| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pyruvate Kinase Deficiency |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lack of Pyruvate Kinase enzyme |
|
| 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 | 21.1 |
| 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 |
|
| 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 |
| To evaluate the efficacy of treatment with AG-348 compared with placebo in increasing hemoglobin (Hb) concentrations |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
• To evaluate the safety of AG-348
• To determine the effect of the study treatment regimens on markers of hemolysis, hematopoietic activity, and other indicators of clinical activity
• To determine the effect of the study treatment regimens on healthrelated quality of life (HRQoL), as determined using patient-reported outcomes (PROs)
• To evaluate the pharmacokinetics of AG-348 after oral administration
• To evaluate the relationship between AG-348 pharmacokinetics and safety parameters
Exploratory:
• To evaluate the relationship of AG-348 pharmacokinetics to indicators of clinical activity
• To evaluate the pharmacodynamic markers of pyruvate kinase deficiency (PK deficiency) and how they are affected by study treatment
• To determine the effect of the study treatment regimens on:
o Number of transfusion events and number of red blood cell (RBC) units transfused
o Markers of iron metabolism and indicators of iron overload |
|
| 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 aged 18 years or older
3. Have documented clinical laboratory confirmation of PK deficiency, defined as 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 central genotyping laboratory
4. Have an Hb concentration less than or equal to 10.0 g/dL (6.21 mmol/L) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
5. Be considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment
6. Have received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation
7. Have adequate organ function, as defined by:
a. Serum aspartate aminotransferase (AST) ≤2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (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 not be associated with choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease. Elevated bilirubin attributed to hemolysis with or without Gilbert's syndrome is not exclusionary.
c. Estimated glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2, measured GFR ≥60 mL/min, or calculated creatinine clearance (CrCL; Cockcroft-Gault) ≥60 mL/min.
d. Absolute neutrophil count ≥1.0 × 109/L (based on an average of at least 2 measurements [separated by a minimum of 7 days] during the Screening Period).
e. Platelet count ≥100 × 109/L in the absence of a spleen, or platelet
count ≥50 × 109/L in the presence of a spleen and in the absence of any
other cause of thrombocytopenia (based on an average of at least 2 measurements [separated by a minimum of 7 days] during the Screening Period).
f. Activated partial thromboplastin time and international normalized ratio ≤1.25 × ULN, unless the subject is receiving therapeutic anticoagulants.
8. For women of reproductive potential, have a negative serum pregnancy test during the Screening Period. Women of reproductive potential are 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 prior to signing informed consent and have an elevated follicle-stimulating hormone level indicative of menopause during the Screening Period)
9. For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study treatment for women and 90 days following the last dose of study treatment for men. A highly effective form of contraception is defined as combined (estrogen and progestin containing) hormonal contraceptives (oral, intravaginal, or transdermal) known to be associated with inhibition of ovulation; progestin-only hormonal contraceptives (oral, injectable, or implantable) known to be associated with inhibition of ovulation; intrauterine device; intrauterine hormone releasing system; bilateral tube occlusion; or vasectomized partner. The second form of contraception can include an acceptable barrier method, which includes male or female condoms with or without spermicide, and cervical cap, diaphragm, or sponge with spermicide. Women of reproductive potential using hormonal contraception as a highly effective form of contraception must also utilize an acceptable barrier method while enrolled in the study and for at least 28 days after their last dose of study treatment.
10. Be willing to comply with all study procedures for the duration of the study |
|
| E.4 | Principal exclusion criteria |
1. Are homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the central genotyping laboratory
2. Have a significant medical condition that confers an unacceptable risk to participating 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 mmHg or diastolic BP >90 mmHg) refractory to medical management
b. History of recent (within 6 months prior to signing 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 >450 msec (average of triplicate ECGs) 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, hepatic, or pancreatic dysfunction
h. Diagnosis of any other congenital or acquired blood disorder or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy. Genetic findings that in isolation are predicted to be insufficient to explain the observed clinical phenotype may be allowed.
i. Positive test for HBsAg or HCVAb 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 rescreened after receiving appropriate hepatitis C treatment
j. Positive test for HIV-1 or -2 Ab
k. Active infection requiring the use of parenteral antimicrobial agents or Grade ≥3 in severity within 2 months prior to the first dose of study treatment
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 Medical Monitor, or designee could compromise the ability of the subject to cooperate with study visits and procedures
3. Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent
4. Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo.
5. Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment
6. Any prior treatment with a pyruvate kinase activator
7. Prior bone marrow or stem cell transplant
8. Are currently pregnant or breastfeeding
9. 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
10. 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 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment
11. Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment
12. History of allergy to sulfonamides if 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
13. History of allergy to AG-348 or its excipients
14. Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to the first dose of study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the hemoglobin response, defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24 during the Fixed Dose Period.
The individual subject's baseline Hb concentration is defined as the average of all available Hb concentrations collected for that subject during the Screening Period up to the first dose of study treatment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weeks 16, 20 & 24 during the fixed dose period |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
• Average change from baseline in Hb concentration at Weeks 16, 20, and 24
Other secondary endpoint:
• Maximal Hb concentration increase from baseline
• Time to first achieve an increase in Hb concentration of 1.5 g/dL (0.93 mmol/L) or more from baseline
• Average change from baseline at Weeks 16, 20, and 24 in markers of hemolysis: bilirubin, LDH, and haptoglobin levels
• Average change from baseline at Weeks 16, 20, and 24 in markers of hematopoietic activity: reticulocyte percentages
• Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA)
• Safety endpoints, including: the type, incidence, severity, and relationship to study treatment of AEs and SAEs; number of discontinuations due to AEs; results of clinical laboratory tests over time (eg, serum chemistry, LFT, hematology, lipids, sex steroids, urinalysis, coagulation); physical examination (PE) findings; dual-energy x-ray absorption (DXA) scans; vital signs; 12-lead electrocardiogram (ECG) data
• Pharmacokinetic endpoints, including plasma concentrations over time and pharmacokinetic parameters of AG-348 (eg, AUC, Cmax, others as applicable)
• Exposure-response relationship between safety parameters and AG348 concentration and relevant AG-348 pharmacokinetic parameters
Exploratory endpoint:
• Exposure-response (or pharmacokinetic-pharmacodynamic) relationship between relevant pharmacokinetic parameters and endpoints that are indicators of clinical activity
• Change from baseline in additional markers of hematopoietic activity
• Change from baseline in markers of iron metabolism and indicators of iron overload
• Change from baseline in PKR protein level
• Relationship between baseline PKR protein level and Hb response status
• Change from baseline in HRQoL PRO scores: European quality of life five-dimensional descriptive system (EQ-5D-5L)
• Change from baseline in PKR flux assay results
• Proportion of subjects requiring transfusions and the total number of RBC units transfused |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary
• Hematology: Scrn, D1, W2, 4, 6, 8, 10, 12, 16, 20, 24 & FUV
• Markers of erythopoietic activity: Scrn, D1, W12 & 24
• Circulating heme: Scrn, D1, W12 & 24
• PKDD: daily thourought Scrn, part 1 & 2
• PKDIA: Scrn, W4, 8, 12, 16, 20, 24,
• Iron panel & markers: Scrn, D1, W12 & 24
• PE: Scrn, D12, W12 & 24
• DXA: Scrn, W24
• ECG: Scrn, D12, W12 & 24, FUV
• Serum chemistry: Scrn, D1, W12, 24 & FUB
• Coag studies & urinalysis: Scrn, D1, W12 & 24
• LFT & LDH: Scrn, D1, W2, 4, 6, 8, 10, 12, 16, 20, 24 & FUV
• AEs: allthrough the study
• PK assessments: D1, W2, 6, 12 & 16
Exploratory:
• Soluble transferrin receptor: D1, W12 & 24
• EQ-5D-5L: Scrn, W12 & 24
• PKR prot: D1; W16
• PKR flux assay: D1, W12
• Liver MRI: Scrn, W24 |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Switzerland |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 13 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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