| 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 determine the efficacy of treatment with mitapivat compared with placebo, as assessed by the reduction in transfusion burden in pediatric subjects with pyruvate kinase deficiency (PK deficiency) who are not regularly transfused |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of treatment with mitapivat compared with placebo, as assessed by the increase in Hb concentrations in pediatric subjects with PK deficiency who are not regularly transfused
- To evaluate the safety of mitapivat compared with placebo in pediatric subjects with PK deficiency who are not regularly transfused
- To evaluate the effect of mitapivat compared with placebo on hemolysis, erythropoietic activity, and iron metabolism and iron overload in pediatric subjects with PK deficiency who are not regularly transfused
- To evaluate the effect of mitapivat compared with placebo on health related quality of life (HRQOL) measures in pediatric subjects with PK deficiency who are not regularly transfused
- To characterize the pharmacokinetics of mitapivat in pediatric subjects with PK deficiency who are not regularly transfused |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent from the subject, or the subject’s legally authorized representative, parent(s), or legal guardian, and the subject’s assent, where applicable (informed consent/assent) must be obtained before any study-related procedures are conducted and subjects must be willing to comply with all study procedures for the duration of the study.
2. Aged 1 to <18 years. Subjects between 12 and 24 months of age must weigh a minimum of 7 kg.
3. 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 study central genotyping laboratory
4. No more than 5 RBC transfusions in the 52-week period before providing informed consent/assent and no RBC transfusions ≤12 weeks before administration of the first dose of study drug
5. Hemoglobin concentration ≤10 g/dL for subjects 12 to <18 years of age or ≤9 g/dL for subjects 1 to <12 years of age during the Screening Period. Hemoglobin concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period.
6. Receiving folic acid supplementation as part of routine clinical care for at least 21 days before administration of the first dose of study drug, to be continued during study participation
7. Female subjects who have attained menarche and/or breast development in Tanner Stage 2, as well as male subjects with partners who have attained menarche, must be abstinent of sexual activities that may induce pregnancy 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 informed consent/assent, throughout the study, and for 28 days after the last dose of study drug (including the time required to dose taper) for female subjects who have attained menarche and 90 days after the last dose of study drug (including the time required to dose taper) for male subjects. The second form of contraception can include an acceptable barrier method (see Appendix 2 for the definition of women of childbearing potential and acceptable contraception methods).
|
|
| E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply:
1. Pregnant or breastfeeding
2. Homozygous for the R479H mutation or have 2 nonmissense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory
3. History of malignancy
4. History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent
5. Hepatobiliary disorders including, but not limited to:
a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis
b. Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible)
c. History of drug-induced cholestatic hepatitis
d. Aspartate aminotransferase >2.5×ULN (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition)
6. Renal dysfunction as defined by an estimated glomerular filtration rate <60 mL/min/1.73 m2 (bedside Schwartz equation; Schwartz et al, 2009)
7. Nonfasting triglycerides >440 mg/dL (5 mmol/L)
8. Active uncontrolled infection requiring systemic antimicrobial therapy
9. Subjects with a high likelihood of exposure to, or parental history of, hepatitis B or hepatitis C who subsequently test positive for hepatitis B antigen or hepatitis C virus antibody with signs of active hepatitis B or hepatitis C virus infection
10. Subjects with a high likelihood of exposure to, or parental history of, HIV who subsequently test positive for HIV 1 or 2 antibodies
11. History of major surgery (including splenectomy) ≤6 months before providing informed consent/assent and/or planning on undergoing a major surgical procedure during the Screening or Double-blind Period
12. Current enrollment or past participation (within 90 days before the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device
13. Prior bone marrow or stem cell transplantation
14. Currently receiving hematopoietic stimulating agents; the last dose must have been administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before randomization
15. Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), before randomization
16. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization
17. Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate)
18. Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Hb 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 12, 16, and 20 during the Double-blind 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 drug. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weeks 12, 16, and 20 during the Double-blind Period |
|
| E.5.2 | Secondary end point(s) |
• Average change from baseline in Hb concentration at Weeks 12, 16, and 20
• Maximal Hb concentration increase from baseline during the Double-blind Period
• Changes in safety assessments including measurement of sex hormones, sexual maturity rating with Tanner stage, development and the assessment of ovarian cysts (female subjects only)
• Changes over time in height-for-age z-score, weight-for-age z score, and body mass index–for age z score
• Changes over time in bone mineral density z score
• Average change from baseline in indirect bilirubin and lactate dehydrogenase at Weeks 12, 16, and 20
• Change from baseline in haptoglobin at Week 16
• Change from baseline in reticulocytes
• Change from baseline in markers of iron metabolism and indicators of iron overload (serum iron, serum ferritin, total iron-binding capacity, transferrin/ transferrin saturation)
• Change from baseline in quality of life assessments: Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment
• Pharmacokinetic parameters including, but not limited to, Cmax (maximum concentration), AUC (area under the concentration-time curve), Css (concentration at steady state), and Ctrough (trough concentration)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 12, 16, and 20
from baseline during the Double-blind Period etc. |
|
| 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) | 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 | No |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Israel |
| Turkey |
| United States |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| United Kingdom |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
Print
