and AEs leading to discontinuation; safety laboratory parameters (hematology, chemistry, urinalysis, coagulation); physical examination findings; vital signs (VS); 12 lead electrocardiograms (ECGs); and DXA scans. Adverse events will be graded using Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.03. Serum sex hormone levels (testosterone [total and free], , estrone, and estradiol), bone turnover markers (serum osteocalcin-N-mid and serum C terminal telopeptide [CTX]), 25-hydroxy vitamin D2 and D3, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and triglycerides will be monitored for evidence of potential inhibition of aromatase by AG-348. Menstruating female patients will also keep a paper-based menstrual cycle diary throughout the study. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The DRT (Data Review Team) will monitor safety on an on-going basis and meet at regular intervals (approximately every 6 weeks), or ad hoc as necessary, to review AEs, VS, clinical laboratory (hematology, clinical chemistry, coagulation, and urinalysis), and ECGs on enrolled patients. The DRT will be comprised of the study Coordinating Investigator, treating Investigators, Medical Monitor, Clinical Pharmacologist, Statistician, and Sponsor’s Responsible Medical Officer. |
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| E.5.2 | Secondary end point(s) |
The PK and PD profile of AG-348 will be evaluated by:
• Approximately the first 10 patients treated, contingent on clinical site feasibility, will undergo extensive PK sampling as detailed in Appendix 15.1, Table 5. The remainder of treated patients will undergo limited PK sampling as detailed in Appendix 15.1, Table 6. Serial blood sampling for determination of concentration-time profiles of AG-348 and its metabolite AGI-8702 will be conducted following the first dose and the morning Day 15 dose, and additional trough levels of AG-348 and AGI-8702 will be obtained.
• Pharmacodynamic assessments will include 2,3-DPG, ATP (secondary objectives), and PKR activity assay, PKR protein, and glycolytic flux assay (exploratory objectives). The PKR Flux assay and PKR activity assay will only be conducted in clinical sites able to perform these assessments. Approximately the first 10 patients treated will undergo extensive PD sampling as detailed in Appendix 15.1, Table 5.
Clinical Activity will be evaluated by
• Monitoring of potential indicators of clinical activity will include evaluating changes in Hb, HCT, reticulocyte count, Hp, COHb, LDH, total and indirect bilirubin, EPO, ferritin, and transferrin saturation.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The DRT will also review (approximately every 6 weeks) available PK/PD data and indicators of clinical activity. PK and PD Observations: including changes in 2,3 DPG and ATP; Indicators of Clinical Activity: including changes in Hb, HCT, reticulocyte count, Hp, COHb, LDH, EPO, total and indirect bilirubin, ferritin, and transferrin saturation. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| France |
| Italy |
| Netherlands |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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After up to 75 subjects have been randomized and completed the final study visit (Week 24 or Week 28), the study will be completed.
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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