| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Pyruvate Kinase Deficiency
Haemolytic anaemia |
|
| E.1.1.1 | Medical condition in easily understood language |
Lack of Pyruvate Kinase enzyme
Lack of red blood cells following their destruction and removal from the bloodstream |
|
| 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 long-term safety and tolerability of AG-348 |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the long-term efficacy of AG-348
• To evaluate the efficacy of AG-348 in increasing hemoglobin (Hb) concentrations in subjects who previously received placebo in Study AG348-C-006 (ie, Cohort 1 only)
• To determine the effect of AG-348 on health-related quality of life (HRQoL) using patient reported outcomes (PROs)
• To evaluate the pharmacokinetics of AG-348 after oral administration (Cohort 1 only)
• To evaluate the relationship between AG-348 pharmacokinetics and safety parameters
(Cohort 1 only) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have signed written informed consent prior to participating in this extension study;
2. Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit;
3. Cohorts 2 and 3: Have demonstrated clinical benefit from AG-348 treatment in the antecedent study, in the opinion of the Investigator;
4. For women of reproductive potential:
a. In Cohort 1, have a negative local serum (human chorionic gonadotropin [hCG]) pregnancy test during screening of this extension study.
b. In Cohort 2 or 3, have a negative local urine pregnancy test during screening of this extension study.
5. 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) 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 drug.
6. Be willing and able to comply with study visits and procedures. |
|
| E.4 | Principal exclusion criteria |
1. Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG-348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the subject to complete study visits and procedures;
2. Are currently pregnant or breastfeeding;
3. Have a splenectomy scheduled during the study treatment period;
4. Meet the withdrawal criteria of his/her antecedent AG-348 study during screening of this extension study.
Withdrawal criteria of the antecedent AG-348 studies are as follows:
- Withdrawal of consent
- Development of an intercurrent medical condition that precludes further participation in the study
- Subject requires use of a prohibited concomitant medication
- Investigator decision
- Persistent nonadherence to protocol requirements
- Pregnancy
- Lost to follow-up
5. Are currently receiving medications that are strong inhibitors of CYP3A4, that have not been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug on this extension study.
6. Have received anabolic steroids, including testosterone preparations, within 28 days prior to start of study drug on this extension study.
7. Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this extension study.
8. Have exposure to any investigational drug other than AG-348, device, or procedure within 3 months prior to start of study drug on this extension study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Type, incidence, severity, and relationship to study drug of treatmentemergent adverse events (TEAEs); serious adverse events (SAEs); AESIs; and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation.
2. Changes from baseline in clinical laboratory tests (ie, serum chemistry, liver function tests [LFTs], hematology, lipids, sex steroids, coagulation, urinalysis), physical examination (PE) findings, bone
mineral density T- and Z-scores (total hip, femoral neck, and lumbar spine), vital signs, and 12-lead electrocardiogram (ECG) data. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to end of study (Week 197) |
|
| E.5.2 | Secondary end point(s) |
Cohort 1 only:
- Proportion of subjects achieving a 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
- Average change from baseline in Hb concentration at Weeks 16, 20, and 24
- 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
All cohorts:
- Change from baseline in Hb concentration
- Change from baseline in markers of hemolysis: bilirubin, lactate dehydrogenase (LDH), and haptoglobin levels
- Change from baseline in markers of erythropoietic activity: reticulocyte percentages
- Change from baseline in the number of transfusion events
- Change from baseline in the number of RBC units transfused
- Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Weeks 16, 20, 24
2) Week 12: pre-dose, post-dose at 30 minutes, 1 hour (h), 2 h, 4 h, 8 h
3) Week 12: pre-dose, post-dose at 30 minutes, 1 h, 2 h, 4 h, 8 h
4) From baseline up to Week 197
5) From baseline up to Week 197
6) From baseline up to Week 197
7) From baseline up to Week 197
8) From baseline up to Week 197
9) From baseline up to Week 197
10) From baseline up to Week 197
11) From baseline up to Week 193
12) From baseline up to Week 193 |
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 22 |
| 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 |
| Brazil |
| Canada |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| Thailand |
| Turkey |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 5 |
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