Conditions: Sickle Cell Disease
Keywords: anemia sickle cell disease vamifeport
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the effect of VIT-2763 on markers of hemolysis (breakdown in red blood cells) in sickle cell disease (SCD). The safety, tolerability and clinical beneficial effects of VIT-2763 for the treatment of SCD are also explored.

Detailed description:
At randomization/baseline, participants are randomized into 3 VIT-2763 dose groups to receive either 60 mg twice daily (BID) (Cohort 1), or 120 mg BID (Cohort 2), or 120 mg 3 times daily (TID) (Cohort 3) and 2 placebo groups (BID, Cohort 4a or TID, Cohort 4b).

The expected duration of patient participation is a maximum of 16 weeks, including a non-treatment screening period of up to 4 weeks, and 8-week treatment period, and a 4-week safety follow-up period.

Arms:
arm 1: Participants receive VIT-2763 60 mg, twice a day during 8 weeks. arm 2: Participants receive VIT-2763 120 mg, twice a day during 8 weeks. arm 3: Participants receive VIT-2763 120 mg, three times a day during 8 weeks. arm 4: Participants receive a placebo, twice a day during 8 weeks. arm 5: Participants receive a placebo, three times a day during 8 weeks.

Interventions: intervention 1: VIT-2763 120 mg intervention 2: VIT-2763 360 mg intervention 3: VIT-2763 240 mg intervention 4: Placebo BID intervention 5: Placebo TID
Intervention descriptions: intervention 1: Participants receive 2 capsules of VIT-2763 30 mg in the morning and in the evening, for 8 weeks.

Capsules are to be taken orally. intervention 2: Participants receive 2 capsules of VIT-2763 60 mg in the morning, in the afternoon and in the evening for 8 weeks.

Capsules are to be taken orally. intervention 3: Participants receive 2 capsules of VIT-2763 60 mg in the morning and in the evening, for 8 weeks.

Capsules are to be taken orally. intervention 4: Participants receive 2 capsules of placebo in the morning and in the evening, for 8 weeks.

Capsules are to be taken orally. intervention 5: Participants receive 2 capsules of Placebo in the morning, in the afternoon and in the evening, for 8 weeks.

Capsules are to be taken orally.

Protocol document:
Prot_000.pdf: 
 
 
The information contained in this document is proprietary to Vifor Pharma and is not to be copied, disclosed or otherwise 
distributed by an outside authority to any person or persons without the prior written permission of Vifor Pharma. 
 
 
CLINICAL STUDY PROTOCOL 
VIT-2763-SCD-202 
 
Title: 
A Phase 2a, double-blind, randomised, 
placebo-controlled, efficacy, and safety study of 
multiple doses of VIT-2763 in subjects with 
sickle cell disease (ViSion Serenity) 
 
 
Clinical Protocol Number: 
VIT-2763-SCD-202 
 
 
Version Date: 
16 March 2023 
 
 
Version Number: 
4.0 
 
 
Prior Version/Amendments: 
Version 3.0/Amendment 2, 9 March 2022 
Version 2.0/Amendment 1, 3 March 2021 
Version 1.0/Original, 17 December 2020 
 
 
Investigational Drug: 
VIT-2763 (INN: Vamifeport) 
 
 
IND Number: 
147878 
 
 
EudraCT Number: 
2020-005072-34 
 
 
Co-ordinating Investigators: 
Dr Banu Kaya, MD and 
Dr Adlette Inati, MD 
 
 
Sponsor Contact: 
 
 
 
Sponsor Address:  
Vifor (International) Inc. 
Rechenstrasse 37 
St. Gallen CH-9014 
Switzerland 
Phone +41 58 851 80 00 
 
 
Medical Monitor: 
 
 
PPD
PPD
PPD


 
 
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SIGNATURE PAGE 
Declaration of Sponsor 
Title: A Phase 2a, double-blind, randomised, placebo-controlled, efficacy, and safety study 
of multiple doses of VIT-2763 in subjects with sickle cell disease (ViSion Serenity). 
Clinical Protocol Number: VIT-2763-SCD-202 
Version/Amendment Number/Date: Version 4.0, 16 March 2023 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the Declaration of Helsinki, and the International Council for Harmonisation 
Guideline for Good Clinical Practice as amended. 
 
 
 
 
 
 
. 
 
Date (day month year) 
 
 
 
 
 
 
 
Date (day month year) 
 
 
 
 
 
. 
 
Date (day month year) 
PPD
PPD
PPD


 
 
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Date (day month year) 
 
 
 
 
 
 
Date (day month year) 
 
PPD
PPD


 
 
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SIGNATURE PAGE 
Declaration of Co-ordinating Investigator 
Title: A Phase 2a, double-blind, randomised, placebo-controlled, efficacy, and safety study 
of multiple doses of VIT-2763 in subjects with sickle cell disease (ViSion Serenity). 
Clinical Protocol Number: VIT-2763-SCD-202 
Version/Amendment Number/Date: Version 4.0, 16 March 2023 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the Declaration of Helsinki, and the International Council for Harmonisation 
Guideline for Good Clinical Practice as amended. 
 
 
 
Signature of Co-ordinating Investigator 
 
Date (day month year) 
Banu Kaya, Dr, Barts Health 
NHS Trust - The Royal London Hospital 
80 Newark Street, London, 
 UK 
Phone: 
 
Email: 
 
 
 
 
 
 
Signature of Co-ordinating Investigator 
 
Date (day month year) 
Adlette Inati, 
 
Hopital Nini, Rue El Maarad 
Tripoli, Lebanon 
Phone: 
 
Email:
 
 
 
 
PPD


 
 
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SIGNATURE PAGE 
Declaration of National Co-ordinating Investigator 
Title: A Phase 2a, double-blind, randomised, placebo-controlled, efficacy, and safety study 
of multiple doses of VIT-2763 in subjects with sickle cell disease (ViSion Serenity). 
Clinical Protocol Number: VIT-2763-SCD-202 
Version/Amendment Number/Date: Version 4.0, 16 March 2023 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the Declaration of Helsinki, and the International Council for Harmonisation 
Guideline for Good Clinical Practice as amended. 
 
 
 
Signature of National Co-ordinating 
Investigator 
 
Date (day month year) 
Name, Title, Address, Telephone Number, 
and Email of National Co-ordinating 
Investigator 
 
 
 


 
 
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INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
Title: A Phase 2a, double-blind, randomised, placebo-controlled, efficacy, and safety study 
of multiple doses of VIT-2763 in subjects with sickle cell disease (ViSion Serenity). 
Clinical Protocol Number: VIT-2763-SCD-202 
Version/Amendment Number/Date: Version 4.0, 16 March 2023 
I have read the attached protocol as specified on this page and agree to abide by all 
provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for 
Good Clinical Practice as amended, and applicable local regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: me (including, 
if applicable, my spouse (or legal partner) and dependent children) my Sub-investigators 
before the start of the study and to report any changes that affect my financial disclosure 
status for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Vifor Pharma and <<licensee’s name>>. 
Signature by the Investigator on this Protocol Signature Page documents review, agreement 
and approval of the requirements contained within this protocol. 
 
 
 
Signature of Principal Investigator 
 
Date (day month year) 
Name, Title, Address, Telephone 
Number, and Email of Principal 
Investigator 
 
 


 
 
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SYNOPSIS 
VIT-2763-SCD-202 
Title: 
A Phase 2a, double-blind, randomised, placebo-controlled, efficacy, and safety 
study of multiple doses of VIT-2763 in subjects with sickle cell disease (ViSion 
Serenity) 
Short Title: 
A Phase 2a study to assess efficacy and safety of VIT-2763 in subjects with sickle 
cell disease 
Study Product(s): 
VIT-2763 (vamifeport) 
Study Population: 
Adults with sickle cell disease (SCD) (sickle haemoglobin (HbS)/S or HbS/βT0 
genotype) 
Phase: 
2a 
Sponsor: 
Vifor (International) Inc. 
Protocol Number: 
VIT-2763-SCD-202 
Co-ordinating 
Investigators:  
Dr Banu Kaya, MD and 
 Dr Adlette Inati, MD 
Objectives: 
Primary Objective: 
The primary objective of this study is to explore the effect of VIT-2763 on markers 
of haemolysis. 
Secondary Objective: 
The secondary objective of this study is to assess the safety and tolerability of 
VIT-2763 in SCD patients. 
Exploratory Objectives: 
• 
To explore the effect of VIT-2763 on haematological indices and vascular 
inflammation. 
• 
To explore the effect of VIT-2763 on iron and erythropoiesis related blood 
parameters. 
• 
To explore the effect of VIT-2763 on patient reported outcomes (pain and 
quality of life). 
• 
To explore the pharmacokinetics (PK) of VIT-2763 using a population PK 
approach. 
• 
To explore changes in abnormal red blood cells (RBCs) (sickling) assessed by 
peripheral blood smear. 
• 
To explore the number of vaso-occlusive crises (VOC) episodes and visceral 
infarctions. 
PPD


 
 
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Design: 
Phase 2a, multiple dose, double-blind, randomised, placebo-controlled study in SCD 
subjects. VIT-2763 will be administered daily during a period of 8 weeks, according 
to Figure 1 and the treatment scheme below: 
Treatment Scheme 
 
Baseline to Week 8 
 
Morning 
Dose 
Evening 
Dose 
Morning 
Dose 
Afternoon 
Dose 
Evening 
Dose 
Cohort 1 
(n=6) 
60 mg 
VIT-2763 
60 mg 
VIT-2763 
 
 
 
Cohort 2 
(n=6) 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
 
 
 
Cohort 3 
(n=6) 
 
 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
Cohort 4a 
(n=4) 
Placebo 
Placebo 
 
 
 
Cohort 4b 
(n=2) 
 
 
Placebo 
Placebo 
Placebo 
Note: 
n=Number of subjects per cohort. 
 
At randomisation/baseline, 24 subjects with SCD will be randomised in a 3:3:3:2:1 
ratio into 3 VIT-2763 dose groups to receive either 60 mg twice daily (BID) (120 
mg/day, Cohort 1), or 120 mg BID (240 mg/day, Cohort 2), or 120 mg 3 times 
daily (TID) (360 mg/day, Cohort 3) and 2 placebo groups (BID, Cohort 4a or TID, 
Cohort 4b). 
All subjects will be dosed for 8 consecutive weeks. 
Duration: 
The expected duration of subject participation is a maximum of 16 weeks, 
including a non-treatment screening period of up to 4 weeks (28 days), an 8-week 
(56±4 days) treatment period, and a 4-week (28±4 days) safety follow-up period. 
Treatment: 
Active Treatment 
VIT-2763 oral capsules of 2 dosage strengths (30 mg and 60 mg) with identical 
size, shape, and colour will be available. Capsules will be administered orally to 
achieve the specified dose and according to the administration schedule below. 
Placebo Treatment 
Matching placebo capsules to VIT-2763 will be available, administered orally, and 
according to the administration schedule below. 
Administration Schedule 
Randomisation to all dosage groups will be done by using a validated centralised 
interactive web response system (IWRS) and will be stratified by genotype 
(HbS/S - HbS/βT0). 


 
 
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Administration Schedule 
Total Daily Dose of VIT-2763 
Number of Capsules/Day 
VIT-2763 
Placebo 
120 mg 
4 × 30 mg  
N/A 
240 mg 
4 × 60 mg 
N/A 
360 mg 
6 × 60 mg 
N/A 
0 mg 
N/A 
4(1) or 6(2) × placebo 
1 Cohort 4a. 
2 Cohort 4b. 
Note: 
N/A=Not applicable. 
Inclusion Criteria: 
1. Subject has provided the appropriate written informed consent before any 
study-specific procedures are performed including screening procedures. 
2. Ability to understand the requirements of the study and abide by the study 
restrictions, and agreement to return for the required assessments. 
3. Male or female subjects with confirmed diagnosis of SCD, including only 
HbS/S or HbS/βT0 genotype. 
4. Subjects who had at least 1 and no more than 10 VOC episodes reported 
within 12 months prior to screening. Note: A VOC episode is defined as a 
documented episode of acute chest syndrome or acute painful crisis for the 
main indication of SCD, which led to health-professional instructed 
prescription or use of opioids (excluding codeine) for moderate to severe pain. 
5. 18 to 60 years of age inclusive at the time of screening. 
6. Body weight ≥40 kg and ≤120 kg at screening and baseline. 
7. Absolute reticulocyte count or percentage reticulocyte count >1.5 × upper limit 
of normal (ULN) during screening. 
8. Subjects on concomitant hydroxyurea treatment must be on a stable dose 
(mg/kg) for ≥3 months prior to screening Visit V1. There should be no planned 
dose adjustments during the course of the study in the opinion of the 
Investigator. 
9. Female subjects of childbearing potential must have negative pregnancy tests 
at screening (serum pregnancy test) and before randomisation (urine 
pregnancy test), must have stopped breastfeeding as of first dose, and must 
either commit to true abstinence from heterosexual contact (which must be 
reviewed on a monthly basis and source documented) or must be willing to use 
adequate contraceptive precautions, i.e., highly effective method of birth 
control. Abstinence should only be used as a contraceptive method if it is in 
line with the subjects’ usual and preferred lifestyle, and periodic abstinence 
(calendar, symptothermal, postovulation methods) is not an acceptable method 
of contraception. Female subjects must agree to use adequate contraception 
during the study and until at least 1 week after the last dose of investigational 
medicinal product (IMP) or requirements from other co-medications taken, 
e.g., hydroxyurea or according to local requirements, whichever is longer. 
Effective contraception (highly effective method of birth control, i.e., with a 
failure rate of <1% per year, when used consistently and correctly) such as 
implants, injectables, combined oral contraceptives (see below), intrauterine 
devices, sexual abstinence, or vasectomised partner must be used. 


 
 
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Non-childbearing potential includes being surgically sterilised at least 
6 months prior to the study. 
Note: For female subjects participating in this study, continuous use of 
hormonal contraception alone is not sufficient, because potential interactions 
via cytochrome P450 (CYP) enzymes may alter the efficacy of hormonal 
contraception. The continuous use of hormonal contraception by a female 
subject should be combined with the use of a condom with spermicide or 
adequate and approved alternatives by the (fertile) male partner. 
Exclusion 
Criteria: 
1. Subjects with confirmed SCD diagnosis other than HbS/S and HbS/βT0. 
2. Haemoglobin (Hb) level <6.0 g/dl in any subject or >10.4 g/dl for female 
and >11.0 g/dl for male subjects at screening Visit V1. 
Note: The Hb value at screening Visit V1 will be used for eligibility 
determination based on the central laboratory result. However, the baseline Hb 
value determined at Visit V2 (Day 1 pre-dose) also needs to be within the 
above specified range based on the local laboratory result. 
3. Having received RBC transfusion therapy within 4 weeks prior to screening, or 
ongoing or planned RBC transfusion therapy during the course of the study 
(including chronic, prophylactic, or preventive transfusion to treat SCD). 
4. Subjects with a serum ferritin level of <30 µg/l at screening. 
5. Calculated transferrin saturation (TSAT) level <25% at screening. However, in 
case the total iron-binding capacity (TIBC) level is within normal ranges of the 
central laboratory values, the subject will not be excluded. 
6. Subjects being hospitalised for SCD-related events (including pain crisis and 
VOC) within 14 days before the screening visit. Note: SCD must have been 
the main cause for the hospitalisation to fulfil this criterion. 
7. Chronic liver disease or history of liver cirrhosis, and/or alanine 
aminotransferase or aspartate aminotransferase, above 3-fold the ULN range at 
baseline. 
8. Estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m2 at screening. 
Note: eGFR should be estimated according to Chronic Kidney Disease 
Epidemiology Collaboration formula (CKD-EPI). 
9. Newly diagnosed folate deficiency anaemia (i.e., folic acid <2 ng/ml), which is 
considered clinically relevant by the Investigator at screening. Subjects with 
known folate deficiency anaemia who are on ≥12 weeks stable replacement 
therapy at screening are eligible. 
10. Subjects with history of partial or total splenectomy within 3 months prior to 
the screening visit. 
11. Any history or clinically important finding of cardiac or pulmonary disorders, 
including (but not limited to) clinically relevant or uncontrolled cardiac 
arrhythmia, cardiomyopathy, coronary disease (unstable angina pectoris or 
myocardial infarction or elective coronary intervention), valve disorder, or 
heart failure according to New York Heart Association classification 3-4. 
12. A diagnosis of any form of pulmonary hypertension. 


 
 
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13. Any clinically relevant abnormal 12-lead electrocardiogram (ECG) finding 
during screening or prior to randomisation (as deemed by the Investigator) 
including (but not limited to) any of the following: 
• 
PR interval >0.21 seconds 
• 
Evidence or history of second- or third-degree atrioventricular block 
• 
QRS interval >0.12 seconds 
14. Family history of long-QT syndrome or sudden death without a preceding 
diagnosis of a condition that could be causative of sudden death (such as 
known coronary artery disease, congestive heart failure, or terminal cancer), or 
subjects with QT interval corrected (QTcF) >450 msec. 
15. Clinically significant bacterial, fungal, parasitic, or viral infection which 
requires therapy. Note: A subject meeting this criterion should delay screening 
and/or enrolment for a minimum of 2 weeks, or if excluded can be re-screened 
at maximum 2 times at a later time point. 
16. Known history, and/or positive result on screening for hepatitis B surface 
antigen, hepatitis B virus, hepatitis C virus, or HIV infection. Note: Subjects 
with known hepatitis B surface antigen positivity and/or hepatitis C virus 
antibody positivity will be allowed to participate only if the disease has been 
treated efficiently/is not active. 
17. Known active COVID-19 infection (positive result of a SARS-Cov-2 virus test 
(nucleic acid or antigen detection) within 2 weeks preceding screening), or any 
other active infection. Note: A subject who tested positive within 2 weeks 
preceding screening or during screening will be excluded but can be re-
screened at a later time point as per Investigator’s judgement and if 
confirmation of a negative SARS-CoV-2 test is available based on standard of 
care. 
18. Use of any prohibited medication(s), including (but not limited to): 
• 
Prior or concomitant use of any medication that is known to prolong the 
QT/QTc interval or the PR/QRS interval, within 4 weeks prior to 
screening and until end of study (EoS). 
• 
Previous oral or intravenous iron therapy or iron chelation therapy 
≤4 weeks prior to screening and until EoS. 
• 
Any known strong or moderate inhibitors and/or inducers of CYP 3A4 
enzyme within 4 weeks prior to randomisation and during treatment 
period, or any known strong CYP 2D6 inhibitors or inducers as of 
4 weeks prior to screening and until EoS. 
• 
Receipt of HbS polymerisation inhibitors (e.g., voxelotor), L-glutamine, 
erythropoietin stimulating/maturation agent treatment, crizanlizumab or 
any other haematopoietic growth factor treatment within 5 half-lives of 
the respective drug prior to screening Visit V1 and until EoS, or 
anticipated need for such agents during the study. 
• 
Any prior gene therapy. 


 
 
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• 
Use of chronic anticoagulant therapy unless treatment stopped at least 
4 weeks prior to randomisation. Anticoagulant therapies used for 
prophylaxis for surgery or high-risk procedures as well as low molecular 
weight heparin for superficial venous thrombosis and chronic platelet 
aggregation inhibitors including acetylsalicylic acid are allowed. 
• 
Participation in any other clinical study with an investigational product 
within 4 weeks prior to screening Visit V1 and until EoS. 
19. Concomitant use of hormonal contraceptives (contraception associated with 
inhibition of ovulation), which are metabolised through CYP 3A4, are not 
allowed as the sole measure to prevent pregnancy within 4 weeks prior to 
screening and until 1 week after the last IMP administration (e.g., combined 
hormonal contraception (oral, intravaginal, transdermal)) and 
progesterone-only hormonal contraception (oral, injectable, implantable). 
20. Known sensitivity to any components of the study products to be administered. 
21. Previous participation to this study with at least 1 administration of the IMP. 
22. History of drug or alcohol abuse within 2 years prior to screening. 
23. Pregnant (e.g., positive serum pregnancy test) or females currently 
breastfeeding. 
24. History or known concomitant solid tumours and/or haematological 
malignancies unless resolved in the ≥2 past years, except for basal or 
squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, 
incidental histologic finding of prostate cancer (T1a or T1b according to the 
Classification of Malignant Tumours clinical staging system). 
25. Vulnerable subjects (e.g., subjects kept in detention, protected adults under 
guardianship, trusteeship, and soldiers) or subjects committed to an institution 
by governmental or juridical order, and any other vulnerable subjects. 
26. Unable to take and absorb oral medications, unable to swallow Size 0 capsules. 
27. Known significant medical condition(s), anticipated need for major surgery 
during the study, or any other kind of disorder that may be associated with 
increased risk to the subject, or may interfere with study assessments, 
outcomes, or the ability to provide written informed consent or comply with 
study procedures, in the Investigator’s opinion. 
28. Acute peptic stomach or duodenal ulcer in the previous 3 months before 
screening and/or not healed after 3 months of proton-pump inhibitors therapy 
(or adequate standard of care therapy). 
29. Occult or evident not controlled haemorrhages (i.e., ulcerations of 
gastrointestinal tract or body surface). 
30. Any employee or their close relatives of the Sponsor, or of a Contract 
Research Organisation (CRO), or a study site involved in the trial. 


 
 
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Endpoints: 
Primary Endpoint: 
• 
Mean change from baseline in haemolysis markers as measured by reduction 
of indirect bilirubin after 8 weeks of treatment. 
Secondary Endpoints: 
• Mean change from baseline in haemolysis markers as measured by direct and 
total bilirubin, lactate dehydrogenase (LDH), potassium, Hb and free 
haptoglobin after 8 weeks of treatment. 
• Frequency and severity of reported or observed adverse events (AEs) by 
system organ class (SOC) and preferred terms (PTs) using Medical Dictionary 
for Regulatory Activities (MedDRA) coded terms, indicating seriousness 
criteria and relatedness over 8 weeks of treatment. 
Exploratory Endpoints: 
• 
Changes in haemolysis markers as measured by indirect, direct, and total 
bilirubin, LDH, potassium, Hb, and free haptoglobin, from baseline after 2, 4, 
and 6 weeks of treatment and 4 weeks after end of treatment (EoT).  
• 
Frequency and severity of reported or observed AEs by SOC and PTs using 
MedDRA coded terms, indicating seriousness criteria and relatedness up to 
4 weeks after EoT 
• 
Changes in clinical laboratory safety tests (serum chemistry, safety 
haematology, and urinalysis) from baseline, 12-lead ECG, physical 
examination findings, vital signs (blood pressure, pulse rate), and 
haematological changes due to iron-restricted erythropoiesis after 2, 4, 6 and 8 
weeks of treatment and 4 weeks after EoT.  
• 
Changes in haematological indices including Hb concentration, RBC count, 
haematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular Hb 
(MCH), mean corpuscular Hb concentration (MCHC), corpuscular 
haemoglobin concentration mean (CHCM), RBC distribution width, white 
blood cell (WBC) analyses including differential WBC counts, platelet, and 
reticulocyte counts, percentage reticulocytes, percentage hypochromic 
microcytic RBCs (RBC volume versus Hb scatterplot analysis), from baseline 
after 2, 4, 6 and 8 weeks of treatment and 4 weeks after EoT. 
• 
Changes in blood inflammatory markers as measured by high sensitivity 
C-reactive protein, interleukin 1 and interleukin 6, tumour necrosis factor 
alpha, soluble vascular cell adhesion molecule 1, endothelin-1, soluble 
platelet-selectin, and xanthine oxidase, from baseline after 2, 4, 6 and 8 weeks 
of treatment and 4 weeks after EoT. 
• 
Assessment of iron-related parameters and markers of erythropoiesis: changes 
in total serum iron, serum ferritin, serum transferrin, TSAT, hepcidin, and 
erythropoietin, from baseline after 2, 4, 6 and 8 weeks of treatment and 
4 weeks after EoT. 
• 
VIT-2763 PK parameters (Cmax, clearance, distribution volume, area under the 
curve (AUC)). Sparse sampling for determination of VIT-2763 plasma 
concentration following multiple dosing will be obtained from pre-dose to 
2 hours, 4 hours and 6 hours post-morning dose at study Visit V4. A 
population PK approach will be applied to estimate PK parameters. 


 
 
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• 
Change in patient reported outcomes using Adult Sickle Cell Quality of Life 
Measurement System (ASCQ-Me) from baseline after 2, 4, 6 and 8 weeks of 
treatment. 
• 
Changes in abnormal RBCs (sickling) assessed by peripheral blood smear 
from baseline after 2, 4, 6 and 8 weeks of treatment and 4 weeks after EoT. 
• 
Number of VOC episodes and visceral infarctions over 8 weeks of treatment 
and 4 weeks after EoT. 
Procedures: 
See Table 1 (Schedule of Events) and the applicable information in Section 8.1 to 
Section 8.7 of the protocol for full details of required procedures and applicable 
visits (and timings of each visit). 
Screening Visit V1 (Day -28 to Day -1) 
• 
The Investigator will obtain written informed consent/assent from potentially 
eligible subjects and/or legally acceptable guardian before any trial-related 
procedure is performed. 
• 
Subjects who have a documented diagnosis of SCD according to inclusion 
criteria will be screened to determine potential eligibility. 
• 
Subject demographics and baseline characteristics will be assessed according 
to Table 1. Events, including medical/surgical history, physical examination, 
body weight and height, and vital signs including seated blood pressure and 
pulse rate will be assessed. 
• 
A single 12-lead ECG will be performed. 
• 
As of the date of informed consent for each subject, the sites will document in 
the electronic Case Report Form (eCRF) all serious adverse events 
(SAEs)/AEs and changes/additions made to previous and concomitant 
medications. SAEs will be reported no later than 24 hours after the 
Investigator’s awareness of the event. 
• 
Blood tests using peripheral venipuncture will be drawn to determine if the 
subject is eligible according to the inclusion and exclusion criteria (including 
an optional genotyping test). 
• 
During the same blood draw, a serum pregnancy test (beta human chorionic 
gonadotropin (hCG)) will be taken for females of childbearing potential. 
• 
A urinary dipstick test will be drawn to test pH, protein, glucose, ketone, and 
blood. 
• 
A spot urinary sample will be collected and analysed for urinary 
microalbumin, creatinine, and microalbumin/creatinine ratio. 
• 
A quality of life questionnaire (ASCQ-Me, 6 forms) will be provided to the 
subject. Subjects will be asked to complete all 6 forms the day before Visit V2. 
Visit V2 (Baseline, Day 1), before randomisation 
If a subject did fulfil the inclusion criteria and did not meet the exclusion criteria 
observed from Visit V1 they will be asked to attend the baseline Visit V2. The 
Investigator will perform/complete the baseline procedures/assessments as shown 
in Table 1. 


 
 
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• 
To accommodate local hospital practice, the subject may attend the V2 visit 
either on the day of the first dose of study treatment (randomisation day), or on 
the day before the planned randomisation day. Subjects may attend Visit V4 
the afternoon/evening before and stay overnight to facilitate compliance and 
study procedures on Visit V4. Note: A planned overnight stay prior to study 
treatment administration or the night before Visit V4 do not fulfil the 
seriousness criteria of an SAE unless there is a medical requirement. 
• 
Eligibility assessment will be conducted during screening and also prior to 
receiving IMP. Re-screening may be considered at the discretion of the 
Investigator and in consultation with the Sponsor. 
• 
A physical examination including body weight will be performed. 
• 
Vital signs will be assessed. 
• 
A single12-lead ECG will be performed. 
• 
Changes/additions made to concomitant medications will be re-assessed since 
signing the Informed Consent Form (ICF) and all SAEs/AEs will be reported. 
• 
In addition, for female subjects of childbearing potential, the urine pregnancy 
test sample must be taken, and the test result must be negative. 
• 
The baseline Hb value will be determined using the Hb value at baseline Visit 
V2. 
• 
All laboratory assessments as per Table 1. 
• 
To determine baseline values, blood tests using peripheral venipuncture will be 
drawn as well as a spot urinary sample will be collected for urinary 
microalbumin, creatinine, and microalbumin/creatinine ratio. 
• 
The subject will be asked for the number of VOC episodes that have occurred 
within the last 8 weeks. Visceral infarctions will be assessed as per standard of 
care. 
Randomisation and Administration of the First Dose of Study Treatment 
• 
Dispense subject identification card. 
• 
Collect samples (pre-dose) for total serum iron, serum ferritin, serum 
transferrin, calculated TSAT, hepcidin and erythropoietin. 
• 
Upon completion of the baseline visit procedures/assessments, eligible 
subjects will be randomised using a validated centralised IWRS to receive 
VIT-2763 or placebo according to the randomisation scheme. 
• 
The first dose of IMP must be administered at the site and the time of 
administration needs to be entered in the eCRF (see ECG measurement 
post-morning dosing). 
• 
The first dose of IMP must be administered at the site and the time of 
administration needs to be entered in the eCRF. The IMP total daily dose will 
be split into 2 or 3 doses per day. For BID: 1 in the morning and 1 in the 
evening. The morning dose of the IMP will be administered with water, at 
least 1 hour before meals between 06:00 and 10:00 a.m. The evening dose will 
be administered 12±1 hours after the morning dose 1 hour apart from meals. 
For TID: 1 in the morning, 1 in the afternoon and 1 in the evening. The 


 
 
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morning dose of the IMP will be administered with water, at least 1 hour 
before meals between 06:00 and 10:00 a.m. The afternoon dose will be 
administered 8±1 hours after the morning dose 1 hour apart from meals. The 
evening dose will be administered 16±1 hours after the morning dose after 
meals, 1 hour apart from any meal. 
• 
A new single 12-lead ECG needs to be performed 2 hours (±30 minutes) 
post-morning dose. 
• 
Subjects will receive IMP for home intake until the next visit. 
• 
All 6 ASCQ-Me forms dispensed at screening and completed by subject will 
be collected. Subjects will receive 2 copies of the following forms: “Emotional 
Impact”, “Pain Impact”, “Sleep Impact”, and “Stiffness Impact”. Subjects will 
be informed to complete 1 copy of each form, 1 week after the visit, and a 
second copy the day before the next visit (Visit V3). 
Post-randomisation Visits V3 to V6 
• 
Dispense IMP at site (via IWRS). Note: The morning dose on the visit day 
needs to be taken at site. 
• 
Perform IMP accountability of returned IMP. 
• 
Subjects will return to the clinical site at 14-day intervals. 
• 
The Investigator will perform the procedures/assessments as shown in Table 1 
for the respective visit. 
• 
Changes/additions made to concomitant medications will be re-assessed and 
all SAEs/AEs will be reported. 
• 
Blood and urine samples will be collected as per Table 1. 
• 
Vital signs, body weight, and physical examination assessments will be 
performed as per Table 1. 
• 
Subjects will be asked to return to the clinical site at Visit V6, 
Day 56±4 days/EoT/early termination (ET) in order to complete all procedures 
as per Table 1. 
• 
Only at Visit V6, the subject will receive the (last) IMP from the bottle 
received at Visit V5 (as at Visit V6 no new IMP dispensation will take place). 
• 
For PK assessments (blood samples taken at pre-dose, 2 hours (±15 minutes), 
4 hours (±30 minutes) and 6 hours (±30 minutes) post-dose), subjects are 
asked to stay in the hospital for 6 hours post-morning dose only at Visit V4. 
• 
For ECG assessments, subjects are asked to stay in the hospital for 2 hours 
post-dose at Visits V3 to V6. 
• 
Subjects who withdraw between signing informed consent and the EoT/Visit 
V6 will be asked to return to the clinical site to perform an ET visit, and all 
assessments and procedures according to Table 1 (Visit V6 EoT/ET visit) will 
be performed. 


 
 
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• 
At Visits V3, V4, V5, and V6 the subject will be asked for VOC episodes – 
number of events and pain intensity (numerical rating scale (NRS): 0-10) 
compared to historical VOC episodes that have occurred since previous visits. 
Visceral infarctions will be assessed as per standard of care. 
• 
For dispensing and collecting of ASCQ-Me questionnaire forms, please refer 
to the respective visit in Section 8. 
EoS/Follow-up Visit V7 
All subjects completing the study will be asked to attend a follow-up Visit V7 
(28±4 days after EoT/Visit V6) in order to complete all procedures as per Table 1. 
• 
A physical examination will be performed, and vital signs will be assessed. 
• 
A single 12-lead ECG will be performed. 
• 
Assess change/additions of concomitant medications will be recorded. 
• 
All laboratory assessments as per Table 1. 
• 
SAEs/AEs will be assessed and reported. 
• 
Assessment of VOC episodes and visceral infarctions. 
Study Safety Oversight 
An independent Data and Safety Monitoring Board (DSMB) will oversee the safety 
and conduct of the trial on an ongoing basis. The DSMB will include medical and 
statistical representatives. The DSMB will regularly, but also in an ad-hoc manner 
as needed, assess the safety information of the enrolled subjects, and can provide 
recommendations to the Sponsor regarding stopping the study, or discontinuing a 
treatment arm, or otherwise modifying the study design or conduct. 
Sample Size: 
This is an exploratory Phase 2a study of VIT-2763 in SCD subjects, therefore no 
formal sample size calculation was conducted. 
A total of 24 subjects will be randomised in a 3:3:3:2:1 ratio at baseline to either 
VIT-2763 or to placebo. 
Eligible subjects will be randomised to either VIT-2763 or placebo using a 
validated centralised IWRS that automates the random assignment of treatment 
groups to randomisation numbers. Stratified randomisation (balanced allocation 
across treatment groups) will be used according to genotype (HbS/S – HbS/βT0). 
If more than 1 subject in any dose cohort withdraws or drops out between signing 
informed consent and the V6 visit, the subject will be replaced until at least 
5 subjects, with no major protocol deviation impacting the primary objective of the 
trial, per treatment/placebo arm have passed Visit V6. 
Study Sites: 
About 20 or more sites in 5 or more countries. 
Statistical 
Methods: 
No formal power calculations will be performed for the sample size due to the 
experimental nature of this trial. 
An interim analysis is not planned for this study. 
Demographic data will be summarised by treatment. 


 
 
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The intent-to-treat (ITT) population includes all subjects randomly assigned to a 
treatment group. The per-protocol set (PPS) consists of all subjects who, in 
addition to the ITT criteria, completed the study, and had no major protocol 
deviations.  
The ITT population will be used for the analysis of the primary and secondary 
endpoints related to haemolysis markers. These analyses will also be repeated on 
the PPS. 
The secondary and exploratory safety endpoints will be calculated based on the 
safety population, including all randomised subjects who received at least one 
VIT-2763 dose or placebo. 
The ITT population and the PPS will be used for the analysis of other exploratory 
endpoints. 
Concerning the safety data, the total number of events and number (%) of subjects 
with an event will be presented by MedDRA SOC and PT on overall subjects 
receiving VIT-2763, by dose group and on all subjects receiving placebo. 
Means, standard deviations, medians, ranges, and confidence intervals will be 
presented for continuous variables, and frequencies and percentages will be 
presented for categorical and ordinal variables. Further details will be specified in 
the Statistical Analysis Plan (SAP). 
A population PK approach will be applied to estimate PK parameters (Cmax, 
clearance, distribution volume, AUC). 
 


 
 
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Figure 1 
Study Schema 
 
Notes: BID=Twice daily; EoS=End of study; EoT=End of treatment; ET=Early termination; n=Number of subjects per cohort; SCD=Sickle cell disease; TID=3 times daily. 
 
Randomisation/
Baseline
Screening/Randomisation
(Up to 4 weeks)
Treatment Phase 
(8 weeks)
Follow up
(4 weeks)
Visit 1
(Day -28 to Day -1)
SCD subjects, 
n=24 
Visit 7 
(Day 84, EoS)
Visit 2
(Day 1)
Visit 5 
(Day 42)
Visit 6 
(Day 56, EoT/ ET)
Follow up 
n=6
n=6
n=6
n=6
Cohort 2: VIT-2763 240 mg (120 mg BID)
Cohort 3: VIT-2763 360 mg (120 mg TID)
Cohort 4: Placebo
(Cohort 4a: n=4 BID; Cohort 4b: n=2 TID)
Cohort 1: VIT-2763 120 mg (60 mg BID)
Visit 4 
(Day 28)
Visit 3 
(Day 14)


 
 
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Table 1 
Schedule of Events
 
Visit 1 
Screen 
Visit 2 
Baseline/ 
Randomisation 
Visit 3 
Visit 4 
Visit 5 
Visit 6  
EoT/ET 
Visit 7 
EoS/ 
Follow-up 
Day -28 
to Day -1 
Day 1 
Day 14 
±2 Days 
Day 28 
±4 Days 
Day 42 
±4 Days 
Day 56 
±4 Days 
Day 84 
28 Days 
±4 Days 
After EoT 
Informed consent 
X 
 
 
 
 
 
 
Eligibility criteria(1) 
X 
X(1) 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Physical examination(2) 
X 
X 
 
X 
 
X 
X 
Vital signs (seated blood pressure, pulse rate)(3) 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
12-lead ECG 
X 
X(4) 
X(4) 
X(4) 
X(4) 
X(4) 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
Dispense subject identification card 
 
X 
 
 
 
 
 
Hb levels 
C 
L 
L 
L 
L 
 
 
hsCRP 
C 
 
 
 
 
 
 
RBC smear preparation 
 
L 
L 
L 
L 
L 
L 
Urine pregnancy test(5) 
 
L 
L 
L 
L 
L 
L 
Serum pregnancy test(6) 
C 
 
 
 
 
 
 
Optional SCD genotyping test(7) 
L 
 
 
 
 
 
 


 
 
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Visit 1 
Screen 
Visit 2 
Baseline/ 
Randomisation 
Visit 3 
Visit 4 
Visit 5 
Visit 6  
EoT/ET 
Visit 7 
EoS/ 
Follow-up 
Day -28 
to Day -1 
Day 1 
Day 14 
±2 Days 
Day 28 
±4 Days 
Day 42 
±4 Days 
Day 56 
±4 Days 
Day 84 
28 Days 
±4 Days 
After EoT 
Serum virology (HbsAg, HBV, HCV, HIV) 
C 
 
 
 
 
 
 
Urinalysis(8) 
C 
C 
C 
C 
C 
C 
C 
Haematology panel/RBC indices(9) 
C 
C 
C 
C 
C 
C 
C 
Serum chemistry panel(10) 
C 
C 
C 
C 
C 
C 
C 
Haemolysis markers(11) 
 
C 
C 
C 
C 
C 
C 
Endothelial inflammation/dysfunction markers(12) 
 
C 
C 
C 
C 
C 
C 
Iron-related parameters/markers of erythropoiesis(13) 
C 
C 
C 
C 
C 
C 
C 
RBC smear assessment for sickle cells 
 
C 
C 
C 
C 
C 
C 
VIT-2763 pharmacokinetic(14) 
 
 
 
C 
 
 
 
VOC episodes/visceral infarctions(15) 
 
X 
X 
X 
X 
X 
X 
Dispense IMP at site (IWRS) 
 
X 
X 
X 
X 
 
 
Collect, dispense, and inform subjects on ASCQ-Me 
questionnaires(16) 
X 
X 
X 
X 
X 
X 
 
IMP accountability 
 
 
X 
X 
X 
X 
 
1 
Any outstanding eligibility criteria (see Section 5.2 and Section 5.3) not available during screening to be available before randomisation. 
2 
Body systems to be assessed include general appearance, head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, musculoskeletal, neurological, lymph nodes, and skin. 
3 
Seated systolic and diastolic blood pressure, and pulse, after subject has rested for at least 5 minutes, pre-dose (trough). 
4 
A single 12-lead ECG to be performed at pre-dose (trough) and 2 hours (±30 minutes) post-morning dose. 
5 
Only in females of childbearing potential. Positive urine pregnancy test results need to be confirmed using a serum beta-hCG test. 
6 
Only in females of childbearing potential. 
7 
Only if genetic diagnosis records do not exist or are unavailable. 
8 
Urinary dipstick including pH, protein, glucose, ketone, RBCs, and WBCs. Quantitative measurement only if positive dipstick. Urinalysis includes also (at Visits V1, V2, V4, and V6) urinary microalbumin, 
creatinine, and microalbumin/creatinine ratio (spot sample, morning void). 


 
 
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9 
Haematology panel/RBC indices sampled at pre-dose (trough) include: Hb, reticulocytes (abs, %), RBC count, Hct, MCH, MCV, MCHC, RDW, % hypochromic RBC, CHCM, WBC, neutrophils (abs, %), 
lymphocytes (abs‚ %), monocytes (abs‚ %), eosinophils (abs‚ %), basophils (abs‚ %), and platelets. At screening/Visit V1, only Hb and reticulocytes will be assessed. At screening, the optional SCD 
genotyping test can be included. 
10 
Serum chemistry sampled at pre-dose (trough) includes calcium, sodium, magnesium, potassium, phosphorus, chloride, bicarbonate, blood urea nitrogen, uric acid, creatinine kinase, creatinine, folic acid, 
albumin, total protein, globulin (calculated), alanine transaminase, aspartate transaminase, alkaline phosphatase, glucose, triglycerides, and cholesterol. 
11 
Haemolysis markers sampled at pre-dose (trough) include LDH, free haptoglobin, and direct/total bilirubin (indirectly calculated). 
12 
Endothelial inflammation/dysfunction markers sampled at pre-dose (trough) include hsCRP, IL-1, IL-6, TNF-alpha, sP-selectin, sVCAM-1, xanthine oxidase, and endothelin-1. 
13 
Iron-related parameters/markers of erythropoiesis sampled at pre-dose and 2 hours post-morning dose include total serum iron, serum ferritin, transferrin, TSAT, hepcidin, and erythropoietin. At Visit V1, 
serum ferritin, and TSAT will be sampled for exclusion criteria only. 
14 
PK samples are collected on Visit V4 at pre-dose, and 2 hours (±15 minutes), 4 hours (±30 minutes), and 6 hours (±30 minutes) post-dose. 
15 
At Visit V2, the subject will be asked for VOC episodes within the last 8 weeks. At Visits V3, V4, V5, and V6, the subject will be asked for VOC episodes (number of events and pain intensity (NRS: 0-10) 
compared to historical VOC episodes) since previous visits. Visceral infarctions will be assessed as per standard of care. 
16 
For more details see the respective visit in Section 8. 
Notes: abs=Absolute; ASCQ-Me=Adult Sickle Cell Quality of Life Measurement System; C=Central laboratory assessment; CHCM=Corpuscular Hb concentration mean; ECG=Electrocardiogram; EoS=End of 
study; EoT=End of treatment; ET=Early termination; Hb=Haemoglobin; HbsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; hCG=Human chorionic gonadotropin; Hct=Haematocrit; 
HCV=Hepatitis C virus; hsCRP=High sensitivity C-reactive protein; IL=Interleukin; IMP=Investigational medicinal product; IWRS=Interactive web response system; L=Local laboratory assessment; 
LDH=Lactate dehydrogenase; MCH=Mean corpuscular Hb; MCHC=Mean corpuscular Hb concentration; MCV=Mean corpuscular volume; NRS=Numerical rating scale; PK=Pharmacokinetic; 
RBC=Red blood cell; RDW=Red blood cell distribution width; SCD=Sickle cell disease; sP=Soluble platelet; sVCAM=Soluble vascular cell adhesion molecule; TNF=tumour necrosis factor; 
TSAT=Transferrin saturation; V=Visit; VOC=Vaso-occlusive crises; WBC=White blood cell. 
 


 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..........................................................................................................2 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE .....................................6 
SYNOPSIS ..........................................................................................................................7 
TABLE OF CONTENTS ................................................................................................23 
LIST OF TABLES ...........................................................................................................27 
LIST OF FIGURES .........................................................................................................28 
LIST OF ABBREVIATIONS .........................................................................................29 
1. 
INTRODUCTION AND BACKGROUND ............................................................31 
1.1 
Background of the Disease and Treatment Options ..............................................31 
1.2 
Summary of Nonclinical and Clinical Data ...........................................................33 
1.2.1 
Nonclinical Pharmacology and Pharmacological Activity .................................33 
1.2.1.1 
Absorption, Distribution, Biotransformation, and Elimination .......................33 
1.3 
Nonclinical Safety Data .........................................................................................34 
1.3.1 
Long-term Toxicity .............................................................................................34 
1.3.2 
Safety Pharmacology ..........................................................................................34 
1.3.3 
Mutagenicity .......................................................................................................35 
1.3.4 
Carcinogenicity ...................................................................................................35 
1.3.5 
Paediatric Use .....................................................................................................35 
1.3.6 
Reproductive Toxicity ........................................................................................35 
1.4 
Summary of Completed Clinical Studies ...............................................................36 
1.4.1 
Study VIT-2763-101 ...........................................................................................36 
1.4.2 
Study VIT-2763-THAL-201 ...............................................................................37 
2. 
RATIONALE ...........................................................................................................38 
2.1 
Rationale to Investigate the Effects of VIT-2763 in SCD .....................................38 
2.2 
Study Design Rationale..........................................................................................38 
2.3 
Dose Selection .......................................................................................................40 
2.3.1 
Summary .............................................................................................................40 
2.3.2 
Justification of Safety .........................................................................................41 
2.3.3 
Justification of Dose ...........................................................................................41 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................43 
3.1 
Primary Objective ..................................................................................................43 
3.2 
Secondary Objective ..............................................................................................43 
3.3 
Exploratory Objectives ..........................................................................................43 
3.4 
Primary Endpoint ...................................................................................................43 
3.5 
Secondary Endpoints .............................................................................................43 
3.6 
Exploratory Endpoints ...........................................................................................43 


 
 
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4. 
INVESTIGATIONAL PLAN .................................................................................45 
4.1 
Overall Study Design .............................................................................................45 
4.2 
Duration of Subject Participation and Study .........................................................45 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................46 
5.1 
Number of Subjects................................................................................................46 
5.2 
Inclusion Criteria ...................................................................................................46 
5.3 
Exclusion Criteria ..................................................................................................47 
5.4 
Withdrawal of Subjects ..........................................................................................50 
5.4.1 
Withdrawal of Subjects from Study ...................................................................50 
5.4.2 
Withdrawal of Subjects from Study Drug ..........................................................51 
5.4.3 
Study Stopping Rules..........................................................................................52 
5.5 
Re-screening of Subjects........................................................................................52 
6. 
STUDY TREATMENTS .........................................................................................53 
6.1 
Treatment Blinding ................................................................................................53 
6.1.1 
Unblinding ..........................................................................................................53 
6.2 
Dosage Forms/Formulation ...................................................................................54 
6.2.1 
VIT-2763 ............................................................................................................54 
6.2.2 
Placebo ................................................................................................................54 
6.3 
Drug Dosage and Administration ..........................................................................55 
6.3.1 
Treatment Arms ..................................................................................................55 
6.3.2 
Dosing and Administration Guidelines...............................................................56 
6.4 
Package and Labelling ...........................................................................................57 
6.5 
Study Treatment Allocation ...................................................................................57 
6.6 
Site Supply, Storage, Accountability .....................................................................57 
6.6.1 
Site Supply ..........................................................................................................57 
6.6.2 
Storage ................................................................................................................58 
6.6.3 
Accountability .....................................................................................................58 
6.7 
Drug Dose Modification ........................................................................................58 
6.7.1 
Procedures for Overdose .....................................................................................58 
6.8 
Prohibited Therapy and Concomitant Treatment ...................................................59 
7. 
RISKS/PRECAUTIONS .........................................................................................60 
7.1 
Special Warnings and Precautions for Use ............................................................60 
7.2 
Fertility, Contraception and Lactation ...................................................................60 
7.2.1 
Fertility................................................................................................................60 
7.2.2 
Pregnancy............................................................................................................61 
8. 
STUDY PROCEDURES .........................................................................................62 
8.1 
Screening Visit/Visit 1 (Day -28 to Day -1) ..........................................................62 
8.2 
Baseline/Randomisation/Visit 2 (Day 1) ...............................................................63 
8.3 
Visit 3 (Day 14±2 Days) ........................................................................................66 
8.4 
Visit 4 (Day 28±4 Days) ........................................................................................67 
8.5 
Visit 5 (Day 42±4 Days) ........................................................................................69 
8.6 
EoT (or ET) Procedures/Visit 6 (Day 56±4 Days) ................................................70 


 
 
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8.7 
EoS (Follow-up) Procedures/Visit 7 (Day 84).......................................................72 
8.8 
Allowed Adaptations for Assessments During Site Visits ....................................73 
8.9 
Allowed Adaptations in Case of Extraordinary Events, e.g., COVID-19 .............74 
9. 
STUDY ASSESSMENTS ........................................................................................76 
9.1 
Demographics and Medical History ......................................................................76 
9.2 
Symptoms and Signs of Anaemia ..........................................................................76 
9.3 
Physical Examination and Vital Signs ...................................................................76 
9.4 
12-lead ECG Assessment .......................................................................................77 
9.5 
Documentation of Prior and Concomitant Treatments ..........................................77 
9.6 
ASCQ-Me ..............................................................................................................78 
9.7 
Laboratory Parameters ...........................................................................................78 
9.7.1 
Local Laboratory Parameters ..............................................................................78 
9.7.2 
Central Laboratory Parameters ...........................................................................79 
10. EVALUATION, RECORDING AND REPORTING OF AES ...........................81 
10.1 
Definition of AE ....................................................................................................81 
10.2 
AE Reporting Period ..............................................................................................81 
10.3 
Eliciting AE ...........................................................................................................81 
10.4 
Assessing AE .........................................................................................................81 
10.4.1 
Intensity/Severity ................................................................................................81 
10.4.2 
Causality and Reporting......................................................................................82 
10.4.3 
Outcome Categorisation .....................................................................................83 
10.5 
Recording and Reporting .......................................................................................83 
10.5.1 
Persistent or Recurrent AE .................................................................................83 
10.5.2 
Diagnosis Versus Signs and Symptoms .............................................................84 
10.5.3 
Pre-existing Medical Conditions ........................................................................84 
10.5.4 
Clinical Laboratory Evaluations .........................................................................84 
10.5.5 
Worsening of the Disease Under Study ..............................................................86 
10.5.6 
Abnormal Vital Signs and Other Abnormalities.................................................86 
10.6 
ADR and Reference Safety Information ................................................................86 
10.6.1 
Adverse Drug Reaction .......................................................................................86 
10.6.2 
Reference Safety Information .............................................................................87 
10.7 
Serious Adverse Event ...........................................................................................87 
10.7.1 
Definition of SAE ...............................................................................................87 
10.7.1.1 
Situations That Are Not Considered SAEs ......................................................88 
10.7.2 
SAE Reporting ....................................................................................................88 
10.7.3 
Suspected Unexpected Serious Adverse Reaction..............................................89 
10.7.3.1 
SAE Expedited Reporting ................................................................................89 
10.7.4 
Unblinding Treatment Allocation .......................................................................89 
10.8 
Special Situations ...................................................................................................89 
10.8.1 
Definition of Special Situations ..........................................................................89 
10.8.2 
Special Situation Recording and Reporting ........................................................90 
10.8.3 
Pregnancy Exposure and Birth Events................................................................90 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events .......................................90 


 
 
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10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting ...................91 
10.8.4 
AEs of Special Interest .......................................................................................92 
10.8.4.1 
Definition of AEs of Special Interest ...............................................................92 
11. DSMB PROCEDURES ...........................................................................................93 
12. STATISTICAL ANALYSIS ...................................................................................94 
12.1 
Statistical Methods .................................................................................................94 
12.2 
Sample Size and Power Calculations .....................................................................94 
12.3 
Randomisation .......................................................................................................94 
12.4 
Analysis Sets ..........................................................................................................95 
12.4.1 
ITT Population ....................................................................................................95 
12.4.2 
Per-protocol Set ..................................................................................................95 
12.4.3 
Safety Set ............................................................................................................95 
12.5 
Background and Demographic Characteristics ......................................................95 
12.6 
Study Medication ...................................................................................................95 
12.7 
Concomitant Therapy.............................................................................................95 
12.8 
Primary and Secondary Efficacy Evaluations........................................................96 
12.9 
Safety Evaluations .................................................................................................96 
12.10 Exploratory Efficacy Evaluations ..........................................................................97 
12.11 Other Evaluations...................................................................................................98 
12.11.1 Pharmacokinetics ................................................................................................98 
13. STUDY ETHICAL CONSIDERATIONS .............................................................99 
13.1 
Ethical Conduct of the Study .................................................................................99 
13.2 
Informed Consent...................................................................................................99 
13.3 
Institutional Review Board or IEC ........................................................................99 
14. QUALITY CONTROL AND QUALITY ASSURANCE ...................................100 
14.1 
Quality Management: Critical Processes and Data ..............................................100 
15. REPORTING AND RECORDING OF DATA ...................................................102 
15.1 
Source Documentation .........................................................................................102 
15.2 
Records Retention ................................................................................................102 
15.3 
Site Documentation ..............................................................................................103 
16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .....................................................................104 
16.1 
Protocol Deviations ..............................................................................................104 
16.2 
Protocol Amendments ..........................................................................................104 
16.3 
Study Termination ...............................................................................................104 
17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ..............105 
18. REFERENCES .......................................................................................................106 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Schedule of Events .....................................................................................20 
Table 2 
Treatment Scheme .....................................................................................55 
Table 3 
Administration Schedule ............................................................................56 
Table 4 
List of Central Laboratory Assays .............................................................79 


 
 
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LIST OF FIGURES 
Page 
Figure 1 
Study Schema.............................................................................................19 
 


 
 
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LIST OF ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
ASCQ-Me 
Adult Sickle Cell Quality of Life Measurement System 
AUC 
area under the curve 
BID 
twice daily 
CHCM 
corpuscular haemoglobin concentration mean 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum concentration 
CRO 
Contract Research Organisation 
CYP 
cytochrome P450 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
EoS 
end of study 
EoT 
end of treatment 
ET 
early termination 
EU 
European Union 
FPN 
ferroportin 
Hb 
haemoglobin 
HbS 
sickle haemoglobin 
hCG 
human chorionic gonadotropin 
Hct 
haematocrit 
HDPE 
high-density polyethylene 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 


 
 
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IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
MATE 
multidrug and toxin extrusion transporter 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no observed adverse effect level 
NRS 
numerical rating scale 
NTD 
non-transfusion dependent 
OCT 
organic cation transporter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per-protocol set 
PT 
preferred term 
QD 
once daily 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCD 
sickle cell disease 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron-binding capacity 
TID 
3 times daily 
TSAT 
transferrin saturation 
ULN 
upper limit of normal 
VOC 
vaso-occlusive crises 
WBC 
white blood cell 


 
 
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1. INTRODUCTION AND BACKGROUND 
VIT-2763 (2-(2-{[2-(1H-benzimidazol-2-yl) ethyl] amino} ethyl)-N-[(3-fluoropyridin-2-yl) 
methyl]-1,3-oxazole-4-carboxamide trihydrochloride) is a small molecule, which has been 
identified by Vifor Pharma as a ferroportin (FPN) inhibitor acting similar to hepcidin. 
FPN is the only known iron transporter in mammals mediating iron transfer into the blood 
stream. FPN is mainly expressed on intestinal enterocytes, spleen and liver macrophages, 
and hepatocytes. On the basolateral membrane of intestinal enterocytes, FPN exports the 
dietary iron into the plasma. On spleen and liver macrophages and hepatocytes, FPN 
exports endogenous iron recycled from the Hb of senescent RBCs and released from the 
liver stores, respectively [1]. The action of FPN is antagonised by hepcidin, a 25-amino 
acid peptide, which is mainly produced in hepatocytes. Its transcription is downregulated 
by erythropoiesis, anaemia, and hypoxia, and it is upregulated by inflammation and high 
systemic iron levels. Hepcidin binds to and triggers internalisation and degradation of FPN, 
and by this causes a rapid drop in serum iron levels [2,3]. 
1.1 
Background of the Disease and Treatment Options 
Iron is essential for cell survival. It is a key component of Hb, cytochromes, myoglobin, 
and of many enzymes. It is involved not only in the transport, storage, and use of oxygen, 
but also in major metabolic pathways. Consequently, iron homeostasis in the body is 
closely regulated, and imbalances may become pathogenic. Iron deficiency may result in 
anaemia; iron overload syndromes in siderosis, i.e., the iron deposition in organs, which 
may lead to multiple organ dysfunction and damage [4]. Primary iron overload syndromes 
arise from mutations, e.g., in genes of human haemochromatosis protein, haemojuvelin, 
hepcidin, transferrin receptor 2, and FPN. Secondary causes for iron overload are SCD, 
other inherited, or acquired anaemias, myelodysplastic syndrome, chronic liver diseases, 
and transfusions [5]. 
SCD is a multisystem disease and is one of the most common severe monogenic disorders 
worldwide. This often-devastating disease is associated with episodes of acute illness and 
progressive organ damage [6,7]. The pathophysiology of SCD arises from a single amino 
acid alteration in adult Hb, the expression of which is primarily limited to RBCs. The 
pathological single amino acid substitution (Glu to Val) at the sixth position of the β-chain 
of HbS results in HbS instability and polymerisation [8]. Following deoxygenation of HbS, 
and aggregating into polymers, the RBC changes shape (‘sickles’) owing to this polymer 
induced distortion. This distortion is the fundamental basis for the haemolytic anaemia, 
vaso-occlusion associated with painful events, organ dysfunction and shortened lifespan in 
patients with SCD [9]. 
The consequences of haemolysis include the immediate effects of RBC loss, such as 
anaemia and expansion of erythropoiesis with increased reticulocytosis. Oxidative changes 
in the sickle RBC promote haemolysis, depletion of nitric oxide, excess reactive oxygen 
species and endothelial activation. It is estimated that about one-third of haemolysis in SCD 


 
 
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is intravascular, owing to mechanical destruction of deformed and inelastic sickle RBCs, 
whereas two-thirds is extravascular, resulting from removal of abnormal sickle RBCs by 
the reticuloendothelial system [10]. 
Erythrocyte transfusion has an established role in the management of both acute and 
chronic complications in SCD. Transfusion corrects anaemia, decreases the percentage of 
HbS, suppresses HbS synthesis, and reduces haemolysis, all of which are of potential 
benefit. Chronic blood transfusion is inevitably associated with iron overload, although the 
pattern of haemosiderosis seems different to that described in thalassaemia; in particular, 
most iron loading occurs in the liver, with little cardiac iron deposition [11]. 
Curative therapies, such as haematopoietic stem cell transplantation or gene therapy are 
limited to a small patient population or are not yet available. Chronic transfusion is 
generally used for primary or secondary stroke prevention [9]. 
Acute pain crisis may be managed with pain medications, including opioids and may 
require additional in-patient or outpatient treatments, including hydration, transfusion, 
supplemental oxygen, and a variety of other treatments. Currently approved therapies such 
as hydroxyurea address some of the pathologies in SCD. Hydroxyurea is used to reduce the 
number of acute pain crises in those with frequent or severe crises and in those with a 
history of acute chest syndrome or severe anaemia. Within the past several years, a few 
new treatment options, such as L-glutamine, crizanlizumab, and voxelotor, have gained 
regulatory approval in the United States; however, the evidence for the clinical 
effectiveness of these treatments has been controversial [12]. 
Drugs that target the broader sequelae of SCD are needed, and prevention of haemolysis 
might provide a novel therapeutic option. Overt iron deficiency in patients with SCD has 
been associated with reduction of HbS in sickle RBCs and decreased markers of haemolysis 
[13,14]. 
VIT-2763 is developed by Vifor Pharma as a novel oral drug targeting FPN, and as such 
for the treatment of secondary iron overload and conditions in which iron metabolism is 
involved: ineffective or otherwise disturbed erythropoiesis, including (but not limited to) 
hereditary haemochromatosis, haemoglobinopathies (e.g., thalassaemia and SCD), or 
myeloproliferative/dysplastic disorders (e.g., polycythaemia vera and myelodysplastic 
syndrome, respectively). Furthermore, the oral FPN inhibitor VIT-2763 has shown positive 
results on haemolysis, haemodynamics, and prevention of vaso-occlusion in a model of 
SCD [15]. 
Since no FPN inhibitors or hepcidin-mimetic drugs are yet available for the treatment of 
iron loading anaemias including SCD, VIT-2763 would be considered as a first-in-class 
drug. 


 
 
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1.2 
Summary of Nonclinical and Clinical Data 
1.2.1 
Nonclinical Pharmacology and Pharmacological Activity 
VIT-2763 is an inhibitor of the iron exporter FPN and acts similarly to hepcidin. Through 
its action on FPN, hepcidin controls the major iron flows into the plasma. Similar to 
hepcidin, VIT-2763 induces FPN internalisation, ubiquitination, and degradation. As a 
consequence, VIT-2763 blocks iron export into plasma. Nonclinical pharmacology studies 
demonstrated that VIT-2763 prevents dietary iron absorption presumably by blocking 
intestinal FPN. In hereditary haemochromatosis, inappropriately low hepcidin expression 
leads to increased dietary iron absorption and organ overload. Accordingly, prevention of 
iron absorption by VIT-2763 decreased liver iron concentration in 2 haemochromatosis 
mouse models. 
In vitro studies in cells expressing FPN have demonstrated that VIT-2763 was similar in 
potency to hepcidin in a hepcidin-FPN binding and internalisation assay (half maximal 
inhibitory concentration: 9±5 versus 13±4 nM). VIT-2763 decreased serum iron levels in a 
dose-dependent manner in mice comparable to hepcidin and inhibited intestinal iron 
absorption in rats. Further studies in disease-specific animal models have demonstrated 
expected effects based on the pharmacology of VIT-2763. Importantly, iron restriction by 
the oral FPN inhibitor VIT-2763 has shown to improve haemolysis, systemic and vascular 
inflammation, to reduce apoptosis of RBCs and thereby improve blood flow in the Townes’ 
mouse model of SCD. 
1.2.1.1 
Absorption, Distribution, Biotransformation, and Elimination 
The oral bioavailability depends on species and dose; it ranged from 16 to 51% in rats and 
up to 85% in dogs. Higher than proportional plasma concentrations with increasing dose 
could be due to nonlinear excretion, resulting from saturation of clearance. 
Distribution in rats was widespread, with the highest measured tissue radioactivity at 1 hour 
post-dose. Rapid accumulation was observed in particular in the kidney pyramid, but also 
in the adrenal medulla and mammary glands (females). Twenty-four hours post-dose, 
radioactivity was not detectable or at very low levels with the exception of adrenal medulla, 
preputial gland, and mammary tissues. 
In vitro, VIT-2763 was shown to be a substrate of P-glycoprotein, organic anion transporter 
3, multidrug and toxin extrusion transporter 1 (MATE1) and MATE-2K, and likely also of 
the organic cation transporter 1 (OCT1) and OCT2. In vitro studies in human hepatocytes 
have shown that VIT-2763 is mainly metabolised by CYP 3A4 and to some extent by 
CYP 2D6. VIT-2763 showed high clearance in rats and moderate clearance in dogs, both 
in vitro and in vivo. In human hepatocytes and liver microsomes, low levels of metabolism 
have been observed. The abundance of individual metabolites was different across species, 
whereby the metabolites in the human in vitro samples (one of them being unique to human) 
were all detected with low quantities. 


 
 
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Mass balance data in rats revealed primary excretion in urine (53.7% of total radioactive 
dose) and bile (20.6% of total radioactive dose). No parent VIT-2763 was detected in 
another bile duct cannulated rat study indicating that VIT-2763 metabolites or conjugation 
products are excreted in bile. The majority of the radioactivity in urine and bile accumulated 
within 8 hours and the vast majority of the radioactivity was eliminated within 24 hours of 
dose administration. The second peak observed in rat plasma was less pronounced in bile 
duct cannulated compared to non-bile duct cannulated animals, suggesting that 
enterohepatic circulation occurs. 
CYP 2B6, CYP 3A4 and CYP 1A2 were not induced by VIT-2763. A weak inhibitory 
potential for CYP 1A2 at a targeted dose of 240 mg and for CYP 2D6 and CYP 3A4 at a 
60 to 240 mg dose was concluded in vitro. In vitro transporter inhibition indicated a weak 
inhibitory potential for OCT2, OCT1, MATE1, and MATE2-K. Clinical studies of 
VIT-2763 with concomitant medications have not been performed. 
1.3 
Nonclinical Safety Data 
1.3.1 
Long-term Toxicity 
VIT-2763 was tested in studies up to 26 weeks in the rat and 39 weeks in the dog. In 
addition, two 28-day studies were conducted in juvenile rats. 
Findings in the rat mainly resulted from the pharmacology of VIT-2763 and included iron 
deficiency anaemia due to decreased circulating iron concentrations and consequences 
thereof (e.g., cardiomegaly). The no observed adverse effect level (NOAEL) was 
600 mg/kg/day, the highest dose tested, in the 14-day study, 100 mg/kg/day in the 13-week 
study (due to significant anaemia at 200 mg/kg/day after 8 weeks) and 150 mg/kg/day, the 
highest dose tested, in the 26-week study.  
Findings emanating from the pharmacology of VIT-2763 were also noted in the dog. The 
NOAEL was 30 mg/kg/day in the 14-day study (due to the severity of the observed clinical 
signs, i.e., vomiting, decreased activity and tremors and other findings at 100 mg/kg/day), 
75 mg/kg/day, the highest dose tested, in the 13-week study and 30 mg/kg/day (due to 
significant anaemia at 75 mg/kg/day after 13 weeks) in the 39-week study. The ECG 
changes identified in the safety pharmacology study were confirmed in all studies, 
i.e., increases in PR, QRS and/or heart rate at ≥30 mg/kg 1 hour after administration. 
1.3.2 
Safety Pharmacology 
VIT-2763 demonstrated no impact on the central nervous and respiratory system in rats and 
the NOAEL was 600 mg/kg. The half maximal inhibitory concentration in the human 
ether-à-go-go related gene assay was 27 μM. The no observed effect level in the dog 
cardiovascular safety study was 10 mg/kg, based on an increase in QRS at 30 and 75 mg/kg. 
Additionally, an increase of PR for 75 mg/kg was observed. There were also sporadic 
increases in heart rate. The magnitude of the PR and QRS increases followed the PK of 
VIT-2763 with most significant increases occurring around 1 hour post-dose. Statistically 
significant QRS increases from baseline were observed 0.5 to 4 hours after 75 mg/kg and 


 
 
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1 to 2 hours after 30 mg/kg. No impact on ECG waveform morphology or on cardiac 
function was observed. 
1.3.3 
Mutagenicity 
VIT-2763 is not genotoxic based on the available weight of evidence. VIT-2763 was 
negative in the Ames test. The mouse lymphoma assay was negative after short-term 
incubation but positive after long-term incubation. The in vivo micronucleus assay and 
comet assay were negative. 
1.3.4 
Carcinogenicity 
Carcinogenicity studies have not been performed. 
1.3.5 
Paediatric Use 
Clinical studies in paediatric patients have not yet been performed. 
Two 28-day studies were conducted in juvenile rats. In 1 study, iron deficiency anaemia 
was induced by feeding 3-week-old male Wistar rats a low iron diet for 9 days, by which 
time all animals had developed anaemia, and which was compared with repeat 
administration of VIT-2763. VIT-2763 and a low iron diet similarly induced iron deficiency 
anaemia in juvenile rats. This effect could only be reversed with administration of 
intravenous iron in animals on a low iron diet. In those administered VIT-2763, intravenous 
iron treatment resulted in iron sequestration in spleen and liver. The second study treated 
3-week-old juvenile rats for 7 days (5 days on drug; 2 days off) and 4 days (3 days on drug 
and 1 day off) with 300 mg/kg VIT-2763 and was well tolerated. Expected pharmacological 
effects on RBC parameters were observed, with no differences between the dosing 
regimens. 
The consequences of iron deficiency in human are well understood and there is extensive 
knowledge of the effects of iron deficiency in developing children. In addition, parameters 
associated with iron metabolism and RBC parameters can be monitored during the clinical 
studies, ensuring that patients on VIT-2763 will not become iron deficient. Both EMA and 
FDA have confirmed that no further studies in juvenile animals are required to include 
adolescents or children as young as 6 months in clinical trials with VIT-2763. 
1.3.6 
Reproductive Toxicity 
There are no data from the use of VIT-2763 in pregnant women. Studies in animals have 
shown reproductive toxicity. 
Data of nonclinical studies of the effect of VIT-2763 on pregnancy and fertility indicate 
that women of childbearing potential should use highly effective methods of contraception 
whilst taking VIT-2763 and until at least 1 week after the last dose. No data on 
breastfeeding has been generated yet, so breastfeeding must be discontinued during 
treatment with VIT-2763 and for at least 1 week after the last dose. 


 
 
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1.4 
Summary of Completed Clinical Studies 
1.4.1 
Study VIT-2763-101 
A Phase 1 study in healthy volunteers with the title “A Phase 1, Double-blind, Randomised, 
Placebo-controlled 
Study 
on 
the 
Safety, 
Tolerability, 
Pharmacokinetics 
and 
Pharmacodynamics of Single and Multiple Ascending Doses of VIT-2763 in Healthy 
Subjects”, Protocol No. VIT-2763-101, EudraCT No. 2017-003395-31, has been 
performed [16]. 
The study consisted of a single ascending dose part (Part A) and a multiple ascending dose 
part (Part B) to assess the safety, tolerability, PK, and pharmacodynamics (PD) of 
ascending single and multiple oral doses of VIT-2763. The primary endpoint in this 
first-in-human study was to collect the incidence of AEs and SAEs by changes in vital signs, 
clinical laboratory, 12-lead ECG and cardiac telemetry examinations and physical 
examination findings following single and multiple oral doses compared to baseline.  
Secondary endpoints were to characterise the PK of VIT-2763 and to measure PD 
parameters to identify potential surrogate markers of VIT-2763 mechanism of action after 
single or multiple oral dosing. 
Treatment with single oral doses ranging from 5 mg to 240 mg and a 7-day treatment with 
oral doses of 60 mg once daily (QD), 120 mg QD, 60 mg every 12 hours, and 120 mg every 
12 hours were well tolerated by healthy male and female volunteers. Following single dose 
all treatment-emergent adverse events (TEAEs) were of mild severity. There were no SAEs 
reported and no discontinuations due to AEs. Following 7-day repeated treatment, all 
TEAEs were mild or moderate. There were no SAEs reported and no discontinuations due 
to AEs. There were no findings of clinical relevance with respect to vital signs, 12-lead 
ECG, telemetry, or physical examination. 
The PK analyses revealed that the initial oral absorption of VIT-2763 was relatively fast, 
most subjects had detectable levels already at 15 to 30 minutes post-dose, and Tmax for 
VIT-2763 ranged from 0.50 to 3 hours post-dose. A second peak or shoulder in the 
concentration-time profile was observed around 3 to 4 hours post-dose (from 15 mg dose). 
The exposure over the dose range of 5 mg to 240 mg was slightly more than dose 
proportional for Cmax, AUC0-last and AUC0-inf. 
Following multiple oral dose for 7 days up to 120 mg every 12 hours there was no apparent 
change in absorption and accumulation was minimal. The apparent volume of distribution 
following single oral administration was moderate ranging from 64.3 to 145 l indicating 
moderate distribution to tissues. The geometric mean t1/2 ranged from 1.9 to 5.3 hours 
following single oral dosing and from 2.07 to 3.80 hours on Day 1 and from 2.61 to 
5.26 hours on Day 7 following repeated dosing. 
Following both single and multiple dosing, a temporary decrease in mean serum iron levels 
and a temporary decrease in mean calculated % TSAT was seen at all VIT-2763 dose levels 


 
 
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between 4-hours and 12-hours post-dose. Following both single and multiple dosing, a 
temporary increase in mean serum hepcidin levels was seen at doses of 60/120/240 mg for 
single dosing and at all VIT-2763 multiple dose levels. Maximum mean serum hepcidin 
levels were observed between 1-hour and 4-hours post-dose for the highest single dose 
levels of 60 mg, 120 mg, and 240 mg, and for all 4 multiple dose levels. No dose related 
effects were observed with respect to serum ferritin, serum transferrin, serum erythropoietin 
and serum soluble transferrin receptor levels on both Day 1 and Day 7. 
1.4.2 
Study VIT-2763-THAL-201 
A Phase 2a trial has recently been completed (Q4, 2021), with study sites in the EU, 
Thailand, Israel, and Lebanon. Study VIT-2763-THAL-201 was a double-blind, 
randomised, placebo-controlled, parallel group trial evaluating the safety, tolerability, PK, 
PD, and preliminary efficacy of multiple doses of VIT-2763 in 25 adult subjects with 
non-transfusion dependent (NTD) thalassaemia. After database lock, topline results were 
generated January 2022. 
The primary safety endpoints were reported or observed AEs and SAEs, changes in vital 
signs (blood pressure and pulse rate and respiratory rate), clinical laboratory safety tests 
(haematology, serum biochemistry, coagulation, and urinalysis), 12-lead ECG, and 
physical examination findings. 
The first subject in Study VIT-2763-THAL-201 was enrolled in June 2020 (in Lebanon). 
Blinded interim results in 10 adult subjects were obtained in Q1/2021 and revealed no 
safety concerns as judged by the Safety Review Committee; topline results of all subjects 
have been analysed (Q1/2022) (Investigational New Drug (IND), Section 1.11.4), 
demonstrating that VIT-2763 was safe and well tolerated. The interim analysis also showed 
that VIT-2763 had significant target engagement with FPN, lowering consistently and 
throughout the treatment period serum iron and TSAT. The study could not show 
significant changes from baseline in clinically relevant blood biomarkers such as Hb, RBC 
count, MCHC, MCV, reticulocyte counts and reticulocyte Hb content. Learnings from 
Study VIT-2763-THAL-201 suggest that TID dosing may be required to achieve the full 
efficacy of vamifeport, and PK and PD samples will needed to be collected at additional 
time points to fully understand the effects of vamifeport. These results led to the 
amendment of this study protocol (see Section 2.3). 


 
 
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2. RATIONALE 
2.1 
Rationale to Investigate the Effects of VIT-2763 in SCD 
While there is good evidence that overt iron deficiency is associated with a decrease in the 
severity of haemolysis, evidence of a clinical benefit is limited because studies are few and 
assessment of the severity of the disease is difficult. It has been shown that overt iron 
deficiency induced by repeated erythrocytapheresis in 2 patients with sickle cell anaemia 
was associated with a decrease in reticulocytes, with only a slight decrease in the blood Hb 
concentration. The lower red cell production from lack of iron appeared to have been 
compensated by the improvement in red cell survival. Following the induction of overt iron 
deficiency, a remarkable decrease in the number of pain crises over 30 months of 
observation was seen in 1 patient and the healing of recalcitrant leg ulcers was seen in the 
other. Iron deficiency did not appear to have any apparent deleterious effects [13]. Other 
authors described 2 patients in whom overt iron deficiency induced by repeated 
phlebotomies was associated with a remarkable decrease in the number of pain crises 
during 4 years of observation [14]. 
In the Townes mouse model of SCD, VIT-2763 showed reduced intravascular haemolysis 
markers, such as plasma LDH, haeme, and bilirubin [17]. Furthermore, VIT-2763 lowered 
markers of vascular inflammation and oxidative stress, for instance soluble vascular cell 
adhesion molecule 1, soluble platelet-selectin, and xanthine oxidase. The RBC indices of 
Townes mice treated with VIT-2763 showed changes attributable to iron-restricted 
erythropoiesis: decrease in RBC counts, Hct, MCV, MCH, reticulocyte Hb content, and 
CHCM. Small changes in CHCM are expected to have a large impact on HbS 
polymerisation rate, which is proportional to HbS concentration in RBCs with a factor of 
about 1030 and therefore on all the ensuing sequelae such as haemolysis and vaso-occlusion 
[18]. Accordingly, VIT-2763 reduced blood cell adhesion in venules, restored blood flow 
and prevented vaso-occlusion in the Townes model of SCD as demonstrated by intravital 
fluorescence video microscopy. In addition, VIT-2763 significantly lowered the relative 
spleen weight of Townes mice, suggesting improved extramedullary erythropoiesis and 
decreased clearance of RBCs. 
Hence, iron restriction by the oral FPN inhibitor VIT-2763 lowers the concentration of HbS 
and has the potential to alleviate VOC and thereby to improve haemodynamics in SCD, 
presumably by reducing haemolysis and vascular inflammation. 
2.2 
Study Design Rationale 
This is a randomised, double-blind, placebo-controlled, parallel group trial that explores 
3 different dosing regimens of VIT-2763: 60 mg BID, 120 mg BID and 120 mg TID. 
The treatment duration of 8 weeks is considered sufficiently long enough to explore the 
effects of VIT-2763 on markers of haemolysis, haematological indices, and vascular 
inflammation, safety and tolerability, iron and erythropoiesis related blood parameters, pain 


 
 
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and quality of life, and at the same time to discern possible negative effects on iron 
restriction over time. 
Subjects in this study will be required to have experienced at least 1 and no more than 
10 VOC episodes reported within 12 months prior to screening, in order to define a 
symptomatic disease status, but to exclude the most severely impacted subjects, e.g., those 
who suffer from additional comorbidities. There is no commonly agreed threshold in the 
number of VOC episodes experienced in patients with SCD. A study including more than 
8,500 patients with a follow-up period of 2.7 years evaluated the prevalence rate of VOC 
episodes (uncomplicated and complicated VOC episodes), and the primary reasons for 
emergency room visits and in-patient admissions for SCD patients [19]. During the 
first-year follow-up period, an average of 2.79 VOC episodes were identified per SCD 
patients, with 1.06 VOC episodes treated in the in-patient setting and 0.90 VOC episodes 
treated in the emergency room without admission. The defined baseline characteristic of 
having experienced at least 1 to no more than 10 VOC episodes ensures that subjects are 
sufficiently stable, while this threshold is in line with the overall prevalence of VOC 
episodes in the target population and compares well with the baseline characteristics of 
SCD patients in similar early clinical trials conducted in the past [20]. Hence, the likelihood 
that subjects will suffer from VOC episodes during the 8-week treatment schedule while 
participating in the main trial is considered low. 
Patients with homozygous HbS/S and the compound heterozygous condition HbS/βT0 
thalassaemia present amongst the most prevalent SCD genotypes and are clinically very 
similar [21]. 
A required Hb threshold between 6.0 g/dl and 10.4 g/dl for female and >11.0 g/dl for male 
subjects at the time of screening is considered appropriate, as it typically covers most 
patients with HbS/βT0 thalassaemia and HbS/S genotype. In addition, ineffective 
erythropoiesis is expected to be more pronounced in HbS/βT0 because of the 
beta-thalassaemia genotype. 
Subjects with absolute reticulocyte count or % reticulocyte count >1.5 × ULN during 
screening are eligible. The reticulocyte count is useful as a marker to estimate the degree 
of erythropoiesis and the appropriateness of the bone marrow response to anaemia. Absence 
of reticulocytosis in anaemia usually signals a problem with the bone marrow such as an 
aplastic anaemia, and points to a lower impact on ineffective erythropoiesis. The 
reticulocyte count is reported to be elevated between 4 to 15% in samples from SCD 
patients [11,22-24]; however, a threshold of 1.5 × ULN seems plausible in this trial to target 
those patients who might respond best following VIT-2763 administration. 
VIT-2763 lowered serum iron in rodents, dogs, and humans (healthy volunteers and 
non-transfusion dependent beta-thalassaemia patients) suggesting similar mechanism of 
action of VIT-2763 in these species [15,16] (see IND, Section 1.11.4). The PD effect of 
VIT-2763 in humans can be monitored by determination of plasma iron levels (acute effect) 
and haematological RBC indices (chronic effect). In addition, biomarkers for haemolysis, 


 
 
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inflammation and haemopoietic/erythropoietic activity in SCD patients will be assessed as 
preliminary efficacy readouts. Data from the completed first-in-human study [16] revealed 
that oral administration of VIT-2763 to healthy male and female volunteers for up to 
7 consecutive days, QD or BID dosing, and at up to 240 mg total daily dose was well 
tolerated with no safety findings of clinical relevance. Short-term treatment in adult 
subjects was well tolerated with no difference between active dose groups and placebo both 
in terms of frequency and intensity of AEs following single and multiple doses. The human 
PK profile exhibited dose linearity and only slight dose super-proportionality for Cmax and 
AUC at steady-state PK.  
Topline results from the first patient study (IND, Section 1.11.4) revealed that oral 
administration of 120 mg QD or 120 mg BID of VIT-2763 to male and female NTD 
beta-thalassaemia patients for 12 weeks was well tolerated with no safety findings of 
clinical relevance. Both treatment regimens were well tolerated with no difference between 
active dose groups and placebo both in terms of frequency and intensity of TEAEs. 
Furthermore, VIT-2763 showed a comparable PK profile, as previously observed in healthy 
volunteers (IND, Section 1.11.4). The Sponsor assumes that the PK profile in the target 
patient population of this study will not differ from previous results in humans. 
Placebo treatment will be used in a minority of adult SCD subjects in order to discriminate 
potential side-effects of active treatment from non-active treatment, and to explore the 
natural variability of haemolysis markers and iron-related markers and biomarkers for 
haemopoietic/erythropoietic activity. Placebo treatment in this study does not bear an 
additional risk for the study participants and will allow subjects to keep their standard of 
care. 
In order to maintain the subjects’ usual medical treatment, subjects will be allowed to be 
concomitantly treated with hydroxyurea and must be on a stable dose for ≥3 months prior 
to screening. Hence, the use of a placebo arm is considered ethically justified. In case there 
is a need for a hospitalisation or further medical care during the course of the trial, based 
on the judgement of the treating physician, subjects may need to be withdrawn from IMP 
intake. In order to assess changes in the laboratory parameters, and changes of the well-
being of subjects randomised into the study, a DSMB will be established to protect the 
safety of study participants. 
2.3 
Dose Selection 
2.3.1 
Summary 
This protocol was amended on the basis of results from Study VIT-2763-THAL-201, where 
-thalassaemia patients were treated with either QD or BID doses of 60 or 120 mg of 
VIT-2763 for 12 weeks. VIT-2763-treated patients experienced dose-dependent reductions 
of total serum iron and TSAT from Week 1 to EoS. However, no changes in relevant 
haematological biomarkers such as Hb could be detected. The Sponsor wants to explore at 
its best the PD range of VIT-2763 in this Phase 2a study, therefore changes in dose and 
dosing frequency have been implemented to ensure a more sustained iron restriction. The 


 
 
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proposed dose levels and dosing frequencies are considered to be safe after an analysis of 
all currently available nonclinical, clinical and simulation data of VIT-2763. 
2.3.2 
Justification of Safety 
The nonclinical risk assessment for the first-in-human study (VIT-2763-101) focused on 
minimising the risk for increase in QRS duration and PR interval, on the basis of 
observations made in dog studies [16]. As this effect was transient and followed the PK 
profile of VIT-2763, Cmax is considered the most relevant parameter for monitoring the risk 
of changes in QRS duration and increased PR-interval. In the current study at each study 
visit pre-dose and 2 hours post-dose (approximately at Tmax) ECG assessments will be 
performed to monitor this risk. 
The Sponsor expects that VIT-2763 will have similar PK characteristics in patients with 
SCD as previously reported for both healthy volunteers [16] and patients with NTD 
beta-thalassaemia (IND, Section 1.11.4). VIT-2763 is quickly eliminated in humans 
(elimination half-life 2-5 hours) and no relevant accumulation has been detected in any of 
the studies where PK measurements have been performed. Therefore, the VIT-2763 Cmax 
values for the proposed dose levels are expected not to exceed the plasma concentrations 
observed previously in humans even with a 120 mg TID dosing regimen. For further 
analysis please refer to the IND, Section 1.11.4. 
Our estimated cumulative 24-hour AUC exposure (20,250.00 ng/ml; IND, Section 1.11.4) 
of 120 mg TID VIT-2763 plasma concentrations at steady-state leaves a safety margin to 
the AUC at NOAEL doses of the rat repeat-dose toxicity studies of 2-12 times [25,26,27] 
and 1-4 times to the AUC at NOAEL doses of the dog repeat-dose toxicity studies 
[28,29,30]. We consider the safety margins for the 120 mg TID VIT-2763 dose level to be 
adequate for this Phase 2a exploratory study in patients. Signs of chronic excessive PD 
effects (i.e., iron deficiency or anaemia) that may occur, can be detected early on with the 
current study setup as haematological safety parameters will be monitored throughout the 
study (every 2 weeks). For a more detailed analysis please refer to the IND, Section 1.11.4. 
2.3.3 
Justification of Dose 
The PD effects after approximately 2 hours of VIT-2763 administration in the 
VIT-2763-THAL-201 study clearly demonstrated that VIT-2763 acted as an FPN inhibitor, 
at both dosing regimens and induced a mean baseline-corrected change in TSAT of -26.2% 
(±18.6%) and -46.8% (±23.6%) for the QD and BID regimens, respectively, after 12 weeks 
of treatment. The placebo group achieved a mean baseline-corrected change in TSAT 
of -1.3% (±2.3%) after 12 weeks of treatment. On the other hand, the PD effects did not 
translate into effects on the ineffective erythropoiesis of treated patients; Hb levels, as well 
as RBC counts, MCHC, MCV, reticulocyte counts and reticulocyte Hb content did not 
change after 12 weeks of treatment (IND, Section 1.11.4). Several hypotheses may explain 
these results; however, the Sponsor believes that an insufficient sustained serum iron 
restriction in between drug administrations may be the cause for such disconnect. VIT-2763 
has a short elimination half-life (2-5 hours) after repeat-dose administration that leads to 


 
 
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insufficient drug concentrations to maintain constant low serum iron levels, in particular 
when VIT-2763 is applied only QD. 
Consequently, in this exploratory Phase 2a study adult subjects will receive for 8 weeks 
either 60 mg BID VIT-2763 (Cohort 1), 120 mg BID VIT-2763 (Cohort 2), 120 mg TID 
VIT-2763 (Cohort 3) or placebo (Cohort 4a and 4b) (see Figure 1 and Table 2). 
Animal models of SCD with 2 administrations of VIT-2763 during the day, showed 
significant clinical benefit. However, data obtained from the VIT-2763-THAL-201 study 
indicate that higher doses or more frequent dosing is required to sustain iron restriction 
throughout the whole dosing period. Signs of chronic excessive PD effects (i.e., anaemia) 
can be detected early on; haematological safety parameters will be monitored throughout 
the study (every 2 weeks). The selected VIT-2763 dose levels and dosing frequencies in 
this Phase 2a exploratory study are considered to be safe and are intended to explore at its 
best the potential therapeutic PD range of VIT-2763 in this patient population. Different 
levels of serum iron restriction (doses of 120 mg, 240 mg and 360 mg) and different 
fluctuations of induced peak and trough serum iron throughout a 24-hour period (BID and 
TID) are explored. It is still unknown if a more sustained serum iron restriction (TID) or 
more fluctuating (BID) serum iron levels translate into better clinical outcomes in SCD. 
That is the reason why in the current protocol a broad range of doses and dosing regimens 
is explored. 


 
 
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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
The primary objective of this study is to explore the effect of VIT-2763 on markers of 
haemolysis. 
3.2 
Secondary Objective 
The secondary objective of this study is to assess the safety and tolerability of VIT-2763 in 
SCD patients. 
3.3 
Exploratory Objectives 
• To explore the effect of VIT-2763 on haematological indices and vascular inflammation. 
• To explore the effect of VIT-2763 on iron and erythropoiesis related blood parameters. 
• To explore the effect of VIT-2763 on patient reported outcomes (pain and quality of 
life). 
• To explore the PK of VIT-2763 using a population PK approach. 
• To explore the changes in abnormal RBCs (sickling) assessed by peripheral blood 
smear. 
• To explore the number of VOC episodes and visceral infarctions. 
3.4 
Primary Endpoint 
• Mean change from baseline in haemolysis markers as measured by reduction of indirect 
bilirubin after 8 weeks of treatment. 
3.5 
Secondary Endpoints 
• Mean change from baseline in haemolysis markers as measured by direct and total 
bilirubin, LDH, potassium, Hb and free haptoglobin after 8 weeks of treatment. 
• Frequency and severity of reported or observed AEs by SOC and PTs using MedDRA 
coded terms, indicating seriousness criteria and relatedness over 8 weeks of treatment. 
3.6 
Exploratory Endpoints 
• Changes in haemolysis markers as measured by indirect, direct, and total bilirubin, 
LDH, potassium, Hb, and free haptoglobin, from baseline after 2, 4, and 6 weeks of 
treatment and 4 weeks after EoT. 
• Frequency and severity of reported or observed AEs by SOC and PTs using MedDRA 
coded terms, indicating seriousness criteria and relatedness up to 4 weeks after EoT. 


 
 
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• Changes in clinical laboratory safety tests (serum biochemistry, safety haematology, 
and urinalysis) from baseline, 12-lead ECG, physical examination findings, vital signs 
(blood pressure, pulse rate), and haematological changes due to iron-restricted 
erythropoiesis after 2, 4, 6, and 8 weeks of treatment and 4 weeks after EoT. 
• Changes in haematological indices, including Hb concentration, RBC count, Hct, MCV, 
MCH, MCHC, CHCM, RBC distribution width, WBC analyses including differential 
WBC counts, platelet and reticulocyte counts, percentage reticulocytes, percentage 
hypochromic microcytic RBCs (RBC volume versus Hb scatterplot analysis), from 
baseline after 2, 4, 6, and 8 weeks of treatment and 4 weeks after EoT. 
• Changes in blood inflammatory markers as measured by high sensitivity C-reactive 
protein, interleukin 1 and interleukin 6, tumour necrosis factor alpha, soluble vascular 
cell adhesion molecule 1, endothelin-1, soluble platelet-selectin, and xanthine oxidase, 
from baseline after 2, 4, 6, and 8 weeks of treatment and 4 weeks after EoT. 
• Assessment of iron-related parameters and markers of erythropoiesis: changes in total 
serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin, from baseline after 2, 4, 6, and 8 weeks of treatment and 4 weeks after 
EoT. 
• VIT-2763 PK parameters (Cmax, clearance, distribution volume, AUC). Sparse 
sampling for determination of VIT-2763 plasma concentration following multiple 
dosing will be obtained from pre-dose to 2 hours, 4 hours and 6 hours post-morning 
dose at study Visit V4. A population PK approach will be applied to estimate PK 
parameters. 
• Change in patient reported outcomes using ASCQ-Me from baseline after 2, 4, 6 and 
8 weeks of treatment. 
• Changes in abnormal RBCs (sickling) assessed by peripheral blood smear from baseline 
after 2, 4, 6 and 8 weeks of treatment and 4 weeks after EoT. 
• Number of VOC episodes and visceral infarctions over 8 weeks of treatment and 
4 weeks after EoT. 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2a, randomised, double-blind, placebo-controlled, parallel group trial in 
SCD subjects. Multiple doses of VIT-2763 will be administered at 3 dose levels and with 
2 different dosing frequencies (60 mg BID, 120 mg BID, 120 mg TID). 
A total of 24 subjects with confirmed diagnosis of SCD will be randomised into 4 cohorts 
(either VIT-2763 or corresponding placebo) (see Figure 1 and Table 2) through a secure 
and validated centralised IWRS that automates the random assignment of treatment groups 
to randomisation numbers. Stratified randomisation (balanced allocation across treatment 
groups) will be used according to genotype (HbS/S - HbS/βT0). 
At baseline, subjects will be assigned to 60 mg BID VIT-2763 (Cohort 1), 120 mg BID 
VIT-2763 (Cohort 2), 120 mg TID (Cohort 3) and placebo (Cohort 4a and 4b). If more than 
1 subject in any dose cohort withdraws or drops out between signing informed consent and 
the V6 visit, the subject will be replaced until at least 5 subjects, with no major protocol 
deviation impacting the primary objective of the trial, per treatment/placebo (Cohorts 4a 
and 4b) arm have passed Visit V6. 
Subjects eligible for randomisation will receive a randomisation number. Randomised 
subjects who terminate their study participation for any reason, regardless of whether the 
IMP was taken or not, will retain their randomisation number. The next subject will be 
given the next randomisation number. 
An independent DSMB will oversee the safety and conduct of the trial on an ongoing basis. 
The DSMB will be comprised of medical and statistical representatives. The DSMB can 
provide recommendations to the Sponsor regarding stopping the study or discontinuing a 
treatment arm or otherwise modifying the study design or conduct. The DSMB will review 
safety data on a periodic, but also as needed on an ad-hoc manner, basis as defined in the 
DSMB Charter. 
Treatment stopping rules for individual subjects are defined in Section 5.4.2. 
The expected duration of subject participation is a maximum of 16 weeks: a non-treatment 
screening period of a maximum of 4 weeks (28 days), an 8-week treatment period and a 
4-week safety follow-up period. The schedule of assessments is provided in Table 1. 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is a maximum of 16 weeks, including a 
non-treatment screening period of up to 4 weeks (28 days), an 8-week (56±4 days) 
treatment period and a 4-week (28±4 days) safety follow-up period. 
The overall end of trial is defined as the date of the last visit of the last patient participating 
in the trial and the end of patient data collection. 


 
 
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5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects 
No specific sample size calculations have been performed for this study. 
It is planned to randomise 24 subjects in a 3:3:3:2:1 ratio into 3 VIT-2763 dose groups and 
2 placebo groups (Cohorts 4a and 4b). 
5.2 
Inclusion Criteria 
The following inclusion criteria must be met for each subject: 
1. 
Subject has provided the appropriate written informed consent before any 
study-specific procedures are performed including screening procedures. 
2. 
Ability to understand the requirements of the study and abide by the study restrictions, 
and agreement to return for the required assessments. 
3. 
Male or female subjects with confirmed diagnosis of SCD, including only HbS/S or 
HbS/βT0 genotype. 
4. 
Subjects who had at least 1 and no more than 10 VOC episodes reported within 
12 months prior to screening. Note: A VOC episode is defined as a documented 
episode of acute chest syndrome or acute painful crisis for the main indication of SCD, 
which led to health-professional instructed prescription or use of opioids (excluding 
codeine) for moderate to severe pain. 
5. 
18 to 60 years of age inclusive at the time of screening. 
6. 
Body weight ≥40 kg and ≤120 kg at screening and baseline. 
7. 
Absolute reticulocyte count or percentage reticulocyte count >1.5 × ULN during 
screening. 
8. 
Subjects on concomitant hydroxyurea treatment must be on a stable dose (mg/kg) for 
≥3 months prior to screening Visit V1. There should be no planned dose adjustments 
during the course of the study in the opinion of the Investigator. 
9. 
Female subjects of childbearing potential, must have negative pregnancy tests at 
screening (serum pregnancy test) and before randomisation (urine pregnancy test), 
must have stopped breastfeeding as of first dose, and must either commit to true 
abstinence from heterosexual contact (which must be reviewed on a monthly basis 
and source documented) or must be willing to use adequate contraceptive precautions, 
i.e., highly effective method of birth control. Abstinence should only be used as a 
contraceptive method if it is in line with the subjects’ usual and preferred lifestyle, 
and periodic abstinence (calendar, symptothermal, postovulation methods) is not an 


 
 
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acceptable method of contraception. Female subjects must agree to use adequate 
contraception during the study and until at least 1 week after the last dose of IMP or 
requirements from other co-medications taken, e.g., hydroxyurea or according to 
local requirements, whichever is longer. Effective contraception (highly effective 
method of birth control, i.e., with a failure rate of <1% per year, when used 
consistently and correctly) such as implants, injectables, combined oral 
contraceptives (see below), intrauterine devices, sexual abstinence, or vasectomised 
partner must be used. Non-childbearing potential includes being surgically sterilised 
at least 6 months prior to the study. 
Note: For female subjects participating in this study, continuous use of hormonal 
contraception alone is not sufficient, because potential interactions via CYP enzymes 
may alter the efficacy of hormonal contraception. The continuous use of hormonal 
contraception by a female subject should be combined with the use of a condom with 
spermicide or adequate and approved alternatives by the (fertile) male partner. 
5.3 
Exclusion Criteria 
The following criteria exclude a subject from participating in this trial: 
1. 
Subjects with confirmed SCD diagnosis other than HbS/S and HbS/βT0. 
2. 
Hb level <6.0 g/dl or >10.4 g/dl for female and >11.0 g/dl for male subjects at 
screening Visit V1. 
Note: The Hb value at screening Visit V1 will be used for eligibility determination 
based on the central laboratory result. However, the baseline Hb value determined at 
Visit V2 (Day 1 pre-dose) also needs to be within the above specified range, based 
on the local laboratory result. 
3. 
Having received RBC transfusion therapy within 4 weeks prior to screening, or 
ongoing or planned RBC transfusion therapy during the course of the study (including 
chronic, prophylactic, or preventive transfusion to treat SCD).  
4. 
Subjects with a serum ferritin level of <30 µg/l at screening. 
5. 
Calculated TSAT level <25% at screening. However, in case the TIBC is within 
normal ranges of the central laboratory values, the subject will not be excluded. 
6. 
Subjects being hospitalised for SCD-related events (including pain crisis and VOC) 
within 14 days before the screening visit. Note: SCD must have been the main cause 
for the hospitalisation to fulfil this criterion. 
7. 
Chronic liver disease or history of liver cirrhosis, and/or alanine aminotransferase or 
aspartate aminotransferase, above 3-fold the ULN range at baseline. 


 
 
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8. 
eGFR <45 ml/min/1.73 m2 at screening. Note: eGFR should be estimated according 
to CKD-EPI formula. 
9. 
Newly diagnosed folate deficiency anaemia (i.e., folic acid <2 ng/ml), which is 
considered clinically relevant by the Investigator at screening. Subjects with known 
folate deficiency anaemia who are on ≥12 weeks stable replacement therapy at 
screening are eligible. 
10. Subjects with history of partial or total splenectomy within 3 months prior to the 
screening visit. 
11. Any history or clinically important finding of cardiac or pulmonary disorders, 
including (but not limited to) clinically relevant or uncontrolled cardiac arrhythmia, 
cardiomyopathy, coronary disease (unstable angina pectoris or myocardial infarction 
or elective coronary intervention), valve disorder, or heart failure according to New 
York Heart Association classification 3-4. 
12. 
A diagnosis of any form of pulmonary hypertension. 
13. Any clinically relevant abnormal 12-lead ECG finding during screening or prior to 
randomisation (as deemed by the Investigator) including (but not limited to) any of 
the following: 
− 
PR interval >0.21 seconds 
− 
Evidence or history of second- or third-degree atrioventricular block 
− 
QRS interval >0.12 seconds 
14. Family history of long-QT syndrome or sudden death without a preceding diagnosis 
of a condition that could be causative of sudden death (such as known coronary artery 
disease, congestive heart failure, or terminal cancer), or subjects with 
QTcF >450 msec. 
15. Clinically significant bacterial, fungal, parasitic, or viral infection which requires 
therapy. Note: A subject meeting this criterion should delay screening and/or 
enrolment for a minimum of 2 weeks, or if excluded can be re-screened at maximum 
2 times at a later time point. 
16. Known history, and/or positive result on screening for hepatitis B surface antigen, 
hepatitis B virus, hepatitis C virus, or HIV infection. Note: Subjects with known 
hepatitis B surface antigen positivity and/or hepatitis C virus antibody positivity will 
be allowed to participate only if the disease has been treated efficiently/is not active. 


 
 
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17. Known active COVID-19 infection (positive result of a SARS-Cov-2 virus test 
(nucleic acid or antigen detection) within 2 weeks preceding screening), or any other 
active infection. Note: A subject who tested positive within 2 weeks preceding 
screening or during screening will be excluded but can be re-screened at a later time 
point as per Investigator’s judgement and if confirmation of a negative 
SARS-CoV-2 test is available based on standard of care. 
18. Use of any prohibited medication(s), including (but not limited to): 
− 
Prior or concomitant use of any medication that is known to prolong the QT/QTc 
interval or the PR/QRS interval, within 4 weeks prior to screening and until EoS. 
− 
Previous oral or intravenous iron therapy or iron chelation therapy ≤4 weeks prior 
to screening and until EoS. 
− 
Any known strong or moderate inhibitors and/or inducers of CYP 3A4 enzyme 
within 4 weeks prior to randomisation and during treatment, or any known strong 
CYP 2D6 inhibitors or inducers as of 4 weeks prior to screening and until EoS. 
− 
Receipt of HbS polymerisation inhibitors (e.g., voxelotor), L-glutamine, 
erythropoietin stimulating/maturation agent treatment, crizanlizumab or any other 
haematopoietic growth factor treatment within 5 half-lives of the respective drug 
prior to screening Visit V1 and until EoS, or anticipated need for such agents 
during the study. 
− 
Any prior gene therapy. 
− 
Use of chronic anticoagulant therapy unless treatment stopped at least 4 weeks 
prior to randomisation. Anticoagulant therapies used for prophylaxis for surgery 
or high-risk procedures as well as low molecular weight heparin for superficial 
venous thrombosis and chronic platelet aggregation inhibitors including 
acetylsalicylic acid are allowed. 
− 
Participation in any other clinical study with an investigational product within 
4 weeks prior to screening Visit V1 and until EoS. 
19. Concomitant use of hormonal contraceptives (contraception associated with 
inhibition of ovulation), which are metabolised through CYP 3A4, are not allowed as 
the sole measure to prevent pregnancy within 4 weeks prior to screening and until 
1 week after the last IMP administration (e.g., combined hormonal contraception (oral, 
intravaginal, transdermal)) and progesterone-only hormonal contraception (oral, 
injectable, implantable). 
20. Known sensitivity to any components of the study products to be administered. 
21. Previous participation to this study with at least 1 administration of the IMP. 


 
 
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22. History of drug or alcohol abuse within 2 years prior to screening. 
23. Pregnant (e.g., positive serum pregnancy test) or females currently breastfeeding. 
24. History or known concomitant solid tumours and/or haematological malignancies 
unless resolved in the ≥2 past years, except for basal or squamous cell carcinoma of 
the skin, carcinoma in situ of the cervix or breast, incidental histologic finding of 
prostate cancer (T1a or T1b according to the Classification of Malignant Tumours 
clinical staging system). 
25. Vulnerable subjects (e.g., subjects kept in detention, protected adults under 
guardianship, trusteeship, and soldiers) or subjects committed to an institution by 
governmental or juridical order, and any other vulnerable subjects. 
26. Unable to take and absorb oral medications, unable to swallow Size 0 capsules. 
27. Known significant medical condition(s), anticipated need for major surgery during 
the study, or any other kind of disorder that may be associated with increased risk to 
the subject, or may interfere with study assessments, outcomes, or the ability to 
provide written informed consent or comply with study procedures, in the 
Investigator’s opinion. 
28. Acute peptic stomach or duodenal ulcer in the previous 3 months before screening 
and/or not healed after 3 months of proton-pump inhibitors therapy (or adequate 
standard of care therapy). 
29. 
Occult or evident not controlled haemorrhages (i.e., ulcerations of gastrointestinal 
tract or body surface) 
30. Any employee or their close relatives of the Sponsor, or of a CRO, or a study site 
involved in the trial. 
5.4 
Withdrawal of Subjects 
5.4.1 
Withdrawal of Subjects from Study 
Subjects may voluntarily withdraw from study participation at any time without having to 
provide a reason. Subjects may be withdrawn because of the appearance of a new health 
condition requiring care or medications prohibited by the protocol, unacceptable AE, 
refusal to continue treatment, or at the Investigator’s discretion if it is in the subject’s best 
interest. 
If a subject withdraws from the study at any time either at his or her request or at the 
Investigator’s discretion, the reason(s) for withdrawal must be recorded on the relevant 
page of the subject’s eCRF and source documentation. Subjects who withdraw from the 
study prematurely (with the exceptions of “withdrawal by subject” and “lost to follow-up”) 
should undergo all study assessments as per Visit V6, if possible. 


 
 
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It is vital to obtain follow-up data on any subject withdrawn because of an AE. In any case, 
every effort must be made to undertake protocol-specified safety follow-up procedures (see 
Section 8.7). If a subject is discontinued due to an AE, the event should be followed by the 
Investigator through contact with the subject until resolution or stabilisation has occurred. 
All AEs should be followed until resolution, stabilisation, or the subject is lost to follow-up 
and cannot be contacted. 
If a subject refuses to continue study procedures, the reason for refusal should be fully 
documented in the subject’s source document and recorded in the study-specific eCRF. 
Although subjects are not obliged to give a reason for withdrawing consent, the Investigator 
will make every effort to obtain the reason, while fully respecting the subject’s rights. If 
the subject withdraws from the trial without providing a reason, the source documents and 
the eCRF should document the reason for discontinuation as “withdrawal by subject”. 
5.4.2 
Withdrawal of Subjects from Study Drug 
IMP must be stopped if any of the below criteria may apply: 
• Serum 
transaminases 
(alanine 
aminotransferase 
or 
aspartate 
aminotransferase) >3 × ULN range and total bilirubin >2 × ULN (confirmed by 
subsequent repeat ≥24 hours apart). 
• Hb level <5.7 g/dl or an Hb decrease of >1.5 g/dl from last visit. 
• Ferritin level <15 µg/l. 
• Increase of QTcF interval of 60 ms over baseline on 2 consecutive 12-lead ECG 
measurements, and/or any QTcF ≥500 ms. Note: Occurrence of this condition would 
qualify the subject for permanent discontinuation from the study (see last paragraph in 
Section 5.4.2). 
• Atrioventricular conduction delays on 2 consecutive 12-lead ECG measurements: 
− 
Absolute PR interval prolongation >240 ms. 
− 
Relative PR interval change >25% from baseline or previous visit. 
− 
Second-degree atrioventricular block or higher. 
− 
Symptoms and signs of decreased cardiac output. 
• Unexpected clinically relevant worsening of complications related to SCD, as per 
Principal Investigator assessment. 
• Major protocol deviations, including noncompliance or lost to follow-up. 
• Participation in any other clinical study during the duration of this clinical study. 


 
 
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• Loss of ability to freely provide consent through imprisonment or involuntary. 
• Incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
• Inability to comply with the protocol or study procedures. 
Any permanent subject withdrawal from study medication needs to be discussed and agreed 
with the Medical Monitor. Withdrawing a subject from study drug can be temporary, and 
the study medication might be reinitiated upon resolution of withdrawal reason and 
consultation and agreement with Medical Monitor. 
5.4.3 
Study Stopping Rules 
A DSMB will regularly, and as needed on an ad-hoc manner, assess the safety information 
of the enrolled subjects, and can provide recommendations to the Sponsor regarding 
stopping the study or discontinuing a treatment arm or otherwise modifying the study 
design or conduct. 
5.5 
Re-screening of Subjects 
A subject can only be randomised once in the trial. If a randomised subject withdraws 
consent for further follow-up, the subject cannot be re-screened. However, a subject who 
fails to meet the protocol inclusion/exclusion criteria (e.g., clinically significant bacterial, 
fungal, parasitic, or viral infections which require therapy, folate deficiency anaemia) can 
be re-screened at a later time point. Before randomisation (Visit V2), re-screening may be 
considered at the discretion of the Investigator and in consultation with the Sponsor. The 
subject must sign a new written informed consent and will be allocated a new screening 
number. 


 
 
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6. STUDY TREATMENTS 
6.1 
Treatment Blinding 
This study is conducted in a double-blind fashion1. The IMPs (VIT-2763 30 mg, 60 mg, or 
placebo) are provided as identical white opaque hypromellose Size 0 hard capsules in white 
high-density polyethylene (HDPE) bottles with identical labels. The appearance of the 
placebo capsules is identical to the VIT-2763 dosage strengths (30 mg and 60 mg) 
expressed as drug substance base. To minimise the potential for bias, treatment 
randomisation information will be kept confidential by the unblinded biostatistician and 
will not be released to the Investigator or site personnel until the study database has been 
locked. The blind will be maintained for subjects and site personnel. The Sponsor (except 
a defined study independent team and clinical trial supply manager), all CRO staff (except 
staff required for the development of the randomisation schedule and outputs for the DSMB) 
are blinded. The DSMB members will be unblinded. 
The Sponsor/CRO staff who may be unblinded will be identified prior to final breaking of 
the blind. If the Investigator or site personnel becomes aware of a subject’s study treatment 
assignment, efforts should be made to not disclose treatment assignments to other study 
staff, subjects, or their caregivers. 
Subjects should refrain from discussion of their IMP with the site staff or other subjects, 
and any questions regarding the physical properties or appearance of the IMP should be 
directed to the dispensing Investigational Pharmacist only. 
During the study, the blind will only be broken under particular conditions that are specified 
in Section 6.1.1. 
6.1.1 
Unblinding 
The study blind will only be broken for an individual subject in the following situations: In 
case of a medical emergency, when knowledge of the treatment arm that was administrated 
is relevant for the treatment of the subject. 
• When reporting of the treatment arm to the Health Authorities is required, e.g., for 
reporting a suspected unexpected serious adverse reaction (SUSAR) (see 
Section 10.7.2). 
• If a subject becomes pregnant during the study, the knowledge of the treatment arm is 
therefore necessary (see Section 10.8.3). 
 
 
1This study is a double-blind study, although subjects receiving oral treatment TID will know that they are not in the 
BID treatment cohorts, subjects will still be blinded for verum and placebo. Similarly, subjects randomised into the BID 
treatment cohorts will know that they are not in the TID treatment cohorts, nevertheless all subjects are blinded within 
their cohort. 


 
 
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If breaking of the blind is required, the unblinded information should be, wherever possible 
accessible only to those clinical site staff who need to be involved in the diagnostic workup, 
treatment, or medical follow-up of the subject (e.g., in case of a medical emergency or a 
pregnancy), or those involved in the safety reporting to external regulatory bodies (e.g., in 
case of a SUSAR or a pregnancy). The responsibility to break the treatment code in 
emergency situations resides solely with the Investigator. However, if in the opinion of the 
Investigator, the situation allows, the study Medical Monitor may be contacted for 
discussion in advance. The Investigator may inform the subject and/or his/her treating 
physician of the treatment assignment. Unblinding by IWRS must always be performed 
according to the procedures that are specified in applicable Standard Operating Procedures. 
6.2 
Dosage Forms/Formulation 
All IMPs used in this study have been manufactured in accordance with current Good 
Manufacturing Practice. 
6.2.1 
VIT-2763 
VIT-2763 will be provided by the Sponsor for this study. 
Active Ingredient: 
VIT-2763 
Chemical Name: 
2-(2-{[2-(1H-benzimidazol-2-yl) ethyl]amino}ethyl)-N-[(3-
fluoropyridin-2-yl) methyl]-1,3-oxazole-4-carboxamide 
trihydrochloride 
Strength:  
Two dosage strengths of VIT-2763 (30 mg, 60 mg) are used 
Excipients:  
Capsule: hypromellose 94.1 mg, titanium dioxide (E171) 1.92 mg 
Appearance: 
Size 0 hard capsules with a white opaque body and cap 
Dosage Form: 
Capsules 
Manufacturer:  
Aptuit S.r.l., Via A. Fleming 4, 37135 Verona, Italy 
Storage:  
VIT-2763 capsules are packed in 60-ml HDPE bottles with desiccant 
and should be stored according to the instructions on the label 
6.2.2 
Placebo 
Placebo will be provided by the Sponsor for this study. 
Excipients: 
Capsule: hypromellose 94.1 mg, titanium dioxide (E171) 1.92 mg 
Filling: 
Microcrystalline cellulose 49.5 mg, magnesium stearate 0.5 mg 
Appearance: 
Identical to VIT-2763. Size 0 hard capsules with a white opaque 
body and cap 


 
 
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Dosage Form: 
Capsules 
Manufacturer:  
Aptuit S.r.l., Via A. Fleming 4, 37135 Verona, Italy 
Storage:  
Placebo capsules are packed in 60 ml HDPE bottles with desiccant 
and should be stored according to the instructions on the label 
6.3 
Drug Dosage and Administration 
6.3.1 
Treatment Arms 
IMPs will be administered during 8 weeks each according to Figure 1 and Table 2. 
Table 2 
Treatment Scheme 
Treatment Scheme 
 
Baseline to Week 8 
 
Morning 
Dose 
Evening 
Dose 
Morning 
Dose 
Afternoon 
Dose 
Evening 
Dose 
Cohort 1 
(n=6) 
60 mg 
VIT-2763 
60 mg 
VIT-2763 
 
 
 
Cohort 2 
(n=6) 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
 
 
 
Cohort 3 
(n=6) 
 
 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
Cohort 4a 
(n=4) 
Placebo 
Placebo 
 
 
 
Cohort 4b 
(n=2) 
 
 
Placebo 
Placebo 
Placebo 
Note: 
n=Number of subjects per cohort. 
 
At randomisation/baseline, 24 subjects with SCD will be randomised in a 3:3:3:2:1 ratio 
into 3 VIT-2763 dose groups to receive either 60 mg BID (120 mg/day, Cohort 1), or 
120 mg BID (240 mg/day, Cohort 2), or 120 mg TID (360 mg/day, Cohort 3) and 2 placebo 
groups (BID, Cohort 4a or TID, Cohort 4b). 
All subjects will be dosed for 8 consecutive weeks. Compliance will be documented in the 
eCRF as detailed in the eCRF completion guidelines. The first dose of IMP will be 
administered in-hospital at the V2 visit (Day 1). The compliance and exact timing of the 
treatment will be ensured by the study personnel. Subjects will receive IMP for home intake 
until the next visit. The subject should return all IMP to site at the following visit where 
accountability is done and receives new IMP according to randomisation and Table 1 to 
ensure compliance. Compliance for the take-home IMP will be assessed on the basis of the 
prescribed number of IMP capsules, the duration of treatment, and the quantity of dispensed 
and returned IMP capsules. 


 
 
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The Investigational Pharmacist or dedicated site staff will inform the study personnel if any 
compliance issues (e.g., <80% of expected usage) are identified so that the subject can be 
retrained on proper dosing and administration. 
6.3.2 
Dosing and Administration Guidelines 
At randomisation/baseline (Visit V2/Day 1) IMP will be assigned by IWRS as per the 
randomisation scheme (see Figure 1) and administration schedule (see Table 3). For 
Cohorts 1, 2, and 4a, the IMP total daily dose will be split into 2 doses per day, 1 in the 
morning and 1 in the evening. The first dose of IMP will be administered at site from the 
assigned IMP kits. A single dose out of the assigned kits of 30 mg or 60 mg VIT-2763 or 
placebo capsules will be administered orally in the morning with about 240 ml water at 
least 1 hour before meals between 06:00 and 10:00 am. The evening dose will be 
administered 12 hours (±1 hour) after the morning dose with water 1 hour apart from meals. 
The evening dose may be administered outside the clinic. 
For Cohorts 3 and 4b, the IMP total daily dose will be split into 3 doses per day, 1 in the 
morning, 1 in the afternoon and 1 in the evening. The first dose of IMP will be administered 
at site from the assigned IMP kits. A single dose out of the assigned kits of 60 mg VIT-2763 
or placebo capsules will be administered orally in the morning with about 240 ml water at 
least 1 hour before meals between 06:00 and 10:00 am. The afternoon dose will be 
administered 8 hours (±1 hour) after the morning dose with water 1 hour apart from a meal. 
The evening dose will be administered 16 hours (±1 hour) after the morning dose with 
water 1 hour apart from any meal. The afternoon and evening dose may be administered 
outside the clinical site. 
Table 3 
Administration Schedule 
Administration Schedule 
Total Daily Dose of VIT-2763 
Number of Capsules/Day 
VIT-2763 
Placebo 
120 mg 
4 × 30 mg 
N/A 
240 mg 
4 × 60 mg 
N/A 
360 mg 
6 × 60 mg 
N/A 
0 mg 
N/A 
4(1) or 6(2) × placebo 
1 Cohort 4a. 
2 Cohort 4b. 
Note: 
N/A=Not applicable. 
 
Subjects will take the assigned IMP for home intake until the next visit. At each visit, the 
IMP for that day will be administered at site (subjects need to be informed that they will be 
receiving the IMP at site for the next visit). 
Two VIT-2763 dosage strengths (30 mg, 60 mg) and placebo are available and will be used 
accordingly to achieve the specified doses and to maintain the blind. 


 
 
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Subjects randomised to placebo will be administered orally 2 or 3 single doses of placebo 
matching to VIT-2763 as per randomisation scheme and administration schedule. The 
placebo will match the VIT-2763 capsules used in the respective cohort. 
If a subject forgets to take an IMP dose (independent of BID or TID dosing), this forgotten 
dose can be safely taken when realised that there are at least 4 hours left to the next planned 
dose. Conversely, if less than 4 hours remain until the next scheduled dose, the 
recommendation is to wait and only take the next dose. 
6.4 
Package and Labelling 
VIT-2763 (30 mg and 60 mg) and placebo capsules in HDPE bottles will be supplied to the 
investigational site as double-blind IMP with identical appearance. 
IMP labels will comply with local requirements. 
6.5 
Study Treatment Allocation 
Each eligible subject will be assigned to 1 of 5 groups through a secure and validated IWRS 
as described in Section 6.3.2. Stratified randomisation (balanced allocation across treatment 
groups) will be used according to genotype (HbS/S - HbS/βT0). 
Subjects will be assigned to VIT-2763 120 mg (Cohort 1), VIT-2763 240 mg (Cohort 2), 
VIT-2763 360 mg (Cohort 3) and placebo (Cohort 4a and 4b). 
All subjects randomised to each cohort will remain on their respective treatment schedules 
until EoT. 
6.6 
Site Supply, Storage, Accountability 
6.6.1 
Site Supply 
Once a site has been approved to receive IMP, the site will be supplied with an initial stock 
of VIT-2763 (dosage strengths of 30 mg and 60 mg) and placebo. The need for IMP 
resupply will be assessed on a regular basis taking into account the number of subjects 
enrolled, and the number of subjects in screening at the site. 
If a subject is not able to visit the site for IMP resupply in case of extraordinary events 
(e.g., COVID-19 pandemic), a direct shipment of the study drug to the subject home/place 
of stay can be implemented, if allowed by the local regulations. The shipment will be 
performed by a logistics provider in a traceable and preferably temperature-controlled 
manner, after agreement with the Investigator and on the basis of an Investigator’s 
prescription. The process will be documented adequately. Written information on the dose 
regimen will be provided to the subject along with contact information to site for any 
questions subject may have. The subject will return any unused IMP and empty IMP 
packages by a logistics provider or during the next on-site visit as instructed by the 
Investigator. For further details refer to Section 8.8. 


 
 
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6.6.2 
Storage 
Upon receipt, all IMPs should be stored according to the instructions specified on the drug 
labels and accessible to authorised personnel only. 
Each site should have a calibrated thermometer that records minimum and maximum 
temperatures daily or the temperature should be monitored continuously using a 
temperature monitoring system. Maintenance of a temperature log is mandatory. The log 
should be updated by site personnel at least every workday. This log must be available for 
review by the Monitor/Clinical Research Associate during on-site monitoring visits. Should 
the storage temperature be outside the range, the IMP must be quarantined immediately, 
and the Sponsor contacted for guidance. 
6.6.3 
Accountability 
The Investigator at each site is responsible for the storage and accountability of the IMP 
supplies. The Investigator will ensure that adequate records of the receipt, dispensation, 
administration, and return of the IMP are kept and that the IMP is used only for subjects 
enrolled in the study. All data regarding the IMP (including kit and/or batch numbers) must 
be recorded in the eCRF and on any other relevant forms provided. 
Each study site will maintain a drug inventory/dispensing record for all IMPs dispensed 
and returned. At the end of the study, 1 copy of the drug inventory/dispensing record should 
be sent to the Sponsor for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all unused materials will 
be returned to the Sponsor. All used IMP containers will be retained at the site by the 
Investigator/qualified designee for the Study Monitor’s verification. The decision to 
destroy IMPs at the site must first be made by the Sponsor. If IMP is destroyed at the site, 
the Investigator will forward the certificate of destruction to the Sponsor. 
6.7 
Drug Dose Modification 
6.7.1 
Procedures for Overdose 
Excessive doses of VIT-2763 could cause severe and transient hypoferraemia. Based on 
nonclinical data, ECG monitoring is recommended, and standard emergency treatment 
should be applied. In addition, it theoretically may warrant acute medical management 
following transient changes in serum iron parameters, e.g., if concurrent (additional) blood 
loss or haemolysis is suspected or if Hb measurements are low enough to cause symptoms 
of decreased oxygen delivery. While it is unlikely that this may occur under the controlled 
environment of this study and based on dose-response relationship examinations obtained 
from the first-in-human trial in healthy volunteers, further dosing in any affected subjects 
must be stopped immediately and depending on the observed or reported signs or symptoms 
of the subject, standard medical care should be provided. When VIT-2763 overdose may 
lead to very unlikely cardiac dysrhythmias or widened PR interval or increased QRS 
duration due to block of sodium channel, further VIT-2763 dosing will be stopped, and it 


 
 
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may warrant administration of sodium bicarbonate in particular in case these subjects are 
hypotensive and/or comatose. Additional emergency and intensive care must be provided 
in case deemed necessary at the discretion of the Investigator. 
6.8 
Prohibited Therapy and Concomitant Treatment 
Prohibited therapies in this study will include the following treatments: 
• Prior or concomitant use of any medication that is known to prolong the QT/QTc 
interval or the PR/QRS interval, within 4 weeks prior to screening and until EoS. 
• Previous oral or intravenous iron therapy ≤4 weeks prior to screening and until EoS. 
• Any known strong or moderate inhibitors and/or inducers of CYP 3A4 enzyme within 
4 weeks prior to randomisation and during treatment period, or any known strong 
CYP 2D6 inhibitors or inducers, as of 4 weeks prior to screening and until EoS. 
• Receipt of HbS polymerisation inhibitors (e.g., voxelotor), L-glutamine, erythropoietin 
stimulating/maturation agent treatment, crizanlizumab or any other haematopoietic 
growth factor treatment within 5 half-lives of the respective drug prior to 
screening/Visit V1, or anticipated need for such agents during the study. 
• Any prior gene therapy. 
• Use of chronic anticoagulant therapy unless treatment stopped at least 4 weeks prior to 
randomisation. Anticoagulant therapies used for prophylaxis for surgery or high-risk 
procedures as well as low molecular weight heparin for superficial venous thrombosis 
and chronic platelet aggregation inhibitors including acetylsalicylic acid are allowed. 
• Iron chelation therapy and RBC transfusion. 
• Current treatment or participation in any other investigational drug study within 
4 weeks prior to screening/Visit V1 and until EoS. 
In case any subject warrants medical care during the course of the study, the Investigator 
will be permitted to prescribe treatment(s) at their discretion, in order to protect the 
subject’s safety and well-being and according to acceptable standards of medical care. 
Any concomitant treatment given for any reason during the course of the study must be 
recorded on the eCRF and in the subject’s medical records, including dosage, start and stop 
dates and reason for use. 


 
 
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7. RISKS/PRECAUTIONS 
7.1 
Special Warnings and Precautions for Use 
The safety, tolerability, and preliminary efficacy of multiple doses of VIT-2763 in adult 
subjects with SCD will be investigated in this Phase 2a clinical trial. 
The results of a Phase 1 clinical trial in 72 healthy volunteers showed that treatment with 
single oral doses of VIT-2763 ranging from 5 mg to 240 mg and 7-day treatment with 
VIT-2763 oral doses of 60 mg QD, 120 mg QD, 60 mg BID, and 120 mg BID was well 
tolerated and no SAEs or discontinuations due to AEs were reported. Safety and tolerability 
data from a Phase 2a clinical study in 25 NTD beta-thalassaemia subjects showed that 
treatment with multiple oral doses of VIT-2763 ranging from 60 mg QD to 120 mg BID 
was well tolerated with a few safety findings of clinical relevance. No SAEs were reported, 
and all AEs were mild to moderate. Treatment regimens showed no differences between 
active and placebo dose groups, both in terms of frequencies and intensity of TEAEs. 
In both studies, there were no findings of clinical relevance with respect to vital signs, 
12-lead ECG, or physical examination throughout the trials. With limited clinical data 
about previously observed adverse reactions from human studies being available, no 
serious adverse drug reactions (ADRs) are considered expected by the Sponsor for the 
purpose of expedited safety reporting of SUSAR and annual/aggregate safety reporting. 
Excessive doses of VIT-2763 could cause severe and transient hypoferraemia. Based on 
nonclinical data, ECG monitoring is recommended, and standard emergency treatment 
should be applied. 
Caution should be exercised in subjects with: 
• Iron deficiency 
• Clinically relevant deviations in RBC or WBC counts 
Based on the nonclinical safety findings, caution should be exercised in subjects with: 
• History or clinical finding of cardiac disorders such as clinically relevant cardiac 
arrhythmia, cardiomyopathy, coronary disease, valve disorder, or heart failure 
• Prior or concomitant use of any medication slowing cardiac conduction (PR and QRS 
interval prolongation), or that prolongs the QT/QTc interval 
7.2 
Fertility, Contraception and Lactation 
7.2.1 
Fertility 
There are no data on the effects of VIT-2763 on human fertility. VIT-2763 produced no 
effects on male or female fertility or early embryonic development at oral doses up to 
200 mg/kg/day in rats. 


 
 
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7.2.2 
Pregnancy 
Data of nonclinical studies of the effect of VIT-2763 on pregnancy and fertility indicate 
that women of childbearing potential should use highly effective methods of contraception 
whilst taking VIT-2763 and until at least 1 week after the last dose. No data on 
breastfeeding has been generated yet, so breastfeeding must be discontinued during 
treatment with VIT-2763 and for at least 1 week after the last dose. 
Highly effective methods of contraception for female subjects participating in this trial are: 
• Intrauterine device, implants 
• Injectables, and combined oral contraceptives 
• Bilateral tubal occlusion 
• Vasectomised partner 
• Sexual abstinence 
• Subject has been surgically sterilised at least 6 months prior to the study 
For female subjects participating in this study, continuous use of hormonal contraception 
alone is not sufficient, because potential interactions via CYP enzymes may alter the 
efficacy of hormonal contraception. The continuous use of hormonal contraception by a 
female subject should be combined with the use of a condom by the male partner; the 
condom should then be used together with a spermicide or adequate and approved 
alternatives. 
For men participating in this study no contraceptive measures are needed. 


 
 
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8. STUDY PROCEDURES 
For a detailed schedule of assessments (including all protocol required assessments, visits 
and visit windows) please refer to Table 1. 
8.1 
Screening Visit/Visit 1 (Day -28 to Day -1) 
Before any study-specific procedures are performed, the subject will receive an explanation 
of all study procedures and must sign and date a written ICF approved by an Institutional 
Review Board (IRB) or equivalent Ethics Committee (EC) (see Section 13.2 for additional 
requirements). 
The following activities will be performed at Visit V1: 
• The Investigator will obtain written informed consent/assent from potentially eligible 
subjects and/or legally acceptable guardian before any trial-related procedure is 
performed 
• Review of inclusion and exclusion criteria. Any outstanding eligibility criteria (see 
Section 5.2 and Section 5.3) not available during screening needs to be available before 
randomisation, 
including 
genotyping 
(local 
laboratory 
haemoglobinopathy 
evaluation/Hb electrophoresis; see Inclusion Criterion 3), in case not available 
previously 
• Collect demographic information 
• Review medical/surgical history 
• Perform physical examination. Body systems to be assessed include general appearance, 
head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, 
musculoskeletal, neurological, lymph nodes, and skin 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes 
• Record body weight and height 
• Perform a single 12-lead ECG 
• As of the date of informed consent for each subject, document in the eCRF all 
SAEs/AEs and changes/additions made to previous and concomitant medications. 
SAEs will be reported as they occur, but no later than 24 hours after the Investigator’s 
awareness of the event 


 
 
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• Draw blood tests using peripheral venipuncture to determine if the subject is eligible 
according to the inclusion and exclusion criteria: 
− 
Blood sample for optional genotyping for SCD in case no genotype diagnosis exists 
(local laboratory) 
− 
Blood sample for assessment of high sensitivity C-reactive protein (central 
laboratory) 
− 
Serum ferritin, and TSAT (for exclusion criteria only) (central laboratory) 
− 
Serum pregnancy test (only in females of childbearing potential) for central 
laboratory assessment 
− 
Serum virology (hepatitis B surface antigen, hepatitis B virus, hepatitis C virus, 
HIV) for central laboratory assessment 
• Collect sample for central laboratory assessment of Hb and reticulocytes 
• Collect sample for central laboratory assessment of serum chemistry 
• Collect urinalysis samples for central laboratory assessment of: 
− 
pH, protein, glucose, ketone, RBCs, and WBCs (urinary dipstick test); quantitative 
measurement only if positive dipstick 
− 
Urinary microalbumin, creatinine, and microalbumin/creatinine ratio (spot urinary 
sample, morning void) 
• Dispense 1 copy of all 6 ASCQ-Me forms 
• Inform subject to complete all ASCQ-Me forms the day before the next visit (baseline 
visit/V2) 
8.2 
Baseline/Randomisation/Visit 2 (Day 1) 
To accommodate local hospital practice, the subject may attend the V2 visit either on the 
day of the first dose of study treatment (randomisation day), or on the day before the 
planned randomisation day. Note: A planned overnight stay prior to study treatment 
administration does not fulfil the seriousness criteria of an SAE unless there is a medical 
requirement. 
If a subject cannot return to the site post-randomisation for a study visit in case of 
extraordinary events (e.g., COVID-19 pandemic), the Investigator will conduct a remote 
visit (e.g., telemedicine, phone call), a visit at the subject home, or in facilities near to the 
subject’s home to evaluate subject safety and eligibility to continue the study therapy, if 
applicable and as per local country guidance (see Section 8.8). 


 
 
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The following activities will be performed at Visit V2: 
Before Randomisation 
• Eligibility assessment will be conducted during screening and also prior to 
randomisation and receiving IMP. Any outstanding eligibility criteria (see Section 5.2 
and Section 5.3) not available during screening need to be available before 
randomisation, 
including 
genotyping 
(local 
laboratory 
haemoglobinopathy 
evaluation/Hb electrophoresis; see Inclusion Criterion 3), in case not available 
previously. If a subject is found to meet eligibility criteria and is enrolled in the study, 
but then has a clinically significant change in status prior to administration of the first 
dose of IMP, for example is hospitalised for sickle cell crisis, the subject should be 
withdrawn from the study. Re-screening may be considered at the discretion of the 
Investigator and in consultation with the Sponsor. 
• Perform physical examination. Body systems to be assessed include general appearance, 
head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, 
musculoskeletal, neurological, lymph nodes, and skin 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes, pre-dose (trough) 
• Record body weight 
• Perform a single 12-lead ECG at pre-dose (trough) 
• Changes/additions made to concomitant medications will be re-assessed since signing 
the ICF and SAEs/AEs will be reported 
• Draw blood sample for assessment of Hb to confirm eligibility (local laboratory) 
• Prepare RBC blood smear (local laboratory) to assess for sickle cells (central laboratory) 
• Urine pregnancy test (only in females of childbearing potential). Positive urine 
pregnancy test results need to be confirmed using a serum beta-hCG test (local 
laboratory assessment) 
• Collect urinalysis samples for central laboratory assessment of: 
− 
pH, protein, glucose, ketone, RBCs, and WBCs (urinary dipstick test); quantitative 
measurement only if positive dipstick 
− 
Urinary microalbumin, creatinine, and microalbumin/creatinine ratio (spot urinary 
sample, morning void) 


 
 
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• Collect blood samples at pre-dose (trough) for central laboratory (as per Laboratory 
Manual) assessment of: 
− Haematology panel/RBC indices (to determine baseline value) 
− Serum chemistry panel 
− Haemolysis markers 
− Endothelial inflammation/dysfunction markers 
− Total serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin (central laboratory assessment) 
• Record number of VOC episodes within the last 8 weeks. Assess visceral infarctions as 
per standard of care 
Randomisation and Administration of the First Dose of IMP 
• Randomisation 
• Dispense subject identification card 
• The first dose of IMP must be administered at the site and the time of administration 
needs to be entered in the eCRF. The IMP total daily dose will be split depending on 
the subject’s randomisation in 2 or 3 doses per day. If randomised to a cohort with BID 
treatment frequency, then dosing will occur in the morning and in the evening. If 
randomised to cohorts with TID treatment frequency, then dosing will occur in the 
morning, afternoon, and evening. For BID dosing the morning dose of the IMP will be 
administered with water, at least 1 hour before meals between 06:00 and 10:00 a.m. 
The evening dose will be administered 12 hours (±1 hour) after the morning dose 1 hour 
apart from meals. For TID dosing morning dose of the IMP will be administered with 
water, at least 1 hour before meals between 06:00 and 10:00 a.m. The afternoon dose 
will be administered 8 hours (±1 hour) after the morning dose 1 hour apart from meals. 
The evening dose will be administered 16 hours (±1 hour) after the morning dose 1 hour 
apart from any meals. 
• Collect all 6 ASCQ-Me forms completed by subject 
• Dispense IMP at site (via IWRS). Note: Only the morning dose on the visit day needs 
to be taken at site 
• Perform a new single 12-lead ECG at 2 hours post-morning dose (±30 minutes). 


 
 
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• Collect samples (2 hours post-morning dose) for total serum iron, serum ferritin, serum 
transferrin, calculated TSAT, hepcidin and erythropoietin (central laboratory 
assessment) 
• Dispense 2 copies of the following forms “Emotional Impact”, “Pain Impact”, “Sleep 
Impact”, and “Stiffness Impact” 
• Inform subject to complete 1 copy of each form, 1 week after the visit, and a second 
copy the day before the next visit (Visit V3) 
8.3 
Visit 3 (Day 14±2 Days) 
The following activities will be performed at Visit V3: 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes, pre-dose (trough) 
• Perform a single 12-lead ECG at pre-dose 
• Assess SAEs/AEs 
• Assess changes/additions to concomitant medications and treatments 
• Collect blood sample for safety assessment of Hb by local laboratory 
• Prepare RBC blood smear (local laboratory) to assess for sickle cells (central laboratory) 
• Urine pregnancy test (only in females of childbearing potential). Positive urine 
pregnancy test results need to be confirmed using a serum beta-hCG test (local 
laboratory assessment) 
• Collect urinalysis samples for central laboratory assessment of pH, protein, glucose, 
ketone, RBCs, and WBCs (urinary dipstick test); quantitative measurement only if 
positive dipstick 
• Collect samples at pre-dose (trough) for central laboratory assessment of: 
− 
Haematology panel/RBC indices 
− 
Serum chemistry panel 
− 
Haemolysis markers 
− 
Endothelial inflammation/dysfunction markers 
− 
Total serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin (central laboratory assessment) 


 
 
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• Record VOC episodes (number of events and pain intensity (NRS: 0-10) compared to 
historical VOC episodes). Assess visceral infarctions as per standard of care 
• Collect 2 copies of the forms “Emotional Impact”, “Pain Impact”, “Sleep Impact”, and 
“Stiffness Impact” 
• Dispense IMP at site (via IWRS). Note: The morning dose on the visit day needs to be 
taken at site 
• Collect samples (2 hours post-morning dose) for total serum iron, serum ferritin, serum 
transferrin, calculated TSAT, hepcidin, and erythropoietin (central laboratory 
assessment) 
• Perform a single 12-lead ECG at 2 hours (±30 minutes) post-morning dose. 
• Dispense 2 copies for all of the following forms “Emotional Impact”, “Pain Impact”, 
“Sleep Impact”, and “Stiffness Impact” and 1 copy of “Social Functioning Impact” 
• Inform subject to complete 1 copy of the following forms “Emotional Impact”, “Pain 
Impact”, “Sleep Impact”, and “Stiffness Impact” 1 week after the visit, and a second 
copy the day before the next visit (Visit V4). The single form “Social Functioning 
Impact” needs to be completed the day before the next visit (Visit V4) 
• Perform IMP accountability 
8.4 
Visit 4 (Day 28±4 Days) 
The subject may attend the V4 visit in the afternoon/evening before to facilitate compliance 
and V4 visit procedures. Note: A planned overnight stay the day before Visit V4 does not 
fulfil the seriousness criteria of an SAE unless there is a medical requirement. The 
following activities will be performed at Visit V4: 
• Perform physical examination. Body systems to be assessed include general appearance, 
head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, 
musculoskeletal, neurological, lymph nodes, and skin 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes, pre-dose (trough) 
• Record body weight 
• Perform a single 12-lead ECG at pre-dose 
• Assess SAEs/AEs 
• Assess changes/additions to concomitant medications 


 
 
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• Collect blood samples for safety assessment of Hb by local laboratory 
• Prepare RBC blood smear (local laboratory) to assess for sickle cells (central laboratory) 
• Urine pregnancy test (only in females of childbearing potential). Positive urine 
pregnancy test results need to be confirmed using a serum beta-hCG test (local 
laboratory assessment) 
• Collect urinalysis samples for central laboratory assessment of: 
− 
pH, protein, glucose, ketone, RBCs, and WBCs (urinary dipstick test); quantitative 
measurement only if positive dipstick 
− 
Urinary microalbumin, creatinine, and microalbumin/creatinine ratio (spot urinary 
sample, morning void) 
• Collect samples at pre-dose (trough) for central laboratory assessment of: 
− 
Haematology panel/RBC indices 
− 
Serum chemistry panel 
− 
Haemolysis markers 
− 
Endothelial inflammation/dysfunction markers 
− 
VIT-2763 PK parameters 
− 
Total serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin (central laboratory assessment) 
• Record VOC episodes (number of events and pain intensity (NRS: 0-10) compared to 
historical VOC episodes). Assess visceral infarctions as per standard of care 
• Collect the ASCQ-Me forms completed by subject 
• Dispense IMP at site (via IWRS). Note: The morning dose on the visit day needs to be 
taken at site 
• Collect additional PK samples at 2 hours (±15 minutes), 4 hours (±30 minutes) and 
6 hours (±30 minutes) post-morning dose (for central laboratory assessment) 
• Collect samples (2 hours post-morning dose) for total serum iron, serum ferritin, serum 
transferrin, calculated TSAT, hepcidin, and erythropoietin (central laboratory 
assessment) 
• Perform a single 12-lead ECG at 2 hours (±30 minutes) post-morning dose. 


 
 
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• Dispense 2 copies of all of the following forms “Emotional Impact”, “Pain Impact”, 
“Sleep Impact”, and “Stiffness Impact” 
• Inform subject to complete 1 copy of each form 1 week after the visit, and a second 
copy the day before the next visit (Visit V5) 
• Perform IMP accountability 
8.5 
Visit 5 (Day 42±4 Days) 
The following activities will be performed at Visit V5: 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes, pre-dose (trough) 
• Perform a single 12-lead ECG at pre-dose 
• Assess SAEs/AEs 
• Assess changes/additions to concomitant medications and treatments 
• Collect blood sample for safety assessment of Hb by local laboratory 
• Prepare RBC blood smear (local laboratory) to assess for sickle cells (central laboratory) 
• Urine pregnancy test (only in females of childbearing potential). Positive urine 
pregnancy test results need to be confirmed using a serum beta-hCG test (local 
laboratory assessment) 
• Collect urinalysis samples for central laboratory assessment of pH, protein, glucose, 
ketone, RBCs, and WBCs (urinary dipstick test); quantitative measurement only if 
positive dipstick 
• Collect samples at pre-dose (trough) for central laboratory assessment of: 
− 
Haematology panel/RBC indices 
− 
Serum chemistry panel 
− 
Haemolysis markers 
− 
Endothelial inflammation/dysfunction markers 
− 
Total serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin (central laboratory assessment) 


 
 
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• Record VOC episodes (number of events and pain intensity (NRS: 0-10) compared to 
historical VOC episodes). Assess visceral infarctions as per standard of care 
• Collect 2 copies of the forms “Emotional Impact”, “Pain Impact”, “Sleep Impact”, and 
“Stiffness Impact” 
• Dispense IMP at site (via IWRS). Note: The morning dose on the visit day needs to be 
taken at site 
• Perform a single 12-lead ECG at 2 hours (±30 minutes) post-morning dose 
• Collect samples (2 hours post-morning dose) for total serum iron, serum ferritin, serum 
transferrin, calculated TSAT, hepcidin, and erythropoietin (central laboratory 
assessment) 
• Inform the subject for the next visit (Visit V6/EoT) to bring the last morning dose of 
the day of Visit V6 to the site in order to be taken at site (no new IMP dispensation at 
Visit V6) 
• Dispense 2 copies for all of the following forms “Emotional Impact”, “Pain Impact”, 
“Sleep Impact”, and “Stiffness Impact” and 1 copy of the forms “Social Functioning 
Impact” and “Pain Episode Frequency and Severity” 
• Inform subject to complete 1 copy of the following forms “Emotional Impact”, “Pain 
Impact”, “Sleep Impact”, and “Stiffness Impact” 1 week after the visit, and a second 
copy the day before the next visit (Visit V6). The single forms “Social Functioning 
Impact” and “Pain Episode Frequency and Severity“ need to be completed the day 
before the next visit (Visit V6) 
• Perform IMP accountability 
8.6 
EoT (or ET) Procedures/Visit 6 (Day 56±4 Days) 
On completion of treatment (or if subject is discontinued/withdrawn early), assessments for 
Visit 6/Day 56±4 days (per Table 1) should be performed: 
• Perform physical examination. Body systems to be assessed include general appearance, 
head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, 
musculoskeletal, neurological, lymph nodes, and skin 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes 
• Record body weight 
• Perform a single 12-lead ECG at pre-dose 


 
 
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• Assess SAEs/AEs 
• Assess changes/additions to concomitant medications and treatments 
• Prepare RBC blood smear (local laboratory) to assess for sickle cells (central laboratory) 
• Urine pregnancy test (only in females of childbearing potential). Positive urine 
pregnancy test results need to be confirmed using a serum beta-hCG test (local 
laboratory assessment) 
• Collect urinalysis samples for central laboratory assessment of: 
− 
pH, protein, glucose, ketone, RBCs, and WBCs (urinary dipstick test); quantitative 
measurement only if positive dipstick 
− 
Urinary microalbumin, creatinine, and microalbumin/creatinine ratio (spot urinary 
sample, morning void) 
• Collect samples at pre-dose (trough) for central laboratory assessment of: 
− 
Haematology panel/RBC indices 
− 
Serum chemistry panel 
− 
Haemolysis markers 
− 
Endothelial inflammation/dysfunction markers 
− 
Total serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin (central laboratory assessment) 
• IMP administered, the morning dose on the visit day needs to be taken at site 
• Perform a single 12-lead ECG at 2 hours (±30 minutes) post-morning dose 
• Collect samples (2 hours post-morning dose) for total serum iron, serum ferritin, serum 
transferrin, calculated TSAT, hepcidin, and erythropoietin (central laboratory 
assessment) 
• Record VOC episodes (number of events and pain intensity (NRS: 0-10) compared to 
historical VOC episodes). Assess visceral infarctions as per standard of care 
• Collect the ASCQ-Me forms completed by subject 
• Perform IMP accountability 


 
 
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8.7 
EoS (Follow-up) Procedures/Visit 7 (Day 84) 
On completion of the study (Visit 7/Day 84±4 days), all assessments per Table 1 should be 
performed. 
All subjects whether completing the treatment or who have withdrawn prematurely, will be 
followed up for 4 weeks (28±4 days after EoT) after their last administration of IMP to 
collect, at a minimum, any potential new AEs and concomitant medications (or other 
endpoints as defined in Table 1). If the Investigator has not seen the subject at in-hospital 
visit at the end of the reporting period, the Investigator must attempt 3 telephone calls to 
the subject, and if there is no response, the source documents and the eCRF should 
document the reason for study discontinuation as “lost to follow-up”. 
The following activities will be performed at Visit V7: 
• Perform physical examination. Body systems to be assessed include general appearance, 
head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, 
musculoskeletal, neurological, lymph nodes, and skin 
• Assess vital signs, e.g., systolic blood pressure, diastolic blood pressure, and pulse, after 
subject has rested for at least 5 minutes 
• Perform a single 12-lead ECG 
• Assess SAEs/AEs 
• Assess changes/additions to concomitant medications 
• Prepare RBC blood smear (local laboratory) to assess for sickle cells (central laboratory) 
• Urine pregnancy test (only in females of childbearing potential). Positive urine 
pregnancy test results need to be confirmed using a serum beta-hCG test (local 
laboratory assessment) 
• Collect urinalysis samples (urinary dipstick test) for central laboratory assessment of 
pH, protein, glucose, ketone, RBCs, and WBCs 
• Collect samples for central laboratory assessment of: 
− 
Haematology panel/RBC indices 
− 
Serum chemistry panel 
− 
Haemolysis markers 
− 
Endothelial inflammation/dysfunction markers 


 
 
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− 
Total serum iron, serum ferritin, serum transferrin, calculated TSAT, hepcidin, and 
erythropoietin 
• Record VOC episodes (number of events and pain intensity (NRS: 0-10) compared to 
historical VOC episodes). Assess visceral infarctions as per standard of care 
8.8 
Allowed Adaptations for Assessments During Site Visits 
To provide some flexibility for specific assessments during the site visits, which can be 
performed post-dose instead of pre-dose as required per the current protocol, the following 
assessments must be performed before VIT-2763 morning dose administration at the site: 
• Collection of AEs and changes/additions made to concomitant medications 
• Vital signs assessment 
• Pre-dose single 12-lead ECG 
• Pre-dose PK blood sample 
• Blood sample to assess Hb to confirm eligibility at Visit V2 to assess whether the study 
therapy can be continued (Visits V2–V5) (local laboratory) 
• Blood sample for pre-dose iron-related parameters 
After Visit V2, the following assessments can also be performed post VIT-2763 morning 
dose administration at the site: 
• Physical examination 
• Body weight recording 
• RBC blood smear (local laboratory) to assess for sickling cells (central laboratory) 
• Urinalysis sample for central laboratory 
• Blood sample for haematology panel/RBC indices (sample for central laboratory) 
• Blood sample for serum chemistry panel (sample for central laboratory) 
• Blood sample for haemolysis markers 
• Blood sample for inflammatory endothelial markers 
• VOC episodes recording and visceral infarction as per standard of care assessment 
• ASCQ-Me Questionnaire collection 


 
 
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Other assessments not mentioned within this list are to be followed as per protocol. 
8.9 
Allowed Adaptations in Case of Extraordinary Events, e.g., 
COVID-19 
Extraordinary events may call for specific measures to maintain subject safety and 
guarantee conduct of clinical investigations according to established general and specific 
guidelines and regulations to meet agreed regulatory, quality, and scientific expectations. 
For this, the following adaptations are considered for specific situations: 
• Site visits are not possible within the defined time window, possibly leading to delayed: 
− 
Physical examination: consultation by local physician, follow-up assessment and 
guidance on drug adaptations via phone, remote visits at subject’s home (e.g., home 
nursing) 
− 
Laboratory assessments: consultation by local physician, visit at local laboratory 
for blood analysis, or via home nursing 
− 
Adaptation of IMP: dispense sufficient amount of IMP at previous visit, delivery to 
subject’s home by qualified designee as assigned by the Principal Investigator, or 
consider handover of IMP to relatives if allowed and in compliance with the 
applicable International Council for Harmonisation (ICH) Good Clinical Practice 
and other applicable laws and regulations, phone call by treating physician to guide 
dose adaptation of drugs 
− 
On-site monitoring: accept delayed on-site monitoring, conduct remote monitoring 
− 
On-site auditing: accept delayed on-site auditing, conduct remote auditing 
− 
AE/SAE/special situation reporting: frequent phone call visits 
• Site visits are not possible within the defined time window, possibly leading to no: 
− 
Physical examination: consultation by local physician, follow-up clinical 
assessment via phone remote visits at subject’s home (e.g., home nursing) 
− 
Laboratory assessments: consultation by local physician, local laboratory for blood 
analysis, or via home nursing 
− 
Adaptation of IMP: dispense sufficient amount of IMP at previous visit, delivery to 
subject’s home by qualified designee as assigned by the Principal Investigator, or 
consider handover of IMP to relatives if allowed and in compliance with the 
applicable ICH Good Clinical Practice and other applicable laws and regulations, 
phone call by treating physician to guide dose adaptation of drugs 


 
 
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− 
On-site monitoring: accept delayed on-site monitoring, conduct remote monitoring 
− 
On-site auditing: accept delayed on-site auditing, conduct remote auditing 
− 
AE/SAE/special situation reporting: frequent phone call visits 


 
 
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9. STUDY ASSESSMENTS 
9.1 
Demographics and Medical History 
Subject’s demographics (gender, age, race, and ethnicity) and baseline characteristics 
including body weight, and medical history will be taken during the baseline visit. 
Information to be collected will include the aetiology and clinical presentation of SCD 
(including HbS/S or HbS/βT0) and SCD-related events (including pain crisis and VOC 
episodes, 8 weeks before baseline), and the date when SCD was first diagnosed, and other 
clinically relevant past and present medical conditions which were diagnosed/occurred up 
to at least 6 months prior to signing the informed consent and/or for which the subject is 
currently treated. Any medically important conditions sustained by the subject which 
extend beyond 6 months prior to informed consent, should also be reported in the medical 
history eCRF. Also, the date of the last RBC transfusion obtained will be recorded in the 
eCRF. 
9.2 
Symptoms and Signs of Anaemia 
The Investigator must assess signs and symptoms associated to anaemia in SCD: 
• Fatigue, weakness 
• Shortness of breath 
• Pale or yellowish skin 
• And others as per standard of care, including laboratory assessments 
Any new clinically relevant symptom or sign of worsening of SCD associated anaemia, or 
any other comorbidity, as assessed by the Investigator, must be reported as an AE (see 
Section 10). 
The SCD associated genotype, clinical presentation and RBC transfusion needs received 
during the past 24 weeks prior to randomisation which are part of the inclusion criteria, 
must be documented in the source data (see Section 5.2). 
9.3 
Physical Examination and Vital Signs 
The body systems to be assessed include: 
• General appearance 
• Head (eyes, ears, nose, and throat) 
• Cardiovascular 
• Respiratory 


 
 
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• Abdomen 
• Musculoskeletal 
• Neurological 
• Lymph nodes 
• Skin 
In the study, physical examination is performed at screening/Visit V1 (i.e., Day -28 to 
Day -1) and on Visits V2 (Day 1), V4 (Day 28), V6 (Day 56), and V7 (Day 84). Facultative 
physical examinations can be performed on indication, i.e., symptom-directed, on all other 
visits. 
Vital signs measurements include diastolic blood pressure, systolic blood pressure, and 
pulse rate. Vital signs are assessed at every visit. Vital signs should be performed before 
IMP administration (trough), after a resting period of at least 5 minutes. Any new clinically 
relevant change as assessed by the Investigator, in blood pressure readings, pulse rhythm 
or rate must be reported as an AE (see Section 10). 
9.4 
12-lead ECG Assessment 
The subject should be resting quietly for a minimum of 5 minutes prior to obtaining the 
single 12-lead ECG (locally). 
Each lead shall be recorded for at least 3 beats at a speed of 25 mm/s. The following 
parameters will be recorded: ventricular rate, PR interval, QRS duration, QT interval and 
QTcF. These parameters plus the judgement by the physician will be entered in the eCRF. 
Print-outs of ECGs will have to be signed, dated, and filed at the site. 
At baseline, the Investigator must document clinically relevant ECG findings on the 
appropriate baseline eCRF pages and in the subject’s hospital records. Any new clinically 
relevant ECG finding, or aggravation/worsening of an already existing finding as assessed 
by the Investigator, must be reported as an AE (see Section 10). 
9.5 
Documentation of Prior and Concomitant Treatments 
All medications and treatments prescribed at the moment of informed consent must be 
documented on the appropriate eCRF pages. In addition, treatments prescribed up to at least 
3 months prior to obtaining the informed consent must be documented on the appropriate 
eCRF pages, irrespective if the treatment is still ongoing at the time of screening. All 
changes to or addition of concomitant treatments as of informed consent must be recorded 
(including changes in dose, change in formulation, starting or stopping medications) in the 
eCRF. If the indication for changing a subject’s concomitant treatment constitutes a new 
medical condition or a worsening of an existing clinical condition which is considered by 


 
 
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the Investigator as being clinically relevant, the indication must be documented as an AE 
(see Section 10). 
9.6 
ASCQ-Me 
The ASCQ-Me system is a set of questions assessing varying aspects of quality of life 
associated with SCD. The total ASCQ-Me measure set consists of both computer-adaptive 
and static (i.e., fixed; short forms) scales [31]. However, in this study the short paper forms 
will be used, and these forms need to be completed out by the subject. 
The paper forms cover 6 topics: 
1. Pain episodes, frequency, and severity (assessing the last 12 months) 
2. Social functioning impact (assessing the last 30 days) 
3. Emotional impact (assessing the last 7 days) 
4. Pain impact (assessing the last 7 days) 
5. Sleep impact (assessing the last 7 days) 
6. Stiffness impact (assessing the last 7 days) 
9.7 
Laboratory Parameters 
In case of pandemic (e.g., COVID-19) related restriction and impossibility of sample 
shipment, or inability of subject to visit the site, inform the Medical Monitor of the study, 
and laboratory assessments may be performed in a local laboratory at site or near to 
subject’s home. In order to ensure subject’s safety and study data continuity, these 
parameters should include at minimum: haematology panel, chemistry panel, and urine 
pregnancy test. 
9.7.1 
Local Laboratory Parameters 
The following laboratory parameters will be assessed locally: 
• Hb levels from Visit V2 to Visit V5. 
• RBC smear sickling preparation from baseline (Visit V2) to EoS (Visit V7). 
• Optional blood sample for SCD genotyping. 
• Urine pregnancy test: beta-hCG for females of childbearing potential from baseline/V2 
to EoS/V7. 


 
 
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9.7.2 
Central Laboratory Parameters 
Details concerning the central blood samples collection, blood withdrawal, processing and 
storage will be provided in a laboratory instruction manual. The following laboratory 
parameters will be assessed by central laboratory according to Table 1. 
See Table 4 for the list of central laboratory assays. 
Table 4 
List of Central Laboratory Assays 
Panel 
Parameters 
Pregnancy Test: 
beta-hCG 
Serum Virology: 
HBsAg, HBV, HCV, HIV 
Haematology/RBC Indices 
Haemoglobin 
Reticulocytes (abs/%) 
RBC count 
Hct 
MCH 
MCV 
MCHC 
RDW 
% hypochromic RBC 
CHCM 
WBC 
Neutrophils (abs, %) 
Lymphocytes (abs‚ %) 
Monocytes (abs‚ %) 
Eosinophils (abs‚ %) 
Basophils (abs‚ %) 
Platelets 
Serum Chemistry: 
Calcium 
Sodium 
Magnesium 
Potassium 
Phosphorus 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Uric acid 
Creatinine kinase 
Creatinine 
Folic acid 
Albumin 
Total protein 
Globulin (calculated) 
Alanine transaminase 
Aspartate transaminase 
Alkaline phosphatase 
Glucose 
Triglycerides 
Cholesterol 
Haemolysis Markers: 
LDH 
Free haptoglobin 
Direct/total bilirubin (indirectly calculated) 


 
 
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Table 4 
List of Central Laboratory Assays (Cont’d) 
Panel 
Parameters 
Endothelial 
Inflammation/Dysfunction: 
hsCRP 
IL-1 
IL-6 
TNF-alpha 
sP-selectin 
sVCAM-1 
Xanthine oxidase 
Endothelin-1 
Iron-related Parameters/ 
Markers of Erythropoiesis: 
Total serum iron 
Serum ferritin 
Transferrin 
TSAT 
TIBC 
Hepcidin 
Erythropoietin 
Sickling: 
Smear assessment 
VIT-2763 Pharmacokinetic: 
Cmax, clearance, distribution volume, AUC 
Urinalysis: 
pH 
Protein 
Glucose 
Ketone 
RBCs 
WBCs 
Spot urine sample for urinary microalbumin, creatinine, and 
microalbumin/creatinine ratio 
Notes: abs=Absolute; AUC=Area under the curve; CHCM=Corpuscular Hb concentration mean; Hb=Haemoglobin; 
HBsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; hCG=Human chorionic gonadotropin; Hct=Haematocrit; 
HCV=Hepatitis C virus; hsCRP=High sensitivity C-reactive protein; IL=Interleukin; LDH=Lactate dehydrogenase; 
MCH=Mean corpuscular Hb; MCHC=Mean corpuscular Hb concentration; MCV=Mean corpuscular volume; RBC=Red 
blood cell; RDW=Red blood cell distribution width; sP=Soluble platelet; sVCAM=Soluble vascular cell adhesion molecule; 
TNF=tumour necrosis factor; TIBC=Total iron-binding capacity; TSAT=Transferrin saturation; WBC=White blood cell. 
 


 
 
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10. EVALUATION, RECORDING AND REPORTING OF AES 
10.1 Definition of AE 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the IMP. 
10.2 AE Reporting Period 
The AE reporting period begins at the time the ICF is signed by the subject. The AE 
reporting period ends at the last study contact Visit 7/28±4 days after EoT. 
10.3 Eliciting AE 
If the subject reports an AE, it is the Investigator’s responsibility to acquire sufficient 
information in order to assess causality and providing rationales for assessment. This may 
require additional laboratory testing, physical examinations, telephone contacts, etc. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, 
such as “How are you feeling?” It is also important to question the subject in a non-leading 
way about changes in their health or concomitant medication usage since their last visit. 
This information should be collected prior to completion of assessments at all study visits. 
In addition, any symptoms/conditions reported during assessments and deemed to be 
clinically significant by the Investigator will be assessed as AEs. 
10.4 Assessing AE 
10.4.1 Intensity/Severity 
The intensity of certain events e.g., laboratory parameters, may be determined according to 
the Common Terminology Criteria for AEs, where the Common Terminology Criteria 
grades relate to severity as follows: 
1. Mild 
2. Moderate 
3. Severe 
4. Life-threatening 
5. Death 
Every change in intensity of a particular AE experienced by the subject during the event is 
recorded. 


 
 
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It is important to note the distinctions between severe AEs and SAEs. Severity is a 
classification of intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); however, the event itself may be of relatively minor medical significance (such 
as severe headache). An SAE is an adverse reaction which either results in death, is 
life-threatening, requires in-patient hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant disability or incapacity, or is a congenital 
anomaly/birth defect. It is an AE that meets any of the regulatory specified criteria required 
for designation as seriousness (described in Section 10.7.1), i.e., a headache may be severe 
(interferes significantly with subject's usual function) but would not be classified as serious 
unless it met one of the criteria for SAEs. 
10.4.2 Causality and Reporting 
An Investigator who is qualified in medicine must make the determination of relationship 
to the IMP and any auxiliary medications for each AE and SAE. The Investigator should 
decide whether, in his or her medical judgement, there is a reasonable possibility that the 
event may have been caused by the investigational product, providing the rationales for his 
assessment. 
If there is no valid reason for suggesting a relationship, then the AE/SAE should be 
classified as unrelated or unlikely related and an alternative suspected aetiology should be 
provided if available (i.e., concomitant medications, intercurrent illness/events). Otherwise, 
if there is any valid reason, even if undetermined or untested, for suspecting a 
cause-and-effect relationship between the investigational product and the occurrence of the 
AE/SAE, then the AE/SAE should be considered certainly, probably/likely, or possibly 
related with a rationale behind this assessment provided. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Certain 
Yes 
• 
Event or laboratory test abnormality, with plausible time relationship to 
drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e., an 
objective and specific medical disorder or a recognised pharmacological 
phenomenon) 
• 
Rechallenge satisfactory, if necessary 
Probable/ 
Likely 
Yes 
• 
Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 


 
 
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Term 
Relationship 
Definition 
Possible 
Yes 
• 
Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear 
Unlikely No 
• 
Event or laboratory test abnormality with a time to drug intake that makes a 
relationship improbable (but not impossible). Disease or other drugs 
provide plausible explanation 
Unrelated No 
• 
Event or laboratory test abnormality which is clearly related to 
circumstances not connected with the drug intake 
 
If the causal relationship between an AE/SAE and the IMP is determined to be “certainly, 
probably/likely, or possibly related”, the event will be considered to be related to the IMP 
for the purposes of expedited regulatory reporting. 
10.4.3 Outcome Categorisation 
Outcome may be classified as: 
recovered/resolved (i.e., without sequelae); 
recovered/resolved with sequelae; recovering/resolving; not recovered/not resolved; fatal; 
or unknown (if follow-up is not possible). 
If the outcome of an SAE is reported as recovered/resolved with sequelae, the Investigator 
should specify the type of sequelae on the SAE form. If the outcome of an SAE is reported 
as unknown, the Investigator should specify (on the SAE form) the rationale why unknown 
was selected. 
“Fatal” should be recorded as an outcome when the AE results in death. If more than 1 AE 
is possibly related to the subject's death, the outcome of death should be indicated for the 
AE that, in the opinion of the Investigator, is the most plausible cause of death. All other 
ongoing AE/SAEs will be recorded as not recovered/not resolved at the time of death. 
In case of a fatal outcome, the Investigator should provide a working diagnosis (event 
which caused outcome, e.g., death due to fatal myocardial infarction) instead of reporting 
only death, and an autopsy report should be provided whenever available where possible. 
If the cause of death later becomes available (e.g., after autopsy), this working diagnosis 
should be replaced by the established cause of death. 
Although “fatal” is usually an outcome of an event, events such as sudden death or 
unexplained death should be reported as SAEs. 
10.5 Recording and Reporting 
10.5.1 Persistent or Recurrent AE 
AEs that extend continuously, without resolution, between trial assessments should only be 
recorded once in the eCRF. 


 
 
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The initial severity of the event should be recorded, and the severity should be updated to 
reflect the most extreme severity any time the event worsens. 
AEs that resolve and subsequently recur should have each recurrence recorded separately 
in the eCRF. 
All AEs persisting at the time of study completion will be followed by the Investigator 
through contact with the subject until resolution or stabilisation, or the subject is lost to 
follow-up and cannot be contacted. The outcome must be documented in the subject’s 
source documents. 
10.5.2 Diagnosis Versus Signs and Symptoms 
Where possible, the Investigator should report a diagnosis rather than individual signs and 
symptoms or abnormal laboratory values. However, if a constellation of signs and/or 
symptoms cannot be medically characterised as a single diagnosis or syndrome at the time 
of reporting, each individual event should be recorded in the eCRF. If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified and replaced by 1 AE report based on the single diagnosis, with a starting date 
that corresponds to the starting date of the first symptom of the eventual diagnosis. 
The Investigator should use standard medical terminology/concepts; avoid colloquialisms 
and abbreviations. Only 1 AE term should be recorded in each event field in the eCRF. 
10.5.3 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the medical history eCRF. A pre-existing medical 
condition should be recorded as an AE only if the frequency, severity, or character of the 
condition worsens during the study. When recording such events on the AE eCRF, it is 
important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
10.5.4 Clinical Laboratory Evaluations 
Not every out-of-range laboratory result qualifies as an AE. A laboratory investigation 
result must be reported as an AE if it is clinically significant and meets any of the following 
criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) 
or a change in concomitant therapy 


 
 
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• Presents shift of a parameter from a normal value to a pathological value, or results in 
a deterioration of Common Terminology Criteria grade, or a further worsening of an 
already pathological value 
• Is clinically significant in the Investigator’s judgement 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgement should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either 
while continuing treatment or after the EoT with the IMP, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration. 
If, at the end of the treatment phase, there are pathological laboratory values which were 
not present at baseline, further clinical or laboratory investigations should be performed 
until the values return to within reference range or until a plausible explanation 
(e.g., concomitant disease) is found for the pathological laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. If the Investigator considers such an AE as serious (e.g., medically 
significant event fulfilling criteria per Section 10.7.1), it must be reported as an SAE. 
If a laboratory abnormality meeting the above criteria is a sign of a disease or syndrome 
only the diagnosis should be recorded in the eCRF. 
If a laboratory abnormality meeting the above criteria is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in the eCRF, along with a descriptor indicating if 
the test result is above or below the normal range (e.g., “elevated potassium,” as opposed 
to “abnormal potassium”). 
If the laboratory abnormality can be characterised by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE; for example, hypercalcaemia or 
hypoglycaemia. Observations of the same laboratory abnormality from visit to visit should 
not be repeatedly recorded in the eCRF unless the aetiology changes. The initial severity 
of the event should be recorded, and the severity or seriousness should be updated any time 
the event worsens. 
All pathological laboratory findings/values diagnosed throughout the treatment period 
should be reviewed by the Investigator to provide a final clinical assessment in view of the 
dynamic of laboratory changes/abnormalities. 


 
 
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10.5.5 Worsening of the Disease Under Study 
Signs or symptoms of the disease under study (SCD) that have unexpectedly worsened in 
severity or frequency or changed in nature at any time during the study should be recorded as 
AEs or SAEs, and clearly marked as worsening of the signs or symptoms in the eCRF.  
10.5.6 Abnormal Vital Signs and Other Abnormalities 
Not every abnormal vital sign, ECG, or other safety assessment qualifies as an AE. A result 
must be reported as an AE if it meets the AE definition (Section 10.1) any of the following 
criteria: 
• Accompanied by clinical symptoms or leads to a diagnosis (in such case the symptom 
or diagnosis will be recorded as an AE) 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• Results in a medical intervention, a change in concomitant therapy, or subject referral 
for further testing outside the protocol 
• Clinically significant abnormality in the Investigator’s judgement 
It is the Investigator’s responsibility to review all vital signs, ECG, and other safety findings. 
Medical and scientific judgement should be exercised in deciding whether an isolated 
abnormality should be classified as an AE. 
If a clinically significant abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded in the eCRF. 
Observations of the same clinically significant abnormality from visit to visit should not be 
repeatedly recorded in the eCRF unless the aetiology changes. The initial severity of the 
event should be recorded, and the severity or seriousness should be updated any time the 
event worsens. 
10.6 ADR and Reference Safety Information 
10.6.1 Adverse Drug Reaction 
An adverse reaction is a response to a medical product (any dose administered) that is 
noxious and unintended related to any dose administrated. A causal relationship between 
an IMP and an AE is at least a reasonable possibility. This means that there are facts 
(evidence) or arguments to suggest a causal relationship. 
All AEs judged as having a reasonable causal relationship to an IMP will be designated as 
ADRs. 


 
 
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10.6.2 Reference Safety Information 
The Reference Safety Information presents the basis for expectedness assessment of an 
adverse reaction for expedite reporting and annual safety reporting, as well as surveillance 
of subject’s safety in a clinical trial by regulatory (and ethic) bodies. 
With limited clinical data about previously observed adverse reactions from human studies 
being available, no serious ADRs are considered expected by the Sponsor for the purpose 
of expedited safety reporting of SUSARs and annual/aggregate safety reporting. 
10.7 Serious Adverse Event 
10.7.1 Definition of SAE 
An SAE is defined as any untoward medical occurrence which either results in death, is 
life-threatening, requires in-patient hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant disability or incapacity, is a congenital 
anomaly/birth defect: 
• Results in death 
• Is life-threatening (the term life-threatening in the definition of serious refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe) 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation, unless 
elective surgery (a planned, non-emergency medical procedure) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (i.e., medically significant) 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events should also be considered as serious. 
Any worsening of a pre-existing medical condition or any new medical condition that meets 
the above SAE criteria should be considered as an SAE. 
The Investigator is encouraged to discuss with the Sponsor (or its delegate, e.g., CRO), any 
AEs for which the issue of seriousness is unclear or questionable. 


 
 
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10.7.1.1 
Situations That Are Not Considered SAEs 
The following situations are not considered as SAEs: 
• Visits to the emergency room or hospital department that do not result in a hospital 
admission lasting more than 24 hours 
• Elective or pre-planned surgery for a pre-existing condition that has not worsened 
• Routine health assessments requiring admission not associated with any deterioration 
in condition 
• Social admission (lack of housing, family circumstances, etc.) 
• A planned overnight stay for logistical reasons only prior to study treatment 
administration does not fulfil the criteria of an SAE unless there is also a medical reason 
for the admission 
10.7.2 SAE Reporting 
The SAE reporting period begins at the time the ICF is signed by the subject. The SAE 
reporting period ends 4 weeks following the last study visit or until at least 4 weeks after 
last IMP administration, whichever is longer. The final follow-up visit may be conducted 
as a telephone call rather than a formal visit, but the Investigator must report any SAEs that 
occur during this period. In circumstances where the Investigator is unable to make contact 
with the subject (or his/her relatives), the Investigator must provide a written statement 
(recorded in the subject’s source documents) to the Sponsor (or its delegate, e.g., CRO), 
confirming that the subject is lost to follow-up. Follow-up information must be handled in 
the same way and reported within the same time frame as the initial SAE report. 
A death occurring during the study or which comes to the attention of the Investigator 
within 4 weeks after the last study visit or until at least 4 weeks after the last IMP 
administration, whichever is longer, whether considered treatment-related or not, must be 
reported to the Sponsor (or its delegate, e.g., CRO). Death is an outcome and not an event; 
therefore, the cause of death is required whenever known. If an autopsy was performed, an 
autopsy report should be provided. If an autopsy was not conducted, a death certificate 
should be provided, if obtainable. 
Any SAE considered to have a causal relationship (i.e., related) to the IMP and discovered 
by the Investigator at any time after the study should be reported. A rationale for the 
assessment of a causal relationship must be provided by the Investigator. Any safety 
information that is obtained after clinical database lock will be documented in the safety 
database and implications for handling the data in the clinical database assessed on an 
individual case basis. 
The occurrence of an SAE must be immediately reported to the Sponsor (or its delegate, 
e.g., CRO) within 24 hours of awareness by facsimile, email, or telephone/via electronic 


 
 
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data capture or as defined in the study monitoring plan. This includes all SAEs (independent 
of relationship to study treatment). 
The onset date of the SAE is defined as the date the signs and symptoms/diagnosis became 
serious (i.e., met at least one of the criteria for seriousness; see Section 10.1). If the 
condition started as a non-serious event and then became serious, 1 AE and 1 SAE will be 
recorded. The resolution date of the SAE is defined as when the symptoms resolve, or the 
event is considered chronic (e.g., sequelae) or stable, and/or if the seriousness criteria are 
no longer applicable. 
10.7.3 Suspected Unexpected Serious Adverse Reaction 
The definition of a SUSAR is any ADR (see Section 10.6.1) that is both serious (see 
Section 10.7.1) and unexpected (per the Reference Safety Information; see Section 10.6.2) 
that, based on the opinion of the Investigator or Sponsor, is felt to have a reasonable 
possibility or suspected causal relationship to an IMP. 
10.7.3.1 
SAE Expedited Reporting 
The Sponsor will notify all Investigators of all SAEs requiring expedited reporting to 
Regulatory Authorities. 
The Investigator is responsible for notifying the Institutional EC in accordance with local 
regulations of all SAEs that occur. The Investigator must review and file the safety report 
with the Investigator’s Brochure. 
10.7.4 Unblinding Treatment Allocation 
The Sponsor will only report SUSARs for which the treatment allocation of the subject is 
unblinded to the pertinent Competent Authority. Investigators should only receive blinded 
information unless unblinded information is judged necessary for safety reasons. 
When an event may be a SUSAR, the blind should be broken only for that specific subject 
(Section 6.1.1). 
Unblinded information should only be accessible to those who need to be involved in the 
safety reporting to pertinent Regulatory Authorities, ECs, and the Medical Monitor (i.e., the 
individual performing ongoing safety evaluations during the study). Unblinding must 
always be performed according to the procedures that are specified in applicable CRO 
Standard Operating Procedures. 
10.8 Special Situations 
10.8.1 Definition of Special Situations 
The following are defined as special situations: 
• Use of an IMP during pregnancy or breastfeeding 


 
 
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• Use of an IMP in a paediatric or elderly population (if this is not the population under 
investigation) 
• Medication error: Any unintentional error in the prescribing, dispensing or 
administration of an IMP during the study 
• Medication misuse: an intentional and inappropriate use of an IMP not in accordance 
with the protocol dose, route of administration, and/or the indication(s) 
• Medication overdose: the administration of a quantity of IMP given per administration 
or cumulatively per day which is above the protocol maximum recommended permitted 
dose 
• Drug interaction involving IMP 
Special situations including medication errors impacting subject’s compliance shall be 
assessed taking into consideration the full period of drug intake and based on criteria 
defined in the study-specific protocol deviation list. 
Suspected AEs associated with medication errors of the IMP or use outside that foreseen 
in the protocol (e.g., overdose,) are also considered as ADRs. Any special situation 
occurring with/without ADR/AE shall be recorded in the study-specific documentation. 
10.8.2 Special Situation Recording and Reporting 
All special situations have to be documented in the subject’s eCRF and source documents. 
The Investigator should also complete and submit the Sponsor paper Special Situation form 
immediately (i.e., within 24 hours of awareness) to the Sponsor, following the same 
procedure as for SAEs (Section 10.7.2). 
If any special situation leads to an SAE (see Section 10.8.1), then the event has to be 
immediately reported to the Sponsor (or its delegate, e.g., CRO) within 24 hours of 
awareness by facsimile, email, or telephone/via electronic data capture, and as defined in 
the safety management plan. 
10.8.3 Pregnancy Exposure and Birth Events 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events 
When a female subject becomes pregnant during the study and study treatment has been 
administered to the subject, the outcome of the pregnancy needs to be monitored and the 
safety of the mother and unborn child need to be safeguarded (as per protocol, pregnancy 
is an exclusion criteria). Therefore, the outcome of all such pregnancies (including normal 
births) must be followed up and documented, even if the subject was withdrawn from the 
study or the study has been completed. 


 
 
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Women of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, must have a negative serum pregnancy test prior to randomisation. IMP should 
not be initiated by the Investigator until a report of a negative pregnancy test has been 
obtained. 
Highly effective contraception must be used in female subjects before beginning IMP, 
during study dosing, and until at least 1 week following discontinuation of IMP or if 
co-medication is used that requires contraception, e.g., hydroxyurea, as per Prescription 
Information, or according to local requirements, whichever is longer, even when there has 
been a history of infertility, unless due to hysterectomy. The Investigator should be always 
consulted in all cases of contraceptive discontinuation during the study. 
Highly effective contraception must be used (refer to synopsis) unless abstinence is the 
chosen method (abstinence should only be used as a contraceptive method if it is in line 
with the subjects’ usual and preferred lifestyle, and periodic abstinence (calendar, 
symptothermal, postovulation methods) is not an acceptable method of contraception) or 
subject has been surgically sterilised at least 6 months prior to the study. Please also refer 
to the exclusion/inclusion criteria (Section 5). 
A female subject must immediately inform the Investigator if she becomes pregnant during 
the study and be instructed to stop taking IMP. The Medical Monitor must be contacted 
immediately to break the blind. The Investigator should counsel the subject and discuss the 
risks of continuing with the pregnancy and the possible effects on the foetus. 
The Investigator/Sponsor is responsible for monitoring the subject and pregnancy outcome. 
Every effort should be made to gather information regarding the pregnancy outcome until 
90 days postpartum (or otherwise as appropriate). It will be the responsibility of the Sponsor, 
together with the appropriate support of the Investigator, to obtain this information. 
10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting 
Any report of pregnancy recorded for any female subject or for a female partner of a male 
subject should be reported to the Sponsor/CRO within the same timelines as an SAE, i.e., 
within 24 hours of awareness. The outcome of all such pregnancies (including normal births) 
must be followed up and documented, even if the subject was discontinued from the study. 
Complications of pregnancy such as abortion (spontaneous or induced), premature birth 
(before 37 weeks gestational age), or congenital abnormality are considered SAEs and 
should be reported using the study-specific Sponsor SAE form. 
All pregnancies occurring in a female subject or the female partner of a male subject within 
30 days after discontinuation of the IMP should be reported within the same timelines as 
an SAE to the Sponsor/CRO. 


 
 
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10.8.4 AEs of Special Interest 
10.8.4.1 
Definition of AEs of Special Interest 
An AE of special interest is a medical occurrence specific to the product or programme, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor is 
appropriate. Such an event, depending on the nature and the outcome, may be serious (see 
Section 10.7.1) or non-serious. 
There are currently no AEs of special interest identified for this study. 


 
 
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11. DSMB PROCEDURES 
An independent DSMB will oversee the safety and conduct of the trial on an ongoing basis. 
The DSMB will be comprised of medical and statistical representatives. 
The DSMB will regularly, but also on an ad-hoc manner as needed, assess the safety 
information of the enrolled subjects, and can provide recommendations to the Sponsor 
regarding stopping the study or discontinuing a treatment arm or otherwise modifying the 
study design or conduct. 
The Sponsor will establish a Charter document explaining the working procedures and 
responsibilities of the DSMB. The Charter should be agreed to by the DSMB. 


 
 
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12. STATISTICAL ANALYSIS 
12.1 Statistical Methods 
All statistical analyses will be performed using SAS Version 9.4 or later (SAS Institute Inc. 
SAS/STAT, Cary, NC). The detailed methodology for summary and statistical analyses of 
the data collected in this trial will be documented in a SAP that will be finalised prior to 
database lock and the unblinding of the study. 
For continuous parameters, summary statistics will include the number of subjects, mean, 
standard deviation, quartiles, minimum and maximum, and the 95% confidence interval of 
the mean (if appropriate). For categorical parameters, summary statistics will include 
counts, percentages, and the 95% confidence interval of the percentages (if appropriate) in 
each category. 
Summary statistics will be provided on overall subjects receiving VIT-2763, by dose and 
for all subjects receiving placebo. Subjects from Cohort 4a and Cohort 4b will be combined 
into 1 placebo group. 
12.2 Sample Size and Power Calculations 
No specific sample size calculations have been performed for this study. 
It is planned to randomise 24 subjects in a 3:3:3:2:1 ratio into 3 VIT-2763 dose groups and 
2 placebo groups. 
12.3 Randomisation 
All subjects enrolled must be identifiable throughout the study. The Investigator will 
maintain a list of subject numbers and subject names to enable records to be found at a later 
date. 
Randomisation of the subject will be performed before start of treatment with IMP using a 
validated centralised IWRS. Stratified randomisation (balanced allocation across treatment 
groups) will be used according to genotype (HbS/S - HbS/βT0). 
Subjects eligible for randomisation will receive a randomisation number. Randomised 
subjects who terminate their study participation for any reason regardless of whether the 
IMP was taken or not, will retain their randomisation number. The next subject will be 
given the next randomisation number. 
Subjects included to replace subjects who withdraw or drop out or with major protocol 
deviations impacting the primary objective of the trial, will be assigned to the same cohort 
as the subjects they are replacing. 


 
 
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12.4 Analysis Sets 
12.4.1 ITT Population 
The ITT population consists of all subjects who are randomly assigned to a treatment group. 
The subjects will be analysed based on the treatment they were randomised to. 
12.4.2 Per-protocol Set 
The PPS consists of all subjects who, in addition to the ITT criteria, completed the study 
and had no major protocol deviations impacting the primary objective of the trial (as 
defined in the SAP and finalised during the blind data review meeting). The subjects will 
be analysed according to the treatment they received. 
12.4.3 Safety Set 
The safety set consists of all randomised subjects who have taken at least 1 dose of IMP. 
The subjects in this group will be analysed based on the treatment they received. 
12.5 Background and Demographic Characteristics 
Demographic characteristics (gender, age, race, ethnicity) and baseline characteristics, 
including body weight, body mass index, blood haemolysis parameters (LDH, indirect/total 
bilirubin), iron parameters (total serum iron, serum ferritin, serum transferrin, calculated 
TSAT, hepcidin, erythropoietin, and TIBC) will be summarised on overall subjects 
receiving VIT-2763, by dose group and on subjects receiving placebo. 
Summary statistics will be provided for the 3 analysis sets. In case some analyses sets are 
identical, summary statistics will not be repeated. 
12.6 Study Medication 
The total amount of IMP taken will be calculated for each subject from the difference 
between the amount of drug given and the amount of drug returned. It will be compared to 
the amount expected to be taken by subject to calculate the percentage compliance to 
treatment. Treatment compliance will be summarised on overall subjects, overall subjects 
receiving VIT-2763, by dose group and on placebo subjects. 
It will be provided for the ITT population and the PPS if they differ. 
12.7 Concomitant Therapy 
Prior and concomitant medications will be categorised according to a standard dictionary 
(World Health Organization Drug Classification). Prior medications are defined as the 
medications that were stopped prior to first IMP intake and concomitant medications as the 
medications ongoing or started after the first IMP intake. 
For both prior and concomitant medications, counts and percentages of subject use for each 
medication will be computed and summarised by Anatomical Therapeutic Chemical Levels 


 
 
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2 and 4 and by preferred name on overall subjects receiving VIT-2763, by dose group and 
on subjects receiving placebo. 
Analyses will be performed on the ITT and the PPS. In case both analysis sets are identical, 
analysis will not be repeated. 
12.8 Primary and Secondary Efficacy Evaluations 
The changes in haemolysis markers from baseline to Visit V6 (after 8 weeks of treatment) 
will be summarised on overall subjects receiving VIT-2763, by dose group and on all 
subjects receiving placebo. 
The ITT population will be used for the analysis of the primary and secondary endpoints 
related to haemolysis markers. These analyses will also be repeated on the PPS. 
12.9 Safety Evaluations 
All safety analyses will be performed on the safety set. 
Adverse Events 
Only TEAEs defined as events with an onset date later or on the same date as first IMP 
intake will be tabulated. AEs that occurred during the study but before first IMP intake will 
be only listed. 
Summary tables with the counts and percentage of subjects and the number of events will 
be provided on overall subjects receiving VIT-2763, by dose group and on all subjects 
receiving placebo for any TEAEs, any severe TEAEs, any serious TEAEs, any TEAEs 
leading to study withdrawal and any TEAEs leading to death. 
All AEs will be coded according to a standard dictionary (MedDRA). 
Tables of the counts and percentages of subjects with at least 1 TEAE by SOC and PT will 
be provided for all TEAEs and TEAEs by severity and by relationship over 8 weeks of 
treatment (secondary endpoint) and up to 4 weeks after EoT. Similar tables will be provided 
for serious TEAEs, TEAEs leading to premature discontinuation of the study and TEAEs 
leading to death. 
Clinical Laboratory Tests 
Values by visit from baseline and changes from baseline by post-baseline visit for the 
haematologic, biochemistry, and urinalysis parameters will be summarised on overall 
subjects receiving VIT-2763, by dose group and on all subjects receiving placebo. 
Shift tables crossing counts of baseline values lower, within and higher than laboratory 
normal range with the counts of each post-baseline visit will be provided for the 
haematologic, biochemistry, and urinalysis parameters on the same treatment groups. 


 
 
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Vital Signs and Body Weight 
Values by visit from baseline and changes from baseline by post-baseline visit for blood 
pressure, pulse rate, and body weight will be summarised on overall subjects receiving 
VIT-2763, by dose group and on all subjects receiving placebo. 
ECGs 
Values by visit from baseline and changes from baseline by post-baseline visit for PR 
interval, QRS duration, QT interval, and QTcF interval will be summarised on overall 
subjects receiving VIT-2763, by dose group and on all subjects receiving placebo. 
Abnormal ECG findings will be listed. 
12.10 Exploratory Efficacy Evaluations 
All exploratory analyses will be performed on the ITT and the PPS. 
Laboratory Parameters 
Exploratory analyses will be performed for blood haemolysis parameters, iron parameters 
and markers of erythropoiesis, blood inflammatory markers, haematological indices, and 
abnormal RBCs measured by peripheral blood smear. 
Values by visit from baseline and changes from baseline by post-baseline visit will be 
summarised for all laboratory parameters on overall subjects receiving VIT-2763, by dose 
group and on all subjects receiving placebo. Shift tables crossing counts of baseline 
categorical values with each post-baseline visit value may also be provided when 
appropriate. 
Quality of Life 
The modified ASCQ-Me questionnaire will be summarised at baseline. The baseline scores 
from the pain episode questionnaire will be summarised as well as individual item response 
levels. 
For the impact questionnaires collected longitudinally, T-Score values by visit from 
baseline and changes from baseline by post-baseline visit will be summarised on overall 
subjects receiving VIT-2763, by dose and on all subjects receiving placebo. 
VOC Episodes and Visceral Infarctions 
Shift tables summarising the number of episodes 8 weeks prior to baseline versus 8 weeks 
after baseline will be provided. Number of events and pain intensity (NRS: 0-10) at each 
visit compared to historical VOC episodes will be described. 


 
 
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12.11 Other Evaluations 
12.11.1 Pharmacokinetics 
The PK concentrations will be listed by subject for each sampling time point for Visit V4 
for all subjects who received VIT-2763. It will be summarised with the addition of the 
geometric mean and its standard deviation and the coefficient of variation to the summary 
statistics performed on overall VIT-2763 subjects, by dose group. 
A population PK approach combined with suitable mathematical/statistical analysis, using 
nonlinear mixed-effects modelling will be applied to estimate PK parameters. Details will 
be specified in a dedicated SAP. 


 
 
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13. STUDY ETHICAL CONSIDERATIONS 
13.1 Ethical Conduct of the Study 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki [32], and the ICH guidelines for Good Clinical Practice [33] as 
amended. The Sponsor will ensure that the study complies with all local, federal, or country 
regulatory requirements. 
The Investigator must ensure the anonymity of all subjects participating in the study. Each 
subject will be assigned a unique subject number, and this should be used on all forms 
associated with the subject’s documents or samples that will be supplied to the Sponsor or 
any party completing testing on behalf of the Sponsor (e.g., blood for central laboratory 
assessments). 
All anonymous data remains the property of the Sponsor. 
13.2 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal 
regulations, and ICH guidelines; and must have been approved by the appropriate 
IRB/Independent Ethics Committee (IEC) prior to use. The Investigator or an authorised 
associate must explain orally and in writing the nature of the study and the treatment in 
such a manner that the subject is aware of potential benefits and risks. Subjects must also 
be informed that participation is voluntary and that they may withdraw from the study at 
any time, without prejudice. Subjects must be provided sufficient time to consider 
participation, including discussion with family members prior to signing the ICF. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation. Subjects must give informed consent in writing. If applicable, 
consent from female partners (who become pregnant during the study) of male subjects will 
also be acquired. 
13.3 Institutional Review Board or IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study 
and any other documents required by the local IRB/IEC must be submitted by the 
Investigator for review and approval to the IRB/IEC. The Investigator must also ensure that 
the IRB/IEC reviews the progress of the study on a regular basis and, if necessary, renews 
its approval of the study on an annual basis. A copy of the approval letter must be forwarded 
to the Sponsor before the study is implemented. 


 
 
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14. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all trial-related site source data, trial-related documents, 
and reports will be available, and that the provision of direct access for monitoring and 
auditing by the Sponsor or its designees will be permitted. In addition, the Investigator must 
ensure that all trial-related site source data, study related documents and reports will be 
made available for Sponsor audit and inspection by the appropriate Regulatory Authority 
and review by the IRB/IEC. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the site’s source data and records by the Medical Monitor (source document 
verification), and the maintenance of a drug dispensing log by the Investigator. The data 
collected will be entered (electronic data capture) into the study database in a timely manner. 
A comprehensive validation check programme will verify the data and queries will be 
generated for resolution by the Investigator and his/her study team. Throughout the study, 
the Sponsor or its designates may review data as deemed necessary. 
The following steps will be taken to ensure that the trial is conducted by the investigational 
site in compliance with the study protocol, Good Clinical Practice, and other applicable 
regulatory requirements: 
• Investigator meeting and/or 
• Investigator site initiation 
• Routine site monitoring 
• Documented protocol and Good Clinical Practice training 
• eCRF and query review against source documents (source data verification) 
• Collection of local laboratory normal ranges 
• All equipment used during the study is to be adequately maintained/calibrated 
14.1 Quality Management: Critical Processes and Data 
The following processes and data have been identified during the risk management 
activities for this trial as critical to ensure human subject protection and the reliability of 
trial results. 
The Sponsor and its designees will ensure a close oversight of the site's activities related to 
the trial. Throughout the study, the clinical study team will work to ensure that the trial is 
operationally feasible and focuses on study activities essential to human subject protection 
and the reliability of trial results, including (but not limited to): 
• Study protocol design and implementation 


 
 
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• Tools and procedures supporting data collection and processing 
• Tools and procedures safeguarding the rights and protection of human subjects 
• Activities essential to trial decision-making and compliance 
 


 
 
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15. REPORTING AND RECORDING OF DATA 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are 
identified on the authorised signature page may enter/correct data in the eCRF. For those 
subjects who withdraw before completion of the study, all available efficacy and safety 
data must be entered in the eCRF. Incomplete or inconsistent data on the eCRF will result 
in data queries addressed to the Investigator for resolution. 
15.1 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which case 
reports for each subject are based. They are to be separate and distinct from eCRFs. These 
records should include detailed notes on: 
• The medical history up to 6 months prior to participation in the study 
• The basic identifying information, such as demographics that link the subject’s source 
documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided and any 
other data on the condition of the subject 
• The subject’s exposure to study treatment 
• All AEs and pregnancies 
• All special situations as defined in Section 10.8.1 
• The subject’s exposure to any concomitant therapy (including date and quantity 
dispensed) 
• All relevant observations and data on the condition of the subject throughout the study 
• The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study). The date of informed consent must be 
recorded in the source documentation 
All data for the trial must be available in the source documentation. 
15.2 Records Retention 
The Investigator must arrange for the retention of all study documentation (such as paper 
CRFs, eCRF files or printed forms, research files, and master files) for the duration 
specified in their respective site contract or as specified by the applicable Regulatory 
Authority, whichever is longer. The Sponsor will inform the Investigator in writing when 


 
 
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files can be destroyed. Archived data may be held on microfiche or electronic record, 
provided that a back-up copy exists and that a hard copy can be generated if required. 
The Investigator must inform the Sponsor immediately if any documents are lost, to be 
transferred to a different facility, or to be transferred to a different owner. 
15.3 Site Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 


 
 
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16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
16.1 Protocol Deviations 
The Investigator will not deviate from the protocol without prior written approval from the 
Sponsor, except in medical emergencies. In the event of a medical emergency, the 
Investigator must notify the Sponsor Medical Expert as soon as possible. Any other change 
to the protocol must be implemented as an amendment to the protocol (see Section 16.2). 
The criteria describing protocol deviation(s) and how they will be handled will be 
documented in the SAP. 
16.2 Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to subjects, 
must be made only with the prior approval of the Sponsor. Each applicable Regulatory 
Authority/IRB/IEC will review and approve amendments prior to their implementation. 
Regulatory Authority/IRB/IEC approval need not be obtained prior to removal of an 
immediate hazard to subjects. 
16.3 Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a site at any time. 
Reasons for termination may include (but are not limited to) unsatisfactory subject 
enrolment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or Good Clinical Practice, or data recording is inaccurate 
and/or incomplete. 
In terminating the study, the Sponsor and the Investigator will assure that adequate 
consideration is given to the protection of the subject’s interests. Both parties will arrange 
the procedures on an individual basis after review and consultation and in accordance with 
the study contract. 
To protect clinical trial subjects from immediate hazards to their health and safety, urgent 
safety measures, e.g., procedures (including temporary halt of a study) that are not defined 
by the protocol, may be initiated immediately by the Investigator or Sponsor and without 
the need to gain prior authorisation by Regulatory Agencies and Competent 
Authorities/Ethic Committees. Detailed guidance and training regarding procedures for 
immediate reporting of urgent safety measures will be provided to the Investigators and 
sites prior to study initiation. 


 
 
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17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The Sponsor is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles [34]. The 
Clinical Trial Agreement describes the Sponsor’s publication terms. 


 
 
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18. REFERENCES 
1. 
Ward DM, Kaplan J. Ferroportin-mediated iron transport: expression and regulation. 
Biochim biophys Acta. 2012;1823:1426-33. Epub 2012 Mar 13. 
2. 
Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. 
Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its 
internalization. Science. 2004 Dec 17;306:2090-3. 
3. 
Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematology 
Am Soc Hematol. 2013:1-8. 
4. 
Gozzelino R, Arosio P. Iron homeostasis in health and disease. Int J Mol Sci. 
2016;130(17):1-14. 
5. 
Siddique A, Kowdley KV. Review article: the iron overload syndromes. Aliment 
Pharmacol Ther. 2012;35:876-93. Epub 2012 Mar 4. 
6. 
Weatherall D, Hofman K, Rodgers G, Ruffin J, Hrynkow S. A case for developing 
North-South partnerships for research in sickle cell disease. Blood. 2005 Feb 
1;105(3):921–23. Epub 2004 Oct 5. 
7. 
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. 
Mortality in sickle cell disease. Life expectancy and risk factors for early death. N 
Engl J Med. 1994 Jun 9;330(23):1639-44. 
8. 
Eaton WA, Bunn HF. Treating sickle cell disease by targeting HbS polymerization. 
Blood. 2017 May 18;129(20):2719-26. Epub 2017 Apr 6. 
9. 
Telen MJ, Malik P, Vercellotti GM. Therapeutic strategies for sickle cell disease: 
towards a multi-agent approach. Nat Rev Drug Discov. 2019;18(2):139-58. 
10. 
Hebbel RP. Reconstructing sickle cell disease: a data-based analysis of the 
"hyperhemolysis paradigm" for pulmonary hypertension from the perspective of 
evidence-based medicine. Am J Hematol. 2011;86:123-54. Epub 2010 Dec 6. 
11. 
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 
11;376:2018-31. 
12. 
Bradt P, Spackman E, Synnott PG, Chapman R, Beinfeld M, Rind DM, et al. 
Crizanlizumab, voxelotor, and L-glutamine for sickle cell disease: effectiveness and 
value. Evidence report. Institute for Clinical and Economic Review. 2020 Mar 12. 
Available 
from: 
https://icer.org/wp-content/uploads/2021/02/ICER_SCD_ 
Evidence-Report_031220-FOR-PUBLICATION.pdf. 
13. 
Castro O, Poillon WN, Finke H, Massac E. Improvement of sickle cell anemia by 
iron-limited erythropoiesis. Am J Hematol. 1994;47:74-81. 
14. 
Bouchaïr N, Manigne P, Kanfer A, Raphalen P, de Montalembert M, Hagege L, et 
al. Prevention of sickle cell crises with multiple phlebotomies. Arch Pediatr. 
2000;7:249-55. French. 


 
 
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15. 
Manolova V, Nyffenegger N, Flace A, Altermatt P, Varol A, Doucerain C, et al. 
Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of 
β-thalassemia. J Clin Invest. 2020 Jan;130(1):491-506. Epub 2019 Dec 9. 
16. 
Richard F, van Lier JJ, Roubert B, Haboubi T, Göhring UM, Dürrenberger F. Oral 
ferroportin inhibitor VIT-2763: first-in-human, phase 1 study in healthy volunteers. 
Am J Hematol. 2020;95:68-77.  
17. 
Manolova V, Nyffenegger N, Flace A, Kalleda N, Doucerain D, Zennadi R, et al. 
The oral ferroportin inhibitor VIT-2763 prevents hemolysis and vaso-occlusion in 
a sickle cell disease model. EHA Library. Abstract S294. 2020;4:S1. p. 108. 
18. 
Eaton WA, Hofrichter J. Sickle cell hemoglobin polymerization. Adv Protein Chem. 
1990;40:63-279. 
19. 
Shah N, Bhor M, Xie L, Paulose J, Yuce H. Sickle cell disease complications: 
prevalence and resource utilization. PLoS ONE. 2019 Jul 5;14(7):e0214355. p. 1-12. 
20. 
Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, et al. A 
phase 1/2 ascending dose study and open-label extension study of voxelotor in 
patients with sickle cell disease. Blood. 2019 Apr 25;133(17):1865-75.  
21. 
National Institutes of Health. Evidence-based management of sickle cell disease. 
Expert Panel Report, 2014. 2014. 
22. 
Bernard AW, Venkat A, Lyons MS. Full blood count and reticulocyte count in 
painful sickle crisis. Emerg Med J. 2006;23(4):302-3.  
23. 
Borba R, Lima CSP, Grotto HZW. Reticulocyte parameters and hemoglobin F 
production in sickle cell disease patients undergoing hydroxyurea therapy. J Clin 
Lab Anal. 2003;17:66-72.  
24. 
Lopez BL, Griswold SK, Navek A, Urbanski L. The complete blood count and 
reticulocyte count-are they necessary in the evaluation of acute vasoocclusive 
sickle-cell crisis? Acad Emerg Med. 1996 Aug;3(8):751-7.  
25. 
Study report FIT-1. 14-day oral repeated dose toxicity study in wistar rats with VIT-
2763 including a 14-day recovery period and toxicokinetics. Vifor (International) 
Ltd., 2017 Mar. Report No.: FIT-1. 
26. 
Study FIT-11: A 13 week study of VIT-2763 by oral gavage in rats. Vifor 
(International) Ltd., 2018 Oct. Report No.: FIT-11. 
27. 
Study FIT-15: A 26 week toxicity study of VIT-2763 by oral (gavage) in rats with 
a 4 week recovery period. Vifor (International) Ltd., 2021 Jul. Report No.: FIT-15. 
28. 
Study report FIT-12. A 13 week study of VIT-2763 by oral gavage in dogs. Vifor 
(International) Ltd.; 2018 Nov. Report No.: FIT-12. 
29. 
Study report FIT-2. A 2 week study of VIT-2763 by oral (capsule) in dogs with a 2 
week recovery period. Vifor (International) Ltd., 2017 Jun. Report No.: FIT-2. 


 
 
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30. 
Study FIT-16: A 39 week toxicity study of VIT-2763 by oral (capsule) in dogs with 
a 4 week recovery period. Vifor (International) Ltd., 2021 Jul. Report No.: FIT-16. 
31. 
Treadwell MJ, Hassell K, Levine R, Keller S. Adult sickle cell quality-of-life 
measurement information system (ASCQ-Me): conceptual model based on review 
of the literature and formative research. Clin J Pain. 2014 Oct30(10):902-14.  
32. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 2013 Oct. 
33. 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline E6(R2): 
Integrated addendum to ICH E6(R1): guideline for good clinical practice. 2016 
Nov 9. 
34. 
PhRMA. Principles on conduct of clinical trials. Communication of clinical trial 
results. Pharmaceutical Research and Manufacturers of America [Internet]. 2014. 
Available from: http://www.phrma.org/principles-and-guidelines-clinical-trials.  

SAP_001.pdf: 
BUSINESS USE 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Investigational Drug: 
VIT-2763 
Treatment: 
VIT-2763 in subjects with sickle cell 
disease 
Study Phase: 
Phase 2a 
Study Title: 
A Phase 2a, double-blind, randomised, 
placebo controlled, efficacy, and safety 
study of multiple doses of VIT-2763 in 
subjects with sickle cell disease (ViSion 
Serenity) 
Protocol Number: 
VIT-2763-SCD-202 
Protocol Version: 
4.0 
Protocol Version date: 
09 March 2023 
Sponsor: 
Vifor (International) Inc. 
Rechenstrasse 37 
St. Gallen CH-9014 
Switzerland 
+41 58 851 80 00 
SAP Version: 
Final Version 2.0 
SAP Version Date: 
26 April 2024 
SAP Author: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPROVAL SIGNATURES FOR SAP 
 
Study Title: 
A Phase 2a, double-blind, randomised, placebo-controlled, 
efficacy, and safety study of multiple doses of VIT-2763 in 
subjects with sickle cell disease (ViSion Serenity) 
Protocol Number: 
VIT-2763-SCD-202 
 
Protocol Version/Amendment 
No. and Date (if applicable): 
4.0/ 09 March 2023 
New SAP Version and Date 
Final Version 2.0 / 26 April 2024 
 
Superseded SAP Version and 
Date (if applicable): 
1.0 
As signed below, I approved the VIT-2763-SCD-202 Statistical Analysis Plan V2.0. 
 
 
 
Prepared by:  
 
 
 
 
 
Signature 
Date 
 
Approved by: 
 
 
 
 
Signature 
Date 
 
Approved by: 
 
 
 
 
 
Signature 
Date 
 
Approved by: 
 
 
 
 
 
Signature 
Date 
 
 
 
 
 
 
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TABLE OF CONTENTS 
SAP REVISION HISTORY .................................................................................................................................. 6 
1 
INTRODUCTION ..................................................................................................................................... 6 
1.1 
OVERALL STUDY DESIGN RATIONALE ....................................................................................................... 6 
1.2 
CHANGES FROM PROTOCOL .................................................................................................................. 7 
2 
STUDY SUMMARY .................................................................................................................................. 8 
2.1 
OBJECTIVES ...................................................................................................................................... 8 
2.1.1 
Primary Objective ...................................................................................................................... 8 
2.1.2 
Exploratory Objectives ............................................................................................................... 8 
2.2 
STUDY DESIGN .................................................................................................................................. 8 
2.3 
SCHEDULE OF EVENTS ........................................................................................................................ 11 
2.4 
SAMPLE SIZE DETERMINATION ............................................................................................................. 14 
2.5 
RANDOMISATION AND BLINDING .......................................................................................................... 14 
2.5.1 
Interim Analysis ....................................................................................................................... 14 
2.5.2 
Data and Safety Monitoring Board ........................................................................................... 14 
2.6 
STUDY ENDPOINTS ........................................................................................................................... 15 
2.6.1 
Primary Endpoint ..................................................................................................................... 15 
2.6.2 
Secondary Endpoint(s) ............................................................................................................. 15 
2.6.3 
Exploratory Endpoint(s) ........................................................................................................... 15 
3 
HYPOTHESES AND DECISION RULES ...................................................................................................... 16 
3.1 
STATISTICAL HYPOTHESES ................................................................................................................... 16 
3.2 
STATISTICAL DECISION RULES .............................................................................................................. 16 
4 
ANALYSIS SETS ..................................................................................................................................... 16 
4.1 
SAFETY SET ..................................................................................................................................... 17 
4.2 
INTENT-TO-TREAT POPULATION ........................................................................................................... 17 
4.3 
PER-PROTOCOL SET .......................................................................................................................... 17 
4.3.1 
Protocol deviations .................................................................................................................. 17 
4.4 
OTHER ANALYSIS SETS ....................................................................................................................... 17 
5 
DESCRIPTION OF THE STATISTICAL ANALYSIS ........................................................................................ 19 
5.1 
GENERAL CONSIDERATIONS ................................................................................................................ 19 
5.1.1 
Standard Descriptive Statistics ................................................................................................. 19 
5.1.2 
Definition of Baseline ............................................................................................................... 20 
5.1.3 
Planned Assessment Windows ................................................................................................. 20 
5.1.4 
Treatment Start/Stop Dates ..................................................................................................... 21 
5.1.5 
Tables and Listings Presentation .............................................................................................. 21 
5.1.6 
Analysis Populations ................................................................................................................ 22 
5.1.7 
Pooling of Sites/Country .......................................................................................................... 22 
5.1.8 
Analysis of Subgroups .............................................................................................................. 22 
5.1.9 
Methods for Handling and Imputation of Missing Data ............................................................. 22 
5.2 
SUBJECT DISPOSITION ....................................................................................................................... 24 
5.3 
DEMOGRAPHICS AND BASELINE SUBJECT CHARACTERISTICS ......................................................................... 24 
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5.4 
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS ...................................................................... 25 
5.5 
PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES ...................................................................... 26 
5.6 
STUDY DRUG EXPOSURE AND COMPLIANCE ............................................................................................. 27 
5.7 
EFFICACY ANALYSES .......................................................................................................................... 28 
5.7.1 
Primary Efficacy Analysis ......................................................................................................... 28 
5.7.2 
Secondary Efficacy Analysis ...................................................................................................... 28 
5.7.3 
Exploratory Efficacy Analysis .................................................................................................... 29 
5.8 
SAFETY ANALYSES ............................................................................................................................ 29 
5.8.1 
Adverse Events ........................................................................................................................ 29 
5.8.2 
Clinical Laboratory Evaluations ................................................................................................ 32 
5.8.3 
Electrocardiogram (ECG) Evaluations ....................................................................................... 33 
5.8.4 
Vital Signs and Body Weight Evaluations .................................................................................. 33 
5.8.5 
Physical Examinations ............................................................................................................. 33 
5.9 
OTHER ANALYSES ............................................................................................................................. 33 
5.9.1 
Iron-related parameters and blood inflammatory markers ....................................................... 33 
5.9.2 
Abnormal RBC sickling ............................................................................................................. 34 
5.9.3 
Quality of Life .......................................................................................................................... 34 
5.9.4 
VOC Episode and Visceral Infarctions ........................................................................................ 36 
5.9.5 
Pharmacokinetics Analyses ...................................................................................................... 37 
REFERENCES ................................................................................................................................................ 38 
APPENDICES ................................................................................................................................................ 39 
APPENDIX A: CLINICAL LABORATORY SAFETY PARAMETERS .......................................................................... 39 
APPENDIX B : ASCQ-ME QUESTIONNAIRES SCORINGS ................................................................................... 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
% 
Percentage 
AE 
Adverse Event 
ASCQ-Me 
Adult Sickle Cell Quality of Life Measurement System 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
BID 
Twice daily 
BMI 
Body Mass Index 
Cmax 
Maximum concentration 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease of 2019 
CRF 
Case report form 
CSP 
Clinical Study Protocol 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
eTMF 
Electronic Trial Master File 
FPN 
Ferroportin 
Hb 
Haemoglobin 
ICH 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IMP 
Investigation Medicinal Product (including VIT-2763 and Placebo) 
INN 
International Nonproprietary Name 
ITT 
Intent- to-Treat 
IWRS 
Interactive Web Response System 
MCH 
Mean cell Hb 
MCHC 
Mean cell Hb concentration 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat 
N 
Number 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
RBCs 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SCD 
Sickle Cell Disease 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment emergent adverse event 
TIBC 
Total Iron Binding Capacity 
TID 
Three times daily 
TFL 
Tables, figures and listings 
VOC 
Vaso-occlusive crises 
 
 
 
 
 
 
 
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SAP REVISION HISTORY 
 
Version 
Effective Date 
Summary of Changes 
Final V1.0 
26Nov2021 
First final version 
Draft V1.2 
24Jun2022 
Updates to account for protocol amendment (V3) including but not 
limited to: 
• 
All sections referring to protocol design or impacted by cohort 
updates (1.1, 2.2, 2.3, 2.5, 5.1, 5.5), 
• 
Safety set section - actual treatment definition, 
• 
New aITT population added for managing data relative to the 
patient enrolled under protocol V2. 
Notion of important/non-important protocol deviation removed 
(minor/major definition kept). 
Draft V1.3 
02Dec2022 
Integration of VUT details 
Draft V1.4 
10NOV2023 
Deletion of VUT details added in V1.3. 
Two additional efficacy endpoints have been added: 
• 
Number of patients who had at least a 20% reduction in 
Indirect Bilirubin by cohort and at each post-baseline visit. 
• 
Number of patients who had at least a 5% reduction in 
CHCM/MCHC by cohort and at each post-baseline visit. 
Final V2.0 
26APR2024 
Implementation of sensitivity analyses with the imputation of the 
missing data due to haemolysed samples at baseline or Visit 6 
1 
INTRODUCTION 
 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under protocol VIT-2763-SCD-202. Pharmacokinetic (PK) analysis will be 
described in a separate analysis document. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol V4.0 dated 09 March 2023 and CRF dated 11 October 
2022. Any further changes to the protocol or CRF may necessitate updates to the SAP. Statistical 
rationale and analysis methods specified in this document take precedence over those described in the 
protocol, should there be any differences. 
1.1 
Overall Study Design Rationale 
 
Sickle cell disease (SCD) is a multisystem disease and is one of the most common severe monogenic 
disorders worldwide. This often-devastating disease is associated with episodes of acute illness and 
progressive organ damage. The pathophysiology of SCD arises from a single amino acid alteration in 
adult haemoglobin (Hb), the expression of which is primarily limited to red blood cells (RBCs). 
VIT-2763 (INN Vamifeport) is developed by Vifor Pharma as a novel oral drug targeting ferroportin 
(FPN), and as such for the treatment of secondary iron overload and conditions in which iron metabolism 
is involved: ineffective or otherwise disturbed erythropoiesis, including (but not limited to) 
 
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haemochromatosis, haemoglobinopathies (e.g., thalassaemia and SCD), or myeloproliferative/ 
dysplastic disorders (e.g., polycythaemia vera and myelodysplastic syndrome, respectively). 
Furthermore, the oral FPN inhibitor VIT-2763 has shown positive results on haemolysis, 
haemodynamics, and prevention of vaso-occlusion in an animal model of SCD. 
 
Patients with homozygous HbS/S and the compound heterozygous condition HbS/βT0 thalassaemia 
present amongst the most prevalent SCD genotypes and are clinically very similar. 
 
A required Hb threshold between 6.0 g/dL and 10.4 g/dL for female and >11.0 g/dL for male subjects at 
the time of screening is considered appropriate, as it typically covers most patients with HbS/βT0 
thalassaemia and HbS/S genotype. In addition, ineffective erythropoiesis is expected to be more 
pronounced in HbS/βT0 because of the beta-thalassaemia genotype. 
 
Since no FPN inhibitors or hepcidin-mimetic drugs are yet available for the treatment of iron-loading 
anaemias, including SCD, VIT-2763 would be considered as a first-in-class drug. 
 
This is a randomised, double-blind, placebo-controlled, parallel-group trial that explores three different 
dosing regimens of VIT-2763: 60 mg twice daily (BID), 120 mg BID and 120 mg 3 times daily (TID). 
 
The treatment duration of 8 weeks is considered sufficiently long enough to explore the effects of VIT- 
2763 on markers of haemolysis, haematological indices, vascular inflammation, safety and tolerability, 
iron and erythropoiesis related blood parameters, pain and quality of life, and at the same time to discern 
possible adverse effects on iron restriction over the treatment time. 
 
Placebo treatment will be used in a minority of adult SCD subjects to discriminate potential side effects 
of active treatment from non-active treatment and to explore the natural variability of haemolysis markers 
and iron-related markers and biomarkers for haemopoietic/erythropoietic activity. Placebo treatment in 
this study does not bear an additional risk for the study participants and will allow subjects to keep their 
standard of care. 
 
The protocol V3.0 was developed based, among other VIT-2763 studies, on results from Study VIT- 
2763-THAL-201, where β-thalassemia patients were treated with either once daily or BID doses of 60 
or 120 mg of VIT-2763 for 12 weeks. VIT-2763-treated patients experienced dose-dependent 
reductions of total serum iron and TSAT% from Week 1 to end of study. However, no changes in 
relevant haematological biomarkers such as Hb could be detected. The sponsor wants to explore at its 
best the pharmacodynamic (PD) range of VIT-2763 in this Phase 2a study. Therefore, changes in 
dose and dosing frequency have been implemented to ensure a more sustained iron restriction. 
Consequently, in this exploratory Phase 2a study, adult subjects will receive for 8 weeks either 60 mg 
BID VIT-2763 (Cohort 1), 120 mg BID VIT-2763 (Cohort 2), 120 mg TID VIT-2763 (Cohort 3) or 
placebo (Cohort 4a and 4b). 
 
1.2 
Changes from Protocol 
Additional analysis sets for analysis purposes not defined in the protocol have been included in the SAP 
(see Section 4.4). 
 
 
 
 
 
 
 
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2 
STUDY SUMMARY 
 
2.1 
Objectives 
 
2.1.1 
Primary Objective 
The primary objective of the study is to explore the effect of VIT-2763 on markers of haemolysis. 
 
2.1.2 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
 
• 
To explore the safety and tolerability of VIT-2763. 
 
• 
To explore the effect of VIT-2763 on haematological indices and vascular inflammation. 
 
• 
To explore the effect of VIT-2763 on iron and erythropoiesis-related blood parameters. 
 
• 
To explore the effect of VIT-2763 on patient-reported outcomes (pain and quality of life). 
 
• 
To explore the PK of VIT-2763 using a population PK approach. 
 
• 
To explore the changes in abnormal RBCs (sickling) assessed by peripheral blood smear. 
 
• 
To explore the number of VOC episodes and visceral infarctions. 
 
2.2 
Study Design 
 
This is a Phase 2a, randomised, double-blind, placebo-controlled, parallel group trial in SCD subjects 
that explores three different dosing regimens of VIT-2763: 60 mg BID, 120 mg BID and 120 mg TID. 
 
A total of 24 subjects with confirmed diagnosis of SCD will be randomised. IMPs will be administered 
for 8 weeks each according to Figure 1, Table 1 and Table 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1 Schema 
 
 
 
 
 
SCD subjects, 
n=24 
 
Follow up 
 
 
 
 
 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
(Day -28 to Day -1) 
(Day 1) 
(Day 14) 
(Day 28) 
(Day 42) 
(Day 56, EoT/ ET) 
(Day 84, EoS) 
 
Screening/Randomisation 
(Up to 4 weeks) 
Treatment Phase 
(8 weeks) 
Follow up 
(4 weeks) 
 
Notes: BID=Twice daily; EoS=End of study; EoT=End of treatment; ET=Early termination; n=Number of 
subjects per cohort; SCD=Sickle cell disease; TID= 3 times daily. 
Table 1 Treatment Scheme 
 
 
Treatment Scheme 
Baseline to Week 8 
 
Notes: n=Number of subjects per cohort. 
 
 
At randomisation/baseline, 24 subjects with SCD will be randomised in a 3:3:3:2:1 ratio into 3 VIT-2763 
dose groups to receive either 60 mg BID (120 mg/day, Cohort 1), or 120 mg BID (240 mg/day, Cohort 
2), or 120 mg TID (360 mg/day, Cohort 3) and 2 placebo groups (BID, Cohort 4a or TID, Cohort 4b). 
 
For Cohorts 1, 2, and 4a, the IMP total daily dose will be split into 2 doses per day, 1 in the morning and 
1 in the evening. The first dose of IMP will be administered at site from the assigned IMP kits. A single 
 
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n=6 
Cohort 1: VIT-2763 120 mg (60 mg BID) 
Randomisation/ 
Baseline 
n=6 
Cohort 2: VIT-2763 240 mg (120 mg BID) 
n=6 
Cohort 3: VIT-2763 360 mg (120 mg TID) 
n=6 
Cohort 4: Placebo 
(Cohort 4a: n=4 BID; Cohort 4b: n=2 TID) 
Morning Dose 
Evening Dose 
Morning Dose 
Afternoon Dose 
Evening Dose 
Cohort 1 (n=6) 
60 mg 
VIT-2763 
60 mg 
VIT-2763 
Cohort 2 (n=6) 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
Cohort 3 (n=6) 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
120 mg 
VIT-2763 
Cohort 4a (n=4) 
Placebo 
Placebo 
Cohort 4b (n=2) 
Placebo 
Placebo 
Placebo 


BUSINESS USE 
 
 
dose out of each of the assigned kits of 30 mg or 60 mg VIT-2763 or placebo capsules will be 
administered orally in the morning with about 240 mL water at least 1 hour before meals between 06:00 
and 10:00 am. The evening dose will be administered 12 hours (±1 hour) after the morning dose with 
water 1 hour apart from meals. 
 
For Cohorts 3 and 4b, the IMP total daily dose will be split into 3 doses per day, 1 in the morning, 1 in 
the afternoon and 1 in the evening. The first dose of IMP will be administered at site from the assigned 
IMP kits. A single dose out of each of the assigned kits of 60 mg VIT-2763 or placebo capsules will be 
administered orally in the morning with about 240 mL water at least 1 hour before meals between 08:00 
and 10:00 am. The afternoon dose will be administered 8 hours (±1 hour) after the morning dose with 
water 1 hour apart from a meal. The evening dose will be administered 16 hours (±1 hour) after the 
morning dose with water 1 hour apart from any meal. 
 
Table 2 Administration Schedule 
 
Administration Schedule 
 
 
Total Daily Dose of VIT-2763 
Number of Capsules/Day 
 
 
VIT-2763 
Placebo 
 
 
120 mg 
4 × 30 mg or 2 × 60 mg 
2 × placebo(1) 
240 mg 
4 × 60 mg 
N/A 
360 mg 
6 × 60 mg 
N/A 
0 mg 
N/A 
4(2) or 6(3) × placebo 
1 Only together with the 60 mg strength. 
2 Cohort 4a. 
3 Cohort 4b. 
Note:  N/A=Not applicable. 
 
 
As specified in the IRT configurable requirements of the study, kits of 30 mg capsules will be dispensed 
to cohort 1 subjects (group with a total daily dose of 120 mg). The administration schedule chosen for 
cohort 1 is then 4 capsules of 30 mg per day (the option with 2 capsules of 60 mg and 2 capsules of 
placebo per day was not retained). 
 
The expected duration of subject participation is a maximum of 16 weeks, including a non-treatment 
screening period of up to 4 weeks (28 days), an 8-week (56±4 days) treatment period and a 4-week 
(28±4 days) safety follow-up period. 
 
The overall end of trial is defined as the date of the last visit of the last subject participating in the trial 
and the end of subject s’ data collection. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3 
Schedule of Events 
Table 3 Schedule of Events 
 
Visit 1 
Screen 
Visit 2 
Baseline/ 
Randomisation 
 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
EoT/ET 
Visit 7 
EoS/ 
Follow-up 
Day 84 
Day -28 
to Day -1 
 
Informed consent 
X 
Day 1 
Day 14 
±2 Days 
Day 28 
±4 Days 
Day 42 
±4 Days 
Day 56 
±4 Days 
28 Days 
±4 Days After 
EoT 
Eligibility criteria(1) 
X 
X(1) 
 
Demographics 
X 
Medical/surgical history 
X 
Physical examination(2) 
X 
X 
X 
X 
X 
Vital signs (seated blood pressure, pulse rate)(3) 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
Height 
X 
12-lead ECG 
X 
X(4) 
X(4) 
X(4) 
X(4) 
X(4) 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
X 
Dispense subject identification card 
X 
Hb levels 
C 
L 
L 
L 
L 
L 
L 
hsCRP 
C 
RBC smear preparation 
L 
L 
L 
L 
L 
L 
Urine pregnancy test(5) 
L 
L 
L 
L 
L 
L 
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Visit 1 
Screen 
Visit 2 
Baseline/ 
Randomisation 
 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
EoT/ET 
Visit 7 
EoS/ 
Follow-up 
 
Day -28 
to Day -1 
Day 1 
Day 14 
±2 Days 
Day 28 
±4 Days 
Day 42 
±4 Days 
Day 56 
±4 Days 
Day 84 
28 Days 
±4 Days After 
EoT 
Serum pregnancy test(6) 
C 
Serum virology (HbsAg, HBV, HCV, HIV) 
C 
Urinalysis(7) 
C 
C 
C 
C 
C 
C 
C 
Haematology panel/RBC indices(8) 
C 
C 
C 
C 
C 
C 
C 
Serum chemistry panel(9) 
C 
C 
C 
C 
C 
C 
C 
Haemolysis markers(10) 
C 
C 
C 
C 
C 
C 
Endothelial inflammation/dysfunction 
markers(11) 
C 
C 
C 
C 
C 
C 
Iron-related parameters/markers of 
erythropoiesis (12) 
C 
C 
C 
C 
C 
C 
C 
RBC smear assessment for sickle cells 
C 
C 
C 
C 
C 
C 
VIT-2763 pharmacokinetic(13) 
C 
VOC episodes/visceral infarctions(14) 
X 
X 
X 
X 
X 
X 
Dispense IMP at site (IWRS) 
X 
X 
X 
X 
Collect, dispense, and inform subjects on 
ASCQ-Me questionnaires(15) 
X 
X 
X 
X 
X 
X 
IMP accountability 
X 
X 
X 
X 
 
 
1 
Any outstanding eligibility criteria (see Section 5.2 and Section 5.3 of Clinical Study Protocol (CSP)) not available during screening to be available before randomisation. 
2 
Body systems to be assessed include general appearance, head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdominal, musculoskeletal, neurological, lymph nodes, and skin. 
3 
Seated systolic and diastolic blood pressure, and pulse, after subject has rested for at least 5 minutes, pre-dose (trough). 
 
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4 
A single 12-lead ECG to be performed at pre-dose (trough) and 2 hours (±30 minutes) post-morning dose. 
5 
Only in females of childbearing potential. Positive urine pregnancy test results need to be confirmed using a serum beta-hCG test. 
6 
Only in females of childbearing potential. 
7 
Urinary dipstick including pH, protein, glucose, ketone, RBCs, and WBCs. Quantitative measurement only if positive dipstick. Urinalysis includes also (at Visits V1, V2, V4, and V6) urinary microalbumin, 
creatinine, and microalbumin/creatinine ratio (spot sample, morning void). 
8 
Haematology panel/RBC indices sampled at pre-dose (trough) include: Hb, reticulocytes (abs, %), RBC count, HCT, MCH, MCV, MCHC, RDW, % hypochromic RBC, CHCM, WBC, neutrophils 
(abs, %), lymphocytes (abs‚ %), monocytes (abs‚ %), eosinophils (abs‚ %), basophils (abs‚ %), and platelets. At screening/Visit V1, only Hb and reticulocytes will be assessed. 
9 
Serum chemistry sampled at pre-dose (trough) includes calcium, sodium, magnesium, potassium, phosphorus, chloride, bicarbonate, blood urea nitrogen, uric acid, creatinine kinase, creatinine, folic 
acid, albumin, total protein, globulin (calculated), alanine transaminase, aspartate transaminase, alkaline phosphatase, glucose, triglycerides, and cholesterol. 
10 
Haemolysis markers sampled at pre-dose (trough) include LDH, free haptoglobin, and direct/total bilirubin (indirectly calculated). 
11 
Endothelial inflammation/dysfunction markers sampled at pre-dose (trough) include hsCRP, IL-1, IL-6, TNF-alpha, sP-selectin, sVCAM-1, xanthine oxidase, and endothelin-1. 
12 
Iron-related parameters/markers of erythropoiesis sampled at pre-dose and 2 hours post- morning dose include total serum iron, serum ferritin, transferrin, TSAT, hepcidin, and erythropoietin. At Visit 
V1, serum ferritin, TSAT, and TIBC will be sampled for exclusion criteria only. 
13 
PK samples are collected on Visit V4 at pre-dose, and 2 hours (±15 minutes), 4 hours (±30 minutes), and 6 hours (±30 minutes) post-dose. 
14 
At Visit V2, the subject will be asked for VOC episodes within the last 8 weeks. At Visits V3, V4, V5, and V6, the subject will be asked for VOC episodes (number of events and pain intensity (NRS: 
0-10) compared to historical VOC episodes) since previous visits. Visceral infarctions will be assessed as per standard of care. 
15 
For more details see the respective visit in Section 8 of CSP. 
Notes: abs=Absolute; ASQ-Me=Adult Sickle Cell Quality of Life Measurement System; C=Central laboratory assessment; CHCM=Corpuscular Hb concentration mean; ECG=Electrocardiogram; EoS=End 
of study; EoT=End of treatment; ET=Early termination; Hb=Haemoglobin; HBsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; hCG=Human chorionic gonadotropin; Hct=Haematocrit; 
HCV=Hepatitis C virus; hsCRP=High sensitivity C-reactive protein; IL=Interleukin; IMP=Investigational medicinal product; IWRS=Interactive web response system; L=Local laboratory assessment; 
LDH=Lactate dehydrogenase; MCH=Mean corpuscular Hb; MCHC=Mean corpuscular Hb concentration; MCV=Mean corpuscular volume; NRS=Numerical rating scale; PK=Pharmacokinetic; 
RBC=Red blood cell; RDW=Red blood cell distribution width; sP=Soluble cell adhesion molecule; TIBC=Total iron-binding capacity; TNF=tumour necrosis factor; TSAT=Transferrin saturation; 
V=Visit; VOC=Vaso-occlusive crises; WBC=White blood cell. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.4 
Sample Size Determination 
 
This is an exploratory Phase 2a study of VIT-2763 in SCD subjects, therefore no formal sample size 
calculations have been conducted. 
2.5 
Randomisation and Blinding 
 
Upon completion of the baseline visit procedures/assessments, it is planned to randomise 24 subjects 
in a 3:3:3:2:1 ratio into 3 VIT-2763 dose groups and 2 placebo groups. 
For randomisation IWRS will be used, a validated centralised procedure that automates the random 
assignment of treatment groups to randomisation numbers. Stratified randomisation (balanced 
allocation across treatment groups) will be used according to genotype (HbS/S - HbS/βT0). 
Subjects eligible for randomisation will receive a randomisation number. Randomised subjects who 
terminate their study participation for any reason regardless of whether the IMP was taken or not, will 
retain their randomisation number. The next subject will be given the next randomisation number. A 
subject can only be randomised once. Randomised subjects who withdraw consent for further follow-up 
cannot be re-screened. Re-screening may be considered at the discretion of the Investigator and in 
consultation with the sponsor at a later point for subjects who fail to meet the protocol eligibility criteria. 
In such a case, the re-screened subject will be allocated a new screening number. 
 
If more than 1 subject in any dose cohort withdraws or drops out between signing informed consent and 
the V6 visit, the subject will be replaced with a number randomization number until at least 5 subjects, 
with no major protocol deviation impacting the primary objective of the trial, per treatment/placebo 
(Cohorts 4a and 4b combined) arm have passed Visit V6. Subjects included to replace subjects who 
withdraw or drop out or with major protocol deviations impacting the primary objective of the trial, will be 
assigned to the same cohort as the subjects they are replacing. 
 
The randomisation schedules, as described in Biostatistics Addendum Subject Randomisation List (BA- 
S) V2.0 dated 16 March 2022, will be generated and maintained by ALMAC Clinical Technologies. The 
schedule and the seed will be sequestered until the study database is locked and the study is unblinded. 
Data will also be unblinded for closed sessions of DSMB meetings. 
 
 
2.5.1 
Interim Analysis 
No interim analysis is planned. 
 
2.5.2 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Committee (DSMB) will oversee the safety and conduct of 
the trial on an ongoing basis. The DSMB will be comprised of medical and statistical representatives. 
The DSMB members will be unblinded. 
 
The DSMB will regularly, but also on an ad-hoc manner as needed, assess the safety information of the 
enrolled subjects, and can provide recommendations to the Sponsor regarding stopping the study or 
discontinuing a treatment arm or otherwise modifying the study design or conduct. 
 
The Sponsor has established a Charter document explaining the working procedures and 
responsibilities of the DSMB. The Charter has been agreed to by the DSMB. 
 
 
 
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2.6 
Study Endpoints 
 
2.6.1 
Primary Endpoint 
• 
Mean change from baseline in haemolysis markers as measured by reduction of indirect bilirubin 
after 8 weeks of treatment. 
 
2.6.2 
Secondary Endpoint(s) 
• 
Mean change from baseline in haemolysis markers as measured by direct and total bilirubin, LDH, 
potassium, Hb and free haptoglobin after 8 weeks of treatment. 
 
• 
Frequency and severity of reported or observed adverse events (AEs) by system organ class (SOC) 
and preferred terms (PTs) using Medical Dictionary for Regulatory Activities (MedDRA) coded 
terms, indicating seriousness criteria and relatedness over 8 weeks of treatment. 
 
2.6.3 
Exploratory Endpoint(s) 
• 
Changes in haemolysis markers as measured by indirect, direct, and total bilirubin, LDH, potassium, 
Hb, and free haptoglobin, from baseline after 2, 4, and 6 weeks of treatment and 4 weeks after end 
of treatment (EoT). 
 
• 
Frequency and severity of reported or observed AEs by SOC and PTs using MedDRA coded terms, 
indicating seriousness criteria and relatedness up to 4 weeks after EoT. 
 
• 
Changes in clinical laboratory safety tests (serum biochemistry, safety haematology, and urinalysis) 
from baseline, 12-lead ECG, physical examination findings, vital signs (blood pressure, pulse rate), 
and haematological changes due to iron-restricted erythropoiesis after 2, 4, 6, and 8 weeks of 
treatment and 4 weeks after EoT. 
 
• 
Changes in haematological indices, including Hb concentration, RBC count, Hct, MCV, MCH, 
MCHC, CHCM, RBC distribution width, WBC analyses including differential WBC counts, platelet 
and reticulocyte counts, percentage reticulocytes, percentage hypochromic microcytic RBCs (RBC 
volume versus Hb scatterplot analysis), from baseline after 2, 4, 6, and 8 weeks of treatment and 
4 weeks after EoT. 
 
• 
Changes in blood inflammatory markers as measured by high sensitivity C-reactive protein, 
interleukin 1 and interleukin 6, tumour necrosis factor alpha, soluble vascular cell adhesion molecule 
1, endothelin-1, soluble platelet-selectin, and xanthine oxidase, from baseline after 2, 4, 6, and 8 
weeks of treatment and 4 weeks after EoT. 
 
• 
Assessment of iron-related parameters and markers of erythropoiesis: total serum iron, serum 
ferritin, serum transferrin, calculated TSAT, hepcidin, and erythropoietin, from baseline after 2, 4, 6, 
and 8 weeks of treatment and 4 weeks after EoT. 
 
• 
VIT-2763 PK parameters (maximum concentration (Cmax), clearance, distribution volume, area 
under the curve (AUC)). Sparse sampling for determination of VIT 2763 plasma concentration 
following multiple dosing will be obtained from pre-dose trough to 2 hours, 4 hours and 6 hours post- 
morning dose at study Visit V4. A population PK approach will be applied to estimate PK parameters. 
 
 
 
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• 
Change in patient reported outcomes using ASCQ-Me from baseline after 2, 4, 6 and 8 weeks of 
treatment. 
 
• 
Changes in abnormal RBCs (sickling) assessed by peripheral blood smear from baseline after 2, 4, 
6 and 8 weeks of treatment and 4 weeks after EoT. 
 
• 
Number of VOC episodes and visceral infarctions over 8 weeks of treatment and 4 weeks after EoT. 
 
3 
HYPOTHESES AND DECISION RULES 
 
3.1 
Statistical Hypotheses 
Due to the exploratory nature of this trial, no formal power calculations will be performed and therefore 
no statistical hypothesis testing has been defined. 
3.2 
Statistical Decision Rules 
There is no formal statistical decision rule for this study, and all analyses are considered descriptive. 
 
4 
ANALYSIS SETS 
 
In accordance with ICH E3 [1] and E9 [2] guidelines, the analysis sets are defined as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.1 
Safety Set 
 
The safety set consists of all randomised subjects under protocol version 3.0 or higher who have taken 
at least one dose of IMP. The subjects in the safety set will be analysed based on the treatment they 
received, regardless of randomisation. 
The actual treatment is determined as the highest dose dispensed during the study for subjects who 
have taken at least one dose of IMP. More precisely: 
- 
If the highest VIT-2763 kit dosage dispensed during the study is 30 mg, then the actual 
treatment will be “Cohort 1: VIT-2763 60 mg BID”. 
- 
If at least one VIT-2763 kit of 60 mg dosage is dispensed during the study AND the maximum 
number of VIT-2763 kits dispensed during a visit is ≤3, then the actual treatment will be 
“Cohort 2: VIT-2763 120 mg BID”. 
- 
If at least one VIT-2763 kit of 60 mg dosage is dispensed during the study AND the maximum 
number of VIT-2763 kits dispensed during a visit is 4, then the actual treatment will be “Cohort 
3: VIT-2763 120 mg TID”. 
- 
If only placebo kits are dispensed during the study, then the actual treatment will be “Cohort 
4: Placebo”. 
4.2 
Intent-To-Treat Population 
 
The Intent-To-Treat (ITT) population consists of all subjects who are randomly assigned to a treatment 
group under protocol version 3.0 or higher. The subjects will be analysed based on the treatment they 
were randomised to. 
4.3 
Per-Protocol Set 
 
The per-protocol set (PPS) consists of all subjects who, in addition to the ITT criteria, completed the 
study and had no major protocol deviations impacting the primary objective of the trial (as defined in the 
protocol deviation plan and finalised during the blind data review meeting). Subjects with a study drug 
compliance (see Section 5.6) lower than 80% of prescribed doses or upper than 110% of prescribed 
doses will be considered as major deviations. 
 
Subjects who did not complete the study as per protocol as indicated in study termination CRF form or 
who discontinued the treatment prematurely as recorded in treatment termination form will be 
considered as not having completed the study and will then be excluded from PPS in addition to subjects 
with major protocol deviations. The subjects will be analysed based on the treatment they were 
randomised to. 
4.3.1 
Protocol deviations 
All subjects with major protocol deviations impacting the primary objective as defined in the latest 
protocol deviations plan will be excluded from PPS. They will be reviewed during the blind data review 
meeting. 
4.4 
Other Analysis Sets 
 
For the purposes of subjects’ disposition tables and listings an additional analysis population is defined: 
 
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• 
Randomized population: all subjects who are randomly assigned to any treatment group under 
protocol version 3.0 or higher. 
• 
Enrolled population: all subjects who have signed informed consent on any protocol version. 
 
• 
Advanced Intent-To-Treat Set: The advanced ITT (aITT) population consists of all subjects 
who are randomly assigned to any treatment group under any protocol version. The subjects 
will be presented based on the treatment they were randomised to. 
The following analysis set may also be defined: 
 
• 
Modified Intent-To-Treat Set (optional): The modified ITT (mITT) will consist of all subjects of 
ITT with no major Coronavirus Disease of 2019 (COVID-19) related protocol deviation (as 
defined in the protocol deviation plan and finalised during the blind data review meeting). This 
population may be used depending of the number of subjects with major COVID-19 related- 
protocol deviations and the potential impact on the analyses. Decision to use or not this analysis 
set for sensitivity analyses will be taken during the blind data review meeting and it will be 
documented in the blind data review minutes before unblinding. 
The analysis population for PK will be described in a separate document. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5 
DESCRIPTION OF THE STATISTICAL ANALYSIS 
 
This section describes the statistical analyses, presentation of the results, and the study 
endpoints/measures that will be collected and/or derived during the study at the time points specified in 
the Schedule of Events (see Section 2.3). 
5.1 
General Considerations 
The software used for all summary statistics and statistical analyses will be SAS® Version 9.4 or later 
(SAS Institute, Inc.). 
MedDRA [Version 24.0] and the current version of the World Health Organization Drug (WHO Drug) 
dictionary [Mar2021 B3] will be used for coding. 
Derived datasets will be generated by the Labcorp/Covance Biostatistics and Programming Department 
from the Clinical Interchange Standard Consortium (CDISC) Study Data Tabulation Model (SDTM 
[version 3.3]) datasets in accordance with CDISC ADaM version 2.1 and the ADaM Implementation 
Guide v1.1. 
 
All blinded study team members will remain blinded to the randomisation arms until complete cleaning 
of the data and blind data review meeting. For the final analysis after final database lock the blinded 
statistical team will be unblinded according to the project specific unblinding plan and following sponsor 
approval. This does not concern the independent unblinded statistician responsible for the DSMB report 
preparation. 
 
The final versions of the SAP (along with TFL shells documents) will be filed at trial completion in the 
electronic trial master file (eTMF) study documentation and eTMF plan will be followed for biostatistics 
documents filing. 
The data collected for the one randomised subject under protocol version 2.0 will be listed only. 
 
5.1.1 
Standard Descriptive Statistics 
Continuous Variables 
 
Unless specified otherwise, the following standard descriptive statistics by treatment group will be 
obtained for continuous variables: number, mean, standard deviation, median, minimum and maximum. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. Mean, median, and quartiles will be displayed to one more decimal place than 
collected value and standard deviation will be displayed to two more decimal place than the collected 
value. 
Categorical Variables 
 
Unless specified otherwise, the following standard descriptive statistics by treatment group will be 
presented for categorical values: total number of available values and missing values, number of values 
in each category and the corresponding percentage of the total number of values available will be 
calculated. The percentages will be displayed using one decimal. 
 
 
 
 
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Percentages will be calculated using the total subjects per randomised treatment group, except for 
outputs in the PPS and the safety set, where percentages are based on the total subjects per actual 
treatment group. 
5.1.2 
Definition of Baseline 
The baseline value for a variable will be defined as the last available (non-missing) value before the first 
administration of study drug. Study day 1 is defined as the day of the first study drug administration. For 
analysis relative day, if considered date is before the first study drug administration date, then analysis 
relative day will be computed as date minus first study drug administration date, otherwise, it will be 
computed as date minus first study drug administration date + 1. 
5.1.3 
Planned Assessment Windows 
Table 4 describes the analysis visit windows (i.e. the relative study day ranges) to be applied to the 
assessments or sample collections dates to determine the analysis visit. 
 
 
Table 4 Planned and Analysis visits Windows 
Analysis Visit 
Label 
Target Day 
Planned Visit 
Window 
(Protocol 
Specified) 
Analysis Visit Window 
Baseline 
1 
-- 
Before first IMP intake 
Visit 3 (Day 14) 
14 
± 2 days 
From Day 2 to Day 21 
Visit 4 (Day 28) 
28 
± 4 days 
From Day 22 to Day 35 
Visit 5 (Day 42) 
42 
± 4 days 
From Day 36 to Day 49 
Visit 6 (Day 56) 
56 
± 4 days 
From Day 50 to Day 70 
Visit 7 (Day 84) 
84 
± 4days 
From Day 71 and higher 
 
 
Assessments (planned and unscheduled) will be re-mapped into the analysis windows. For a parameter, 
the following rules will be applied: 
- 
if several assessments fall into the same analysis window, the closest to the target day will 
be considered for the analysis. 
- 
When there are 2 assessments closest to the target day, the latest one will be considered for 
the analysis. 
- 
if several assessments are available at the selected day, the average of the values will be 
taken. 
In all statistical tables by visit, the analysis visits will be considered. In listings presenting data by visit, 
both nominal and analysis visits will be provided. 
 
 
 
 
 
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5.1.4 
Treatment Start/Stop Dates 
Treatment start date is collected at baseline visit in the study treatment administration form of the CRF. 
If there is no treatment date available in this CRF page, date of randomisation will be imputed as the 
start of treatment date, if it is known that the subject received study drug (information recorded in the 
study treatment administration page or in patient supply accountability log page of the CRF or any 
information from monitoring). 
Treatment stop date is collected in the treatment termination form of the CRF. If the date of last intake 
of study medication is missing in this form, the latest start date from study treatment administration page 
(CRF does not record the end date) would be used to impute end of treatment date. 
5.1.5 
Tables and Listings Presentation 
For all analyses, summary statistics will be tabulated for the 5 following treatment groups as presented 
in Table 5 and corresponding to the 3 VIT-2763 cohorts, the pooling of the 2 placebo cohorts and the 
pooling of all VIT-2763 subjects. 
Table 5 Treatment groups labels 
 
 
Treatment Groups Labels 
Treatment Groups Short Labels 
Table order1 
Cohort 1: VIT-2763 60 mg BID 
VIT-2763 60 mg BID 
1 
Cohort 2: VIT-2763 120 mg BID 
VIT-2763 120 mg BID 
2 
Cohort 3: VIT-2763 120 mg TID 
VIT-2763 120 mg TID 
3 
Cohorts 1-2-3: All VIT-2763 
All VIT-2763 
4 
Cohort 4a/4b: Placebo 
Placebo 
5 
1 From left to right in statistical tables 
 
 
Shorts labels will be used in tables while entire labels will be used in listings and figures for both 
randomized and actual treatment arms. 
The listings will display all the data contained in the CRF, including the screen failure patients collected 
information if appropriate. The listings will be ordered by dose (from lowest to highest) and for all subjects 
receiving placebo (Cohorts 4a and 4b combined) and subject number. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.1.6 
Analysis Populations 
The safety set will be used for all safety analyses. 
 
The safety set excluding subjects who did not received any dose of VIT-2763 will be used for PK 
concentration summary statistics analyses. PK concentration listings will be done on the ITT. 
The ITT population will be used for the analysis of the primary and secondary endpoints related to 
haemolysis markers. These analyses will also be repeated on the PPS if it differs. 
 
All exploratory analyses will be performed on the ITT and will be repeated on the PPS if it differs and on 
the mITT (except for ASCQ-Me, VOC and visceral infarctions endpoints) if applicable. 
 
The mITT may be used depending on the number of subjects with major COVID-19 protocol deviations 
and the impact on analyses. The decision to use or not this population will be made prior to unblinding. 
In case the decision is to use mITT, all primary, secondary and exploratory endpoints tables will be 
repeated on mITT. 
Demographics and baseline characteristics will be summarised on the safety set, ITT, and the PPS (and 
mITT if applicable). Medical history and concurrent medical conditions, prior and concomitant 
medications and procedure and study drug exposure and compliance will be described on the ITT and 
the PPS. 
Only sets with different attributes will be presented. The enrolled or aITT populations will be used as 
applicable for listings except specific safety listings to be generated on safety set (see Section 5.8.1), 
5.1.7 
Pooling of Sites/Country 
Not applicable for this study 
 
5.1.8 
Analysis of Subgroups 
Not applicable for this study 
 
5.1.9 
Methods for Handling and Imputation of Missing Data 
Missing and/or incomplete dates/times for AEs will be imputed in a manner resulting in the earliest onset 
or the longest duration during the treatment period, taking additionally into account that the start 
date/time should not be after the stop date/time. Stop dates/times will not be imputed if the AE is 
ongoing. This will be done as follows: 
For a missing/incomplete start date/time the minimum of the following will be imputed: 
 
• 
The maximum of the earliest possible start date/time and the date/time of first study medication 
administration. 
• 
The latest possible start date/time. 
 
• 
The latest possible stop date/time. 
 
For a missing/incomplete stop date/time the maximum of the following will be imputed: 
 
• 
The minimum of the latest possible stop date/time and the date/time of last study medication 
administration. 
 
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• 
The earliest possible stop date/time. 
 
• 
The earliest possible start date/time. 
 
The earliest/latest possible date is defined as: 
 
• 
The date itself if it is complete. 
 
• 
The date of the first/last day of the month, if month and year are available but day is missing. 
 
• 
The date of the first/last day of the year, if year is available but day and month are missing. A 
very early/late date, e.g., 01JAN2000 (01JAN2100), if the date is completely missing. 
 
For medications and procedures, imputation of missing or partial dates will be done to identify 
concomitant medications and procedures as follows: 
• 
If the start date of the medication/procedure is unknown (i.e., complete missing date), the worst- 
case scenario will be assumed. The medication/procedure will be considered as both a prior 
medication/procedure and a concomitant medication/procedure. 
• 
If the month and the day of the start date of the medication/procedure are missing, the month 
and the day will be imputed to January, 1st of the year specified. 
• 
If the day of the start date of the medication/procedure is missing, the day will be imputed to the 
first day of the month specified. 
• 
If the end date is unknown (i.e., missing), the date will be kept as missing however the 
medication/procedure will be considered concomitant. 
• 
If the month and the day of the end date of the medication/procedure are missing, the month 
and the day will be imputed to December, 31st of the year specified. 
• 
If the day of the end date of the medication/procedure is missing, the day will be imputed to the 
last day of the month specified. 
For treatment group dose intake day missing (or Unknown), the day will be imputed to the end day of 
the previous visit. 
The original incomplete, missing or partial dates and corresponding imputed dates will be presented in 
the listings. 
 
During the conduct of the study, a non-neglectable number of missing data for the primary endpoint 
(indirect bilirubin) have been observed at baseline and Visit 6. Sensitivity analyses will be performed for 
the primary endpoint with different imputations for the missing data. Only missing data due to 
haemolysed samples will be imputed as they can be considered as missing at random while missing 
data because of withdrawal of the study cannot. Imputations will be as following: 
• 
Missing baseline data will be imputed with the median of the non-missing baseline indirect 
bilirubin of the pooled subjects of all cohorts. 
• 
For missing data at visit 6, 3 types of imputation will be performed: the minimal value, the mean 
and the maximal value within the Cohort of the subject. 
 
 
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5.2 
Subject Disposition 
The subject disposition data will be summarised as follows: 
 
Number of subjects screened will be summarised overall. Number and percentage of subjects re- 
screened, will be also summarised overall along with number and percentage of subjects that failed 
screening with the reason of screen failure. This will be tabulated on the enrolled population. 
Number and percentage of subjects randomised, treated, receiving a different treatment than they were 
randomised to and subjects that were randomised but not treated, will be summarised on the ITT by 
treatment group as described in Table 5. 
Subjects included and excluded from safety set, ITT, PPS and mITT (in case applicable) with the reason 
of exclusion from any analysis set will be summarised and listed on the ITT. Subjects discontinued from 
treatment with reasons and who did not complete the study with reasons for discontinuations will be 
summarised on the ITT and listed on the aITT. Additionally, the time on study in days will be described 
in this table. It will be computed as the number of days from the randomisation date to the last known 
date of the subject in the study. 
 
 
The following data will be presented in the listings: 
 
• 
Date of informed consent. 
 
• 
Date of randomisation. 
 
• 
Date of completion/discontinuation from study 
 
• 
Date of first and last intake of study medication. 
 
Classification of protocol deviations into major and minor sponsor’s definitions will be applied as per 
Project Specific Protocol Deviation Category List. The protocol deviations will be identified for all 
subjects by either site monitoring, medical review process or programming. The classification will be 
confirmed prior to database lock i.e. they will be classified prior to unblinding of treatment. 
The number of unique subjects with at least one major protocol deviation as well as the number of 
subjects in each major protocol deviation category will be presented by default descriptive summary 
statistics on the ITT. 
All protocol deviations will be listed on the aITT, including the nature of the protocol deviation, major or 
minor and their relation with Covid-19. 
5.3 
Demographics and Baseline Subject Characteristics 
The following subject demographic data collected on the Demographics CRF page will be summarised: 
• 
Sex 
• 
Age (years) 
• 
Age in categories for adults: <18/18-29/30-49/50-65/ >65 years 
• 
Race: American Indian or Alaska Native/Asian/Black or African American/Native Hawaiian or 
Other Pacific Islander/White/Not Reported/Unknown, Other, Multiple 
 
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• 
Ethnicity: Hispanic or Latino/Not Hispanic or Latino/Not Reported/Unknown 
The following baseline characteristics collected at screening or at baseline will be tabulated: 
• 
Height (cm), body weight (kg), body mass index (BMI) (kg/m²) [derived as body weight / 
(height)2], BMI in categories for adults: <18.5/ 18.5 to <25/ 25 to <30/ ≥30 kg/m² 
Heights collected in inches will be converted in cm for analysis (multiplied by 2.54). Body weights 
collected in lb will be converted in kg for analysis (multiplied by 0.4536). 
• 
Aetiology of SCD collected on the Aetiology and Clinical Presentation CRF page and including 
underlying genotype (HbS/S or HbS/βT0), time between sickle cell disease diagnosis and 
informed consent (months) (derived as date of written informed consent obtained - date of sickle 
cell disease diagnosis / (365.25/12), number of VOC episodes within 12 months prior to 
screening, time between last hospitalization due to SCD and informed consent (months) (date 
of written informed consent obtained-derived as last hospitalization due to SCD/(365.25/12)). 
• 
Visceral infarctions within the last 8 weeks before baseline (yes/no), number of visceral 
infarctions within the last 8 weeks before baseline, VOC episodes within the last 8 weeks before 
baseline (Yes/No), number of VOC episodes within the last 8 weeks before baseline and 
maximum duration of VOC episodes and maximum pain intensity in categories (0 = No pain, 1- 
3 = Mild pain, 4-6 = Moderate pain, 7-10 = Severe pain). 
The Demographics and baseline characteristics will be summarised for the ITT, safety set, PPS and 
mITT (if applicable). In case some analyses sets are identical, summary statistics will not be repeated. 
Listings will be provided on the Enrolled Population for demographics characteristics and on aITT for 
baseline characteristics. 
 
Serum virology parameters (HbsAG, HBV, HCV, HIV) and serum pregnancy test will be listed at baseline 
on aITT population. 
 
5.4 
Medical History and Concurrent Medical Conditions 
Medical history will consist of significant conditions or diseases that stopped at or before screening. 
Ongoing medical conditions recorded in medical history will be considered as concurrent medical 
conditions. Medical history and concurrent medical conditions will be coded using MedDRA [Version 
24.0]. All medical history and associated concurrent medication condition will be listed on aITT, and the 
number and percentage of subjects with any medical history will be summarised by SOC and PT on the 
ITT and PPS. 
The SOC and PTs are to be sorted by decreasing order frequency of SOC and PTs in the overall 
subjects receiving VIT-2763. In case of equal frequency of SOC or PT, alphabetical order will be used. 
Subjects are included only once in each SOC and PT, even if they experienced multiple events in that 
SOC or PT. 
 
 
 
 
 
 
 
 
 
 
 
 
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5.5 
Prior and Concomitant Medications and Procedures 
Medications: 
 
All medications will be coded using the current version of the World Health Organization Drug (WHO 
Drug) dictionary [Mar2021 B3]. 
Prior medications will be defined as all medications taken before the first dose of study drug with a stop 
date prior to the first dose of study drug. 
Concomitant medications will be defined as all medications with a start date before, on or after the first 
dose of study drug and with a stop date on or after the first dose of study drug or with a missing stop 
date. 
Prior and concomitant medication will be summarised by number and percentage of subjects by 
treatment group as defined in Table 5- on ITT and PPS. The summary tables will be sorted by decreasing 
frequency of overall subjects receiving VIT-2763 and decreasing frequency of drug or procedure name 
in a given drug class (therapeutic subgroup [2nd level of the anatomical therapeutic chemical (ATC) 
classification], chemical subgroup [4th level of the ATC classification] and Preferred Name). In case of 
equal frequency regarding drug or procedure class, alphabetical order will be used. A same medication 
or procedure during the study for one subject will be counted once. 
A listing with all prior and concomitant medications will be provided including the flag for prior or 
concomitant on Enrolled population. 
Procedures: 
 
Prior procedures will be defined as all procedures performed before the first dose of study drug with a 
stop date prior to the first dose of study drug. 
Concomitant procedures will be defined as all procedures with a stop date on or after the first dose of 
study drug or with a missing stop date. 
All procedures will be coded using the MedDRA 24.0. 
 
A listing with all prior and concomitant procedures will be provided including the flag for prior or 
concomitant on Enrolled population. Procedures will not be tabulated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.6 
Study Drug Exposure and Compliance 
The following durations of study drugs (including VIT-2763 and Placebo) will be computed in days: 
 
Duration of study drug (in days) = Treatment stop date – Treatment start date + 1 
Treatment start and stop dates will be derived as defined in Section 5.1.4. 
The total amount of VIT-2763 taken in mg will be calculated for each subject from the difference between 
the amount of VIT-2763 dispensed in mg and the amount of VIT-2763 returned in mg. It will be compared 
to the amount expected to be taken for subjects randomised in a VIT-2763 cohort to calculate the 
percentage compliance to VIT-2763. Derivation details are provided below. 
Total amount of VIT-2763 (mg) = 30*(Number of VIT-2763 30 mg capsules dispensed - Number of 
VIT-2763 30 mg capsules returned) + 60*(Number of VIT-2763 60 mg capsules dispensed - Number of 
VIT-2763 60 mg capsules returned). 
The total amount of VIT-2763 taken will be computed for all randomised subjects and will be equal to 0 
if no dispensation error occurred in Placebo cohort. In case of miss allocation for a patient receiving 
VIT-2763 instead of Placebo, the amount will be counted for VIT-2763. 
Expected amount of VIT-2763 (mg) for cohort 1 = 120*(Duration of study drug in days -1) + 60. 
Expected amount of VIT-2763 (mg) for cohort 2 = 240*(Duration of study drug in days -1) + 120. 
Expected amount of VIT-2763 (mg) for cohort 3 = 360*(Duration of study drug in days -1) + 120. 
VIT-2763 compliance (%) = (Total amount of VIT-2763 (mg) / Expected amount of VIT-2763 (mg)) for 
cohort 1-2-3 *100. 
 
 
The total number of capsules of study drug (VIT-2763 or Placebo) taken will be calculated for each 
subject from the difference between the total number of capsules dispensed and the total number of 
capsules returned. It will be compared to the expected number of capsules to be taken by subject to 
calculate the percentage compliance to study drug. 
Total amount of study drug (number of capsules) = Number of capsules dispensed - Number of 
capsules returned 
Expected amount of study drug (number of capsules) for cohorts 1, 2, 4a = 4 * (Duration of study 
drug in days -1) +2 
Expected amount of study drug (number of capsules) for cohort 3, 4b = 6 * (Duration of study drug 
in days -1) +2 
Study drug compliance (%) = (Total number of capsules taken / Expected number of capsules taken) 
*100 
 
Duration of study drug, total and expected amount of VIT-2763 and total and expected amount of study 
drug in terms of number of capsules taken will be summarised using standard descriptive statistics for 
continuous variables on the ITT population and the PPS if they differ. 
 
 
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The calculated percentages of compliance will be categorized as: 
• 
< 80% compliance 
• 
≥ 80% to ≤ 110% compliance 
• 
> 110% compliance 
 
Compliances for VIT-2763 and for study drug will be summarized for the ITT population and the PPS if 
they differ as follows: 
• 
Percent compliance presented by default summary statistics for continuous variables. 
• 
Number and percentage of subjects within each of the compliance categories. 
 
 
The number and percentage of subjects who had at least one incidence of a change/interruption to their 
dosing will be summarised along with reasons of dose change/interruption for the ITT population and 
the PPS if they differ. 
 
A listing of exposure data will also be presented together with compliance on ITT. 
 
5.7 
Efficacy Analyses 
 
5.7.1 
Primary Efficacy Analysis 
The changes in indirect bilirubin from baseline to Visit 6 (after 8 weeks of treatment) will be summarised 
using standard descriptive statistics for continuous variables with 95% confidence interval (CI) of the 
mean on the ITT population by randomised treatment groups as described in Table 5. 
 
Analysis visit windows will be considered for the primary efficacy analysis (see Section 5.1.2). The 
analysis will be repeated on the PPS by actual treatment group and on mITT if applicable. 
 
Three sensitivity analyses will be run on the ITT population as the primary analysis, with the imputation 
of the missing data due to haemolised samples at baseline or Visit 6 (see section 5.1.9). Analyses will 
be: 
 
• 
Imputation of missing baseline with the median of the non-missing baseline of the pooled 
subjects. Imputation of Visit 6 missing data using the minimal value within the same cohort. 
 
• 
Imputation of missing baseline with the median of the non-missing baseline of the pooled 
subjects. Imputation of Visit 6 missing data using mean value within the same cohort. 
 
• 
Imputation of missing baseline with the median of the non-missing baseline of the pooled 
subjects. Imputation of Visit 6 missing data using maximum value within the same cohort. 
 
5.7.2 
Secondary Efficacy Analysis 
Summaries of change from baseline values will be reported at Visit 6 (after 8 weeks of treatment) for 
direct and total bilirubin, LDH, potassium, Hb and free haptoglobin using standard descriptive statistics 
for continuous variables with 95% CI of the mean by randomised treatment groups as described in Table 
5 on the ITT population. 
The analysis will be repeated on the PPS as well by actual treatment group and on mITT if applicable. 
 
 
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5.7.3 
Exploratory Efficacy Analysis 
Summaries of values and changes from baseline for each haemolysis marker (indirect, direct and total 
bilirubin, LDH, potassium, Hb and free haptoglobin) will be reported for each visit using standard 
descriptive statistics for continuous variables on the ITT population by randomised treatment groups as 
described in Table 5. Analyses will be repeated on the PPS by actual treatment group and on mITT if 
applicable. 
 
Summaries of absolute and percent changes from baseline for indirect bilirubin, CHCM and MCHC will 
also be reported for each visit using the same approach. 
 
Number and percentage of subjects who had at least 20% reduction in Indirect Bilirubin from baseline 
will be summarized at each post-baseline visit. 
 
Number and percentage of subjects who had at least 5% reduction in CHCM and MCHC from baseline 
will be summarized at each post-baseline visit. 
 
Analyses will be repeated on the PPS by actual treatment group and on mITT if applicable. 
For each haemolysis marker, 3 figures will be provided: 
• 
Line plots by subject: individual marker values (y-axis) in function of target visit day (x-axis) 
joined by subject and plotted in separate windows for the randomised cohorts (1, 2, 3, 4). 
 
• 
Line plots by subject in log scale: same plot as previous with individual marker values 
displayed in a log10 scale (y-axis) 
 
• 
Means with 95% CIs of changes from baseline marker values for the 4 randomised cohorts 
(y-axis) in function of target visit day (x-axis). Means will be joined by group. 
 
All graphics will be done on the ITT. 
 
5.8 
Safety Analyses 
 
Safety evaluations will be performed using the safety set and analysed according to the analysis 
methods described in 5.1.1 unless specified otherwise. Missing values will not be imputed unless stated 
otherwise. 
5.8.1 
Adverse Events 
AE data are collected from the time that ICF has been signed. 
 
A treatment-emergent adverse event (TEAE) is defined as an AE that occurred or increased in severity 
on the same date or after the first dose of study medication. 
A serious TEAE is defined as a serious adverse event (SAE) occurring or increasing in severity on the 
same date or after the first dose of study medication. An AE will be classified as related to study 
medication if the causality was recorded as certain, probable/likely and possible. An AE will be classified 
as unrelated to study medication if it was recorded as unlikely and unrelated. Additionally, AEs that have 
missing causality (after data querying) will be assumed to be related to study medication. 
 
 
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An AE leading to study discontinuation will be defined as an AE where the reason for study withdrawal 
was recorded as being due to this AE on the Study Termination CRF page or the response to Other 
Action taken on the Adverse Events CRF page, was recorded as early study termination. 
An AE leading to treatment discontinuation is defined as an AE where the reason for treatment 
discontinuation was recorded as being due to this AE on the Treatment Termination CRF page or the 
action taken with study drug of the event was recorded as drug withdrawn on the Adverse Events CRF 
page. 
AEs will be reported on a per-subject basis and per-event. On a per-subject basis, subjects with more 
than one AE overall or within a particular SOC/PT will be counted only once for that SOC/PT or overall. 
On a per-event basis (event counts), all severities of a same AE will be counted as only 1 AE. As, in 
CRF, every change in severity of a particular AE is recorded as a new AE log line and with a new AE 
number (the previous AE is reported with a resolved outcome and end date specified as the date the 
previous grade ended) a AE group number will be derived at time of analysis (regrouping all severities 
of a same AE) using the following rule: 
• 
Any AE record with a start date on the day or 1 day after the stop date of another AE record of 
the same PT will be considered as a continuation of the previous AE and will have the same AE 
group number as the previous log line. AE group numbers with more than one record overall or 
within a particular SOC/PT will be counted as only 1 AE for that SOC/PT or overall in tables 
presenting AEs counts. 
The imputation methods for completely or partially missing dates of AEs described in Section 5.1.9 will 
only be used to derive treatment emergence flag and to determine the day of the event relative to the 
first administration of study medication. 
Only TEAEs will be tabulated. AEs that occurred during the study but before first IMP intake will be only 
listed on the Enrolled population. 
 
The overall summary of TEAEs table will include the counts and percentage of subjects with at least 1 
TEAE and the number of events with each of the following, tabulated on actual treatment: 
• 
Any TEAEs 
 
• 
Any TEAEs of severity ≥ 3 
 
• 
Any TEAEs related to study medication 
 
• 
Any TEAEs of severity ≥ 3 related to study medication 
 
• 
Any TEAEs leading to discontinuation of study medication 
 
• 
Any TEAEs leading to study discontinuation 
 
• 
Any serious TEAEs 
 
• 
Any serious TEAEs related to study medication 
 
• 
Any TEAEs leading to death (outcome “fatal”) 
 
• 
Any TEAEs leading to death related to study medication 
 
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The number and percentage of subjects reporting each TEAE and the count of number of events will be 
summarized by SOC and PT for the following types of TEAEs: 
• 
All TEAEs 
• 
TEAEs related to study medication 
• 
TEAEs of severity ≥ 3 related to study medication 
• 
Serious TEAEs 
• 
TEAEs by maximum severity 
• 
TEAEs by relationship to study medication 
The SOC and PTs are to be sorted by decreasing order frequency of SOC and PTs in the overall 
subjects receiving VIT-2763. 
 
For summaries by maximum severity, subjects with multiple TEAEs within a particular SOC/PT will be 
counted under the category of their most severe TEAE within that SOC/PT. TEAEs with missing severity 
will be counted in a missing category. 
Listings of all AEs, all SAEs, all AEs leading to death, all AEs leading to treatment discontinuation, all 
AEs leading to study discontinuation and all AEs related to Study Drug with flag for AE within the 
treatment emergent period will be provided including relative day and duration of AE. Listings of all 
SAEs, all AEs leading to death and all AEs leading to treatment discontinuation will be specifically 
provided on safety set. Listings of all AEs will be provide on Enrolled population. Listings on all AEs 
leading to study discontinuation and all AEs related to Study Drug will be provided on the aITT. 
 
 
Secondary Safety Endpoint 
 
Secondary safety endpoint is the frequency and severity of reported or observed AEs by SOC and PTs 
using MedDRA coded terms, indicating seriousness criteria and relatedness over 8 weeks of treatment. 
 
All TEAEs with a start date in the 88 days (corresponding to the target day 84 of the end of treatment 
visit plus the 4 days of visit window allowed in protocol) will be selected for this analysis. If missing start 
date, imputation method described in Section 5.1.9 will apply. 
 
The number and percentage of subjects and the count of number of events reported in the 60 days after 
first dose of study treatment will be summarized by SOC and PT for the following types of TEAEs: 
• 
All TEAEs 
• 
TEAEs related to study medication 
• 
Serious TEAEs 
• 
TEAEs by maximum severity 
The SOC and PTs are to be sorted by decreasing order frequency of SOC and PTs in the overall 
subjects receiving VIT-2763). 
 
 
 
 
 
 
 
 
 
 
 
 
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5.8.2 
Clinical Laboratory Evaluations 
The list of all protocol specified clinical laboratory safety tests (serum biochemistry, safety haematology 
and urinalysis) is given in Appendix A Table 6. Laboratory safety tests will be performed at each study 
visit in accordance with the Schedule of Events in Section 2.3. For tabulations, analysis windows (see 
Section 5.1.2) are considered for each visit. 
Clinical laboratory tests are planned to be performed by central laboratory. However, in case of 
pandemic (e.g., COVID-19) related restriction and impossibility of sample shipment, or inability of subject 
to visit the site or inform the Medical Monitor of the study, the laboratory assessments may be performed 
in a local laboratory at site or near to subject’s home. If any, the total number of values tabulated 
provided from a local laboratory will be indicated in the footnote of tables. 
All laboratory data will be reported in standard international (SI) units. All quantitative values for 
haematology and serum biochemistry parameters at each assessed visit will be compared with the 
relevant reference range in SI and categorized as: 
o 
Low: Below the lower limit of the reference range. 
o 
Normal: Within the reference range (upper and lower limits included). 
o 
High: Above the upper limit of the reference range. 
 
 
For analysis purposes, values preceded by a “<” or a “>” sign (i.e. those below or above the limits of 
quantification) will be considered equal to the lower or upper limit of quantification, respectively. 
 
 
For all haematology and serum biochemistry parameters displayed in Appendix A Table 6, descriptive 
statistics will be performed on a continuous scale for the values by visit (from baseline) and for changes 
from baseline by post-baseline visit for actual treatment groups on the safety set. This analysis will be 
repeated on the ITT, PPS and mITT if applicable (see Section 4.4 for the mITT definition). Urinalysis 
results will only be listed on the aITT. Abnormal haematology and serum biochemistry results (defined 
as results below or above reference range) will also be listed separately on the safety set. 
The number and percentage of subjects within each categorized shift relative to the reference range 
(low, normal and high) at baseline compared to each post-baseline visit for haematology and serum 
chemistry will be tabulated by actual treatment groups on the safety set. Subject with missing values will 
be classified in a missing category. 
All laboratory results (serum biochemistry, safety haematology and urinalysis) will be listed, including all 
unscheduled visits for the aITT. 
In addition, listings will be provided for urine Pregnancy Test and for hemoglobin local laboratories 
measurements. 
 
 
 
 
 
 
 
 
 
 
 
 
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5.8.3 
Electrocardiogram (ECG) Evaluations 
PR interval (ms), QRS duration (ms), QT interval (ms), RR interval (ms), QTcF (ms) interval and 
ventricular rate (bpm) will be evaluated at each visit at pre-dose and 2 hours (±30 minutes) post-morning 
dose. 
 
QT corrected using Fridericia formula is defined as: 
 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄(𝑚𝑚𝑚𝑚) = 𝑄𝑄𝑄𝑄(𝑚𝑚𝑚𝑚)/3√𝑅𝑅𝑅𝑅 (𝑚𝑚𝑚𝑚) 
 
Pre-dose and 2 hours post morning dose values will be described by visit from baseline as well as 
changes from baseline (pre first dose measures) to each post baseline measures at pre-dose and at 2 
hours post morning dose for all parameters by actual treatment groups on the safety set. For tabulations, 
analysis windows (see Section 5.1.3) will be considered for each visit but no window will be considered 
for the time-points (pre or 2 hours post-dose). 
For each ECG parameter, the following figure will be provided: individual values (y-axis) in function of 
target visit day and time-point (nominal x-axis scale: “D1”, “D1+2h etc…) joined by subject and plotted 
in separate windows for the randomised cohorts (1, 2, 3, 4) and for overall subjects randomised in VIT- 
2763 (5-window panel plot). All graphics will be done on the Safety set. 
 
All ECG parameters results will be listed with changes from baseline as well as overall ECG 
interpretation on the aITT. 
5.8.4 
Vital Signs and Body Weight Evaluations 
The values and changes from baseline results of Systolic Blood Pressure (SBP) (mmHg), Diastolic 
Blood Pressure (DBP) (mmHg), pulse rate (bpm) and body weight (kg) will be summarised by visit by 
actual treatment groups on the safety set. For tabulations, analysis windows (see Section 5.1.3) will be 
considered for each visit. 
Vital sign results with changes from baseline will be presented for individual subjects in data listings on 
the aITT. 
5.8.5 
Physical Examinations 
All clinically significant abnormalities in physical examination will be collected in the general medical 
history or the adverse event eCRF pages as appropriate. Therefore, no specific analysis of physical 
examination will be performed. 
5.9 
Other Analyses 
 
5.9.1 
Iron-related parameters and blood inflammatory markers 
Iron-related parameters include total serum iron, serum ferritin, transferrin, TSAT, hepcidin and 
erythropoietin. 
Blood inflammatory markers include high sensitivity C-reactive protein, interleukin 1 and interleukin 6, 
tumour necrosis factor alpha, soluble vascular cell adhesion molecule 1, endothelin-1, soluble platelet- 
selectin, and xanthine oxidase. 
 
 
 
 
 
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All data will be reported in SI. For analysis purposes, values preceded by a “<” or a “>” sign (i.e. those 
below or above the limits of quantification) will be considered equal to the lower or upper limit of 
quantification, respectively. 
For all iron-related parameters and blood inflammatory markers, standard descriptive statistics for 
continuous variables will be tabulated for the values by visit (including baseline) and for changes from 
baseline by post-baseline visit for randomised treatment groups as described in Table 5 on the ITT. 
Analysis windows (see Section 5.1.3) will be considered for each visit. 
Analyses will be repeated on the PPS by actual treatment group if it differs and on mITT if applicable. 
 
For each iron-related parameter and blood inflammatory marker, the following figure will be provided: 
individual values (y-axis) in function of target visit day (x-axis) joined by subject and plotted in separate 
windows for the randomised cohorts (1, 2, 3, 4) and for overall subjects randomised in VIT-2763 (5- 
window panel plot). All graphics will be done on the ITT. 
 
Finally, all parameter results with changes from baseline will be listed, including all unscheduled visits, 
for the aITT. 
5.9.2 
Abnormal RBC sickling 
RBC smear assessment for sickle cells from central laboratory will include sickle cell counts in 
percentage. 
 
Standard descriptive statistics for continuous variables will be tabulated for the values by visit (including 
baseline) and for changes from baseline by post-baseline visit for treatment groups, as described in 
Table 5 on the ITT. Analysis windows (see Section 5.1.3) will be considered for each visit. 
 
Analyses will be repeated on the PPS by actual treatment group if it differs and on mITT if applicable. 
All parameters’ results will be listed, including all unscheduled visits, for the aITT. 
5.9.3 
Quality of Life 
The Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) is a patient-centered data 
collection tool that is made available for clinical study of adults who have SCD for understanding: (1) the 
impact of SCD, and (2) interventions to improve the treatment of adults with SCD on their functioning 
and wellbeing. 
 
The health domains assessed by ASCQ-Me include: 
 
1. Emotional impact (5 questions assessing the past 7 days with 5 possible answers) 
 
2. Pain impact (5 questions assessing the past 7 days with 5 possible answers) 
 
3. Sleep impact (5 questions assessing the past 7 days with 5 possible answers) 
 
4. Stiffness impact (5 questions assessing the past 7 days with 5 possible answers) 
 
5. Social functioning impact (5 questions assessing the past 30 days with 5 possible answers) 
 
 
 
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6. Pain episodes, frequency, and severity (5 questions assessing the past 12 months with 5 to 12 
possible answers). 
 
The 4 impact domains emotional, pain, sleep and stiffness were assessed at baseline, Visit 3, Visit 4, 
Visit 5 and Visit 6. 
 
The social functioning impact domain was assessed at baseline, Visit 4 and Visit 6. 
 
The Pain episodes, frequency, and severity domains were assessed at baseline and Visit 6. 
 
Impact short-forms T-score computation: 
 
Each of the 5 impact domains will be scored by summing the values for each response (1 worst health 
to 5 best health) and using the conversion tables presented in Appendix B to obtain the T-scores (for 
ease of interpretation, each T-score is on the same scale, which was done by standardizing the scores 
to have a mean of 50 and a standard deviation of 10). A higher score always represents a healthier 
status. For example, if a subject chooses the worst health response on all five items, that subject’s total 
raw score will be 5. If this were the Emotional Impact short form, that subject’s T-score will be 26.8 on 
emotional impact. 
A score could be approximated if a subject skips one out of the five questions in a short form. However, 
a short form cannot be scored if three or fewer items were answered. If four responses were provided 
on a short form, the sum of the response scores will be computed from the items that were answered, 
then multiply this sum by the total number of items in the short form (5), and finally, divide by the number 
of items that were answered (4). If the result is a fraction, the pro-rated score will be rounded up to the 
nearest whole number and then translated into a final T-score using Table 7 in Appendix B (from ASCQ- 
Me User’s Manual http://www.healthmeasures.net/images/ASQMe/ASCQ-Me_Scoring_Manual.pdf). 
Individual items scoring for pain episodes, frequency, and severity short-form: 
 
The ASCQ-Me Pain Episode question set includes five questions regarding the frequency, timing, and 
severity of sickle cell pain events. Each answer to the 5 questions will be scored according to Table 8 
in Appendix B. All five items have an option with some variant of “I never had a pain attack.” This 
response category is always initially coded as a 99 to examine the frequency distribution of responses 
for each item. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Frequency measure computation for pain episodes short-form: 
 
The two first questions refer to frequency of pain episodes—one to a simple count of the number of 
attacks (more attacks indicate worse experience), and one to how long ago the most recent pain attack 
occurred. For these items, more pain attacks or having a more recent attack, respectively, is considered 
a worse experience. The frequency composite score is the sum of the values for these two first items 
which results in a raw composite score with a potential range of 0 to 11. The raw response score of 99 
must be replaced with a zero, before calculating any composite scores. The composite score will then 
be standardized. This will be done by creating z-scores, which are also called standard scores, because 
this method makes scores derived from different raw score units comparable. The formula for the z- 
score is the individual score in question minus the mean of the score distribution divided by the standard 
deviation of the score distribution. The means and standard deviations used to create z-scores for the 
Pain Episode Frequency are in Table 9 appendix B. T-score transformation will finally be performed by 
multiplying the score by 10 so that the range of scores is greater than absolute 1 and by adding 50 so 
that the range of scores is positive. 
 
 
Severity measure computation for pain episodes short-form: 
 
Three questions refer to the severity of pain during a pain episode: one question asks the respondent 
to rate the severity of the pain for the most recent attack, the second asks the respondent to indicate 
the degree to which the most recent attack interfered with his or her ability to be active, and the third 
refers to the duration of the pain attack. The Severity composite represents the sum of the values for 
these three items, which results in a raw composite score with a potential range of 0 to 22. The 
composite score will be transformed in a T-score using the same methodology as described for 
frequency measure. 
 
 
Analyses: 
 
The baseline and Visit 6 scores for each individual item of the pain episodes, frequency, and severity 
questionnaire will be summarised with standard descriptive statistics for qualitative variables. 
 
For the 5 impact questionnaires and for pain episode frequency and severity measures, T-Score values 
by visit and changes from baseline at each post-baseline visit will be summarised. Analysis windows 
(see Section 5.1.3) will be considered for each visit. 
 
The ITT population will be used, and summaries will be repeated on the PPS as well. 
 
 
 
5.9.4 
VOC Episode and Visceral Infarctions 
The number of VOC episodes occurring over 8 weeks of treatment will be computed as the number of 
VOC episodes collected with a start date in the 60 days after baseline (corresponding to the target day 
56 of the end of treatment visit plus the 4 days of visit window allowed in protocol). 
The number of visceral infarctions occurring over 8 weeks of treatment will be computed as the sum of 
the number of visceral infarction collected at Visit 3, Visit 4, Visit 5 and Visit 6 (number of infarction since 
last visit collected at each visit in CRF). 
 
 
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Episodes counts will be categorized as: 
o 
0 
o 
1 
o 
2 
o 
>2 
 
 
Shift tables summarising the number of VOC episodes and the number of visceral infarctions in 
categories in the 8 weeks after baseline versus 8 weeks prior baseline will be provided. 
 
The number of VOC episodes occurring over 4 weeks after end of treatment will be computed as the 
number of VOC episodes collected with a start date in the 28 days after treatment stop date. 
The number of visceral infarctions occurring over 4 weeks after end of treatment will be the number of 
visceral infarction collected at Visit 7. 
The number of VOC episodes occurring over 4 weeks after end of treatment, the number of visceral 
infarctions recorded at each visit and occurring over 4 weeks after end of treatment will be listed on the 
aITT. Each VOC episode with its pain intensity (NRS: 0-10) will be described by visit in a listing. 
 
The ITT population will be used, and summaries will be repeated on the PPS as well. 
 
 
5.9.5 
Pharmacokinetics Analyses 
Sparse sampling for determination of VIT 2763 plasma concentration following multiple dosing will be 
obtained from pre-dose trough to 2, 4 and 6 hours post-morning dose at study Visit 4 (V4). 
The population pharmacokinetic analysis will be described in a separate analysis plan. 
 
Pharmacokinetic plasma concentration of VIT-2763 will be summarised for the ITT and listed by subject 
for the aITT for each sampling time point by visit for cohorts 1, 2 and 3 (Placebo group not displayed), 
using descriptive statistics (including geometric mean and CV%, arithmetic mean, standard deviation, 
arithmetic CV%, median, maximum, minimum, and N). No formal statistical tests are planned. 
The observed plasma concentration-time profiles will be plotted by subject using spaghetti plots for 
cohorts 1, 2 and 3. 
The following rules will be applied if there are values that are below the limit of quantification (BLQ) or if 
there are missing values in a plasma concentration data sets to be summarised. 
• 
For the calculation of summary statistics, BLQ values will be set to the limit of quantification. 
 
• 
If non-missing values are obtained from at least 3 subjects in a treatment group, the summary 
statistics will be calculated. 
• 
If non-missing values are obtained from less than 3 subjects in a treatment group, only minimum 
and maximum will be displayed, other arithmetic and geometric summary statistics will be 
denoted as NC (not computed). 
If an embedded BLQ value is considered anomalous within the concentration time profile, it may be 
decided to update this analysis excluding this value from the summary statistics. 
 
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REFERENCES 
 
1. ICH E3: Structure and Content of Clinical Study Reports, 30 Nov 1995. 
 
2. ICH E9: Statistical Principles for Clinical Trials, 05 Feb 1998. 
 
3. Treadwell MJ, Hassell K, Levine R, Keller S. Adult sickle cell quality-of-life measurement information 
system (ASCQ-Me): conceptual model based on review of the literature and formative research. Clin 
J Pain. 2014 Oct30(10):902-14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDICES 
 
APPENDIX A: CLINICAL LABORATORY SAFETY PARAMETERS 
 
Table 6 Clinical laboratory safety parameters (from central laboratory) 
 
 
Haematology 
Test 
Serum Chemistry 
Test 
Urinalysis 
• Haemoglobin 
• Reticulocytes (abs and %) 
• Red Blood Cell Count 
• Hct 
• MCH 
• MCV 
• MCHC 
• RDW 
• % hypochromic RBC 
• CHCM 
• White Blood Cell Count 
• Differential WBC (abs 
and %) 
o Neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
• Platelet count 
• Calcium 
• Sodium 
• Magnesium 
• Potassium 
• Phosphorus 
• Chloride 
• Bicarbonate 
• Blood Urea Nitrogen 
• Uric acid 
• Creatinine Kinase 
• Creatinine 
• Folic acid 
• Albumin 
• Total protein 
• Globulin (calculated) 
• Alanine transaminase 
• Aspartate transaminase 
• Alkaline phosphatase 
• Glucose 
• Triglycerides 
• Cholesterol 
• pH 
• Protein 
• Glucose 
• Ketone 
• Red Blood Cell 
• White Blood Cell 
• Microalbumin 
• Creatinine 
• Microalbumin/Creatinine 
ratio 
All these parameters will be analysed in SI unit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX B : ASCQ-ME QUESTIONNAIRES SCORINGS 
 
 
Table 7 Translation of Raw Scores to T-scores for ASCQ-Me Impact Short-Forms Measures 
 
 
Emotional 
Impact 
Social 
Functioning 
Impact 
Pain 
Stiffness 
Sleep 
Raw 
Score 
T-score 
Raw 
Score 
T-score 
Raw 
Score 
T-score 
Raw 
Score 
T-score 
Raw 
Score 
T-score 
5 
26.8 
5 
26.0 
5 
24.8 
5 
24.9 
5 
27.9 
6 
30.8 
6 
29.8 
6 
28.8 
6 
29.0 
6 
32.3 
7 
33.3 
7 
32.5 
7 
31.0 
7 
31.5 
7 
35.1 
8 
35.3 
8 
34.7 
8 
33.0 
8 
33.5 
8 
37.3 
9 
37.0 
9 
36.8 
9 
34.9 
9 
35.3 
9 
39.5 
10 
38.5 
10 
38.7 
10 
36.7 
10 
36.9 
10 
41.4 
11 
39.9 
11 
40.4 
11 
38.3 
11 
38.4 
11 
43.2 
12 
41.2 
12 
42.1 
12 
39.9 
12 
39.9 
12 
45.0 
13 
42.5 
13 
43.9 
13 
41.5 
13 
41.3 
13 
46.7 
14 
43.7 
14 
45.6 
14 
43.0 
14 
42.7 
14 
48.2 
15 
44.9 
15 
47.2 
15 
44.4 
15 
44.0 
15 
49.7 
16 
46.2 
16 
48.8 
16 
45.7 
16 
45.4 
16 
51.1 
17 
47.4 
17 
50.5 
17 
47.1 
17 
46.7 
17 
52.5 
18 
48.7 
18 
52.2 
18 
48.5 
18 
48.1 
18 
53.9 
19 
50.1 
19 
54.0 
19 
49.9 
19 
49.5 
19 
55.3 
20 
51.5 
20 
55.8 
20 
51.2 
20 
51.0 
20 
56.7 
21 
53.3 
21 
57.7 
21 
52.5 
21 
52.7 
21 
58.2 
22 
55.2 
22 
59.8 
22 
54.0 
22 
54.7 
22 
59.9 
23 
57.3 
23 
62.1 
23 
55.8 
23 
57.0 
23 
61.9 
24 
60.5 
24 
64.9 
24 
58.0 
24 
59.9 
24 
64.4 
25 
65.6 
25 
69.8 
25 
63.8 
25 
65.4 
25 
69.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 8 Individual item scoring for Pain Episode Measures 
 
 
Questions 
Responses 
Score 
Recoded 
Score 
Pain Episode Q1. 
I did not have a pain 
In the past 12 months, how 
attack (crisis) in the past 
99 
0 
many 
sickle 
cell 
pain 
12 months 
attacks (crises) did you 
1 
1 
have? 
2 
2 
3 
3 
4 or more 
4 
Pain Episode Q2. 
When was your last pain 
attack (crisis)? 
I’ve never had a pain 
attack/crisis 
99 
0 
More than 5 years ago 
1 
1–5 years ago 
2 
7–11 months ago 
3 
1–6 months ago 
4 
1–3 weeks ago 
5 
Less than a week ago 
6 
I have one right now 
7 
Pain Episode Q3. 
No pain 
0 
Using any number from 0 
1 
1 
to 10, where 0 is no pain 
2 
2 
and 10 is the worst 
3 
3 
imaginable pain, how 
4 
4 
severe was your pain 
5 
5 
during your last pain 
6 
6 
attack (crisis)? 
7 
7 
8 
8 
9 
9 
Worse pain imaginable 
10 
Pain Episode Q4. 
I’ve never had a pain 
99 
0 
How much did your last 
attack (crisis) 
pain attack (crisis) 
interfere with your life? 
Not at all, I did everything 
I usually do 
1 
I had to cut down on 
2 
some things I usually do 
I  could  not  do  most 
3 
things I usually do 
I could not take care of 
4 
myself and needed some 
help 
from 
family 
or 
friends 
I could not take care of 
5 
myself 
and 
needed 
constant 
care 
from 
family, friends, doctors, 
or nurses 
Pain Episode Q5. 
I’ve never had a pain 
99 
0 
About how long did your 
attack (crisis) 
most recent pain attack 
Less than 1 hour 
1 
(crisis) last? 
1–12 hours 
2 
13–23 hours 
3 
 
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1–3 days 
4 
4–6 days 
5 
1–2 weeks 
6 
More than 2 weeks 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 9 Pain Episode Frequency and Severity Mean & Standard Deviation 
 
Measure 
Mean 
Standard Deviation 
Frequency 
7.525 
2.573 
Severity 
15.018 
4.275 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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select the check-box indicating you wish to withdraw your consent, or you may; 


 
ii. send us an email to 
 and in the body of such request you must state 
your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent.. The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
 
Required hardware and software 
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide- 
signing-system-requirements. 
 
 
Acknowledging your access and consent to receive and sign documents electronically 
 
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
• 
You can access and read this Electronic Record and Signature Disclosure; and 
• 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
• 
Until or unless you notify Fortrea Enterprise (Part 11) as described above, you consent to 
receive exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you by Fortrea Enterprise (Part 11) during the course of your relationship 
with Fortrea Enterprise (Part 11). 
PPD