| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Sickling of red blood cells |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040644 |
| E.1.2 | Term | Sickle cell disease |
| 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 assess (maximum) efficacy of treatment with AG-348 on sickling as evaluated by change in Point of Sicking (PoS, expressed in mmHg), as quantified by the Oxygenscan. During the Dose Finding Period the maximum efficacy is defined as the lowest PoS measured during the treatment period relative (%) to the mean PoS during the Screening Period (Day -50 to Day -1) and D0. During the Fixed Dose Extension Period and the Prolonged Fixed Dose Extension Period, the efficacy of treatment with AG-348 is evaluated by mean PoS during this treatment period relative (%) to the mean PoS during the Screening Period (Day -50 to Day -1) and D0.
- To evaluate safety of AG-348 (including the type, incidence, severity and relationship of AG-348 to AE and SAE; number of medication discontinuations due to AE; physical examination findings, vital signs and 12-lead electrocardiogram (ECG) data). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of AG-348 on changes in hemoglobin (Hb) and other hematological parameters, lactate dehydrogenase (LDH), bilirubin, carboxy hemoglobin (HbCO), red cell 2,3-DPG and ATP levels. - To evaluate the effect of AG-348 on changes of surrogate markers of mortality and organ damage in SCD (NT-proBNP, urinary albumin to creatinine ratio (ACR), CRP, LDH/HbCO).
- To evaluate the effect of AG-348 on RBC deformability using the Osmoscan (osmotic gradient ektacytometry)
- To evaluate the effect of AG-348 on clinical characteristics: Health Related Quality of Life (HRQoL) (EQ-5D-5L, SF-36), movement behaviour (accelerometer Activ8), dyspnea (MRC dyspnea) and fatigue (PROMIS fatigue short form) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female with documented homozygous sickle cell anemia (HbSS) or HbS/beta(0 or +)-thalassemia).
2. Documented history of VOCs, and number of days admitted in hospital for acute sickle cell related complications during 24 months before inclusion.
3. SCD with at least one of the following conditions:
I. Had at least 1 (but no more than 10) VOC in the past 12 months prior to the first day of study treatment;
II. any sickle cell related hospital admission in the past 12 months prior to the first day of study treatment;
III. any history of sickle cell related complications (such as osteonecrosis, osteoporosis, nephropathy, retinopathy, leg ulcer, acute chest syndrome, acute hemolytic crisis);
IV. presence of any clinical biomarkers associated with increased mortality in SCD prior to the first day of study treatment (NT-proBNP >160 pg/mL, LDH/HbCO ratio >1,200, tricuspid regurgitant jet velocity ≥2.5 m/s).
4. Age 16 years and older, inclusive; subjects age 16 or 17 years must be documented Tanner Stage 5.
5. Hemoglobin ≤6.9 mmol/L (approx 11.1 g/dL) and >2.5 mmol/L (approx 4.0 g/dL).
6. For subjects on hydroxyurea: the dose must have been stable for at least 3 months prior the 1st day of study treatment.
7. Subjects must start or continue taking at least the equivalent of daily 0.7 mg oral folic acid for the duration of the study.
8. Have adequate organ function based on ALT, AST, bilirubin, creatinine, neutrophil and platelet count and INR.
9. Willing and able to give written informed consent and comply to all study procedures.
10. Patients with increased albumin to creatinine ratio are prioritized above patients with a normal albumin to creatinine ratio. Both are eligible.
11. For women of reproductive potential: have a negative serum pregnancy test at screening.
12. If fertile, agree to use double anticonception during the study plus 90 days (for males) or 28 days (for females) after the last dose of the study drug. |
1. Man of vrouw met homozygote sikkelcelziekte (HbSS) of HbS/beta(0 of +)-thalassemie)
2. Gedocumenteerde historie van vaso-occlusieve crisis (VOC) en aantal dagen dat hij/zij is opgenomen geweest in het ziekenhuis voor acute sikkelcelgerelateerde complicaties gedurende 24 maanden vóór inclusie.
3. SCZ met ten minste één van de volgende punten:
I. Ten minste 1 (maar niet meer dan 10) VOC in de afgelopen 12 maanden voor de eerste dag van studiebehandeling;
II. een sikkelcelgerelateerde ziekenhuisopname in de afgelopen 12 maanden voor de eerste dag van studiebehandeling;
III. voorgeschiedenis van sikkelcelgerelateerde complicatie(s) (zoals osteonecrose, osteoporose, nefropathie, retinopathie, been ulcus, acute chest syndrome, acute hemolytische crisis);
IV. aanwezigheid van klinische biomarker(s) geassocieerd met verhoogde mortaliteit bij SCZ voor de eerste dag van studiebehandeling (NT-proBNP >160 pg/mL, LDH/HbCO ratio >1,200, tricuspid regurgitant jet velocity ≥2.5 m/s).
4. Leeftijd 16 jaar en ouder, inclusief; bij personen van 16 of 17 jaar moet Tannerstadium 5 gedocumenteerd zijn.
5. Hemoglobine ≤6.9 mmol/L (ong 11.1 g/dL) en >2.5 mmol/L (ong 4.0 g/dL).
6. Mensen op hydrea: the dosis moet stabiel zijn voor ten minste 3 maanden voor de eerste dag van studiebehandeling.
7. Deelnemers moeten ten minste de equivalent van dagelijks 0.7 mg oraal foliumzuur gaan of blijven gebruiken gedurende de hele studie.
8. Goede orgaanfunctie gebaseerd op ALT, AST, bilirubine, creatinine, neutrofielen- en bloedplaatjesgetallen, en INR.
9. Bereid en in staat zijn om schriftelijke toestemming te geven en zich te houden aan alle studieprocedures.
10. Patiënten met een verhoogde ACR worden geprioriteerd boven de anderen. Beide kunnen deelnemen.
11. Voor vruchtbare vrouwen: een negatieve serum zwangerschapstest op screening.
12. Indien vruchtbaar, bereid zijn om dubbele anticonceptie te gebruiken gedurende de studie plus 90 dagen (voor mannen) of 28 dagen (voor vrouwen) na inname van laatste dosis van studiemedicatie. |
|
| E.4 | Principal exclusion criteria |
1. More than 10 vaso-occlusive crises within the past 12 months.
2. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior to the first day of study treatment (rescreening is allowed).
3. Have a point of sickling (PoS) ≤24.6 mmHg as quantified by the Oxygenscan during screening to exclude subjects with no clinical relevant detectable sickling.
4. Subjects age 16 or 17 years who are documented Tanner stage 1-4 (see Appendix II).
5. Receiving regularly scheduled (red blood cell) transfusion, defined as more than 4 transfusions in the 12 months prior to the first day of study treatment, and/or have received a transfusion within the past 3 months prior to the first day of study treatment.
6. Have a significant medical condition that confers an unacceptable risk to participation in the study, and/or that could confound interpretation of the study data (such as poorly controlled hypertension, cardiac diseases, cholelithiasis, cholecystitis, cholestatis hepatitis, iron overload that could result in cardiac/hepatic/pancreatic dysfunction, have diagnosis of other congenital or acquired blood disorder, active hepatitis B or C infection or antibodies, HIV-1 of HIV-2 antibodies, active infections, poorly controlled diabetes mellitus, history of primary malignancy (except for non-melanomatous skin cancer, curatively treated cervical or breast carcinoma in situ with no known active disease present and no treatment administered during the last 3 years, unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise, severe hepatic fibrosis/cirrhosis or NASH, current or recent history of psychiatric disorder that could compromise the ability of the subject to cooperate with study visits and procedures.
7. Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Participation in registry studies is allowed.
8. Have exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment.
9. Have had any prior treatment with a pyruvate kinase activator.
10. Have a prior bone marrow or stem cell transplant.
11. Are currently pregnant or breastfeeding, or planning to become pregnant during the course of the study.
12. 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.
13. Are currently receiving medications that are strong inhibitors of CYP3A4 or strong inducers of CYP3A4 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.
14. Are currently receiving hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment.
15. Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) or history of acute allergic reaction to drugs 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.
16. For men and women of reproductive potential: unwillingness to use double anticonception during the trial period. |
1. Meer dan 10 vaso-occlusive crisen hebben gehad in de afgelopen 12 maanden.
2. Opgenomen geweest voor sikkelcelziekte of andere vaso-occlusive events in de 14 dagen voorafgaand aan de eerste dag van de onderzoeksbehandeling (her-screening is toegestaan).
3. Point of sickling (PoS) ≤24.6 mmHg gekwantificeerd door de Oxygenscan tijdens screening om personen zonder klinische relevant detecteerbaar sikkelen uit te sluiten.
4. 16 of 17-jarigen met gerapporteerd Tanner stadium 1-4
5. Regelmatig (rode bloedcel) transfusie heeft ontvangen, gedefinieerd als meer dan 4 transfusies in de laatste 12 maanden voorafgaand aan de eerste dag van onderzoeksbehandeling en/of transfusie heeft ontvangen in de afgelopen 3 maanden voorafgaand aan de eerste dag van de onderzoeksbehandeling.
6. Heeft een ernstige medische aandoening dat een onacceptabel risico vormt om deel te nemen in de studie, en/of dat de interpretatie van de studie data kunnen beïnvloeden (zoals slecht beheersbare hypertensie, hartziekten, galstenen, galblaasontsteking, cholestatische hepatitis, ijzeroverschot dat zou kunnen leiden tot een hart/lever/alvleesklier disfunctie, heeft een diagnose of andere congenitale of verworven bloedziekte, actieve hepatitis B or C infectie of antistoffen, HIV-1 of HIV-2 antistoffen, actieve infecties,slecht beheersbare diabetes mellitus, geschiedenis van primaire maligniteit (uitzonderingen: niet-melanomateuze huidkanker, curatief behandelde cervix of borst carcinoom in situ waarvan niet bekend is dat ze op dit moment actief zijn en geen behandeling hebben ontvangen in de afgelopen 3 jaar, unstabiele extramedullaire hematopoiese wat een risico zou kunnen vormen voor dreigende neurologische schade, ernstige leverfibrose/cirrhose of NASH, huidige of in het verleden psychologische ziekte die de mogelijkheid tot deelname aan studievisites en procedures in gevaar kan brengen.
7. Momenteel geïncludeerd zijn in een andere therapeutische studie met een onderzoeksmiddel of geregistreerd middel of placebo. Deelname in registries is toegestaan.
8. Blootgesteld zijn geweest aan een onderzoeksmiddel medisch hulpmiddel, of procedure in de laatste 3 maanden voorafgaand aan de eerste toediening van het onderzoeksmiddel.
9. Een eerdere behandeling met een pyruvaat kinase activator hebben of hebben gehad.
10. Een eerdere beenmergtransplantatie of stamceltransplantatie hebben gehad.
11. Momenteel zwanger of borstvoeding gevend, of verwacht zwanger te worden gedurende de loop van de studie.
12. Grote operatie heeft gehad in de afgelopen 6 maanden voorafgaand aan ondertekening van het informed consent. Procedures zoals laparoscopische galblaas operaties worden niet als groot beschouwd in deze context.
13. Momenteel medicatie krijgen die sterke remmers zijn van CYP3A4 of sterke CYP3A4 inducerende middelen, die niet zijn gestopt voor tenminste 5 dagen of een tijdsbestek wat overeenkomt met 5 halfwaardetijden (welke het langste is) voorafgaand aan de eerste toediening van de studiebehandeling.
14. Krijgt momenteel middelen om de hematopoiese te stimuleren (zoals erythropoietines, granulocyten kolonie stimulerende factoren, trombopoietines) die niet gestopt zijn gedurende ten minste 28 dagen voorafgaand aan de eerste toediening van de studiebehandeling.
15. Bekende allergie tegen mitapivat of diens hulpstoffen (microcrystalline cellulose, croscarmellose natrium, natriumstearylfumaraat en mannitol) of een geschiedenis van acute allergische reactie tegen medicijnen die kunnen leiden tot acute hemolytische anemie, leverschade, anaphylactische reactie, erythema multiforme uitslag of Stevens-Johnson syndroom, cholestatische hepatitis, of andere ernstige klinische manifestaties.
16. Voor vruchtbare mannen en vrouwen: niet bereid zij om dubbele anticonceptie te willen gebruiken tijdens het onderzoek. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Safety of AG-348 including the type, incidence, severity and relationship of AG-348 to AE and SAE; number of medication discontinuations due to AE; physical examination findings, vital signs and 12-lead electrocardiogram (ECG) data.
- Efficacy of treatment of AG-348 as evaluated by changes in sickling behaviour (Point of Sickling) as quantified by the Oxygenscan (= primary main study parameter). For the Dose Finding Period this is calculated as the maximum absolute change in PoS at any study visit during this treatment period compared to the mean of PoS from Screening and D0. During the Fixed Dose Extension Period the efficacy of treatment with AG-348 is evaluated by mean PoS during this treatment period relative (%) to the mean POS during the Screening Period (Day -50 to Day -1) and D0.
- Efficacy of treatment of AG-348 evaluated by percentage of responders defined as:
o Anti-sickling response: percentage of patients that has an improvement in absolute PoS at D56 (for the Dose Finding Period) or mean PoS during Fixed Dose Extension Period on study drug (for the Fixed Dose Extension Period) compared to baseline (mean of Screening and D0) of at least 10%.
o Hematological response: percentage of patients that has an improvement in hemoglobin level at any time point compared to baseline (mean of Screening and D0) or mean hemoglobin level during Fixed Dose Extension Period on study drug (for the Fixed Dose Extension Period) compared to baseline (mean of Screening an D0) of at least 1 g/dL. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Day 56 (end of Dose Finding Period)
- Week 52 (end of Fixed Dose Extension Period)
- Prolonged Fixed dose phase ( 24 months)
- Extension period ( 36 months)
- End of Study |
|
| E.5.2 | Secondary end point(s) |
- Maximum change in Hb, bilirubin, HbCO, p50 (TCS HEMOX Analyzer), 2,3-DPG and ATP levels.
- Maximum change in RBC deformability, dehydration and cell membrane stability, ex vivo (Osmotic gradient ektacytometry (Osmoscan). - Changes in clinical characteristics:
o Health related Quality of Life (HRQoL) (EQ-5D-5L, SF-36).
o Movement behaviour (accelerometer Activ8)
o Dyspnea (MRC dyspnea) o Fatigue (PROMIS fatigue short form)
- Changes in surrogate markers of organ damage or biomarkers associated with mortality at D56 compared to baseline:
o Urinary albumin to creatinine ratio o NT-proBNP o CRP
o LDH/HbCO ratio o Endothelial activation: D-dimer, von Willebrand factor-antigen (VWF), soluble vascular cell adhesion molecule (sVCAM) o Change in number of crises compared to historical rate |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
Print
