Clinical Trials Register

Summary
EudraCT Number:	2021-001674-34
Sponsor's Protocol Code Number:	AG348-C-020
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-12-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2021-001674-34

A.3

Full title of the trial

A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease.

Studio multicentrico di fase 2/3, in doppio cieco, randomizzato, controllato con placebo, per valutare l’efficacia e la sicurezza di Mitapivat in soggetti con anemia falciforme

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical study to check the Efficacy and Safety of Mitapivat in Patients with Sickle Cell Disease

Studio clinico per controllare l’efficacia e la sicurezza di Mitapivat in pazienti affetti da anemia falciforme

A.3.2

Name or abbreviated title of the trial where available

Clinical study to check the Efficacy and Safety of Mitapivat in Patients with Sickle Cell Disease

Studio clinico per controllare l’efficacia e la sicurezza di Mitapivat in pazienti affetti da anemia

A.4.1

Sponsor's protocol code number

AG348-C-020

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AGIOS PHARMACEUTICALS, INC.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Agios Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Agios Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Director, Scientific Communications
B.5.3	Address:
B.5.3.1	Street Address	88 Sidney Street
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02139-4169
B.5.3.4	Country	United States
B.5.4	Telephone number	+18446332332
B.5.5	Fax number	00000000
B.5.6	E-mail	medinfo@agios.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mitapivat
D.3.2	Product code	[AG-348]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mitapivat
D.3.9.1	CAS number	2151847-10-6
D.3.9.2	Current sponsor code	AG-348 solfato idrato
D.3.9.3	Other descriptive name	AGI-1480, AGX-0841, AG-348, AG-348 hemisulfate
D.3.9.4	EV Substance Code	SUB181978
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mitapivat
D.3.2	Product code	[AG-348]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mitapivat
D.3.9.1	CAS number	2151847-10-6
D.3.9.2	Current sponsor code	AG-348 solfato idrato
D.3.9.3	Other descriptive name	AGI-1480, AGX-0841, AG-348, AG-348 hemisulfate
D.3.9.4	EV Substance Code	SUB181978
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mitapivat
D.3.2	Product code	[AG-348]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mitapivat
D.3.9.1	CAS number	2151847-10-6
D.3.9.2	Current sponsor code	AG-348 solfato idrato
D.3.9.3	Other descriptive name	AGI-1480, AGX-0841, AG-348, AG-348 hemisulfate
D.3.9.4	EV Substance Code	SUB181978
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Sickle Cell Disease

Anemia falciforme

E.1.1.1

Medical condition in easily understood language

Sickle cell disease is an inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally and become rigid and shaped like a crescent (sickle shape).

L’anemia falcif è una malatt eredit del sangue in cui i globuli rossi, che trasport l’ossige in tutto il corpo, si svilupp in modo anomalo, si irrigidiscono e assumono una forma a mezzaluna(falce).

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

Phase 2)
To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on:
• Anemia in subjects with sickle cell disease (SCD)
• Safety

Phase 3)
To determine the effect of mitapivat versus placebo on:
• Anemia in subjects with sickle cell disease (SCD)
• Sickle cell pain crises (SCPCs) in subjects with SCD

Fase 2
Determinare la dose raccomandata di mitapivat per la fase 3, valutando l’effetto di 2 livelli di dosaggio di mitapivat rispetto al placebo su:
• Anemia in soggetti affetti da anemia falciforme (AF)
• Sicurezza
Fase 3
Determinare l’effetto di mitapivat rispetto al placebo su:
• Anemia in soggetti affetti da anemia falciforme (AF)
• Crisi dolorose da cellule falciformi (Sickle Cell Pain Crises, SCPC) in soggetti con AF

E.2.2

Secondary objectives of the trial

Phase 2)
To evaluate the effect of 2 doses of mitapivat versus placebo on:
- Anemia
- Markers of hemolysis and erythropoiesis
- Patient-reported fatigue
- Sickle cell pain crises (SCPCs).
To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.

Phase 3)
To evaluate the effect of mitapivat versus placebo on:
• Anemia in subjects with SCD
• Markers of hemolysis
• Markers of erythropoiesis
• Patient-reported fatigue
• Additional clinical efficacy measures related to SCPC

Fase 2
Valutare l’effetto di 2 dosi di mitapivat rispetto al placebo su:
- Anemia
- Marcatori di emolisi ed eritropoiesi
- Affaticamento riferito dal paziente
- Crisi dolorose da cellule falciformi (SCPC)
Valutare gli effetti farmacocinetici e farmacodinamici di mitapivat.
Fase 3
Valutare l’effetto di mitapivat rispetto al placebo su:
• Anemia in soggetti con AF
• Marcatori di emolisi
• Marcatori di eritropoiesi
• Affaticamento riferito dal paziente
• Ulteriori misure di efficacia clinica correlate alle SCPC

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age =16 years; subjects age 16 or 17 years must physically have completed puberty.
• Documented diagnosis of SCD (HbSS, HbSC, HbS/ß0-thalassemia, HbS/ß+ thalassemia, or other sickle cell syndrome variants).
• At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the past 12 months.
• Hemoglobin =5.5 and =10.5 g/dL.
• If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug.
• Women capable of becoming pregnant and men with partners who are women that are capable of becoming pregnant must agree to use 2 forms of contraception.
• Other protocol-defined inclusion criteria may apply.

• Età =16 anni; i soggetti di età pari a 16 o 17 anni devono aver completato fisicamente la pubertà.
• Diagnosi documentata di AF (HbSS, HbSC, talassemia HbS/ß0, talassemia HbS/ß+ o altre varianti della sindrome delle cellule falciformi).
• Almeno 2 crisi dolorose da cellule falciformi (SCPC) e non più di 10 SCPC negli ultimi 12 mesi.
• Emoglobina tra =5,5 e =10,5 g/dl.
• Se si assume idrossiurea, la dose di idrossiurea deve essere rimasta stabile per almeno 90 giorni prima di iniziare l’assunzione del farmaco in studio.
• Le donne in età fertile e gli uomini con partner in età fertile devono accettare di utilizzare 2 forme contraccettive.
• Possono applicarsi altri criteri di inclusione definiti dal protocollo.

E.4

Principal exclusion criteria

• Pregnant or breastfeeding.
• Receiving regularly scheduled transfusions.
• Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease.
• Severe kidney disease.
• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
• Currently receiving treatment for SCD (eg, voxelotor, crizanlizumab, L glutamine), with the exception of hydroxyurea. The last dose of such therapies must have been administered at least 90 days before starting study drug.
• Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug.
• Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial.
• Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).
• Other protocol defined exclusion criteria may apply.

• Gravidanza o allattamento al seno.
• Ricezione di trasfusioni regolarmente programmate.
• Disturbi epatobiliari, tra cui, a titolo esemplificativo ma non esaustivo, malattia epatica o malattia della colecisti significativa.
• Grave malattia renale.
• Precedente esposizione a una terapia genica o precedente trapianto di midollo osseo o cellule staminali.
• Attualmente in trattamento per l’AF (per es. voxelotor, crizanlizumab, L-glutamina), ad eccezione dell’idrossiurea. L’ultima dose di tali terapie deve essere stata somministrata almeno 90 giorni prima di iniziare l’assunzione del farmaco in studio.
• Attuale trattamento con agenti stimolanti l’ematopoiesi; l’ultima dose deve essere stata somministrata almeno 90 giorni prima di iniziare l’assunzione del farmaco in studio.
• Ricezione di un trattamento nell’ambito di un’altra sperimentazione nei 90 giorni precedenti l’inizio del farmaco dello studio o intenzione di partecipare a un’altra sperimentazione su un farmaco sperimentale.
• Assunzione di farmaci che sono forti inibitori del CYP3A4/5 o forti induttori del CYP3A4 che non possono essere interrotti in un lasso di tempo accettabile prima di iniziare l’assunzione del farmaco in studio (il lasso di tempo sarà discusso con il proprio medico).
• Possono applicarsi altri criteri di esclusione definiti dal protocollo.

E.5 End points

E.5.1

Primary end point(s)

Phase 2 Primary Endpoints:
• Percentage of participants with hemoglobin (Hb) response
• Percentage of participants with treatment emergent adverse events (AEs) and treatment emergent serious adverse events (SAEs)

Phase 3 Primary Endpoints
• Percentage of participants with hemoglobin (Hb) response
• Annualized rate of Sickle Cell Pain Crises (SCPCs)

Endpoint primari della fase 2:
• Percentuale di partecipanti con risposta dell’emoglobina (Hb)
• Percentuale di partecipanti con eventi avversi (EA) emergenti dal trattamento ed eventi avversi seri (Serious Adverse Events, SAE) emergenti dal trattamento
Endpoint primari della fase 3
• Percentuale di partecipanti con risposta dell’emoglobina (Hb)
• Tasso annualizzato di crisi dolorose da cellule falciformi (SCPC)

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 2 primary endpoint of percentage of participants with Hb response: Week 12

Phase 2 primary endpoint of percentage of participants with treatment emergent AEs and treatment emergent SAEs: Up to Week 12

Phase 3 primary endpoint of percentage of participants with Hb response: Week 52

Phase 3 primary endpoint of annualized rate of sickle cell pain crises: Up to Week 52

Endpoint primario di fase 2 della percentuale di partecipanti con risposta dell’Hb: Settimana 12
Endpoint primario di fase 2 della percentuale di partecipanti con EA emergenti dal trattamento e SAE emergenti dal trattamento: fino alla Settimana 12
Endpoint primario di fase 3 della percentuale di partecipanti con risposta dell’Hb: Settimana 52
Endpoint primario di fase 3 del tasso annualizzato di crisi dolorose da cellule falciformi: fino alla Settimana 52

E.5.2

Secondary end point(s)

Phase 2 Secondary Endpoints
1. Change from baseline in Hb concentration
2. Change from baseline in indirect bilirubin
3. Change from baseline in lactate dehydrogenase (LDH)
4. Change from baseline in absolute reticulocyte count
5. Change from baseline in percent reticulocytes
6. Change from baseline in erythropoietin
7. Change from baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score
8. Annualized Rate of SCPCs
9. Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG)
10. Mitapivat Concentration Over Time
11. Mitapivat Area Under the Concentration-time curve
12. Mitapivat Maximum (Peak) Concentration

Phase 3 Secondary Endpoints
1. Change From Baseline in Hb Concentration
2. Change From Baseline in Indirect Bilirubin
3. Change From Baseline in Percent Reticulocytes
4. Change From Baseline in PROMIS® Fatigue 13a SF Scores
5. Annualized Frequency of Hospitalizations for SCPC
6. Change From Baseline in LDH Concentration
7. Change From Baseline in Absolute Reticulocytes
8. Change From Baseline in Erythropoietin
9. Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue
10. Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue
11. Time to First SCPC
12. Time to Second SCPC
13. Annualized Rate of Hospitalization Days for SCPC
14. Annualized Rate of Emergency Room Visits for SCPC
15. Change From Baseline in 6-Minute Walk Test (6MWT)
16. Change From Baseline in PROMIS Pain Intensity
17. Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact
18. PGIC of Pain
19. Change From Baseline in PGIS of Pain
20. Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)
21. Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels
22: Mitapivat Concentration Over Time
23: Mitapivat Area Under the Concentration Curve
24: Mitapivat Maximum (Peak) Concentration

Endpoint secondari della fase 2
1. Variazione rispetto al basale nella concentrazione di Hb
2. Variazione rispetto al basale nella bilirubina indiretta
3. Variazione rispetto al basale nella lattato deidrogenasi (Lactate Dehydrogenase, LDH)
4. Variazione rispetto al basale nella conta reticolocitaria assoluta
5. Variazione rispetto al basale nella percentuale di reticolociti
6. Variazione rispetto al basale nell’eritropoietina
7. Variazione rispetto al basale nel punteggio del Modulo breve (Short Form, SF) 13a sull’affaticamento del Sistema informativo per la misurazione degli esiti riferiti dal paziente (Patient-Reported Outcomes Measurement Information System®, PROMIS®)
8. Tasso annualizzato di SCPC
9. Relazione farmacocinetica/farmacodinamica: Valutare
l’esposizione di mitapivat alla variazione nei livelli di adenosina trifosfato (ATP) e 2,3-difosfoglicerato (2,3-DPG)
10. Concentrazione di mitapivat nel tempo
11. Area sotto la curva concentrazione-tempo di mitapivat
12. Concentrazione massima (picco) di mitapivat

Endpoint secondari della fase 3
1. Variazione rispetto al basale nella concentrazione di Hb
2. Variazione rispetto al basale nella bilirubina indiretta
3. Variazione rispetto al basale nella percentuale di reticolociti
4. Variazione rispetto al basale nei punteggi SF 13a sull’affaticamento del sistema PROMIS®
5. Frequenza annualizzata di ricoveri per SCPC
6. Variazione rispetto al basale nella concentrazione di LDH
7. Variazione rispetto al basale nei reticolociti assoluti
8. Variazione rispetto al basale nell’eritropoietina
9. Percentuale di partecipanti con miglioramento del punteggio dell’Impressione globale del paziente sulla gravità (Patient Global Impression of Severity, PGIS) - Affaticamento
10. Percentuale di partecipanti con miglioramento del punteggio dell’Impressione globale del paziente sul cambiamento (Patient Global Impression of Change, PGIC) - Affaticamento
11. Tempo alla prima SCPC
12. Tempo alla seconda SCPC
13. Tasso annualizzato di giorni di ricovero per SCPC
14. Tasso annualizzato di visite al Pronto Soccorso per SCPC
15. Variazione rispetto al basale nel test del cammino in 6 minuti (6-Minute Walk Test, 6-MWT)
16. Variazione rispetto al basale nell’intensità del dolore secondo il sistema PROMIS
17. Variazione rispetto al basale nell’impatto del dolore secondo il Sistema informativo per la misurazione della qualità della vita negli adulti con anemia falciforme (Adult Sickle Cell Quality of life Measurement, ASCQ-Me)
18. PGIC del dolore
19. Variazione rispetto al basale nella PGIS del dolore
20. Percentuale di partecipanti con eventi avversi (EA) emergenti dal trattamento ed EA seri (SAE) emergenti dal trattamento
21. Relazione farmacocinetica/farmacodinamica: Valutare l’esposizione di mitapivat alla variazione nei livelli di ATP e 2,3-DPG
22: Concentrazione di mitapivat nel tempo
23: Area sotto la curva di concentrazione di mitapivat
24: Concentrazione massima (picco) di mitapivat

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase 2
Endpoints #1,2,3,4,5,6,7: Baseline, Week 10 up to Week 12
Endpoint #8: Up to Week 12
Endpoints #9,10,11,12: Day 1 up to Week 8

Phase 3
Endpoints #1,2,3,4,6,7,8: Baseline, Week 24 up to Week 52
Endpoint #5,11,12,13,14: Up to Week 52
Endpoints #9,10: Baseline, Weeks 24, 28, 40, and 52
Endpoints #15,18,19: Baseline, Week 52
Endpoints #16,17: Baseline, Week 24 and 52
Endpoint #20: Up to 56 weeks
Endpoints #21,22,23,24: Day 1 up to Week 40

Fase 2
Endpoint n. 1, 2, 3, 4, 5, 6, 7: Basale, dalla Settimana 10 fino alla Settimana 12
Endpoint n. 8: fino alla Settimana 12
Endpoint n. 9, 10, 11, 12: dal Giorno 1 alla Settimana 8
Fase 3
Endpoint n. 1, 2, 3, 4, 5, 6, 7, 8: Basale, dalla Settimana 24 fino alla Settimana 52
Endpoint n. 5, 11, 12, 13, 14: fino alla Settimana 52
Endpoint n. 9, 10: Basale, Settimane 24, 28, 40 e 52
Endpoint n. 15, 18, 19: Basale, Settimana 52
Endpoint n. 16, 17: Basale, Settimane 24 e 52
Endpoint n. 20: fino a 56 settimane
Endpoint n. 21, 22, 23, 24: dal Giorno 1 alla Settimana 40

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

È previsto un periodo di estensione in aperto dopo il completamento del periodo in doppio cieco.

There is an open label extension period following completion of the double blind period.

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Information not present in EudraCT

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

Egypt

Kenya

Lebanon

Nigeria

Oman

Saudi Arabia

Turkey

Belgium

Brazil

Canada

Germany

Israel

Italy

Netherlands

United Kingdom

United States

France

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

The end of the study is defined as the time at which all subjects complete all study visits, are lost to follow-up, have withdrawn consent for further participation in the study, or when the Sponsor terminates the study. Study completion is the date of the last visit of the last subject in the study.

La fine dello studio è definita come il momento in cui tutti i soggetti completano tutte le visite dello studio, risultano persi al follow-up, hanno revocato il consenso per l’ulteriore partecipazione allo studio o quando lo sponsor pone fine allo studio. Il completamento dello studio è la data dell’ultima visita dell’ultimo soggetto partecipante allo studio.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

240

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

For subjects under 18 Years of age written informed assent/consent will be obtained from parents and child assent. It must be obtained before any study-related procedures are conducted.

Per i soggetti di età inferiore ai 18 anni, l’assenso/consenso informato scritto sarà ottenuto dai genitori e l’assenso dal minore. Deve essere ottenuto prima che venga condotta qualsiasi procedura correlata allo studio.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

267

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Nessuno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-02-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-20

P. End of Trial
P.	End of Trial Status	Ongoing

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