Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202408476236496 Date of Approval: 08/08/2024
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title FLORAL: A research study looking at long-term treatment with etavopivat in people with sickle cell disease or thalassaemia
Official scientific title An open-label, multi-centre, rollover study to characterise long-term safety andefficacy of etavopivat in adults, adolescents and children who have sickle cell disease orthalassaemia and have completed a treatment period in an etavopivat study
Brief summary describing the background and objectives of the trial Sickle cell disease (SCD) and thalassaemia are among the most common inherited disorders in the world. In 2007, the World Health Organization estimated that 5.2% of the population worldwide carries a haemoglobinopathy gene variant, classifying the disease group as a growing global health problem.1 SCD and thalassaemia are characterised by an abnormal and/or an inadequate amount of haemoglobin (Hb) and unhealthy red blood cells (RBC), that lead to haemolytic anaemia and organ damage. People diagnosed with haemoglobinopathies often have a poor quality of life and a life expectancy reduced by 20−30 years.2 The lack of effective treatment strategies for patients with haemoglobinopathies reflects a critical unmet medical need. Etavopivat is an orally bioavailable, selective activator of erythrocyte pyruvate kinase (PKR), currently under development in clinical studies as a potential treatment for inherited haemoglobinopathies, including SCD and thalassaemia. The scope of this rollover study is to investigate long-term safety and efficacy of etavopivat in adults, adolescents and children with SCD or thalassaemia, who have completed a treatment period with etavopivat in previous etavopivat studies. This is an interventional, multi-national, multi-centre, open-label, phase 3b study in adults (participants ≥ 18 years old), adolescents (participants ≥ 12 to < 18 years old) and children (participants ≥ 11 months to < 12 years old) with sickle cell disease (SCD), with SCD who have been on chronic transfusions to prevent primary stroke or recurrence of stroke (SCDTD), non-transfusion-dependent thalassaemia (NTDT) or transfusion-dependent thalassaemia (TDT). Rationale: The purpose of this rollover study is to investigate the long-term safety of etavopivat in participants 11 months of age and older with SCD or thalassaemia who have completed a treatment period in previous etavopivat studies (parent studies, see Section 4.1). Long-term clinical efficacy measures of etavopivat trea
Type of trial Non-Randomised
Acronym (If the trial has an acronym then please provide) FLORAL
Disease(s) or condition(s) being studied Haematological Disorders
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 31/07/2025
Actual trial start date
Anticipated date of last follow up 31/07/2026
Actual Last follow-up date
Anticipated target sample size (number of participants) 325
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Crossover: all participants receive all interventions in different sequence during study Non-randomised Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Etavopivat 400 mg QD 260 weeks PKR activation initiates a molecular and cellular cascade that reduces the level of 2,3 diphosphoglycerate (2,3-DPG), thus decreasing RBC sickling and increasing Hb levels in the blood. Moreover, PKR activation increases adenosine triphosphate (ATP) levels and reduces polymerisation of sickle Hb into rigid aggregates that deform RBCs, contributing to an improved RBC membrane.9, 10 Through these mechanisms, PKR activation is predicted to lessen the clinical manifestation of individuals with SCD and thalassaemia, by impacting the health and lifespan of RBCs and reducing haemolysis 325
Control Group NA N/A N/A N/A 0 Uncontrolled
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Informed consent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study. United Kingdom: Please see country-specific requirements in Appendix 8 2. Participant must have ongoing participation in an etavopivat parent study (Table 4-1) for treatment of SCD or thalassaemia and have completed at least a treatment period of the parent study. 3. Participant must have derived clinical benefit from treatment with etavopivat, as determined by the investigator. 4. Any participant with dose reduction or temporary discontinuation will need to be rechallenged before transferring. 5. Participants on hydroxyurea (HU), crizanlizumab or l-glutamine oral powder (Endari®) treatment at the time of consent may be eligible if they: a. Have been on a stable dose during participation in the parent study (i.e., no changes to the dose except for changes to weight or age reasons). b. Have been compliant with the treatment regimen at the discretion of the investigator during participation of the parent study. 1. Previous participation in this study. Participation is defined as signed informed consent. 2. Female who is pregnant or intends to become pregnant or is of childbearing potential and not using adequate contraceptive method, as defined in Appendix 4 (Section 10.4). 3. Any disorder, except for conditions associated with SCD or thalassaemia, which in the investigator’s opinion might jeopardise participant’s safety or compliance with the protocol. 4. Participant withdrew or had permanent treatment discontinuation from an etavopivat clinical study. 5. Participants on permanent treatment dose reduction or temporary treatment discontinuation. 6. Use of any of the following within the timeframes prior to the transfer visit as stated: a. Use of voxelotor within participation of the parent study or anticipated need for this agent during this study. b. Use of an experimental selectin antagonist (e.g., monoclonal antibody or small molecule) within the parent study or anticipated need for such agents during this study. c. Use of erythropoietin or other haematopoietic growth factor treatment within the parent study or anticipated need for such agents during this study. d. Receiving or use of concomitant medications that are strong inducers of cytochrome P450 (CYP) 3A4 within 2 weeks of the transfer visit or anticipated need for such agents during the study. 7. Current participation in a study that is not a designated parent study, or planned participation in any other clinical trial, for the duration of FLORAL. Infant: 0 Month(s)-12 Month(s) 11 Month(s) 12 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/07/2024 University of Nigeria Teaching Hospital Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
University of Nigeria Teaching Hospital Enugu, PMB 01129 Enugu State Nigeria enugu 460000 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 02/08/2024 University of Ibadan Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Queen Elizabeth II Road Ibadan Ibadan 200212 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 05/08/2024 Lagos University Teaching Hospital ethics commitee
Ethics Committee Address
Street address City Postal code Country
Room 107, Central Administration Block, Lagos University Teaching Hospital lagos 100254 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 30/07/2024 University of Abuja ethics committee
Ethics Committee Address
Street address City Postal code Country
Gwagwalada. P.M.B. 228 Abuja 228 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 09/08/2024 Aminu Kano Teaching Hospital
Ethics Committee Address
Street address City Postal code Country
Zaria Road, Kano State Nigeria kano P.M.B 345 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 09/08/2024 Aminu Kano Teaching Hospital Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Zaria Road, Kano State Nigeria kano P.M.B 345 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 22/08/2024 Barau dikko teaching hospital ethics committee
Ethics Committee Address
Street address City Postal code Country
Lafia Road by Yakubu Gowon Way, City Centre, Kaduna kaduna kaduna Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/07/2024 Kintampo Health Research Center Institutional Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Brong Ahafo Region Kintampo 0000 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 30/08/2024 Korle Bu Teaching Hospital Institutional Review Board
Ethics Committee Address
Street address City Postal code Country
Medical Directorate, Central Admin Block Accra 0000 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/07/2024 KEMRI Scientific Ethics Review Unit
Ethics Committee Address
Street address City Postal code Country
Off mbagathi Road Nairobi 00200 Kenya
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/07/2024 Getrudes Childrens Hospital Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
Off Muthaiga Road Nairobi 00200 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome 1. Number of TEAEs, reported for each indication and age group separately 2. Number of adverse reactions, reported for each indication and age group separately Baseline from week 0 of FLORAL to end of study that is week 264, or earlier
Secondary Outcome 1. Annualised VOC rates, reported for each age group separately 2. Change in VOCs, reported for each age group separately 3. Change in Hb concentration, reported for each age group separately 4. Annualised number of hospitalisations, reported for each age group separately 5. Average length of stay of hospitalisations, reported for each age group separately 6. Change in Hb concentration 7. Number of RBC units transfused, reported for each indication separately 8. Change in RBC units transfused, reported for each indication separately Baseline that is week 0 of FLORAL to end of treatment at week 260, or earlier and Baseline that is of parent study to end of treatment at week 260, or earlier
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Kintampo Health Research Centre BRONG AHAFO REGION GHANA BRONG AHAFO REGION GHANA BOX 200 Ghana
Ghana Institute of Clinical Genetics Guggisberg Ave Accra Ghana
Ahero County Hospital KEMRI Kisumu Kisumu 54-40100 Kenya
Gertrudes Childrens Hospital 34 Muthaiga Road Nairobi 42325-001 Kenya
KEMRI Kombewa Clinical Research Centre Within Jaramogi Odinga road Kisumu 54-40100 Kenya
Kombewa Clinical Research Centre Namba Kosea Road Kisumu 54-40100 Kenya
KEMRI Kericho Walter reed Hospital road Kericho 1357 Kericho 20200 Kenya
KEMRI CRDR SIAYA RESEARCH ANNEX SIAYA COUNTY HOSPITAL Siaya 47855-001 Kenya
Lagos University Teaching Hospital Idi-Araba Lagos Nigeria
University of Abuja Teaching Hospital 228 Abuja Abuja Nigeria
University of Nigeria Teaching Hospital Ozalla,P.M.B. 01129.Enugu Enugu Nigeria
University of Ibadan Oduduwa Road, Oyo State Oyo State Nigeria
Aminu Kano Teaching Hospital Zaria road Kano state Nigeria
Barau Dikko Teaching Hospital Lafia Road, City Center, Kaduna, Kaduna Nigeria
FUNDING SOURCES
Name of source Street address City Postal code Country
Novo Nordisk Novo Alle 2880 Bagsvaerd Denmar Novo Alle Denmark
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Novo Nordisk Novo Alle 2880 Bagsvaerd Denmar Novo Alle Denmark Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Public Enquiries Michell Botha michelle.botha@iqvia.com +27126712334 1021 Cnr Lenchen Avenue North John Voster Street Centurion 0157
City Postal code Country Position/Affiliation
Centurion South Africa Assc Dr Global site Activation
Role Name Email Phone Street address
Principal Investigator Iheanyi Okpala iheanyi.okpala@unn.edu.ng +2348025453354 Kwame Nkuruma Way ,Enugu
City Postal code Country Position/Affiliation
enugu Nigeria National coordinating PI
Role Name Email Phone Street address
Scientific Enquiries Bernhards Ogutu ogutu6@gmail.com +254733812613 Kakamega road, Kondele, Kisumu
City Postal code Country Position/Affiliation
Nairobi Kenya National Coordinating Investigator
Role Name Email Phone Street address
Principal Investigator Seyram Kaali kaali.seyram@kintampo-hrc.org +233546381925 Brong Ahafo Region,
City Postal code Country Position/Affiliation
Kintampo Box 200 Ghana Principal investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes all IPD will be stripped off identifies and may be available upon request Informed Consent Form Approximately 18 months after trial completion N/A
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Official scientific title 08/08/2024 PACTR Admin An open-label, multi-centre, rollover study to characterise long-term safety and efficacy of etavopivat in adults, adolescents and children who have sickle cell disease or thalassaemia and have completed a treatment period in an etavopivat study An open-label, multi-centre, rollover study to characterise long-term safety andefficacy of etavopivat in adults, adolescents and children who have sickle cell disease orthalassaemia and have completed a treatment period in an etavopivat study
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Trial description 01/08/2024 Background information was missing This is an interventional, multi-national, multi-centre, open-label, phase 3b study in adults (participants ≥ 18 years old), adolescents (participants ≥ 12 to < 18 years old) and children (participants ≥ 11 months to < 12 years old) with sickle cell disease (SCD), with SCD who have been on chronic transfusions to prevent primary stroke or recurrence of stroke (SCDTD), non-transfusion-dependent thalassaemia (NTDT) or transfusion-dependent thalassaemia (TDT). Rationale: The purpose of this rollover study is to investigate the long-term safety of etavopivat in participants 11 months of age and older with SCD or thalassaemia who have completed a treatment period in previous etavopivat studies (parent studies, see Section 4.1). Long-term clinical efficacy measures of etavopivat treatment will also be assessed. This study will also ensure that participants who are benefiting from etavopivat treatment have prolonged access to the drug in the time before it is commercially available in their country. The primary objective is to investigate long-term safety of etavopivat in adults, adolescents and children with SCD, SCDTD, TDT or NTDT transferring from other studies with etavopivat. The secondary objective is to: i) To investigate long-term clinical efficacy measures of etavopivat treatment in adults, adolescents and children with SCD transferring from other studies with etavopivat ii) To evaluate the effects of etavopivat on hospitalisations in adults, adolescents and children with SCD transferring from other studies with etavopivat. iii) To investigate long-term clinical efficacy measures of etavopivat treatment in adults and adolescents with NTDT transferring from other studies with etavopivat. iv) To investigate long-term clinical efficacy measures of etavopivat treatment in adults and adolescents with TDT or SCDTD, transferring from other studies with etavopivat Sickle cell disease (SCD) and thalassaemia are among the most common inherited disorders in the world. In 2007, the World Health Organization estimated that 5.2% of the population worldwide carries a haemoglobinopathy gene variant, classifying the disease group as a growing global health problem.1 SCD and thalassaemia are characterised by an abnormal and/or an inadequate amount of haemoglobin (Hb) and unhealthy red blood cells (RBC), that lead to haemolytic anaemia and organ damage. People diagnosed with haemoglobinopathies often have a poor quality of life and a life expectancy reduced by 20−30 years.2 The lack of effective treatment strategies for patients with haemoglobinopathies reflects a critical unmet medical need. Etavopivat is an orally bioavailable, selective activator of erythrocyte pyruvate kinase (PKR), currently under development in clinical studies as a potential treatment for inherited haemoglobinopathies, including SCD and thalassaemia. The scope of this rollover study is to investigate long-term safety and efficacy of etavopivat in adults, adolescents and children with SCD or thalassaemia, who have completed a treatment period with etavopivat in previous etavopivat studies. This is an interventional, multi-national, multi-centre, open-label, phase 3b study in adults (participants ≥ 18 years old), adolescents (participants ≥ 12 to < 18 years old) and children (participants ≥ 11 months to < 12 years old) with sickle cell disease (SCD), with SCD who have been on chronic transfusions to prevent primary stroke or recurrence of stroke (SCDTD), non-transfusion-dependent thalassaemia (NTDT) or transfusion-dependent thalassaemia (TDT). Rationale: The purpose of this rollover study is to investigate the long-term safety of etavopivat in participants 11 months of age and older with SCD or thalassaemia who have completed a treatment period in previous etavopivat studies (parent studies, see Section 4.1). Long-term clinical efficacy measures of etavopivat trea
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Trial type 08/08/2024 PACTR Admin CCT Non-Randomised
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 01/08/2024 Incorrect entry made Experimental Group, Etavopivat, 400 mg QD, 260 weeks, PKR activation initiates a molecular and cellular cascade that reduces the level of 2,3 diphosphoglycerate (2,3-DPG), thus decreasing RBC sickling and increasing Hb levels in the blood. Moreover, PKR activation increases adenosine triphosphate (ATP) levels and reduces polymerisation of sickle Hb into rigid aggregates that deform RBCs, contributing to an improved RBC membrane.9, 10 Through these mechanisms, PKR activation is predicted to lessen the clinical manifestation of individuals with SCD and thalassaemia, by impacting the health and lifespan of RBCs and reducing haemolysis, 3, Experimental Group, Etavopivat, 400 mg QD, 260 weeks, PKR activation initiates a molecular and cellular cascade that reduces the level of 2,3 diphosphoglycerate (2,3-DPG), thus decreasing RBC sickling and increasing Hb levels in the blood. Moreover, PKR activation increases adenosine triphosphate (ATP) levels and reduces polymerisation of sickle Hb into rigid aggregates that deform RBCs, contributing to an improved RBC membrane.9, 10 Through these mechanisms, PKR activation is predicted to lessen the clinical manifestation of individuals with SCD and thalassaemia, by impacting the health and lifespan of RBCs and reducing haemolysis, 325,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 01/08/2024 Incorrect entry made Control Group, NA, N/A, N/A, N/A, 3, Uncontrolled Control Group, NA, N/A, N/A, N/A, 0, Uncontrolled
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 21/02/2025 Approval received FALSE, University of Nigeria Teaching Hospital Health Research Ethics Committee, University of Nigeria Teaching Hospital Enugu, PMB 01129 Enugu State Nigeria, enugu , 460000 , Nigeria, 31 Jul 2024, , 08034079903, mazionyimba@yahoo.com, FALSE, University of Nigeria Teaching Hospital Health Research Ethics Committee, University of Nigeria Teaching Hospital Enugu, PMB 01129 Enugu State Nigeria, enugu , 460000 , Nigeria, 31 Jul 2024, , 08034079903, mazionyimba@yahoo.com, 30660_29737_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 21/02/2025 Approval received FALSE, University of Abuja ethics committee, Gwagwalada. P.M.B. 228, Abuja, 228, Nigeria, 30 Jul 2024, , +2347040045614, info@uath.gov.ng, TRUE, University of Abuja ethics committee, Gwagwalada. P.M.B. 228, Abuja, 228, Nigeria, 30 Jul 2024, 30 Jan 2025, +2347040045614, info@uath.gov.ng, 30660_29743_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 21/02/2025 Approval received FALSE, Barau dikko teaching hospital ethics committee, Lafia Road by Yakubu Gowon Way, City Centre, Kaduna, kaduna, kaduna, Nigeria, 22 Aug 2024, , +2347053856556, bdth@kdsg.gov.ng, TRUE, Barau dikko teaching hospital ethics committee, Lafia Road by Yakubu Gowon Way, City Centre, Kaduna, kaduna, kaduna, Nigeria, 22 Aug 2024, 02 Dec 2024, +2347053856556, bdth@kdsg.gov.ng, 30660_29746_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Contact People Contacs List 01/08/2024 Missing information Principal Investigator, Seyram, Kaali, Dr., kaali.seyram@kintampo-hrc.org, , +233546381925, Brong Ahafo Region, , Kintampo, , Ghana, Principal investigator Principal Investigator, Seyram, Kaali, Dr., kaali.seyram@kintampo-hrc.org, , +233546381925, Brong Ahafo Region, , Kintampo, Box 200, Ghana, Principal investigator
Section Name Field Name Date Reason Old Value Updated Value
Contact People Contacs List 01/08/2024 Information was missing Principal Investigator, Seyram, Kaali, Dr., kaali.seyram@kintampo-hrc.org, , +233546381925, Brong Ahafo Region, , Kintampo, , Ghana, Principal investigator