| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Transfusion-Dependent Thalassemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Thalassemia (genetic blood disorder where not enough hemoglobin is produced), not requiring lifelong regular transfusion for survival |
|
| 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 | LLT |
| E.1.2 | Classification code | 10074356 |
| E.1.2 | Term | Non-transfusion dependent thalassemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 this study is to evaluate the efficacy of treatment with AG-348 in increasing hemoglobin (Hb) concentrations in subjects with non-transfusion-dependent thalassemia (NTDT). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• To evaluate the safety of AG-348
• To determine the effect of AG-348 on markers of hemolysis and erythropoietic activity
• To evaluate the pharmacokinetics of AG-348
Exploratory objectives:
• To determine the effect of AG-348 in subjects with NTDT on the following:
o Pharmacodynamic (PD) markers of thalassemia
o Other markers of erythropoietic activity
o Markers of iron metabolism and indicators of iron overload
o Markers of oxidative stress and other related markers
o Transfusion burden
o Spleen size
• To evaluate the relationship between AG-348 pharmacokinetics and indicators of clinical activity in subjects with NTDT
• To evaluate the relationship between the dose of AG-348 and change in Hb concentrations in subjects with NTDT |
|
| 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 a known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes.
4. Have documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or DNA analysis, either from medical records or during the Screening Period.
5. Have an Hb concentration ≤10.0 g/dL, regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the Screening Period.
6. Be considered non-transfusion-dependent, defined as having no more than 5 units of RBCs transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug.
7. Have adequate organ function, as defined by:
a. Serum aspartate aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN) and alanine aminotransferase (ALT) ≤2.5 × ULN.
b. 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.
c. Normal levels of serum bilirubin; or if 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.
d. Absolute neutrophil count (ANC) ≥1.0 × 109/L.
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.
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, have a negative serum pregnancy test during the Screening Period and a negative serum or urine pregnancy test on Day 1. 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 (FSH) 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 drug for women and 90 days following the last dose of study drug for men. A highly effective form of contraception is defined as combined (estrogen and progestin containing) hormonal contraceptives (oral, intravaginal, or transdermal) associated with inhibition of ovulation; progestin-only hormonal contraceptives (oral, injectable, or implantable) 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 drug.
10. Be willing to comply with all study procedures for the duration of the study. |
|
| E.4 | Principal exclusion criteria |
1. Have known history of diagnosis of Hb S or Hb C forms of thalassemia.
2. Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
a. Poorly controlled hypertension refractory to medical management.
b. History of recent congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
c. Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac, hepatic, or pancreatic dysfunction.
d. Cardiac dysrhythmias judged as clinically significant by the Investigator.
e. Heart-rate corrected QTcF >450 msec with the exception of subjects with right or left bundle branch block.
f. Liver disease with histopathological evidence of liver cirrhosis/fibrosis on liver biopsy.
g. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary.
h. History of drug-induced cholestatic hepatitis.
i. Have a diagnosis of any other congenital or acquired blood disorder or any other hemolytic process. Allo-immunization will be allowed unless the subject has an ongoing hemolytic process related to antibodies.
j. Positive test for HBsAg or HCV antibody (Ab) with evidence of active hepatitis B or C virus infection.
k. Positive test for HIV-1 or -2Ab.
l. Active infection requiring the use of parenteral anti-microbial agents or Grade ≥3 in severity within 1 month prior to the first day of study drug.
m. 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.
n. 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.
o. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
p. Current or recent history of psychiatric disorder that, in the opinion of the Investigator or Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures.
q. 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 subject to complete the study.
r. Lung disease, including pulmonary fibrosis clinical syndrome or pulmonary hypertension requiring oxygen (O2) therapy.
s. Pulmonary hypertension with TRV ≥3.2 m/s by echo Doppler (obtained within 6 months of Screening).
t. Proteinuria >2 mg/kg.
u. Clinical diagnosis of osteoporosis
v. Grade ≥3 triglyceride elevations
3. Have a splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent.
4. Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo.
5. Have exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug.
6. Have prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy.
7. Have a prior bone marrow or stem cell transplant.
8. Are currently pregnant or breastfeeding.
9. 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.
10. Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, 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 day of study drug.
11. Are currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug.
12. Are currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug.
13. Are currently receiving hematopoietic stimulating agents, if initiated ≤8 weeks prior to the first day of study drug.
14. Have a 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.
15. Have a history of allergy to AG-348 or its excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the Hb response (HR), defined as a ≥1.0 g/dL increase in Hb concentration from baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). An individual subject’s baseline Hb concentration is defined as the average of all of the subject’s available Hb concentrations during the Screening Period up to the first dose of study drug. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• The mean change from baseline in Hb concentrations over a continuous 12-week interval from Week 12 to Week 24
• The sustained Hb response (sHR), defined as a subject who has achieved an HR and has achieved a ≥1.0 g/dL increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 Visit and Week 24 Visit (ie, Weeks 12, 16, 20, and 24)
• The delayed Hb response, defined as a subject who has not achieved an HR, but has achieved a ≥1.0 g/dL increase in Hb concentration at 1 or more Hb assessments after Week 12 (ie, Weeks 16, 20, and 24)
• Change from baseline in Hb concentration over the duration of the Extension Period
• Time to first ≥1.0 g/dL increase in Hb concentration
• Change from baseline in markers of hemolysis: reticulocyte count, bilirubin, lactate dehydrogenase (LDH), and haptoglobin
• Change from baseline in markers of erythropoietic activity: nucleated red blood cell (NRBC), erythropoietin (EPO), and soluble transferrin receptor
Safety Endpoints:
o The type, incidence, severity, and relationship to treatment with AG-348 of adverse events (AEs) and serious adverse events (SAEs), AEs of special interest (AESIs), AEs leading to study drug dose reduction, study drug interruption, and study drug discontinuation
o Changes over time in clinical laboratory tests (serum chemistry, liver function tests
(LFTs), LDH, hematology, coagulation, lipids, sex steroids, and urinalysis), physical
examination (PE) findings, bone mineral density (BMD) of the hip and lumbar spine,
vital signs, and 12-lead electrocardiogram (ECG) findings
Pharmacokinetic Endpoints:
o Pharmacokinetic endpoints include drug concentrations over time and pharmacokinetic parameters of AG-348, including area under the plasma concentration × time curve (AUC), maximum (peak) concentration (Cmax), and others as applicable
Exploratory Endpoints:
• Change from baseline in alpha(α)-, beta(β)-, and gamma(γ)-hemoglobin absolute levels and/or
ratios
• Change from baseline in other markers of erythropoietic activity: growth differentiation factor
(GDF)-15, GDF-11, and erythroferrone
• Change from baseline in markers of iron metabolism and indicators of iron overload
• Change from baseline in markers of oxidative stress: urinary 8-isoprostane, methylmalonic
acid, total homocysteine, and other red blood cell (RBC) metabolite measurements
• Proportion of subjects requiring transfusions and the total number of RBC units transfused
• Change from baseline in spleen size as assessed by magnetic resonance imaging (MRI)
• Change in Hb concentrations in relation to the dose of AG-348
• Pharmacokinetic/PD Endpoints:
o Change from baseline in adenosine triphosphate (ATP), 2,3 diphosphoglycerate
(2,3-DPG) concentrations, RBC-specific form of pyruvate kinase (PKR) activity, PKR
protein levels, and PKR flux assay results
o Exposure-response (or pharmacokinetic-PD) relationship between relevant
pharmacokinetic parameters and endpoints that are indicators of clinical activity
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
• Hb: baseline, wk 12 & 24
• Haptoglobin: all visits except wk1, 3, 7, 9 & 10, safety FU
• Bilirubin (LFT): Scr, all visits except wk1 & 3, safety FU
• LDH: D1, wk2, 4, 6, 8, 12, 16, 20, 24, 48, 72, 96, 120 & safety FU
Safety:
• AEs, concomitant med & procedures, physical exams & vital signs: all visits except wk7, 9 & 10, safety FU
• ECG: Scr, D1, wk6, 12, 24
• Serum chem: Scr, D1, wk4, 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, safety FU
• Lipids: Scr, D1, wk2, 4, 6, 8, 12, 16, 20, 24 36, 48, 60, 72, 84, 96, 108, 120, safety FU
• Sex steroids: D1, wk6, 8, 12, 16, 20, 24 36, 48, 60, 72, 84, 96, 108, 120, safety FU
PK:
• Through: wk1, 2, 3, 4, 6, 8, 16, 20 & 24
• Intensive: D1, wk12
PD:
D1, wk12 (all), wk 6, 8 (ATP, 2,3DPG), wk24 (ATP, 2,3DPG, PKR prot) |
|
| 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 | No |
| 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 | 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 | 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.8.3 |
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 | No |
| 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 |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
