Clinical trial NCT05172050
Conditions: SARS CoV 2 Infection
Keywords: COVID-19 SARS-CoV-2 severe pneumonia pneumonia
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2021-01-22; Completion date: 2021-06-12
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to evaluate the efficacy and safety of two different doses of raloxifene orally administered compared to placebo in patients with early diagnosis of paucisymptomatic COVID-19.

Primary objectives:

* Evaluation of the effectiveness of therapy in reducing the proportion of subjects who still have viruses in the upper airways after 7 days of therapy
* Evaluation of the effectiveness of therapy in reducing the proportion of subjects who requires supplemental oxygen therapy and/or mechanical ventilation within 14 days of starting therapy

Secondary objectives:

* Evaluation of the effectiveness of therapy in reducing the proportion of subjects who still have viruses in the upper airways after 14 and 28 days of therapy
* Evaluation of the effectiveness of therapy in reducing the proportion of subject patients who requires supplemental oxygen therapy and/or mechanical ventilation within 7 or 28 days of starting therapy
* 7, 14 and 28 days drug safety and tolerability profile
* Assessment of body temperature, blood and biochemical parameters between T0 and T28

Detailed description:
The study is a phase 2/3, multicenter, adaptive, randomized, placebo-controlled, double blind, parallel-group study to evaluate efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-19 patients.

Arms: arm 1: After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 60 mg was administered; the treatment was taken by the patients for two weeks. arm 2: After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 120 mg was administered; the treatment was taken by the patients for two weeks. arm 3: After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing placebo), a single daily oral dose of placebo (2 capsules guarantee the blinding design) was administered; the treatment was taken by the patients for two weeks.
Interventions: intervention 1: Raloxifene intervention 2: Placebo
Intervention descriptions: intervention 1: Raloxifene was administered as 60 mg hard gelatine capsule(s) once a day. Starting from day 2 of treatment: one single capsule (plus one of placebo to guarantee the blinding) containing 60 mg raloxifene was administered in Group 1, and 2 capsules 60 mg each for a total of 120 mg in Group 2. intervention 2: Placebo was administered orally once a day as 2 capsules (for maintaining the blinding design)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
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RLX0120 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: Multicenter, adaptive, randomized, placebo-controlled, double blind, parallel-group Phase 2/3 
trial, to study efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-
19 patients. 
 
 
 
 
Study Number: 
RLX0120 
 
EudraCT Number/IND: 
2020-003936-25 
 
Investigational Product: 
Raloxifene 
 
Phase of the study: 
II/III, adaptive trial 
 
 
Protocol Version - Date: 
Version No. 3.0 – FINAL 22/DEC/2020 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential 
information that is the property of Dompé farmaceutici s.p.a. It is understood that the information will 
not be used, divulged, or published without prior written consent of Dompé farmaceutici s.p.a., except 
to the extent such disclosure is required by applicable laws and regulations. 
 
 
 
 


 
 
 
 
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CONTACT INFORMATION 
 
SPONSOR 
Dompé farmaceutici s.p.a. [Dompé] 
 
Via Santa Lucia 6; 20122 Milan, Italy 
 
 
Medical Expert 
Flavio Mantelli, MD, PhD – Chief Medical Officer 
Direct Line: +39 338 4064830; Fax: +39 02 58383324 
email: flavio.mantelli@dompe.com  
 
 
 
Clinical Trial Manager  
Giuseppe Terpolilli, PharmD – Clinical Development Specialist 
Direct Line: +39 02 58383378;Fax: +39 02 58383324 
email: giuseppe.terpolilli@dompe.com 
 
 
Safety Study contact (Pharmacovigilance Dompé & Pharmacovigilance EXOM) 
 
 email: rlx0120-safety@exomgroup.com 
 
 Fax: +39 02 36026913 
 
 Laura Boga - Global Head of Pharmacovigilance & EU Qualified 
Person for Pharmacovigilance 
 
 
 
 
 
CLINICAL RESEARCH 
ORGANIZATION 
EXOM Group 
Viale F. Restelli, 3/1 – 20124 Milan (Italy) 
Tel +39 0236725592 
Fax +39 0236725580 
email: info@exomgroup.com 
 
 
COORDINATING INVESTIGATOR: 
 
 
 
 
Prof. Emanuele Nicastri, MD,  
Direttore UOC Divisione di Malattie Infettive ad Alta Intensità di 
Cura e Altamente Contagiose 
 
INMI Lazzaro Spallanzani, Via Portuense 292, 00149 Roma, Italy 
 
 
 
 
 


 
 
 
 
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Table of Contents 
1. 
STUDY SYNOPSIS ................................................................................................ 9 
2. 
SCHEDULE OF EVALUATIONS ...................................................................... 16 
2.1. 
BACKGROUND INFORMATION ....................................................................... 19 
2.2. 
RELEVANT NON-CLINICAL PHARMACOLOGY ........................................... 19 
2.3. 
A SUMMARY OF TOXICOLOGY DATA ........................................................... 21 
2.4. 
PHARMACOKINETICS AND PRODUCT METABOLISM ............................... 21 
2.5. 
A SUMMARY OF CLINICAL DATA .................................................................. 23 
2.5.1. 
Main Phase III Efficacy Studies: Prevention of Osteoporosis ................................ 23 
2.5.2. 
Main Phase III Osteoporosis Treatment Efficacy Study (GGGK) ......................... 25 
2.5.3. 
Safety ...................................................................................................................... 27 
2.6. 
DISEASE REVIEW AND STUDY RATIONALE ................................................ 29 
2.6.1. 
Alternative treatments ............................................................................................. 33 
2.6.2. 
Risk - benefit evaluation ......................................................................................... 33 
2.6.3. 
Description of the Investigational Product ............................................................. 35 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ................. 37 
3.1. 
STUDY OBJECTIVES ........................................................................................... 37 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE ........................................................ 37 
3.3. 
OVERALL STUDY DESIGN ................................................................................ 37 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study
 ................................................................................................................................ 38 
4. 
SELECTION OF STUDY POPULATION ........................................................ 39 
4.1. 
INCLUSION CRITERIA ....................................................................................... 39 
4.2. 
EXCLUSION CRITERIA ...................................................................................... 40 
4.3. 
ASSIGNMENT OF SUBJECT NUMBER ............................................................. 41 
5. 
STUDY MEDICATION ....................................................................................... 42 
5.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................. 42 
5.1.1. 
Presentation of Investigational Medicinal Product ................................................. 42 
5.1.2. 
Manufacturing, Packaging and Labelling of IMP ................................................... 42 
5.1.3. 
Supply, Storage and Handling of IMP .................................................................... 43 
5.1.4. 
Blinding .................................................................................................................. 44 
5.2. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION ..................... 44 
5.3. 
ACCOUNTABILITY OF THE IMP ...................................................................... 45 


 
 
 
 
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5.4. 
CONCOMITANT MEDICATION ......................................................................... 45 
5.4.1. 
Prior and concomitant medications ......................................................................... 45 
6. 
STUDY PROCEDURE AND ASSESSMENTS ................................................. 47 
6.1. 
SCREENING AND RANDOMIZATION VISITS ................................................ 47 
6.1.1. 
Randomization ........................................................................................................ 47 
6.2. 
STUDY VISITS AND FOLLOW-UP ASSESSMENTS ....................................... 47 
6.2.1. 
Treatment arms ....................................................................................................... 48 
6.2.2. 
Standard Patient monitoring ................................................................................... 48 
6.2.3. 
Other therapies allowed .......................................................................................... 49 
6.2.4. 
Safety monitoring and individual stopping rules .................................................... 49 
6.3. 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT ..................... 50 
6.4. 
END OF STUDY (EOS) ......................................................................................... 51 
7. 
ENDPOINTS ......................................................................................................... 52 
7.1. 
STUDY ENDPOINTS ............................................................................................ 52 
7.1.1. 
Primary endpoints ................................................................................................... 52 
7.1.2. 
Secondary endpoints ............................................................................................... 52 
8. 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION . 53 
8.1. 
DEFINITIONS........................................................................................................ 53 
8.2. 
MONITORING FOR ADVERSE EVENTS .......................................................... 54 
8.3. 
RECORDING ......................................................................................................... 55 
8.3.1. 
Relationship of AEs to the Investigational Product ................................................ 55 
8.3.2. 
Severity of AEs ....................................................................................................... 56 
8.3.3. 
Follow-Up of patients with Adverse Events ........................................................... 56 
8.4. 
SERIOUS ADVERSE EVENT REPORTING ....................................................... 57 
8.4.1. 
Reporting Procedure for Investigators .................................................................... 57 
8.4.2. 
Adverse Events of Special Interest (AESI) ............................................................. 58 
8.4.3. 
Conditions that should not be reported as serious adverse events .......................... 58 
8.4.4. 
Reporting Procedure to Ethics Committee (EC) and to Regulatory Authorities .... 58 
8.5. 
EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY ... 59 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ............ 59 
8.7. 
OVERDOSE ........................................................................................................... 59 
8.8. 
UNBLINDING ....................................................................................................... 60 
9. 
STATISTICS ......................................................................................................... 61 
9.1. 
SAMPLE SIZE ....................................................................................................... 61 
9.2. 
RANDOMIZATION .............................................................................................. 61 
9.3. 
STATISTICAL METHODOLOGY ....................................................................... 62 
9.4. 
PATIENT POPULATION ...................................................................................... 63 


 
 
 
 
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9.5. 
STATISTICAL METHODOLOGY ....................................................................... 64 
9.5.1. 
Demographic and baseline characteristics .............................................................. 64 
9.5.2. 
Analysis of efficacy variables ................................................................................. 64 
9.5.3. 
Analysis of exploratory variables ........................................................................... 65 
9.5.4. 
Analysis of safety variables .................................................................................... 65 
9.5.5. 
Missing data ............................................................................................................ 66 
9.5.6. 
Specification of subgroups for analysis .................................................................. 66 
9.5.7. 
Study termination .................................................................................................... 66 
9.5.8. 
Changes to the statistical plan ................................................................................. 66 
10. 
ETHICAL CONSIDERATIONS ......................................................................... 67 
10.1. 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE ......................................................................................................... 67 
10.2. 
ETHICAL CONDUCT OF THE STUDY .............................................................. 67 
10.3. 
PATIENT INFORMATION AND CONSENT ...................................................... 67 
10.4. 
CONFIDENTIALITY AND DATA PROTECTION ............................................. 68 
10.5. 
ADMINISTRATIVE ASPECTS ............................................................................ 68 
11. 
DATA HANDLING AND RECORD KEEPING ............................................... 69 
11.1. 
CASE REPORT FORMS ....................................................................................... 69 
11.2. 
PATIENT DIARY .................................................................................................. 69 
11.3. 
PROTOCOL DEVIATION .................................................................................... 69 
11.4. 
DATA MANAGEMENT ....................................................................................... 70 
11.5. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING 
THE STUDY .......................................................................................................... 70 
11.6. 
ESSENTIAL DOCUMENT RETENTION ............................................................ 70 
12. 
STUDY MANAGEMENT .................................................................................... 72 
12.1. 
MONITORING ....................................................................................................... 72 
12.2. 
ACCESS TO RECORDS ........................................................................................ 73 
12.3. 
AUDIT AND INSPECTION .................................................................................. 73 
12.4. 
PROTOCOL AMENDMENTS .............................................................................. 73 
12.5. 
DISCONTINUATION OF THE STUDY .............................................................. 73 
12.6. 
PUBLICATIONS.................................................................................................... 73 
13. 
APPENDICES ....................................................................................................... 75 
13.1. 
APPENDIX 1 - SPONSOR APPROVAL PAGE ................................................... 75 
13.2. 
APPENDIX 2 - COORDINATING INVESTIGATOR AND INVESTIGATOR’S 
SIGNATURE PAGE .............................................................................................. 76 


 
 
 
 
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13.3. 
APPENDIX 3 - COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) VERSION 5.0 ........................................................................ 77 
14. 
REFERENCES...................................................................................................... 78 


 
 
 
 
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List of Abbreviations and Definitions of Terms 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOAC 
Attributable-Legible-Contemporaneous-Original-Accurate-Complete 
ARDS 
Acute RespiratoryDistress Syndrome 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
BT 
Body Temperature 
CFR 
Code of Federal Regulations 
CM 
Concomitant Medications 
CP 
Conditional Power 
CPMP 
Committee for Proprietary Medicinal Products 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB 
Data Base 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
e-CRF/CRF 
Electronic/Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ER 
Estrogen Receptors 
EU 
European Union 
FAS 
Full Analysis Set 
FAV 
Favipiravir 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRT 
Hormone replacement therapy  
eICF 
electronic Informed Consent Form 
ICH 
International Conference on Harmonisation 
IP/IMP 
Investigational Product/ Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 


 
 
 
 
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NEWS 
National Early Warning Score 
OVX 
Ovariectomised 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PI 
Principal Investigator 
PP 
Per Protocol 
PR 
Pulse Rate 
PT 
Preferred Terms 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SERMs 
Selective Estrogen Receptor Modulators 
SO 
Standard Of Treatment 
SOC 
System Organ Class 
SPC / SmPC 
Summary of Product Characteristics  
SpO2 
Oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse events 
TESAE 
Treatment-emergent serious adverse events 
TRHP 
Total Raloxifene in Hydrolysed Plasma 
VTE 
Venous Thromboembolism  
 
 


 
 
 
 
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1. 
STUDY SYNOPSIS  
 
Title: Multicenter, adaptive, randomized, placebo-controlled, double blind, parallel-group Phase 2/3 trial, to 
study efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-19 patients.  
Protocol number: Sponsor code RLX0120 
EudraCT Number: 2020-003936-25 
Clinical phase: Phase 2/3 adaptive trial  
Timelines  
Enrollment period: 12 weeks 
Screening period: ≤ 1 week 
FPI-FPO: 4 weeks 
TX period: 2 weeks 
FU period: 2 weeks 
Post study QoL assessment: 3 months  
Rationale: At present, there are no standard approaches to care paucisymptomatic patients with COVID-19 
related symptoms. Currently intensive care life-support therapies represent the only effective intervention to 
reduce mortality for patients with critical COVID-19. Several antivirals have been currently proposed as 
potential effective therapies against COVID-19. Among the most promising compounds there are  a broad-
spectrum inhibitor of viral RNA polymerase, Favipiravir (FAV) and Remdesivir. The proven antiviral efficacy 
of this drugs is generally limited in COVID-19 patients by the low bioavailability in lungs. 
Recently through the Exscalate supercomputing platform were found several promising molecules able to fight 
the SARS-CoV-2, that shown low serum concentrations and high lung concentrations. Among these, raloxifene 
was found as a promising molecule to treat mild to moderate COVID-19 patients due to its dual activity: 
modulate the replication and activity of Sars-CoV-2 and interact with the estrogen receptors (that would seem 
to play a key role in the protection against the virus via a cascade of events including an anti-inflammatory 
effect).  
The aim of this study is to assess the efficacy of two different doses of raloxifene (60 mg and 120 mg) for 
preventing the evolution of COVID-19 towards severe and critical disease and their capability to reduce the 
mean time of viral shedding in COVID-19 patients who did not show yet severe symptoms. 
Study design: Multicenter, adaptive, double-blind, randomized, placebo controlled, double blind, parallel-
group, to study efficacy and safety, with the following adaptive components: 
- 
Parallel multi-arms (2 interventional arms and 1 placebo control arm); 
- 
A 2-stage sequential design (1 interim analysis + 1 final analysis); 
- 
Sample size re-calculation at interim stage; 
- 
Stopping rule for efficacy or futility at interim stage. 
Planned nr. of countries: 3: Italy, France, Spain 
Coordinating centre: Prof. Emanuele Nicastri, MD, Direttore UOC Divisione di Malattie Infettive ad Alta 
Intensità di Cura e Altamente Contagiose, INMI Lazzaro Spallanzani, Via Portuense, 292, 00149 Roma, Italy. 
Investigational product: 
 


 
 
 
 
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TEST (T):  
Hard gelatine capsule containing 60 mg of raloxifene, for oral administration. 
REFERENCE (R): 
Hard gelatine capsule containing placebo, for oral administration. 
Dose regimen:After an administration of two oral doses in the first day of treatment (one dose in the morning 
and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance 
or placebo), a single daily oral dose of raloxifene (60 mg Group 1, 120 mg Group 2 – treatment groups) or 
placebo (Group 3 - control group) will be taken on by the patients for two weeks. The patients will be randomly 
(1:1:1) assigned to receive either raloxifene treatment or placebo. 
Treatment groups: 
 
- 
Group 1: 
will receive one capsule of raloxifene 60 mg and 1 capsule of placebo. 
- 
Group 2: 
will receive two capsules of raloxifene 60 mg.  
Control group: 
- 
Group 3: 
will receive two capsules of placebo. 
Objectives: 
The objective of this study is to evaluate the efficacy and safety of two different doses of raloxifene orally 
administered compared to placebo in patients with early diagnosis of paucisymptomatic COVID-19. Efficacy 
will be assessed based on the proportion of patients with undetectable SARS-CoV-2 at day 7 after randomization 
and the proportion of patients who requires supplemental oxygen therapy and/or mechanical ventilation by day 
14 after randomization. Safety will also be assessed. 
Primary objectives:  
- 
evaluation of the effectiveness of therapy in reducing the proportion of subjects who still have viruses 
in the upper airways after 7 days of therapy; 
- 
evaluation of the effectiveness of therapy in reducing the proportion of subjects who requires 
supplemental oxygen therapy and/or mechanical ventilation within 14 days of starting therapy. 
Secondary objectives: 
- 
evaluation of the effectiveness of therapy in reducing the proportion of subjects who still have viruses 
in the upper airways after 14 and 28 days of therapy; 
- 
evaluation of the effectiveness of therapy in reducing the proportion of subject patients who requires 
supplemental oxygen therapy and/or mechanical ventilation within 7 or 28 days of starting therapy; 
- 
7, 14 and 28 days drug safety and tolerability profile; 
- 
Assessment of body temperature, blood and biochemical parameters between T0 and T28.  
 
Endpoints: 
Primary endpoints: 
Virologic outcome. Proportion of participants with undetectable SARS-CoV-2 at PCR at day 7 after 
randomization. 
Clinical outcome. Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) 
and/or mechanical ventilation at day 14 after randomization. 
Secondary endpoints: 
➢ Proportion of participants with undetectable SARS-CoV-2 at PCR at day 14 after randomization at day 
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➢ Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or 
mechanical ventilation at day 7 and 28 after randomization; 
➢ Proportion of patients in each NEWS category at time 7, 14 and 28 after randomization; 
➢ Mean value of NEWS category at time 7, 14 and 28 after randomization; 
➢ Proportion of participants with any adverse event with grade ≤ 2 according to CTCAE at day 7, 14 and 
28 after randomization; 
➢ Proportion of participants with any severe adverse events (grade ≥ 3 according to CTCAE) at day 7, 
14 and 28 after randomization; 
➢ Proportion of hospitalized participants who at the beginning of the study were at domicile isolation at 
day 7, 14 and 28 after randomization; 
➢ Proportion of participants admitted to intensive care at day 7, 14 and 28 after randomization; 
➢ Proportion of survivors at day 7, 14 and 28 after randomization; 
➢ Mean variation of value of the following biomarker parameters, from base line to day 7, 14, 21 and 28 
after randomization: 
o 
Complete blood cell counts; 
o 
Hepatic function (ALT, AST and bilirubin); 
o 
Coagulation (PT, aPTT and INR); 
o 
Other markers including (D-dimer, CPK, LDH); 
➢ Quality of life questionnaire 3 months after the randomization. 
Safety and tolerability assessments: All patients will daily self-monitor the following parameters and may 
call a doctor if needed.Treatment-emergent adverse events (TEAEs); vital signs (blood pressure [BP], pulse rate 
[PR], body temperature [BT]), transdermal oxygen saturation (SpO2). 
(see appendix 1).  
Sequential design procedures: The group sequential design includes 3-arm 2-stage procedure allowing for 
early stopping rule according to efficacy and futility of at least one active arm. In case of continuation after 
interim analysis, the actual number of new participants will be calculated according to the observed efficacy of 
the best favourable and promising arm at the interim analysis. Pocock’s spending functions and conditional 
power will be used to control the type I and II errors, considering that interim analysis will be performed when 
half of the initial planned patients have been reached the primary endpoints (i.e. assessments available). 
Bonferroni method is used to adjust for multiple endpoint and treatment comparisons. 
Sample size: Sample size will significantly change according to the observed effect within the trial sample (in 
case of no early stop, expected sample size is between 250 and 450 randomized participants). In particular, it is 
plan to randomize 50 participants per arm at the interim stage (N=150) and then, in case of continuation of the 
study to the final stage, it is expected to randomize on average additional 174 patients, depending on sample 
size reassessment and possible drop of an uneffective treatment arm. Drop-outs of randomized subjects will not 
be replaced. 
Main selection criteria: 
Inclusion criteria: 
 


 
 
 
 
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1. Subject autonomously provides informed consent prior to initiation of any study procedures;  
2. Males and females > 40 years old at time of enrolment; 
3. Understands and agrees to comply with planned study procedures, has the availability of an email 
address as well as an Internet connection at domicile location; 
4. Agrees to the collection of nasopharyngeal swabs and venous blood samples per protocol; 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by an approved molecular test (PCR) 
in Europe within 10 days at the screening time; 
 
6. Patient paucisymptomatic who complains at the screening time at least one of the following symptoms 
mild to moderate: fever, dyspnea, headache, cough, dysgeusia, conjunctivitis, vomiting, diarrhea, 
anosmia, muscle or body aches or other symptoms which in the opinion of the Investigator are part of 
the COVID-19 clinical picture; 
7. No need of supplemental oxygen therapy, mechanical ventilation;  
8. Females of child-bearing potential and with an active sexual life must not wish to get pregnant within 
30 days after the end of the study and must be using at least one of the following reliable methods of 
contraception: 
a) Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at 
least 2 months before the screening visit until 30 days after final visit 
b) A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive 
sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 
2 months before the screening visit until 30 days after final visit 
c) A male sexual partner who agrees to use a male condom with spermicide 
d) A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will 
be admitted. For all female subjects, with child-bearing potential, pregnancy test result must be 
negative before first drug intake on T7 and T14. 
 
Exclusion criteria: 
 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study. 
1. Being totally asymptomatic at the screening time;  
 
2. Requires supplemental oxygen therapy or mechanical ventilation; 
 
3. Being already under raloxifene or other SERM treatment for another medical condition at the time of 
randomization; 
 
4. Being concurrently involved in another trial with IP or participation in any clinical trial with IP for 1 
months before this study. The 1-month interval is calculated as the time between the last visit of the 
previous study and the first day of the present study (date of the informed consent signature); 
 


 
 
 
 
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5. Clinically significant abnormal physical findings which could interfere with the objectives of the 
study; 
 
6. Diseases: 
a) history of stroke and/or venous thromboembolism; 
b) known moderate / severe renal impairment: Chronic Kidney Disease (CKD) stage 3 or higher;  
c) known liver disease (Child-Pugh Class A or higher); 
d) presence of known hypoalbuminemia; 
e) endometrial bleeding; 
f) 
signs or symptoms of endometrial cancer; 
 
7. Autoimmune diseases receiving therapy at the time of randomization; 
 
8. Risk of venous thrombosis or any condition/disease that could bring to an extended period of 
immobilization; 
 
9. Ascertained or presumptive hypersensitivity to the active principles (raloxifene) and/or excipients or 
allergic reactions in general, which the Investigator considers may affect the outcome of the study; 
 
10. Medications: in particular cholestyramine (or any ion exchange resin), medications used in treatment 
of early or advanced breast cancer (including adjuvant therapy), warfarin, any drug that cannot be co-
administered with the experimental compound; 
 
11. Pregnancy: 
 
a) positive or missing pregnancy test before first drug intake or day 1; 
b) pregnant or lactating women; 
 
12. Women of childbearing potential and fertile men who does not agree to use at least one primary form 
of contraception for the duration of the study. 
 
Statistical plan and data analysis:  
This is a multi-arm parallel randomized controlled clinical trial with the aim to show superiority of raloxifene 
orally administered compared to placebo in terms of either virologic or clinical outcome. 
The sample size of the study has been based on the following assumptions: 
- 
Virologic assumption: Early treatment with antivirals increases the proportion of patients with 
undetectable SARS-CoV-2 in upper respiratory tract at day 7 after therapy from 25% to 50%; 
- 
Clinical assumption: Early treatment with antivirals increases the proportion of participants who 
recover without need of mechanical ventilation and/or supplemental oxygen therapy by the day 14 
after therapy from 50% to 75%. 
Based on these assumptions, the planned sample size will allow to achieve a power greater than 80% to show 
superiority of raloxifene vs placebo in terms of either one primary endpoint, controlling the one-sided alpha 
below 0.025. 
Summary statistics have been defined for quantitative variables (number of observations, mean, standard 
deviation, median, minimum and maximum) and qualitative variables (number and percentage per category).  
The proportion of participants with undetectable SARS-CoV-2 at day 7 after randomization, and the proportion 
of participants who not requires mechanical ventilation and/or supplemental oxygen therapy (NEWS < 2) at 


 
 
 
 
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day 14 after randomization will be analysed and compared by treatment (raloxifene vs placebo) by means of 
logistic regression. 
All secondary endpoints will be analysed at each available timepoint by means of descriptive statistics and by 
appropriate parametric tests. Change from baseline value and shift tables versus baseline will be summarized 
for all post-baseline visits, if applicable.  
AEs will be presented in terms of the number of AEs and incidence. Other safety parameters will be summarized 
by treatment at each available visit by means of descriptive statistics.  
The Safety and the Full Analysis Set population will consist of all patients who will be randomized and received 
at least one dose of the investigational product. Safety population will be analysed according to the actual 
treatment received; Full Analysis Set population will be analysed according to ITT principle, i.e. by treatment 
allocation. Primary and secondary efficacy analyses will be conducted on the FAS population while the SAF 
population will be used for safety analyses. 
A Statistical Analysis Plan (SAP) will be issued with more technical and detailed elaboration of the principal 
features of statistical analyses. Any deviation from the original statistical plan will be described in the Clinical 
Study Report.  
 
 
 
 


 
 
 
 
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Appendix 1 
 
Biochemistry (T0, T7, T14, T21, T28) 
Sodium  
Potassium  
Chloride  
Urea 
Uric acid 
Creatinine 
Calcium 
Inorganic phosphorus 
Fasting Glucose  
Total and direct bilirubin  
Total protein 
Albumin 
Alpha-1 Globulins 
Alpha-2 Globulins 
Beta Globulins 
Alkaline phosphatase  
AST 
ALT 
Gamma glutamyl transferase 
Total Cholesterol 
Triglycerides 
 
 
Haematology (T0, T7, T14, T21, T28) 
Haemoglobin 
Red cell count  
Packed cell volume  
Mean cell volume  
Mean cell haemoglobin 
Mean cell haemoglobin concentration 
Platelet count  
White cell count  
Neutrophils  
Lymphocytes  
Monocytes  
Eosinophils 
Basophils 
 
Coagulation (T0, T7, T14, T21, T28) 
Prothrombin time 
Activated partial thromboplastin time 
INR 
 
Virology (T7, T14, T28) 
PCR 
 
Other markers (T0, T7, T14, T21, T28) 
D-dimer; 
Creatine phosphokinase (CPK); 
Lactate dehydrogenase (LDH). 
 
 
 


 
 
 
 
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2. 
SCHEDULE OF EVALUATIONS 
 
Study 
procedures 
Pre-
screening 
Screening1 
(from day -7 
to day 0) 
Baseline 
(T0) 
T7 
T14 
(End of 
treatment) 
T21 
T28 
ETDV
5 
3 
Months 
Week 
1 
Week  
2 
Week 
3 
Week 
4 
Laboratory-
confirmed 
SARS-CoV-2 
infection 
X* 
 
 
 
 
 
 
 
 
Electronic 
Informed 
Consent 
signature 
 
X 
 
 
 
 
 
 
 
Demographic 
data and life 
style recording 
 
X 
 
 
 
 
 
 
 
Medical/surgical 
History and 
underlying 
disease 
 
X 
 
 
 
 
 
 
 
Vital signs daily 
measurement 
(BP, PR, BT) 
and transdermal 
oxygen 
saturation 
(SpO2) 
 
 
X 
 
Pregnancy Test2 
(female only) 
 
 
X 
X 
X 
 
 
 
 
Laboratory 
analyses3 
 
 
X 
X 
X 
X 
X 
 
 
NEWS score 
evaluation 
 
 
X 
X 
X 
 
X 
 
 
Inclusion/Exclus
ion Criteria 
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
IMP daily 
administration 
 
 
 
X** 
 
 
 
 
Nasopharyngeal
swabs 
 
 
 
X 
X 
 
X 
 
 
Supplemental 
oxygen therapy 
(NEWS >2) 
and/or 
 
 
 
X 
X  
 
X 
 
 


 
 
 
 
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Study 
procedures 
Pre-
screening 
Screening1 
(from day -7 
to day 0) 
Baseline 
(T0) 
T7 
T14 
(End of 
treatment) 
T21 
T28 
ETDV
5 
3 
Months 
Week 
1 
Week  
2 
Week 
3 
Week 
4 
mechanical 
ventilation 
(Yes/No) 
ICU admission 
(Yes/No) 
 
 
 
X 
X 
 
X 
 
 
Study drug 
dispensation 
 
 
X 
 
 
 
 
 
 
Verify study 
medication 
dosing 
compliance 
 
 
 
X 
X 
 
 
 
 
AEs / SAEs / 
CMs Record 
and assessment4 
 
X 
X 
 
QoL 
questionnaire 
(EQ5D5L) 
 
 
 
 
 
 
 
 
X 
 
* Confirmation of SARS-CoV-2 infection must be available before the screening visit. Only diagnosed COVID-
19 paucisymptomatic patients will be evaluated for the trial participation   
 
** After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in 
the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), patiens 
will take on a single daily oral dose, for a total of 14 days of treatment  
1. 
Screening visit will be carried out within 7 days from the diagnosis of SARS-CoV-2 infection 
2. 
Urine pregnancy test will be done at patient’s domicile  
3. 
Laboratory Analyses: 
 
Biochemistry (T0, T7, T14, T21, T28) 
Sodium  
Potassium  
Chloride  
Urea 
Uric acid 
Creatinine 
Calcium 
Inorganic phosphorus 
Fasting Glucose  
Total and direct bilirubin  
Total protein 
Albumin 
Alpha-1 Globulins 
Haematology (T0, T7, T14, T21, T28) 
Haemoglobin 
Red cell count  
Packed cell volume  
Mean cell volume  
Mean cell haemoglobin 
Mean cell haemoglobin concentration 
Platelet count  
White cell count  
Neutrophils  
Lymphocytes  
Monocytes  
Eosinophils 
Basophils 


 
 
 
 
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Alpha-2 Globulins 
Beta Globulins 
Alkaline phosphatase  
AST 
ALT 
Gamma glutamyl transferase 
Total Cholesterol 
Triglycerides 
 
 
 
 
Coagulation (T0, T7, T14, T21, T28) 
Prothrombin time 
Activated partial thromboplastin time 
INR 
 
Virology (T7, T14, T28) 
PCR 
 
Other marker (T0, T7, T14, T21, T28) 
D-dimer; 
Creatine phosphokinase (CPK); 
Lactate dehydrogenase (LDH). 
 
 
4. 
AEs will be monitored from the screening visit, immediately after electronic informed consent, up to the final 
visit. 
5. 
In case of discontinuation, subjects will undergo an Early Trial Discontinuation Visit  
 


 
 
 
 
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2.1. 
BACKGROUND INFORMATION 
In December 2019, a new identified coronavirus (SARS-CoV-2) outbreak in Wuhan causes public health 
crisis in China and spreads worldwide. On February 11, 2020, the World Health Organization officially 
named the disease caused by the new coronavirus “COVID-19”. The Chinese Government takes 
stronger and harsher measures to control the progression of its outbreak. Meanwhile, five editions of 
“Diagnosis and Treatment for Novel Coronavirus-Infected Pneumonia” has been timely and 
countinuosly issued, which play extremely important roles in guiding the clinical management of 
COVID-19 nationwide in China. Common symptoms of COVID-19 include fever, cough, shortness of 
breath and dyspnea that may eventually progress towards acute respiratory distress syndrome and death. 
About 80% of patients have mild to moderate disease, 14% have severe disease and 6% are critical 
(namely, they develop respiratory failure, septic shock, and/or multiple organ dysfunction/failure)1.The 
first known case of SARS-CoV occurred in Foshan, China in November 2002 and new cases emerged 
in mainland China in February 2003. The first emergence of MERS-CoV occurred in June 2012 in Saudi 
Arabia. These events demonstrated that the threats of CoVs must not be underestimated and that it is 
important to advance the knowledge on these viruses, their replication and interactions with the hosts to 
develop new pharmacological treatments and vaccines. 
In this situation, new strategies that can mitigate the impact of COVID-19 on the National Health System 
are urgently needed. Specifically, these strategies should be aimed at: a) preventing patients with mild 
COVID- 19 to progress towards severe/critical disease, for lightening the impact on hospitals; b) 
shortening time of viral shedding in order to curb individual infectivity and reduce the average number 
of secondary cases. At present, there are neither standard approaches nor approved drugs to care patients 
with COVID-19 and intensive care life-support therapies represent the only effective intervention to 
reduce mortality for patients with critical COVID-19. In addition, there are no standard approaches to 
care patients with mild to moderate COVID-19 related symptoms. Several antivirals have been currently 
proposed as potential effective therapies against COVID-19. Among the most promising compounds 
there are  a broad-spectrum inhibitor of viral RNA polymerase, Favipiravir (FAV) and Remdesivir. The 
proven antiviral efficacy of this drugs is generally limited in COVID-19 patients by the low 
bioavailability in lungs. 
Recently through the Exscalate supercomputing platform were found several promising molecules able 
to fight the SARS-CoV-2, that shown low serum concentrations and high lung concentrations. Among 
these, raloxifene was found as a promising molecule to treat mild to moderate COVID-19 patients due 
to its dual activity: modulate the replication and activity of Sars-CoV-2 and interact with the estrogen 
receptors (that would seem to play a key role in the protection against the virus via a cascade of events 
including an anti-inflammatory effect). 
The aim of this clinical study is to assess the efficacy of the well-known drug, Raloxifene, already 
marketed in other indications, emerged from a repurposing approach as a promising agent for preventing 
the evolution of COVID-19 towards severe and critical disease. 
2.2. 
RELEVANT NON-CLINICAL PHARMACOLOGY 
Several preclinical animal studies to investigate effects of raloxifene on bone were performed. These 
studies, which have been conducted mainly in rats and cynomolgus monkeys, have used ovariectomised 
(OVX) or sexually immature animals as a model of estrogen deficiency. Several analytical methods 


 
 
 
 
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have been applied to evaluate different aspects of the effects on bone including analysis of bone mineral 
density, biomechanical strength, histomorphometry, and biochemical markers of bone metabolism.The 
doses used (0.001-30 mg/kg/day in rats and 1-5 mg/kg/day in monkeys) result in an exposure consistent 
with that in women receiving the proposed daily dose of 60 mg. 
The duration of some studies (particularly the two chronic studies of 12 months in OVX rats and 2 years 
in OVX cynomolgus monkeys) is adequate to demonstrate the beneficial effects on bone turnover. 
There is sufficient preclinical evidence that raloxifene has a tissue-selective estrogen-receptor (ER) 
agonist or antagonist profile. Concerning the mimetic actions, there is sufficient preclinical evidence 
supporting the anti-osteoporotic properties of raloxifene in conditions of estrogen deficiency. 
Furthermore, the studies also demonstrated that raloxifene lowers serum cholesterol levels in OVX rats, 
rabbits and monkeys mimicking actions of estrogens (however raloxifene is less potent than estrogens 
in reducing cholesterol levels and does not prevent the development of atherosclerotic alterations). 
On the other hand, raloxifene behaves in reproductive sites, such as mammary tissue and uterus, like an 
ER antagonist. Its lack of uterine stimulation distinguishes raloxifene from other antiestrogens, like 
tamoxifen, which have partial agonist activity on the endometrium.2 
General pharmacodynamics studies 
A wide range of studies has been performed in vitro and in vivo (rabbit, mouse, guinea pig). At oral 
doses up to 600 mg/kg/day raloxifene showed no marked cardiovascular, renal, gastrointestinal or 
smooth muscle activity. 
Pharmacokinetics/Toxicokinetics studies 
The majority of the pharmacokinetic studies were performed in rats, mice and monkeys, with a few 
studies performed in dogs. Many studies relied on 14C-raloxifene; authentic raloxifene was also 
measured by HPLC. 
The data have shown good oral absorption, extensive “first-pass” metabolism in the intestinal mucosa 
and liver to form glucuronide conjugates, a high level of plasma protein binding and faecal excretion of 
raloxifene and its metabolites via the bile. 
A wide range of oral doses was used in pharmacology studies (1-5 mg/kg) with much higher doses in 
toxicology studies (up to 600-1700 mg/kg). In general, plasma concentrations of raloxifene increased 
with dose in mice, rats and monkeys, but increases were not always proportional, especially at high 
doses. A similar pattern was observed in postmenopausal women given doses up to 600 mg orally. 
The results seen in the animal models are consistent with the higher exposure levels in animals compared 
to humans. Systemic exposure to raloxifene after 1 year or more of daily dosing was approximately 41, 
505 and 13 times greater in mice, rats and monkeys, respectively, than in postmenopausal women given 
60 mg/day for two years. It can be concluded that animals were appropriately exposed to the compound 
in these studies2. 


 
 
 
 
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2.3. 
A SUMMARY OF TOXICOLOGY DATA 
Raloxifene was evaluated for toxicity in two rodent (mice and rats) and two non-rodent (Beagle dogs 
and rhesus monkeys) species, by oral and intraperitoneal (in rats) route. Acute toxicity was low. No 
mortality was observed with doses up to 5000 mg/kg orally to mice and rats. Few rats showed toxicity 
after i.p. injection of a 2000 mg/kg dose of raloxifene. 
Repeated dose toxicity was investigated in mice (3 months), rats (up to 1 year), dogs (6 months) 
andcynomolgus monkeys (up to 1 year) following oral administration. In general, raloxifene was 
welltolerated and observations from these studies were considered to reflect the pharmacodynamic 
actionsof raloxifene on reproductive tissues and estrous cycle due to the SERM-like activity. A no-
effectlevel was not determined. 
Reproductive toxicity studies was performed in rats andrabbits. The observed effects were all consistent 
with the known action of raloxifene on the estrogenreceptor. At doses of 0.1 to 10 mg/kg/day in female 
rats, raloxifene disrupted estrous cycles of femalerats during treatment, but did not delay fertile matings 
after treatment termination and only marginallyreduced litter size, increased gestation length, and altered 
the timing of events in neonataldevelopment. When given during the preimplantation period, raloxifene 
delayed and disrupted embryoimplantation resulting in prolonged gestation and reduced litter size but 
development of offspring toweaning was not affected. Teratology studies were conducted in rabbits and 
rats. In rabbits, abortionand a low rate of ventricular septal defects (≥ 0.1 mg/kg) and hydrocephaly(≥ 
10 mg/kg) were seen. In rats, retardation of foetal development, wavy ribs and kidney cavitationoccurred 
(≥ 1 mg/kg). 
Results from the standard battery of in vitro and in vivo mutagenicity tests show that raloxifene is devoid 
of genotoxic potential.  
Carcinogenicity studies to assessthe oncogenic/carcinogenic potential of raloxifene has been 
performedin mice (21 month study) and in rats (24 month), with appropriate exposure multiples over 
human doses. An increased incidence of ovarian neoplasias was observed in both species, as well as an 
increase of serum ALT levels. Treatment of female rodents with raloxifene throughout their lives 
produced specific hormonal imbalances. Such imbalances are known to result in ovarian tumours in 
rodents, which have not been observed in women who have received raloxifene2. 
2.4. 
PHARMACOKINETICS AND PRODUCT METABOLISM 
Prevention indication 
The pharmacokinetics of raloxifene has been studied in healthy volunteers, postmenopausal women, and 
patients with hepatic impairment (5 subjects with cirrhosis). 
The mean oral bioavailability of raloxifene was low, approximately 2%. However, the median estimate 
of absorption of total drug-related substance is much higher and the absolute oral bioavailability is 
dependent on metabolic interconversion between raloxifene and its glucuronides. Most of the raloxifene 
in the systemic circulation appears to be derived from deconjugation of the glucuronides. 
Raloxifene is a high clearance drug, with a clearance approximately equal to liver blood flow. It 
undergoes significant enterohepatic circulation. 


 
 
 
 
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Following single oral doses (study GGGI), the Tmax for raloxifene was approximately 6 hours (ranging 
from 1-24 hours), t1/2 was 33 hours (23-92 hours). According to a study with 14C-raloxifene, peak 
concentrations of total raloxifene in hydrolysed plasma (TRHP) represented more than 99% of total 
radioactivity in plasma, indicating rapid glucuronidation. The terminal half-lives of raloxifene, TRHP 
and glucuronides were similar, ranging from 15.6 to 21.8 hours. After repeated oral doses, raloxifene 
kinetics (e.g. elimination rate constant, clearance and volume of distribution) was linear with respect to 
time. The raloxifene concentration-dose relationship was linear, but not dose-proportional. 
Raloxifene and its glucuronides are highly bound to plasma proteins, including both albumin (>95%) 
and alpha-1-glycoprotein (89%). Neither raloxifene nor the glucuronides are distributed into the cellular 
component of blood. 
The only metabolites detected in plasma and urine are glucuronide conjugates (raloxifene-4’- 
glucuronide, -6’-glucuronide and –6,4’-diglucuronide). No oxidative metabolites have been found.  
Raloxifene and its metabolites are primarily excreted in the faeces, less than 6% is recovered in urine. 
The amount of unchanged raloxifene in urine is negligible. 
The effect of food on the pharmacokinetic parameters of raloxifene is not significant. 
Population pharmacokinetic analyses (NONMEM model) confirmed the results from individual 
pharmacokinetic studies. The pharmacokinetics of raloxifene and TRHP are characterised by large intra- 
and inter-subject variability. Pharmacokinetics was not affected by age, dose or ethnic factors. Self-
reported alcohol consumption (>3 drinks per week) did not influence raloxifene pharmacokinetics. In 
smokers, raloxifene clearance was approximately 20% greater than in nonsmokers, but this difference 
is less than the 30% within-subject variability. 
A formal study in patients with renal impairment has not been performed, as renal excretion of raloxifene 
is a minor pathway. Dose adjustment does not appear necessary in subjects with mild renal impairment 
on the basis of population pharmacokinetic analysis. In the absence of data, raloxifene is contraindicated 
in severe renal impairment. 
In subjects with hepatic cirrhosis and mild hepatic impairment (Child-Pugh Class A), the Cmax and AUC 
for plasma raloxifene, TRHP and raloxifene-glucuronide (single dose of raloxifene) were significantly 
higher than in healthy control subjects. A statistically significant association was observed between 
raloxifene-glucuronide, TRHP and raloxifene AUC versus serum total bilirubin. Raloxifene is 
contraindicated in hepatic impairment, including cholestasis. 
A number of tablet formulations have been used in clinical trials. The different formulations and the 
market-image tablets have been shown to be bioequivalent. 
Treatment indication 
Population pharmacokinetic analyses from patients (postmenopausal women with osteoporosis) in 
Study GGGK demonstrated that the pharmacokinetics of raloxifene were not clinically significantly 
affected by age, body weight or BMI, cigarette smoking, chronic alcohol use or decreased renal function. 
However, in the absence of data, raloxifene is contraindicated in severe renal impairment. 


 
 
 
 
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Interaction studies 
In in vitro studies, significant plasma protein binding interactions were not observed with warfarin, 
phenytoin, tamoxifen or testosterone. 
In in vivo studies, an approximately 40% reduction in systemic raloxifene exposure was observed after 
cholestyramine, therefore cholestyramine should not be co-administered with raloxifene. Calcium 
carbonate and aluminium hydroxide/magnesium hydroxide antacid did not modify the absorption and 
exposure to raloxifene and metabolites. Oral ampicillin therapy resulted in lower raloxifene 
concentrations, but the interaction is probably not of significant consequence during short-term 
antibiotic treatment. Raloxifene reduces the efficacy of warfarin treatment. A significant decrease in the 
peak and AUC of the prothrombin time response to warfarin was observed after multiple doses of 
raloxifene; careful monitoring of prothrombin time is necessary over several weeks. Concomitant 
administration of raloxifene resulted in increase in Cmax of digoxin (by less than 5%), but did not affect 
overall exposure.  
In the population pharmacokinetic analyses, histamine H1-receptor antagonists, laxatives and fibre were 
associated with slight decreases in observed average raloxifene concentrations. 
For other frequently co-administered drugs such as paracetamol, non-steroidal anti-inflammatory drugs 
(e.g. acetylsalicylic acid, ibuprofen and naproxen), oral antibiotics, H1 antagonists, H2 antagonists and 
benzodiazepines, no clinically relevant effects of co-administration on raloxifene plasma concentrations 
were identified. 
The Phase I study GGIP, which assessed the pharmacokinetic interaction of raloxifene after multiple 
administration of methilprednisolone in postmenopausal women with no concomitant hormone 
replacement therapy, showed that raloxifene has no effect on the pharmacokinetics of 
methylprednisolone given as a single dose2. 
2.5. 
A SUMMARY OF CLINICAL DATA 
The core clinical documentation for the prevention of osteoporosis in postmenopausal womenindication 
consisted of three main Phase III studies (randomised, multicentre, double-blind, placebocontrolled 
parallel groups) and several Phase II studies.The core clinical documentation for the treatment of 
osteoporosis in postmenopausal women indication was based on 3-year data from a single, very large 
Phase III study (randomised, multicentre, double-blind, placebo-controlled parallel group) (Study 
GGGK) involving 7705 women with osteoporosis. 
2.5.1. 
Main Phase III Efficacy Studies: Prevention of Osteoporosis 
These main studies enrolled a total of 1754 postmenopausal women for long-term double-blind 
treatment with placebo or raloxifene (30, 60 or 150 mg/day). Study GGGH enrolled subjects who had 
undergone hysterectomies, and included an unopposed conjugated estrogen treatment arm (0.625 
mg/day). Two-year interim reports with intention-to-treat and per protocol analyses have been provided. 
The study population was women (mean age of 54 years) who were 2 to 8 years postmenopausal, except 
for the study GGGH in which women who were 0 to 15 years postmenopausal were included. The 


 
 
 
 
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inclusion criteria comprised subjects with T-scores for lumbar spine BMD ranging from -2.5 to +2.0 
inclusive. The osteopenic population, with T-scores from -2.5 to -1, is considered most relevant for the 
claimed indication; approximately 50% of the study population had osteopenia. 
The primary efficacy criteria in these studies were change and percent change from baseline to endpoint 
in lumbar spine (L1-L4) and total hip BMD. Secondary efficacy criteria included markers of bone 
metabolism (serum osteocalcin, serum total and bone-specific alkaline phosphatase, urinary type I 
collagen fragment C-telopeptide), serum lipids, measures of coagulation and fibrinolytic activity and 
assessment of endometrial thickness2. 
Effects on bone 
GGGF was a European study to establish the effects of long-term therapy with three doses ofraloxifene 
compared to placebo on BMD of the lumbar spine and total hip. Randomised patientsreceived placebo 
(n=150) or raloxifene 30 mg (n=152), 60 mg (n=152), or 150 mg (n=147)daily. 
After 24 months of treatment, the mean percentage changes from baseline for lumbar spine BMD were 
–0.8% (placebo), +1.3% (30 mg), +1.6% (60 mg) and +2.2% (150 mg). At the level of the total hip, the 
changes were –0.8% (placebo), +1.0% (30 mg), +1.6% (60 mg) and +1.5% (150 mg). Increases in BMD 
were statistically significant compared to placebo at all measurements sites (except the distal and 
ultradistal radius) for all doses of raloxifene. The results are clinically significant and relevant with 
respect to the proposed indication. The biochemical markers of bone metabolism decreased significantly 
in all raloxifene groups versus placebo, consistent with decreased bone turnover. 
GGGG was a US study to establish the effects of long-term therapy with three doses of raloxifene 
compared to placebo on BMD of the lumbar spine and total hip. Randomised patients received placebo 
(n=136) or raloxifene 30 mg (n=136), 60 mg (n=134), 150 mg (n=138) o.d. 
Over 24 months of treatment, the mean percentage changes from baseline for lumbar spine BMD were 
–1.2% (placebo), +0.4% (30 mg), +0.8% (60 mg) and +0.8% (150 mg). At the level of the total hip, the 
changes were –0.8% (placebo), +1.0% (30 mg), +1.2% (60 mg) and +1.6% (150 mg). Although the 
effects of raloxifene on lumbar spine and total hip BMD (except for the radius and total body BMD) 
and bone markers (except for the specific alkaline phosphatase in the raloxifene 30 mg group) were 
clearly distinguishable from placebo, the effects on lumbar spine BMD were weaker compared to study 
GGGF. Nevertheless, the effect of raloxifene 60 mg/day was statistically significant compared to 
placebo. Raloxifene 30 mg appeared to be less effective than 60 mg and 150 mg. 
GGGH was a study to establish the effects of long-term therapy with two doses of raloxifene or 
unopposed conjugated estrogen compared to placebo on BMD of the lumbar spine and total hip. 
Randomised patients received placebo (n=152) or raloxifene 60 mg (n=152), 150 mg (n=157), or 
conjugated equine estrogen 0.625 mg (n=158) o.d. 
After 24 months of treatment, the mean percentage changes from baseline for lumbar spine BMD were 
–1.6% (placebo), +0.2% (60 mg), +0.4% (150 mg) and +3.8% (estrogen). At the level of the total hip, 
the changes were –0.5% (placebo), +0.8% (60 mg), +0.5% (150 mg) and +2.4% (estrogen). 
At both doses, raloxifene had a weak, but statistically significant effect compared to placebo on lumbar 
and total hip BMD. However, the magnitude of the effect of estrogen was significantly greater. The 
actual “mean benefit” from raloxifene and estrogen compared to placebo was 1.8% and 5.0% 
respectively. A slight downward slope in the lumbar spine and total hip BMD curves was noted during 
the second year of raloxifene, but not in the estrogen groups. This was only observed at the 150-mg/day 


 
 
 
 
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doses, not at 30 mg/day, 60 mg/day or in other phase III studies. However, the mean BMD values 
remained at, or slightly above baseline for up to 24 months. Raloxifene and estrogen had similar effects 
on biochemical markers of bone metabolism, but the magnitude of the effect ofestrogen was also clearly 
more pronounced than that of raloxifene.  
Raloxifene has a well-documented effect compared with placebo on lumbar spine and total hip BMD. 
Although qualitatively the effects of raloxifene on BMD and biochemical markers of bone metabolism 
are similar to those of estrogen, their magnitude is less. Hence, evidence of fracture benefit in patients 
with osteoporosis was required, even for the proposed osteoporosis prevention claim. 
A 2-year interim analysis of an ongoing double blind, placebo-controlled phase III study in osteoporotic 
postmenopausal women was provided. This study enrolled a total of 7705 patients randomly assigned 
to one of three treatment groups: raloxifene 60 mg, 120 mg or placebo. Both postmenopausal women 
with osteoporosis and established osteoporosis (prevalent vertebral fractures) were included. The 
diagnostic criteria and evaluation for incident fractures are appropriate. 
Both raloxifene doses significantly reduced the proportion of patients having at least one incident 
vertebral fracture during 24 months of treatment compared to vitamin D and calcium supplemented 
placebo. The reduction in the risk of experiencing at least one incident fracture was in the range of 35% 
to 55% in patients with and without prevalent vertebral fracture at baseline, showing the same range of 
figures as those reported in observational studies evaluating the anti-fracture efficacy of estrogen (HRT). 
The 3-year analysis of this study was submitted in 1999 to support the extension of the indication to 
include treatment of postmenopausal osteoporosis. In contrast to estrogen, no data are currently available 
on the ability of raloxifene to prevent non-vertebral fractures. 
Similar efficacy related subgroup analyses were carried out in studies GGGF and GGGG. Raloxifene 
was observed to improve BMD regardless of BMI (Body mass index). Population pharmacodynamic 
analyses for the main efficacy studies supported the proposed dose of raloxifene 60 mg/day2. 
Effects on serum lipid profile 
Raloxifene has clear effects on serum lipid profile. At 60 mg/day, raloxifene decreases total cholesterol 
by approximately 3-6%, LDL cholesterol by 4-10%, HDL cholesterol by 1-4%, LDL/HDL ratio by 7% 
and total cholesterol/HDL ratio by 5% over 24 months. However, HDL cholesterol has decreased 
slightly more during placebo than raloxifene. Raloxifene does not affect serum triglyceride levels, which 
may increase during estrogen treatment. It also slightly decreased lipoprotein A and apolipoprotein B 
levels. Overall, the effects of raloxifene (60 mg/day) on serum lipids were similar to those of estrogen, 
but weaker. Raloxifene did not have adverse effects on lipid profile. In contrast to estrogen, no data are 
yet available to demonstrate the benefit of raloxifene on atherosclerotic cardiovascular disease. Similar 
efficacy related subgroup analyses carried out in studies GGGF and GGGG indicated that in smokers, 
the reduction in LDL cholesterol was less pronounced than in nonsmokers2. 
2.5.2. 
Main Phase III Osteoporosis Treatment Efficacy Study (GGGK) 
GGGK was a Phase 3, multicentre, double-blind, placebo-controlled, randomised clinical study which 
compared raloxifene 60 mg/day, raloxifene 120 mg/day and placebo in the treatment of postmenopausal 
women with osteoporosis or established osteoporosis. It was designed as a completed 36-month core 
treatment phase and a 12-month extension phase. It randomly assigned 7705 eligible patients to one of 
the three treatment groups (placebo, N=2576; raloxifene 60 mg, N-2557 and raloxifene 120 mg, 


 
 
 
 
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N=2572). All patients were supplemented with calcium and vitamin D. The study population was 
postmenopausal women (mean age 66.5 years) who had osteoporosis. 
GGGK was designed as two separate substudies. Substudy I included patients with osteoporosis by 
BMD criteria (BMD T-score <-2,5 in either the femoral neck or lumbar spine). Substudy II included 
patients who were osteoporotic by BMD and also had at least one moderate or 2 mild prevalent vertebral 
fractures or at least 2 moderate prevalent vertebral fractures regardless of BMD. Approximately twice 
as many patients were enrolled into Substudy I (n=5064) as into Substudy II (n=2641)2. 
Primary efficacy objectives of this study and each substudy were to assess the effects of raloxifene 60 
mg and 120 mg compared with placebo on incidence of new vertebral fractures and change and 
percentage change in lumbar spine (L1-L4) and femoral neck BMD. Additional secondary efficacy 
objectives included the effects of raloxifene compared with placebo on nonvertebral fractures, on total 
body and radial BMD, on biochemical markers of bone turnover, and on serum lipids and other markers 
of cardiovascular risk. 
Effects on bone 
Based on the three-year analysis of data from Study GGGK, each dose of raloxifene (60 mg and 120 mg 
per day) in each substudy statistically and clinically significantly decreased the proportion of women 
with at least one adjudicated new incident vertebral fracture vs placebo. In patients in Substudy I, 
raloxifene 60 mg-day was associated with a 47% reduction (RR 0.53, 95% CI 0.35, 0.79) in the risk of 
new vertebral fractures and raloxifene 120 mg/day was associated with a 38% risk reduction (RR 0.62, 
CI 0.44, 0.93). In patients in Substudy II, there was a 31% risk reduction (RR 0.69, CI 0.56, 0.86) with 
raloxifene 60 mg and a 49% risk reduction (RR 0.51, CI 0.40, 0.65) with raloxifene 120 mg. The 
proportion of women with at least one adjudicated incident vertebral fracture was statistically 
significantly lower in the 120-mg group than in the 60-mg group in Substudy II, but not in Substudy I. 
However, no statistically significant differences were observed between the raloxifene doses for the 
reduction of new clinical or multiple vertebral fractures in patients in Substudy II or I. Overall, raloxifene 
60 mg/day was associated with a 41% reduction and raloxifene 120 mg/day was associated with a 52% 
reduction in the risk of new clinically apparent vertebral fractures. The CPMP has agreed that the overall 
risk/benefit assessment favours the 60-mg dose over the 120-mg dose for the treatment of 
postmenopausal osteoporosis regardless of baseline disease severity. No effect on hip fractures has been 
demonstrated. 
Each dose of raloxifene in each substudy statistically significantly increased BMD at the lumbar spine 
and femoral neck by 2-3% vs placebo at 36 months. Total body and ultradistal radius BMD increased 
1-2% vs placebo at 24 months. The doses were equivalent in their effects on BMD in both patients with 
and without prevalent vertebral fractures. Raloxifene treated patients had 15 to 25% greater reductions 
in markers of bone turnover (osteocalcin, bone specific alkaline phosphatase and Urinary Type I 
Collagen Fragment/Cr) than placebo treated patients who had 10 to 20% reductions. Each dose of 
raloxifene in each study was effective in reducing skeletal turnover2. 
Effects on serum lipids and markers of cardiovascular risk 
In the osteoporosis treatment population, raloxifene also has clear effects on serum lipids and other 
markers of cardiovascular risk. Compared with placebo, raloxifene treated patients had consistent 


 
 
 
 
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decreases of 6 to 7%, 10 to 12%, 10 to 13% and 7 to 9% in total cholesterol, LDL-cholesterol, fibrinogen 
and Apolipoprotein B, respectively at 36 months. There were no effects of raloxifene on HDL-
cholesterol or glycosylated hemoglobin. While median percentage reductions in triglycerides were 
observed in raloxifene treated patients, the reductions were greater for the placebo group. A 3% increase 
in Apolipoprotein A was observed with raloxifene treatment compared with placebo. However, no data 
are available to demonstrate benefit of raloxifene on cardiovascular disease2. 
2.5.3. 
Safety 
Raloxifene is registered in EU with Centralized Procedures since 1998 for the treatment and prevention 
of osteoporosis in postmenopausal women with a recommended dose of 60 mg/day and is intended for 
long term use. This means more than 20 years in post-marketing exposure, in addition to extensive 
clinical studies in supporting the indication approved.  
Raloxifene safety profile is supported by a huge number of data from long-term treatments; more than 
7.700 post-menopausal women with osteoporosis have been exposed to raloxifene (the MORE Study) 
with a long follow-up period. 
In addition, as reported in the European SmPC, raloxifene therapy for 8 years did not significantly affect 
the risk of cardiovascular events in patients enrolled in the osteoporosis treatment study. Similarly, in 
the RUTH study (multinational, double-blind, randomized, placebo controlled trial conducted in 
postmenopausal women at risk for major coronary events) in which a total of 10,101 women were 
enrolled and randomized to one of two therapy groups, raloxifene did not affect the incidence of 
myocardial infarction, hospitalization acute coronary syndrome, stroke or overall mortality, including 
overall cardiovascular mortality, compared to placebo. The relative risk of venous thromboembolic 
events observed during raloxifene treatment was 1.60 (CI 0.95, 2.71) when compared to placebo, and it 
was 1.0 (CI 0.3, 6.2) when compared to estrogen or hormonal replacement therapy. The risk of a 
thromboembolic event was greater in the first four months of therapy.  
Then, other 19,747 postmenopausal women at increased risk of invasive breast cancer were included 
into STAR trial and the safety results were combined with the above-mentioned studies and enclosed in 
the current European SmPC3. Therefore, in this population the safety profile of Raloxifene is very well 
known and described into Patient Information approved by Regulatory Agencies. 
Even if not authorized for use in men, male subjects have been exposed and Raloxifene is well tolerated 
in men4. Given at the dose of 120 mg/day for 6 months to male healthy subjects, raloxifene increases 
levels of LH, FSH and total testosterone5. 
The safety profile was assessed also in special populations of patients (renal impairment, hepatic 
dysfunction). Risk of venous thromboembolic events is considered negligible for short term treatments 
and concomitant use of antiplatelet therapy. Regarding higher doses of raloxifene doses up to 600 
mg/day were used in clinical studies in healthy postmenopausal women. 
In several dose-ranging clinical studies (raloxifene 200 mg and 600 mg), no significant difference 
between active treatment groups was observed. The two doses of raloxifene demonstrated comparable 
efficacy, but the higher dose (600 mg) resulted in a greater frequency of hot flushes3. 


 
 
 
 
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Raloxifene up to 150 mg once-a-day or twice-a-day was used in clinical studies in postmenopausal 
women with osteoporosis to establish the effects of long-term therapy and prevention indication. 
In osteoporosis prevention the proportion of subjects treated with 150 mg/day Raloxifene reported 
accidental injuries3. 
Lastly, raloxifene (60 mg/day) + current standard of care (SOC) treatment at the time [i.e.pegylated 
interferon (PegIFN) α2a plus ribavirin (RBV)], has been used in Japan for the treatment of 
postmenopausal women with genotype 1b chronic hepatitis C. It improved the efficacy of SOC in the 
treatment of postmenopausal women with chronic hepatitis C and didn’t show an increase of the risks. 
Only one raloxifene -treated patient discontinued the drug because of a systemic rash following 2 weeks 
of treatment6. 
The assessment of safety should take the difference in the target population into consideration.  
Raloxifene is approved for the treatment and prevention of osteoporosis in postmenopausal women. It 
has been suggested that women with osteoporosis are at greater risk of venous thromboembolism (VTE) 
than non-osteoporotic patients7.  On the contrary, this is not the case for paucisymptomatic out-patients 
with COVID-19.  The lack of risk for VTE is reflected in the recommendations made for the 
management of such patients8: “In non-hospitalized patients with COVID-19, there are currently no data 
to support the measurement of coagulation markers (e.g., D-dimers, prothrombin time, platelet count, 
fibrinogen)” “For non-hospitalized patients with COVID-19, anticoagulants and antiplatelet therapy 
should not be initiated for prevention of venous thromboembolism (VTE) or arterial thrombosis, unless 
there are other indications”. 
In conclusion, raloxifene has been extensively studied and administered in the post marketing setting 
since 22 years, in post-menopausal women (long term use) with a resulting positive safety profile in the 
authorised conditions for use. The drug has also been studied in men, and no additional safety risk was 
highlighted. 
Although the safety profile of raloxifene in the treatment of COVID-19 is not known, considering the 
planned treatment duration (see the overall study design), the dosage and the target population 
(paucisymptomatic), no significant major risk could be anticipated. Safety will be closely monitored 
through the reporting and collection of adverse event and the timely evaluation of potential safety signal. 
The table below gives the adverse reactions and frequencies observed in treatment and prevention 
studies involving over 13,000 postmenopausal women along with adverse reactions arising from 
postmarketing reports. The duration of treatment in these studies ranged from 6 to 60 months. The 
majority of adverse reactions have not usually required cessation of therapy. 
The following convention has been used for the classification of the adverse reactions: very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), 
very rare (<1/10,000)3. 
 
Blood and lymphatic system disorders 
Uncommon: Thrombocytopenia a 
Nervous system disorders 


 
 
 
 
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Common:Headache, including migraine a 
Uncommon: Fatal strokes 
Vascular disorders  
Very common: Vasodilation (hot flushes) 
Uncommon: Venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, retinal 
vein thrombosis, superficial vein thrombophlebitis, Arterial thromboembolic reactions a 
Gastrointestinal disorders 
Very common: Gastrointestinal symptoms a such as nausea, vomiting, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash a 
Musculoskeletal and connective tissue disorders 
Common: Leg cramps 
Reproductive system and breast disorders 
Common: Mild breast symptoms a such as pain, enlargement and tenderness 
General disorders and administration site conditions 
Very common: Flu syndrome 
Common: Peripheral oedema 
Investigations 
Very common: Increased blood pressure a 
a Term(s) included based on postmarketing experience3.  
2.6. 
DISEASE REVIEW AND STUDY RATIONALE 
Coronaviruses (Covs) are a large family of viruses belonging to the family Coronaviridae. The limited 
number of coronaviruses known to be circulating in humans were considered to cause mild infections 
and they were regarded in the past as relatively harmless respiratory human pathogens. However, in the 
last years the emergence of the severe acute respiratory syndrome coronavirus (SARS-CoV) and the 
Middle East Respiratory Syndrome (MERS) virus revealed that some coronaviruses can cause severe 
and sometimes fatal respiratory tract infections in humans9. 
Investigations of the epidemiological and clinical characteristics, and outcomes of patients infected by 
SARS-CoV-2 demonstrated that the infection causes clusters of severe respiratory illness similar to the 
known SARS-CoV. The symptoms of human infection with SARS-CoV-2 are generally fever, fatigue, 
dry cough and dyspnea. Noteworthy, a considerable percentage of COVID-19 cases rapidly progress to 
severe and critical types, among which acute lung injury (ALI) and acute respiratory distress syndrome 
(ARDS) are the most common complications, resulting in a large number of pneumonia hospitalized 
patients requiring supplemental oxygen, mechanical ventilation, or even ECMO. Pulmonary edema is a 
detrimental feature as well as a key causal factor of ALI/ARDS. 
In this situation, new strategies that can mitigate the impact of COVID-19 on the National Health System 
are urgently needed. Specifically, these strategies should be aimed at: a) preventing patients with mild 
COVID-19 to progress towards severe/critical disease, for lightening the impact on hospitals; b) 
shortening time of viral shedding in order to curb individual infectivity and reduce the average number 
of secondary cases. At present, there are neither standard approaches nor approved drugs to care patients 
with COVID-19 and intensive care life-support therapies represent the only effective intervention to 
reduce mortality for patients with critical COVID-19. In addition, there are not standard approaches to 
care patients with mild to moderate COVID-19 related symptoms. Several antivirals have been currently 
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there are  a broad-spectrum inhibitor of viral RNA polymerase, Favipiravir (FAV) and Remdesivir. The 
proven antiviral efficacy of this drugs is generally limited in COVID-19 patients by the low 
bioavailability in lungs. 
From a clinical development perspective, the identification and development of new drugs is a lengthy 
process not adequate to face the emergency of the immediate global challenge generated by the COVID-
19 outbreak, so the repurposing approach of drugs already tested, “safe in man”, or already approved 
for different therapeutic uses is considered a rapid solution, since the pharmacokinetic, toxicological, 
and manufacturing data are available and validated for immediate application in clinical settings10.   
To this aim, the analysis of a compound library containing commercial drugs and clinical candidates 
“safe in man” or characterized up to late clinical stage was conducted to identify a number of molecules 
able to inhibit SARS-Cov-2 replication by using Computer Associated Drug Design (CADD) 
techniques, and in vitro screening and testing. 
In particular, E4C (Exscalate4CoV) is a public-private consortium supported by the European 
Commission’s Horizon 2020 programs for projects to counter the Coronavirus pandemic and improve 
the management and care of patients. At the core of E4C is Exscalate (EXaSCalesmArtpLatform Against 
paThogEns), at present the most powerful and cost-efficient intelligent supercomputing platform in the 
world able to screen extremely huge "chemical libraries" of 500 billion molecules, and process more 
than 3 million molecules per second, with the aim to predict and select the best molecules for further 
characterization. The combination of advanced CADD (Computer Associated Drug) with high 
throughput biochemical and phenotypic screening allows rapid evaluation and shortening of discovery 
time of new drugs, in an approach extremely useful in case of pandemic viruses and other pathogens, 
where an immediate response and the identification of effective treatments are of paramount importance. 
Exscalate supercomputing platform were found several promising molecules able to fight the SARS-
CoV-2, that shown low serum concentrations and high lung concentrations. Among these, raloxifene 
was found as promising molecule to treat paucisymptomatic COVID-19 patients. 
Raloxifene is the generic name of 1-[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-1-[4-[2-(1-
piperidinyl)ethoxy]phenyl]methanone and is a selective benzothiophene Estrogen Receptor Modulator 
(SERM) with lipid lowering effects and activity against osteoporosis, approved for the treatment and 
prevention of osteoporosis in postmenopausal women.  
Three main reasons support the rationale of using raloxifene against Convid19 infection. 
The first resides in the observed gender disparity in COVID-19 severe cases and in fatality rate that has 
been reported in China, where the infection rate among males and females was similar, but the death 
rate among males was 4.7% compared with 2.8% for females. Likewise, in Italy a higher death rate in 
male patients (14.8%) than in female patients (8.2%) was reported by the Italian National Institute of 
Health. 
Several factors, genetic, hormonal and behavioural, can contribute to the observed gender disparity, 
although experimental data are lacking so far. It is well-known that male and female subjects respond 
differently to many viral infections, or to pathogens in general due to a more intense and stronger 
immune responses, either innate and adaptive, to viral infection, that favours viral clearance. Sex 
hormones have shown to influence sex-specific response to viral infection by directly modulating 


 
 
 
 
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immune responses11. A recent paper reports results of a cross-sectional study of COVID-19 patients in 
China12 demonstrating that females have a better prognosis than males, non-menopausal women have 
shorter length of hospital stays, and AMH and estradiol are negatively correlated with COVID-19’s 
severity. Further, there is a negative correlation between estradiol and the levels of IL-6, IL-8, IL-2R 
and TNF-α, which are significantly correlated with disease severity or composite endpoint. 
It has to be noted that estrogen is able to upregulate the expression of ACE2, the functional receptor for 
SARS-CoV as well as for the recently identified SARS-CoV-2. A recent publication potentially 
correlates sex hormones to disease severity by relating pre-existing chronic diseases and insulin 
resistance to defective ER signalling in humans13. 
In animal models, ERα knockout mice of both sexes present insulin resistance, glucose tolerance and 
obesity, all comorbidities associated with COVID-19 aggravation14. 
Previous results in literature (both animals and humans) highlight sex-specific differences in 
susceptibility to SARS-CoV and perhaps other coronavirus infections.  Experimental studies in male 
and female mice infected with SARS-CoV, have shown that male mice have a higher susceptibility to 
SARS-CoV infection and a higher mortality, compared to females, consistently with the human disease.  
Ovariectomy in female mice or treatment with estrogen antagonists increased the death rate of females, 
which could be rescued by treatment with agents belonging to SERM class. Those experiments in animal 
models emphasized an evident protective role of estrogens in coronavirus infection, and a protective 
action of SERM in a relevant in vivo model. The results are consistent with the sex-bias observed in 
human SARS-CoV-2 infections and provide mechanistic insights into the differences in disease severity 
in men and women15. 
Scientific literature highlights sex differences in immune response and its influence on the incidence 
and severity of diseases. Considering trauma, shock, and infection, the female sex is associated with 
advantageous outcomes. Since the hormonal context exerts an important influence on the homeostasis 
control and the defense mechanisms, it is important to consider the beneficial effects and pleiotropic 
role of estrogens with regard to providing better control of defense and the different immune cells 
involved, in addition to cardiovascular system protection and flow maintenance16. 
Direct and indirect mechanisms underlying the effects of these compounds were investigated, both in 
relevant preclinical models17 and in clinical trials (NCT04359329), and the results show a possible 
positive effect in viral infections suggesting that estradiol and estrogen-related compounds could play a 
major role in antiviral therapies for SARS-CoV-2 as potential new agents to treat COVID-19 patients. 
The second resides in the well described and documented antiviral activity of raloxifene. In particular 
the antiviral activity of SERMs (Estrogen Receptor Modulator) were mainly focused on three infections: 
human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Ebola virus (EBOV). Tamoxifen, 
first generation SERM, was found active against HIV, HCV, and herpes simplex virus 1 (HSV-1)18. The 
antiviral rationale has been further confirmed in models of SARS-CoV and MERS-CoV where classical 
SERMs showed the capacity to delay virus infection, in a similar way to what was seen with Ebola virus 
infection19 for which hypotheses of mechanism of action were also generated20, thus highlighting the 
evidence that estrogen and estrogen-related compounds can play a relevant role in antiviral therapies 
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The third resides in data obtained so far through the repositioning programs, with specific deepenings 
on Raloxifene interaction with Covid proteases, the validation of a poly-pharmacology hypothesis, and, 
finally, the in vitro characterization. 
Indeed, E4C (Excalate for Covid) selected, by using an integrated approach between the EXSCALATE 
platform and the virtual screening protocols, raloxifene as a clinical candidate against SARS-CoV-2, 
predicting the high probability of the drug to interact with the main SARS-CoV-2 protease, the 3C-like 
protease, as main result of the parallel screening on different SARS-CoV-2 target’s proteins. 
Moreover, the potential of raloxifene in the treatment of COVID-19 with a specific focus on the 
mechanisms underlying the observed drug effect and complex interactions within biological systems 
involving SERMs has been explored. Specifically, raloxifene and its activity against SARS-CoV-2 have 
been evaluated with the aim to validate a poly-pharmacology hypothesis.  
Two systems were considered: 
a. Genes identified in GWAS (Genome-Wide Association Study) as relevant for viral response. 
They are: ANKRD32, CDRT4, PSMD13, ERO1L, LZTFL1, XCR1, FYCO1, IFNAR2, 
CXCR6, CCR9, AP000295.9, AK5 
b. Molecular networks so far identified of SARS-CoV-2-host interactome (359 elements) and 
consensus on the modulated expression during SARS-CoV-2 infection (14052 elements) (in the 
figure below the SARS-CoV-2-host interactome is reported; in red the viral proteins).  
 
 
The following 3 molecular pathways are believed to be mainly involved and attributable to raloxifene:  
1. A pathway including the genes modulated by raloxifene molecular target, specifically ESR2, 
and connected with inflammation; 


 
 
 
 
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2. A pathway including the genes expressed in the lungs, modulated by raloxifene molecular 
target, specifically ESR that, when deregulated, are linked to severe asthma, in agreement with 
the genes enrichment in GWAS studies whose unfavourable variants cause worse respiratory 
consequences; 
3. A pathway directly modulated by the virus, both during the cell entry phase and replication 
phase, where the virus not only binds some cell proteins, but they are upstream of other proteins 
modulated by expression in the 14052 element consensus network, and downstream of the 
raloxifene-controlled pathways. 
Finally, Raloxifene was tested on SARS-CoV 2 VeroE6 cells for antiviral assay. This assay is based on 
viral infection of VeroE6 cells followed by monitoring of cytopathic and antiviral effects. Data were 
generated by two different groups and in both cases an IC50 value in 1-5 microMolar (M) range was 
determined.  
This value is the best value so far found within the class of SERMs, and is in line with in vitro outcomes 
from previous experiments conducted with raloxifene on other viruses. To be noted that the range of 
activity of Raloxifene (1-5 M) perfectly suits with the distribution of raloxifene in tissue (in particular 
lungs). Indeed, despite a low serum bioavailabily, raloxifene concentrated at tissues level and exerts its 
cytopathic and antiviral effects, overcoming some of the limitations showed by other antiviral drugs 
currently in use as remdesivir, that reaches low levels in lungs. 
2.6.1. 
Alternative treatments 
Nowadays there are no approved drugs for the treatment of paucysimptomatic COVID-19 patients.  
2.6.2. 
Risk - benefit evaluation 
The clinical pharmacology of raloxifene has been adequately studied. The minimum effective dose was 
not reliably established by the short-term dose ranging studies. 
In 3 well conducted, double blind clinical trials, the primary and secondary criteria of efficacy are 
relevant. Raloxifene was statistically significantly superior to placebo (calcium supplementation only) 
with respect to the primary efficacy criteria. Although the three-raloxifene doses examined (30, 60 and 
150 mg) were not statistically different and the dose response relationship was weak, the population 
pharmacodynamic analyses support the proposed raloxifene dose of 60 mg/day. Qualitatively the effects 
of raloxifene on bone mineral density and resorption are similar to those of estrogen, but of lesser 
magnitude. Moreover, a reduction in the risk of incident vertebral fractures has been demonstrated in 
women with osteoporosis compared to placebo. 
In studies involving over 2000 women with a treatment duration ranging from 2-24 months, the majority 
of undesirable effects did not usually require cessation of therapy. Discontinuation of therapy due to any 
clinical adverse experience occurred in 10.7% of 581 raloxifene-treated patients and 11.1% of 584 
placebo-treated patients. The treatment-emergent events associated with the use of raloxifene that 
occurred with a significant difference between raloxifene and placebo treatment were: venous 
thromboembolic events (occurred in a frequency of 0.8%), superficial vein thrombophlebitis, modest 
increase of vasodilatation (hot flushes), leg cramps and peripheral oedema. 


 
 
 
 
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When comparing raloxifene patients (n=317) with continuous combined HRT (n=110) or cyclic HRT 
(n=205) patients in some clinical trials, the incidence of breast symptoms and uterine bleeding in 
raloxifene treated women was significantly lower than in women treated with either form of HRT. 
Raloxifene does not have adverse effects on the lipid profile. No clinically significant changes in vital 
signs and safety laboratory tests have been seen. 
The Phase III study GGGK showed that at 36 months raloxifene 60 mg/day and 120 mg/day statistically 
and clinically significantly decreased the proportion of women with at least one adjudicated new incident 
vertebral fracture vs placebo regardless of baseline disease severity. Both raloxifene 60 mg and 120 mg 
effectively increased lumbar spine, femoral neck and total body BMD and decreased markers of bone 
turnover. Raloxifene significantly decreased LDL cholesterol and other intermediate markers of 
cardiovascular disease (fibrinogen) without a concomitant rise in serum triglycerides.  
Raloxifene, in the osteoporosis treatment population, did not induce endometrial proliferation or vaginal 
bleeding and was not associated with an increased risk of uterine or endometrial malignancy. Raloxifene 
did not cause breast pain and was associated with a reduction in the risk of breast cancer (median 
duration 40 months). Vasodilatation and leg cramps were side effects also observed in thispopulation. 
The only serious risk was that of VTE and the risk continues to be similar to that reported for estrogen 
use. Current or past history of VTE is a contraindication to raloxifene therapy.  
The CPMP agreed that the benefit/risk was positive for the proposed indications. It was also concluded 
that the overall risk/benefit assessment favours the 60 mg dose over the 120 mg dose. Therefore the 
CPMP considered that the data presented were sufficient to recommend that the indications prevention 
and treatment of postmenopausal osteoporosis should be granted. 
In March 2003, the sections 4.4 and 5.1 of the SPC were updated on the basis of the cumulative four 
years results on new clinical safety and efficacy data of the MORE (Comparison of Raloxifene 
Hydrochloride and Placebo in the Treatment of Postmenopausal Women With Osteoporosis) study. The 
study confirmed that treatment with raloxifene for 4 years decreased the rate of new vertebral fractures 
by 46% in osteoporotic patients. In addition, in the 4th year alone, raloxifene reduced the new vertebral 
fracture risk by 39% (during the 4th year, patients were permitted the concomitant use of 
bisphosphonates, calcitonin and fluorides). There was no significant difference in the number of 
nonvertebral fractures. A cumulative analysis also showed a reduction of clinical vertebral fractures.  
No indicators for an increased risk of malignant endometrial tumours were shown. The overall rate of 
breast cancer was reduced in the raloxifene groups as compared to the placebo group. raloxifene 
treatment compared to placebo reduced the risk of total breast cancer by 62%, the risk of invasive breast 
cancer by 71% and the risk of invasive estrogen receptor (ER) positive breast cancer by 79%. The 
decrease was explained by the decrease of ER-positive (invasive) tumours.A significant increase in the 
number of venous thromboembolic events was seen in the raloxifene groups, especially in the early 
phase of the treatment. However, this risk is already acknowledged in the SPC. No significant 
differences between the groups were seen in the ECG and in the reporting of clinical cardiac and 
cerebrovascular events. There were favourable changes in the lipid profile, except for a small increase 
in serum triglycerides. 


 
 
 
 
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Hormone replacement therapy aggravates certain complications of pelvic floor relaxation, but safety 
information following 3 years of raloxifene treatment supported that raloxifene treatment did not 
increase pelvic floor relaxation and pelvic floor surgery. 
Potential benefit of Raloxifene in COVID-19 patients treatment 
Distribution of oral raloxifene is concentrated into body tissue with relevant levels in lungs, kidneys and 
liver, where they are higher than in serum21. Raloxifene exerts its pharmacological activity at very low 
circulating concentrations (nM) but with wide distribution in the tissues22 and high concentrations 
reached in non-reproductive tissues highly sensitive to viral infections, like lungs where the drug has a 
better distribution than Remdesivir, thus suggesting that a targeted distribution and concentration of 
raloxifene into the lungs can be achieved together with parallel minimization of side effects due to 
distribution in unwanted organs. High need exists of anti-COVID-19 drugs with good distribution into 
lungs23 to optimize tissue distribution and maximize the inhibition of viral replication.  
Taken together, these data suggest that ER modulation may be a suitable pharmacological approach for 
preventing/attenuating the cytokine storm and inflammation associated with COVID-19 and in 
particular the use of SERMs, specifically raloxifene, may represent a promising pharmacological option. 
Such a therapeutic approach would be particularly useful for treatment of both male and female patients 
in early phase with mild/moderate symptoms of the disease, in order to prevent or mitigate the possible 
evolution towards more serious and dangerous forms of the disease, due to the onset of the cytokine 
storm. 
Furthermore, given the encouraging data obtained with raloxifene so far, if the ability of raloxifene to 
reduce the mean time of viral shedding in COVID-19 patients who did not show yet severe symptoms 
(paucisymptomatic patients), is confirmed, it could certainly help to reduce the risk of a second epidemic 
wave.  
2.6.3. 
Description of the Investigational Product 
 
Raloxifene is the generic name of 1-[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-1-[4-[2-(1-
piperidinyl)ethoxy]phenyl]methanone, having the below chemical structure: 
 


 
 
 
 
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The compound is a selective benzothiophene Estrogen Receptor Modulator (SERM) with lipid lowering 
effects and activity against osteoporosis, approved for the treatment and prevention of osteoporosis in 
postmenopausal women. Raloxifene is the active ingredient of branded (Optruma®-Eli Lilly or Evista®-
Daiichi Sankyo) or generic drugs (RaloxifeneTeva), and is marketed as 60 mg oral tablets. The drug is 
registered in Europe since 1998 for the treatment and prevention of osteoporosis in postmenopausal 
women, and in the US is registered since 1997 for treatment and prevention of osteoporosis and 
reduction of risk of invasive breast cancer in postmenopausal women. 
Mechanism of action 
Raloxifene is a second-generation SERM with a double activity as estrogen agonist in some tissues 
(bone, lipid metabolism) and estrogen antagonist in others, like endometrium and breast, producing 
some of the estrogen’s beneficial effects without producing its adverse events. Raloxifene decreases 
bone resorption and overall bone turnover, thus increasing bone density with little or no effect on the 
endometrium, resulting in no predisposition to uterine cancer. The drug is able to lower total cholesterol 
LDL in the serum, with no effect on HDL. 
Raloxifene, like Estradiol (E2), crosses the cytoplasmic membrane and the nuclear membrane and binds 
to the Estrogen Receptor (ER) in the nucleus. The benzothiophene ring of raloxifene binds to the ER 
with a comparable affinity to E2. The rationale for the estrogen antagonist effects of the drug on uterine 
and breast tissues could reside in the ER blockade mediated by raloxifene. 
In bone and in other non-reproductive tissues, raloxifene bound to ER (RLX-ER) should activate a 
specific sequence of DNA known as the Raloxifene Responding Element (RRE), a group of genes that 
regulates the synthesis of specific cell proteins responsible for the estrogen agonist effect of the drug in 
these non-reproductive tissues. In addition, raloxifene exerts two other direct actions on bone tissue: 1) 
decrease up to 50% of interleukin-6 (IL-6) production and 2) decrease up to 30% of the production of 
tumor necrosis factor α (TNF-α). 
 


 
 
 
 
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3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN 
3.1. 
STUDY OBJECTIVES 
 
The objective of this study is to evaluate the efficacy and safety of two different doses of raloxifene 
orally administered compared to placebo in patients with early diagnosis of paucisymptomatic COVID-
19. Efficacy will be assessed based on the proportion of patients with undetectable SARS-CoV-2 at day 
7 after randomization and the proportion of patients who requires supplemental oxygen therapy and/or 
mechanical ventilation by day 14 after randomization. Safety will also be assessed. 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE 
This study will be performed in clinical centers located in Europe (Italy, France, Spain). At each study 
center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted 
according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.  
The PI at each study center will be responsible for the management of the study, which will consist of 
maintaining the study file and the patient records, corresponding with the IRB/IEC, and completing the 
electronic case report form (eCRF) and reporting SAEs within 24 hours of initial awareness.  
 
The PI is responsible for supervising any individual or party to whom the investigator delegates trial 
related duties and functions conducted at the trial site. If the investigator/institution retains the services 
of any individual or party to perform trial-related duites and functions, the investigator/institution should 
ensure this individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated. 
3.3. 
OVERALL STUDY DESIGN 
 
This clinical study will be a multicenter, adaptive, double-blind, randomized, placebo controlled, parallel-
group, to study efficacy and safety, with the following adaptive components: 
 
- 
Parallel multi-arms (2 interventional arms and 1 placebo control arm); 
- 
A 2-stage sequential design (1 interim analyses + 1 final analysis); 
- 
Sample size re-calculation at interim stage; 
- 
Stopping rule for efficacy or futility at interim stage. 
 
The study will be a total of 5 weeks in duration: a screening period of 7 days, followed by 2 weeks of 
double-blind treatment and a 2-week follow-up period. At the end of the screening period, patients 
meeting the entry criteria for this study will be randomized (1:1:1) to 1 of 3 treatment groups (group 1, 
group 2 or group 3) and instructed by a physician on the correct self-administration of the treatment and 
completion of the patient diaries. 


 
 
 
 
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After an administration of two oral doses in the first day of treatment (one dose in the morning and one 
dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or 
placebo), a single daily oral dose of raloxifene (60 mg Group 1, 120 mg Group 2 – treatment groups) or 
placebo (Group 3 - control group) will be take on by the patients for two weeks.  
Treatment groups: 
- 
Group 1: will receive one capsule of raloxifene 60 mg and 1 capsule of placebo. 
- 
Group 2: will receive two capsules of raloxifene 60 mg.  
Control group: 
- 
Group 3: will receive two capsules of placebo. 
Following the completion of the double-blind treatment or premature discontinuation during the double-
blind phase, patients will be followed up for safety assessments until the planned last study visit. In case 
of early treatment termination an End of Follow Up will be seeked at the same timepoint.  
 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study 
A double-blind study design was adopted to minimize systematic bias. Randomization is expected to 
minimize patient selection bias and increase baseline comparability between treatment groups. The use 
of placebo control is critical to the study design for, providing an accurate estimate of the additive benefit 
of pharmacotherapy.  
Even if the actual dosage form of raloxifene approved for the treatment of osteophorosis is 60 mg, due 
to its well assessed safety profile (for 60 mg and 120 mg), for the execution of this study will be used 
also the raloxifene 120 mg, for a total of 3 treatment arms (see section 2.5). 
The group sequential design includes 3-arm 2-stage procedure allowing for early stopping rule according 
to efficacy and futility of at least one active arm. In case of continuation after interim analysis, the actual 
number of new participants will be calculated according to the observed efficacy of the best favourable 
and promising arm at the interim analysis. 
Patients with insufficient therapeutic response, tolerability issues, or worsening of symptoms may be 
discontinued at any time during the study. 


 
 
 
 
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4. 
SELECTION OF STUDY POPULATION 
For the purpose of the study the following definition are applied. 
A case of COVID-19 is a person with SARS-CoV-2 infection as determined by an approved molecular 
test (PCR) from an adequate sampling of upper respiratory tract irrespective of clinical signs and 
symptoms. 
A paucisymptomatic case of COVID-19 who does not need immediate admission to hospital and has a 
national early warning score (NEWS) ≤ 2. 
NEWS score has been revised on 2019 by England and Wales National Health Service as following24: 
 
Element 
Score 
3 
2 
1 
0 
1 
2 
3 
Respiratory rate 
≤ 8 
 
9-11 
12-20 
 
21-24 
≥ 25 
SpO2 
≤ 91 
92-93 
94-95 
≥ 96 
 
 
 
Oxygen 
 
Yes 
 
NO 
 
 
 
Systolic Blood 
Pressure 
≤ 90 
91-100 
101-110 
111-219 
 
 
≥ 220 
Pulse 
≤ 40 
 
41-50 
51-90 
91-110 
111-130 
≥ 131 
ACVPU 
 
 
 
A 
 
 
C,V,P,U 
Temperature, oC 
≤ 35.0 
 
35.1-36.0 
36.1-38.0 
38.1-39.0 
≥ 39.1 
 
 
ACVPU: Alert, Confusion, Voice, Pain, Unresponsive 
 
 
4.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria. 
1. Subject autonomously provides informed consent prior to initiation of any study procedures;  
2. Males and females > 40 years old at time of enrolment; 
3. Understands and agrees to comply with planned study procedures, has the availability of an 
email address as well as an Internet connection at the domicile location;  
4. Agrees to the collection of nasopharyngeal swabs and venous blood samples per protocol; 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by an approved molecular test 
(PCR) in Europe within 10 days at the screening time; 
 
6. Patient paucisymptomatic who complains at the screening time at least one of the following 
symptoms mild to moderate: fever, dyspnea, headache, cough, dysgeusia, conjunctivitis, 
vomiting, diarrhea, anosmia, muscle or body aches or other symptoms which in the opinion of 
the Investigator are part of the COVID-19 clinical picture; 


 
 
 
 
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7. No need of supplemental oxygen therapy, mechanical ventilation;  
8.  Females of child-bearing potential and with an active sexual life must not wish to get pregnant 
within 30 days after the end of the study and must be using at least one of the following reliable 
methods of contraception: 
a. Hormonal 
contraception, 
systemic, 
implantable, 
transdermal, 
or 
injectable 
contraceptives for at least 2 months before the screening visit until 30 days after final 
visit 
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or 
contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap 
with spermicide for at least 2 months before the screening visit until 30 days after final 
visit 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 1 
year will be admitted. For all female subjects, with child-bearing potential, pregnancy test result 
must be negative before first drug intake, on T7 and T14. 
 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study. 
1. Being totally asymptomatic at the screening time;  
 
2. Requires supplemental oxygen therapy or mechanical ventilation; 
 
3. Being already under raloxifene or other SERM treatment for another medical condition at the 
time of randomization; 
 
4. Being concurrently involved in another trial with IP or participation in any clinical trial with 
IP for 1 months before this study. The 1-month interval is calculated as the time between the 
last visit of the previous study and the first day of the present study (date of the informed 
consent signature); 
 
5. Clinically significant abnormal physical findings which could interfere with the objectives of 
the study; 
 
6. Diseases: 
a) history of stroke and/or venous thromboembolism; 
b) known moderate / severe renal impairment: Chronic Kidney Disease (CKD) stage 3 or 
higher; 
c) known liver disease (Child-Pugh Class A or higher); 
d) presence of known hypoalbuminemia; 
e) endometrial bleeding; 


 
 
 
 
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f) signs or symptoms of endometrial cancer;  
 
7. Autoimmune diseases receiving therapy at the time of randomization; 
 
8. Risk of venous thrombosis or any condition/disease that could bring to an extended period of 
immobilization; 
 
9. Ascertained or presumptive hypersensitivity to the active principles (raloxifene) and/or 
excipients or allergic reactions in general, which the Investigator considers may affect the 
outcome of the study; 
 
10. Medications: in particular cholestyramine (or any ion exchange resin), medications used in 
treatment of early or advanced breast cancer (including adjuvant therapy), warfarin, any drug 
that cannot be co-administered with the experimental compound; 
 
11. Pregnancy:  
 
a) positive or missing pregnancy test before first drug intake or day 1; 
b) pregnant or lactating women; 
 
12. Women of childbearing potential and fertile men who do not agree to use at least one primary 
form of contraception for the duration of the study. 
 
 
4.3. 
ASSIGNMENT OF SUBJECT NUMBER 
All the subjects will sign the electronic informed consent, via GENIUS ENGAGE for the present 
study.  
Genius ENGAGE is the EXOM solution for the electronic Informed Consent (eICF) with multimedia 
tools like audio, video, and links, accessible through a any device like a mobile, tablet or laptop, fully 
integrated with the the eCRF. 
All the patients will be coded with “unique subject identifiers”. The unique subject identifier consists 
of the sponsor study code (i.e. study code), the 3-digit site number (i.e. 101), the 4-digit screening 
number (e.g. S001, S002, etc.).  
Study code, site number and screening number are separated by slashes (“/”). Randomization numbers 
will be assigned automatically via EXOM GENIUS IWRSTM.  
 


 
 
 
 
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5. 
STUDY MEDICATION 
5.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT 
After an administration of two oral doses in the first day of treatment (one dose in the morning and one 
dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance 
or placebo), a single daily oral dose of raloxifene (60 mg Group 1, 120 mg Group 2 – treatment groups) 
or placebo (Group 3 - control group) will be take on by the patients for two weeks. The patients will be 
randomly (1:1:1) assigned to receive either raloxifene treatment or placebo.  
Treatment groups: 
- 
Group 1: 
will receive one capsule of raloxifene 60 mg and 1 capsule of placebo. 
- 
Group 2: 
will receive two capsules of raloxifene 60 mg.  
Control group: 
- 
Group 3: will receive two capsules of placebo. 
5.1.1. 
Presentation of Investigational Medicinal Product 
The investigational product is in the form of oral 60 mg capsules containing the active ingredient 
raloxifene. Raloxifene 60 mg capsules are orange hard gelatine capsules, size 0. 
Raloxifene capsules contain the following excipients: sodium starch glycolate, citric acid monohydrate, 
microcrystalline cellulose, dibasic calcium phosphate, poloxamer 407, magnesium stearate, 
hypromellose, lactose monohydrate, titanium dioxide (E171) and macrogol / PEG 4000. 
Placebo capsules are orange hard gelatine capsules, size 0 containing the inert excipient microcrystalline 
cellulose. 
5.1.2. 
Manufacturing, Packaging and Labelling of IMP 
Raloxifene and Placebo capsules are packaged in PVC-ALU blisters in the form of patient kits, 
numbered to maintain blinding. Raloxifene and placebo capsules do not require special storage 
conditions. 
Raloxifene and placebo capsules are manufactured by STM PHARMA PRO S.r.l. according to current 
Good Manufacturing Practice requirements. 
Medication labels will comply with the Competent Authority requirements and will be printed in a 
Multilanguage format where needed.  


 
 
 
 
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The formulation labelling will report all the information requested according to the Annex 13 to the 
Good Manufacturing Practice (published by the Commission in The rules governing medicinal products 
in the European Community, Volume 4) as follows: 
a. Name, address and telephone number of the sponsor, contract research organisation or investigator 
(the main contact for information on the product, clinical study and emergency unblinding) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units 
c. The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and sponsor if not 
given elsewhere 
e. The study subject identification number/treatment number and where relevant, the visit number 
f. The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document intended for 
the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 
i. 
The storage conditions 
j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format and in a 
manner that avoids any ambiguity 
k. “Keep out of reach of children” 
Labels will be in local language. 
The hospital pharmacist (Investigators in those countries where it is required that shipment is made 
directly to them) is responsible for receipt, proper storage and delivery of study drug to qualified and 
duly authorized study nurse. Partially used or unused study drug boxes should be destroyed on site (and 
documentation of destruction provided to Dompé farmaceutici s.p.a.) or returned to Dompé farmaceutici 
s.p.a., at the end of the study. The Hospital Pharmacist or Investigator, who will keep a cumulative 
inventory and dispensing records, will maintain all supplies under adequate security. Adequate record 
of receipt, use or loss of drug will be retained. 
 
5.1.3. 
Supply, Storage and Handling of IMP 
An appropriate number of packages will be initially sent to the Hospital Pharmacy as soon 
regulatory/ethics approvals have been obtained and a financial agreement has been signed with the site. 
IMP re-supply will be planned on demand, according to enrolment rate.  
The IMP must be kept at a temperature not exceeding 30°C and must not be frozen.  
A temperature probe will accompany the drug on shipment. Temperature range reached during shipment 
will be verified on receipt, so that potential stability concerns during shipment can be investigated and 
appropriate action taken. 
Once received at the Hospital Pharmacy, the Pharmacist (or designee) will check the package and 
acknowledge the receipt; any deviations from expected package content (inconsistency, damages) 


 
 
 
 
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should be immediately reported to Dompé (or designee) and the use of the drug suspended until 
authorization for its continued use has been given by Dompé (or designee).   
The IMP must be stored in a secure location, in a temperature controlled room. Temperature records 
must be available for the CRA to review; any deviations from the recommended storage conditions 
should be immediately reported to Dompé (or designee) and the use of the drug suspended until 
authorization for its continued use has been given by Dompé (or designee). 
Treatment Box will be brought to the patient's domicile by a properly qualified and duly authorized 
study nurse once randomized. Each patient will receive the Treatment Box matching his/her 
randomization number. 
5.1.4. 
Blinding 
Appearance, including packaging and labelling, of the IMP (capsules, packaging) will not allow to 
recognize actual treatment (either raloxifene or placebo). 
As described in Section 8.8, during the trial, blinding may be broken by the Investigator for emergency 
purposes only, where knowledge of the blinded treatment could influence further patient care. 
Unblinding will be performed by Sponsor Pharmacovigilance for safety reasons and in case of Serious 
Adverse Events qualifying for regulatory reporting (SUSAR), in line with regulatory requirements. 
Study blind will be broken after database lock. 
5.2. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
The experimental treatment will be orally self-administered by the patients who signed the electronic 
informed consent.  
After an administration of two oral doses in the first day of treatment (one dose in the morning and one 
dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or 
placebo), a single daily oral dose of raloxifene (60 mg Group 1, 120 mg Group 2 – treatment groups) or 
placebo (Group 3 - control group) will be taken on by the patients for two weeks.  
Treatment groups: 
- 
Group 1: will receive one capsule of raloxifene 60 mg and 1 capsule of placebo. 
- 
Group 2: will receive two capsules of raloxifene 60 mg.  
Control group: 
- 
Group 3: will receive two capsules of placebo. 


 
 
 
 
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5.3. 
ACCOUNTABILITY OF THE IMP 
All IMP supplies will be accurately and adequately accounted for, from receipt at the depot up to deliver 
to the patients; each step will be recorded in study-specific documents, as detailed below, that will be 
available for verification by the CRA at each monitoring visit.    
Drug accountability records at the depot level will include: 
1. Shipment/receipt confirmation of the IMP at the depot of the logistic provider, as per documentation 
provided by or on behalf of Dompé. 
2. IMP stored at the depot at any time as per IMP Accountability Log, to include IMP received, 
delivered to the patients, accidentally destroyed, or disposed of at expiration or at the end of the trial. 
3. IMP delivered to each patient/treatment cycle, as per the eCRF. 
The administration of the IMP (date/time for each administration) will be recorded by the patient on an 
electronic patient Diary.  
eDiary data will be collected via dedicated tele-medicine platform named EXOM Genius ROSA. 
This is a dual way (Investigator - Patient) private, study specific, fully encrypted, multichannel 
application for remote patient visits and monitoring. It is 21 CFR Part 11 & GDPR compliant and ISO 
27001 Class IIA medical device. 
eDiary data will be then transferred directly to the eCRF and will be checked in a timely manner by the 
Investigator. 
All the records will include, as appropriate: dates, quantities (kits, treatment boxes, blisters, capsules), 
batch numbers, expiration dates (if applicable), and any unique code numbers assigned to the IMP and/or 
patients, so that the following can be adequately documented: 
- the patients were provided with the doses specified by the protocol/amendment(s), 
- the IMP provided to the site has been fully reconciled at the site. 
The CRA will review the IMP records above and check actual content of IMP boxes/blisters (both 
unused and used) and will reconcile quantities up to the level of capsules, prior to making arrangements 
for their disposal. 
Any IMP supply remaining at the end of the trial will be returned to Sponsor or its delegate or disposed 
of on site. 
5.4. 
CONCOMITANT MEDICATION 
5.4.1. 
Prior and concomitant medications 
All concomitant medications taken by the patients during the Screening will be recorded by the 
Investigator in the eCRF. 
All the concomitant medications (administration started after the first dose of IMP up to the end of trial 
participation) will be recorded by the patient on the electronic patient Diary and reported in the 
appropriate section of the eCRF.  


 
 
 
 
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All the details as per the eCRF fields (sequential number, drug name, indication, starting dose, start/stop 
date, route of administration) will be recorded. No change in dose will be tracked. 
The following agents do not need to be recorded: homeopathic medications; elective vitamins and 
minerals; osmotic laxatives and locally acting antacids; topical medication. 
 


 
 
 
 
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6. 
STUDY PROCEDURE AND ASSESSMENTS 
A schedule for the tests and evaluations to be conducted in this study is found in the Schedule of 
Evaluations (See section 2). Details are reported below. Any deviation from these protocol procedures 
will be reported in the study-specific Protocol Deviation (PD) form. 
For all measurements, the actual date and time of assessment, including date of sampling and self-
monitoring assessment, will be recorded in the eCRF. Where a time window is acceptable, this is clearly 
indicated in the following sections. 
6.1. 
SCREENING AND RANDOMIZATION VISITS 
6.1.1. 
Randomization 
 
Patients will be randomized in a 1:1.1 fashion to either: 
GROUP 1 (1 capsule of raloxifene 60 mg and 1 capsule of placebo) 
GROUP 2 (2 capsules of raloxifene 60 mg) 
GROUP 3 (2 capsules of placebo) 
The randomization groups will be generated with a computer procedure by the method of random 
permuted blocks. The randomization system GENIUS IWRS will be prepared and implemented by the 
CRO and the platform will be part of the eCRF. The randomization platform includes also a special 
functionality for electronically obtaing the code breaking in case of an urgent medical need.  
Moreover as a backup unblinding procedure, each site will be provided with sealed evenvelopes 
containing the name of the assigned treatment. 
Similarly, the randomization list will be provided to the facility responsible for IMP packaging/labelling 
for the purpose of IMP preparation. 
The randomization code will be broken at study completion, i.e. when the last patient has completed 
his/her last follow-up visit, and once the database has been locked. 
 
6.2. 
STUDY VISITS AND FOLLOW-UP ASSESSMENTS 
Since all paucisymptomatic patients with COVID-19 must remain in trust isolation at home or at an 
appropriate location, a specifically trained and authorized team of study nurses will take care of 
collecting blood samples and nasopharyngeal swabs at patient’s domicile. 
For each patient the study will be a total of 5 weeks in duration: a screening period of 7 days, followed 
by 2 weeks of double-blind treatment and an 2-week follow-up period. Three months after the 
randomization patients will be asked to fill in a Quality of life questionnaire. 
At the end of the screening period, patients meeting the entry criteria for this study will be randomized 
(1:1:1) to 1 of 3 treatment groups (group 1, group 2 or group 3) and instructed on the correct self-
administration of the treatment, self measurements of blood pressure, heart rate, transdermal oxygen and 
body temperature through individual medical devices and completion of the patient diaries. 


 
 
 
 
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After an administration of two oral doses in the first day of treatment (one dose in the morning and one 
dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or 
placebo), a single daily oral dose of raloxifene (60 mg Group 1, 120 mg Group 2 – treatment groups) or 
placebo (Group 3 - control group) will be taken on by the patients for two weeks.  
After the treatment period patients will record in the patient diary their parameters self measured (blood 
pressure, heart rate, transdermal oxygen and body temperature) for an 2-week follow up period. 
 
Three months after the randomization patients will be asked to fill in a Quality of life questionnaire. 
 
6.2.1. 
Treatment arms 
Treatment groups: 
- 
Group 1: will receive one capsule of raloxifene 60 mg and 1 capsule of placebo. 
- 
Group 2: will receive two capsules of raloxifene 60 mg.  
Control group: 
- 
Group 3: will receive two capsules of placebo. 
 
6.2.2. 
Standard Patient monitoring 
All patients will daily self-monitor their parameters and may call the Investigator if needed. In case the 
enrolled person cannot perform the daily self-monitoring, a close relative may support him, provided 
that all possible preacautions and safety devices are used. Patients will be provided with individual 
electronic device for measuring blood pressure, heart rate, body temperature and transdermal SpO2. 
Patients will be also provided with an electronic patient diary in which report the information about the 
daily drug self-administration, the above mentioned parameters recorded, the AEs (if any) and the 
concomitant medications (if any). 
 
The Investigator will remotely regularly assess NEWS and evaluate the need for immediate visit or 
hospitalization.  
 
The Investigator will contact the General Practitioner who will decide to directly involve emergency 
service for immediate visits for critical patients presenting: 
 
A. SpO2 ≤ 95%;  
B. Systolic blood pressure >180 mmHg or <100 mmHg  
C. Body temperature >39°C or less than 35.0 °C;  
D. Heart rate >110 bpm or less than 40 bpm;  
E. Sensorial deterioration according to doctor’s judgment.  
 
Patients will receive a Study Nurse visit at the day 0, 7, 14, 21 and 28.  
At day 7, 14, 28 patients will be tested for viral shedding. At day 0, 7, 14 patients will undergo pregnancy 
test (female only). At day 0, 7, 14, 21, 28 patients will undergo blood test including hepatic function, 
renal function, coagulation, LDH, CPK and complete blood counts. 


 
 
 
 
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Venous blood samples (⁓ 20 mL) will be collected from a forearm vein. 
Healthcare workers approaching COVID-19 patients will use personal protective equipment including 
a FFP3 (or FFP2) mask, gloves, gown and googles. FFP3 should be used always in case of any procedure 
on respiratory tract (including nasopharyngeal swab). 
6.2.3. 
Other therapies allowed 
Any concomitant medication that the participant receives during the participation in this study will also 
be recorded (see Sections 5.4.1 and 6.2.2.). Specifically, dose, posology, frequency of administration, 
start and end date and reason of use will be required and collected. 
As for SmPC the following medications are not allowed as concomitant medications: cholestyramine 
(or any ion exchange resin), medications used in treatment of early or advanced breast cancer (including 
adjuvant therapy), any antiretroviral medication, warfarin or other coumarin derivatives (the 
combination with raloxifene may cause modest decreases in the prothrombin time). 
 
6.2.4. 
Safety monitoring and individual stopping rules 
 
Safety data to be recorded: 
 
- 
vital signs: blood pressure (systolic and diastolic) and heart rate will be measured daily the 
patient him/herself using an electronic device. BP and HR measurements will be done with the 
subject comfortably seated on a chair, with the middle of the cuff on the upper arm at the level 
of the right atrium (the midpoint of the sternum). Also the body temperature will be measured 
by 10:00 am using an electronic device.  
- 
SpO2 will be measured by transdermal oximetry to be collected once daily concomitantly with 
the BP / HR measurement.  
- 
laboratory tests will be performed on venous blood samples taken from the patient at domicile 
(drawings performed by a nurse sent to the patient’s domicile and delivered to the study site’s 
laboratory).The lab results should be reviewed by the Investigator and clinically relevant 
changes recorded as AEs. Training to the personell in charge of the samples collection and 
delivering to the laboratory, and instructions to the laboratory personnel for reporting the lab 
assessments will be performed at the initial site visit.  
 
Any sign or symptom associated to adverse events will be reported by the patient in an electronic patient 
diary EXOM GENIUS ROSA and reported during the telemedicine consult. The eDiary should be filled 
in daily by the patient by 09:00 pm. 
All patients will be withdrawn from the study when criteria for supplemental oxygen therapy and/or 
mechanical ventilation are met. Another stopping rule (patient’s withdrawal from study) includes drug 
related adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 [Common Terminology Criteria for Adverse Events (CTCAE) Last Updated: 
03/01/18 available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm] 
Patients are free to withdraw from participation in the study at any time upon request, without any 
consequence. Patients should be listed as having withdrawn consent only when they no longer wish to 
participate in the study and no longer authorize the Investigators to make efforts to continue to obtain 
their outcome data. Every effort should be made to encourage patients to remain in the study for the 


 
 
 
 
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duration of their planned outcome assessments. Patients should be educated on the continued scientific 
importance of their data, even if they discontinue the study. In the case of a patients becoming lost to 
follow-up, attempts to contact the patient should be made and documented in the patient’s medical 
records. 
6.3. 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT 
Patients will be informed that they have the right to withdraw from the study at any time (withdrawal of 
consent), without prejudice to their medical care, and are not obliged to state their reasons.   
Likewise if a patient declares his/her wish to discontinue from the study e.g. for personal reasons, an 
attempt should be made to establish that the true reason is not a SAE (bearing in mind the patient is not 
obliged to state his/her reasons).  
Patients who discontinue the treatment with the IMP will not be withdrawn from the study, but will be 
asked to complete observations as per the protocol, unless otherwise they withdraw their consent. It is 
important that any randomized patient remains in the study and is followed for both efficacy and safety 
outcomes, regardless he/she has completed or discontinued the study treatment. Investigators will be 
trained about the importance of patient retention through the duration of the trial.       
Any withdrawal must be fully documented in the eCRF. 
Patients who will have a negative swab test result during the treatment phase will stop the treatment, 
and will be followed for the following two weeks for safety reason only. 
Premature discontinuation 
A premature discontinuation will occur when a patient who signed the ICF ceases participation in the 
study, regardless of circumstances, before the completion of the study protocol procedures. Patients can 
be prematurely discontinued from the study for one of the following reasons:  
• 
Failure to meet inclusion/exclusion criteria  
• 
Hypoalbuminemia at a level considered clinically relevant by the investigator 
 
• 
Withdrawal of consent  
• 
Lost to follow-up (Every effort must be made to contact the patient; a registered letter must be 
sent)  
• 
Study terminated by the Sponsor  
• 
Other reasons, such as administrative reasons or pregnancy  
• 
Documented disease progression 
• 
Severe protocol violations, such as an incorrect treatment administration, or a concomitant use 
of not permitted medications. Before removal, these cases should first be discussed with 
Dompé farmaceutici s.p.a. 


 
 
 
 
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• 
Development of AE or unacceptable toxicity, precluding further therapy with the study drug.  
 
The investigator should advise patients that prematurely discontinue on any therapies or treatments for 
their condition and refer them for further treatment as appropriate. 
 
In case of discontinuation, subjects will undergo a remote Early Trial Discontinuation Visit aimed to 
assess physical abnormalities, vital signs and transdermal oxygen saturation measurement. 
 
Replacement Procedures  
No patient who has been randomized and withdraws from the study for any reason will be replaced. 
6.4. 
END OF STUDY (EOS) 
The EOS is defined as the last day the last patient completes the last study assessment, or retracts the 
consent to participate in the study, or withdraws from the study, or is deceased or otherwise lost to 
follow-up. 
 


 
 
 
 
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7. 
ENDPOINTS 
7.1. 
STUDY ENDPOINTS 
7.1.1. 
Primary endpoints 
Virologic outcome. Proportion of participants with undetectable SARS-CoV-2 at PCR at day 7 after 
randomization. 
Clinical outcome. Proportion of participants who not requires supplemental oxygen therapy (NEWS 
≤2) and/or mechanical ventilation at day 14 after randomization.  
7.1.2. 
Secondary endpoints 
➢ Proportion of participants with undetectable SARS-CoV-2 at PCR at day 14 after randomization 
at day 28 after randomization; 
➢ Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) 
and/or mechanical ventilation at day 7 and 28 after randomization; 
➢ Proportion of patients in each NEWS category at time 7, 14 and 28 after randomization; 
➢ Mean value of NEWS category at time 7, 14 and 28 after randomization; 
➢ Proportion of participants with any adverse event with grade ≤ 2 according to CTCAE at day 7, 
14 and 28 after randomization; 
➢ Proportion of participants with any severe adverse events (grade ≥ 3 according to CTCAE) at 
day 7, 14 and 28 after randomization; 
➢ Proportion of hospitalized participants who at the beginning of the study were at domicile 
isolation at day 7, 14 and 28 after randomization; 
➢ Proportion of participants admitted to intensive care at day 7, 14 and 28 after randomization; 
➢ Proportion of survivors at day 7, 14 and 28 after randomization; 
➢ Mean variation of value of the following biomarker parameters, from base line to day 7, 14, 21 
and 28 after randomization: 
o Complete blood cell counts; 
o Hepatic function (ALT, AST and bilirubin); 
o Coagulation (PT, aPTT and INR); 
o Other marker including (D-dimer, CPK, LDH); 
➢ Quality of life questionnaire 3 months after the randomization. 
 


 
 
 
 
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8. 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
8.1. 
DEFINITIONS 
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal 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 product, whether or not related to the medicinal product.  
Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is defined as an adverse experience which is a reasonably likely to 
have been caused by the drug. Adverse events are to be considered unsuspected if the relationship to the 
study drug as described in the table in section 8.2.1 is none or unlikely; whereas any AE reported in the 
study having a possible, probable or highly probable relationship to study drug will be considered as an 
ADR. The definition covers also medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.  
Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (i.e. the patient 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 were more severe), 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency 
ward for observation and/or treatment (usually involving an overnight stay) that would not have 
been appropriate in the physician's office or an out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred, the event 
should be considered serious. 
• results in persistent or significant disability/incapacity, 
NOTE: This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental 
trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions, but do not 
constitute a substantial disruption. 
• is a congenital anomaly/birth defect, 
• is medically significant or important medical condition, i.e.an important medical event that based 
upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 


 
 
 
 
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An important medical condition is an event that may not result in death, be life-threatening, or 
require hospitalization but may be considered a SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in patient hospitalization, or the development of drug dependency or drug abuse. 
 
Pre-planned hospitalization or hospitalization for routine treatment or monitoring of the studied 
indication, not associated with any deterioration in condition are not considered to be SAEs (see Par. 
8.3.2).  
These events must be recorded in the AE page of the eCRF where a variable will be ticked to indicate 
that they are not SAEs.  
Death shall always be reported as SAE and the cause of death shall always be specified when known. 
Death due to progression of disease may be unrelated to study treatment and causality shall be assessed 
by the Investigator. The investigator should report the event immediately to the sponsor and the sponsor 
shall comply with regulatory reporting, unless there is no reasonable possibility that the drug may have 
caused the fatal outcome of the disease progression.  
Expectedness 
Despite raloxifene has been on the market for many years with an authorised Summary of Product 
Characteristics, considering that this trial is investigating raloxifene in a new condition and patient 
population, all events (AE and SAE) will be assessed as unexpected by the Sponsor. The authorised 
SmPC may be considered the reference document for safety information, but shall not be used for the 
evaluation of the expectedness. 
Suspected serious unexpected adverse reaction (SUSAR) 
A suspected serious unexpected adverse reaction is defined as an adverse reaction that is both 
unexpected (not consistent with the applicable product information) and also meets the definition of a 
Serious Adverse Reaction. 
Adverse event of special interest (AESI)  
An adverse event of special interest (serious or non-serious) is an event thought to be [potentially] 
associated with the investigational compound or disease under study and for which close monitoring is 
advised. Reporting on Adverse Events of Special Interest is an emerging and ever more critical aspect 
related to characterizing the safety profile of a compound, for which ongoing monitoring and 
communication by the investigator to the sponsor as SAE is requested. 
 
8.2. 
MONITORING FOR ADVERSE EVENTS 
All patients will daily self-monitor their parameters, AEs (if any) and concomitant medications (if any), 
and fill in an electronic study diary GENIUS ROSA. All patients may call the Investigator if needed. 


 
 
 
 
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During the study visit, the subject shall have the opportunity to spontaneously mention any problem and 
the investigator will search for possible adverse events by asking generic questions to the patient without 
pointing to specific events which may have occurred. 
AEs should be reported for any clinically relevant change in concomitant condition(s) that is the result 
of an untoward (unfavorable and unintended) change in a subject’s medical health. Changes in any 
protocol-specific systemic parameter evaluated during the study are to be reviewed by the Investigator. 
In addition, the subject’s responses to any questionnaire utilized during the study are to be reviewed by 
the Investigator. Any untoward (unfavorable and unintended) change in a protocol-specific parameter 
or questionnaire response that is clinically relevant is to be reported as an AE. These clinically relevant 
changes will be reported regardless of causality. 
8.3. 
RECORDING 
AEs will be collected and recorded for any untoward event that occurs in a patient from the time he or 
she signs the ICF for the trial up to the end of the follow up period. Thus, any untoward medical 
occurrences or unfavorable and unintended signs, symptoms, or diseases that occur in the pretreatment, 
in treatment, or post treatment period are to be considered AEs and/or SAEs, and consequently recorded 
and reported as such. Should a non-serious AE become serious, the Investigator will then follow the 
same reporting procedures as for SAEs. 
Each AE will be described by:  
• 
Its duration (start and stop dates).  
• 
Its seriousness. 
• 
Its relationship to the study drug (suspected/unsuspected). 
• 
Severity grade: The severity of AEs and SAEs will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE), version 5.0 (Appendix 3). 
• 
Action(s) taken. 
• 
Outcome. 
Medical conditions/diseases and related signs/symptoms present before starting study treatment shall be 
documented in the medical history section of the eCRF; these conditions are considered AEs only if 
they increase either in frequency or severity once informed consent has been signed. 
8.3.1. 
Relationship of AEs to the Investigational Product 
The Investigator will assess the possible relationship between the AE and the investigational medication, 
according to the criteria in Table below: 


 
 
 
 
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Relationship of the Adverse Event to the IMP 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational Product, e.g. 
patient is a passenger in a road traffic accident.  
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test 
abnormality with temporal relationship to drug administration which makes 
a causal relationship improbable and in which other drugs, chemicals or 
underlying disease provide more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s 
condition or treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Investigational 
Product and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational 
Product and, if applicable, re-appears upon repeat exposure 
 
8.3.2. 
Severity of AEs 
The Investigator will grade the severity of any AE using the classification according the CTCAE 
dictionary, as reported in Appendix 3. 
The severity of AEs and SAEs will be graded using the CTCAE version 5.0. Any AE not listed in 
the CTCAE will be graded as follows:  
Grade Definition:  
1. Mild  
2. Moderate  
3. Severe  
4. Life-threatening or disabling  
5. Death.  
 
8.3.3. 
Follow-Up of patients with Adverse Events 
The Investigator is responsible for adequate and safe medical care of subjects during the trial and for 
ensuring that appropriate medical care and relevant follow-up procedures are maintained after the trial. 
All AEs should be followed-up to determine outcome of the reaction. The Investigator should follow up 
the event until resolution or stabilization of the condition. It is the Investigator's responsibility to ensure 
that the subjects experiencing AEs receive definite treatment for any AE, if required. 
If subject was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to the 
Study Safety Contact as soon as it becomes available. 


 
 
 
 
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In addition, a letter from the Investigator that summarizes the events related to the case as well as results 
of any relevant laboratory tests also may be requested. Further, depending upon the nature of the SAE, 
Dompé may request copies of applicable segments of the patient’s medical records. In case of death, a 
copy of the autopsy report, if performed, should also be provided. 
The Investigator shall inform the Study Safety Contact with an appropriate written communication, 
whenever he becomes aware of new available information regarding the SAE, once the condition is 
resolved or stabilized and when no more information about the event is expected. Follow-up SAE 
information should be processed as initial SAE notification (see Par. 8.4.1). 
For pharmacovigilance purposes, all SAEs should be followed-up in order to clarify as completely as 
possible their nature and/or causality and until all queries have been resolved. All SAEs will be followed 
up until the events resolve or the events or sequelae stabilize, or it is unlikely that any additional 
information can be obtained after demonstration of due diligence with follow-up efforts (i.e. subject or 
Investigator is unable to provide additional information, or the subject is lost to follow up), unless subject 
has withdrawn his/her consent. 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. 
Reporting Procedure for Investigators 
The investigator must report all SAEs, regardless of presumed causal relationship to Study Safety 
Contact (i.e. Dompé Pharmacovigilance and Contract Research Organization Pharmacovigilance expert) 
recording the SAE data on the AEs section of the eCRF within 24 hours of learning of the event. The 
paper SAE forms are only intended as a back-up option when the eCRF system is not accessible. In this 
case, the original paper forms are to remain on site and copies are to be transmitted via email or 
confirmed facsimile (fax) transmission to: 
• 
e-mail address: rlx0120-safety@exomgroup.com 
• 
Fax number: +39 02 36026913 
Contact details for SAE reporting are provided in the section “Contact Information”. 
 
The investigator should also report information on SAEs that continue after patient has completed 
his/her participation in the study (whether study completion or withdrawal), unless patient has 
withdrawn his/her consent. 
Information on SAEs will be recorded on the AEs section form in the eCRF. Follow-up reports (as many 
as required) should be completed following the same procedure; the system will mark the SAE form as 
“Follow up no. XX” 
Whenever more than one SAE is observed, the Investigator should identify which is the primary adverse 
event, i.e. the most relevant one. If other events are listed in the same report, the Investigator, along with 
their relatedness to the Investigational Product, should identify which adverse events are serious and 
which are non-serious. In any case, the Investigator is requested to record his/her opinion about the 
relatedness of the observed event(s) with the investigational medication. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not usually 
need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes aware of 


 
 
 
 
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a SAE occurring to a patient after that patient has ended his/her participation in the study (whether study 
completion or withdrawal), the SAE should be reported by the Investigator using the following email 
address: farmacovigilanza@dompe.com or fax: +39 02 36026913. Such “post-study cases” should be 
regarded for expedited reporting purposes by Dompé, as though they were study reports. Therefore, a 
causality assessment and determination of expectedness are needed for a decision on whether or not 
expedited reporting is required. 
 
8.4.2. 
Adverse Events of Special Interest (AESI) 
During the study all AESI will be considered equivalent to a SAE and will be reported following the 
procedures described above for the reporting of a SAE. The following events will be considered adverse 
events of special interest: 
- 
Venous thromboembolic events (including deep vein thrombosis) 
➢ pulmonary embolism 
➢ retinal vein thrombosis 
➢ superficial vein thrombophlebitis 
- 
Arterial thromboembolic reactions 
- 
Thrombocytopenia 
 
8.4.3. 
Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to be SAE 
and shall not be reported as such, but only need to be recorded in the eCRF: 
• 
Hospitalization for routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition. 
• 
Trial end points 
• 
Abnormal lab values or test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are clinically significant. 
 
8.4.4. 
Reporting Procedure to Ethics Committee (EC) and to Regulatory Authorities 
In addition to informing the Study Safety Contact, the Investigator shall notify SAE to his/her EC as 
applicable (in particular in case of death); in addition, for reported deaths of a subject, the Investigator 
shall supply Study Safety Contact and the Ethics Committee with any additional information requested. 
Copies of all correspondence relating to reporting of any SAEs to the EC should be maintained in the 
Investigator’s Files. 
Dompé Pharmacovigilance shall submit any suspected unexpected serious adverse reaction (SUSAR) 
to the concerned EC and Regulatory Authority (via Eudravigilance), as soon as possible and in no event 
later than: 
• 
seven calendar days after becoming aware of the information if the event is fatal or life 
threatening; to be followed by any relevant information within eight days. 


 
 
 
 
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• 
fifteen calendar days after becoming aware of the information if the serious event is neither fatal 
nor life threatening. 
Dompé Pharmacovigilance shall report any relevant updated follow-up safety information as soon as 
available. 
If the results of an investigation show that an ADR not initially determined to be reportable is reclassified 
as reportable, Dompé Pharmacovigilance shall report such reaction in a written safety report as soon as 
possible, within the timeframes defined by current law requirements. 
Dompé shall be responsible to prepare and submit annual safety reports (Development Safety Update 
Report – DSUR) to relevant Regulatory Authorities, as applicable. In addition, Investigator will receive 
from Dompé Pharmacovigilance appropriate periodic safety updates, as per applicable local 
requirements and regulations. 
Dompé will ensure ongoing safety evaluation to be conducted periodically during the study on the safety 
data received, including monitoring of AESI. 
8.5. 
EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY 
Women of childbearing potential are not excluded from the study as long as adequate birth control 
methods are being utilized. Women of childbearing potential are defined as all women physiologically 
capable of becoming pregnant. Prior to enrolment in the clinical trial, female patients of childbearing 
potential and their partners must be advised of the importance of avoiding pregnancy during the entire 
course of the study treatment and for the 30 days after the study treatment period ends and of the potential 
risks associated with an unintentional pregnancy. During the trial, female patients are to be instructed to 
contact the Investigator immediately if they suspect they might be pregnant. In the same way, male 
patients who become aware that the partner might be pregnant, are to be instructed to contact the 
Investigator immediately. 
The Investigator must report every pregnancy on a Pregnancy Report Form as soon as possible (within 
24 hours of learning of the pregnancy to the Study Safety Contact (contacts specified in the section 
“Contact Information”), even if no AE has occurred, and follow it up to term. If, however, the pregnancy 
is associated with an SAE (e.g., if the mother is hospitalized for dehydration), in addition to the 
Pregnancy Report Form, a separate SAE Report Form must be filed as described in Section 8.4.1 with 
the appropriate serious criterion (e.g., hospitalization) indicated on the SAE Report Form. Miscarriage, 
stillbirth and any malformation/disease must be reported as a SAE. 
Any pregnancy leads to the immediate exclusion from the trial.  
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded in the eCRF, 
and the patient must be followed up until the resolution of the AE or as instructed by the medical 
monitor. 
8.7. 
OVERDOSE 
Cases of overdose (accidental or intentional) which may or may not result in serious adverse reactions 
are to be reported to Study Safety Contact, following the same procedure for SAE, within 24 hours from 


 
 
 
 
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the Investigator’s knowledge of its occurrence. The Medical Expert should be contacted to discuss 
corrective treatment, if necessary. 
An overdose of the study drug is defined as: 
- 
Capsules: The administration of more than 50% of the daily dose 
Overdose includes reports related to drug intake through different routes (e.g. ingestion) or with suicidal 
intentions and consequent drug overdose. 
The Investigator shall provide in the SAE form information about symptoms, corrective treatment and 
outcome of overdose. 
8.8. 
UNBLINDING 
During the trial, blinding may be broken by the Investigator for emergency purposes only, when 
knowledge of the treatment identity is essential for treating the subject, or by Sponsor 
Pharmacovigilance for safety reasons and in case of Serious Adverse Events qualifying for regulatory 
reporting (SUSAR), in line with regulatory requirements. 
If the treatment code needs to be broken in the interest of patient’s safety for a medical emergency, the 
Investigator is allowed to break the treatment code for the specific patient, even before informing the 
Sponsor. Investigator will be allowed to unblind study medication electronically through a specific 
procedure within the eCRF (GENIUS IWRS). The system will notify the unmasking via e-mail to the 
Study Safety Contact and Dompé Medical Expert without revealing the treatment identity, but only 
referring to the kit number involved in the unmasking in order to avoid a dissemination of unmasked 
information. Proper training as well a specific user’s manual   is provided to investigators for the  use of  
GENIUS IWRS and of the unblinding functionality.  As a backup solution, sealed envelopes containing 
the individual treatment codes will be available at sites and must be kept by the Investigator in a secure 
location accessible only to designated staff in order to avoid  dissemination of treatment identification 
to personnel involved in study conduct who must remain blind. During the study, the integrity of the 
envelopes will be regularly checked by the Site Monitor, during the visits at site. At the end of the study, 
all the individual envelopes must be returned to Dompé.  
Dompé Drug Safety may need to unmask a patient’s treatment for safety reason or if a reported SAE 
meets criteria of a SUSAR in order to fulfil expedited regulatory reporting requirements. Dompè Drug 
Safety will be allowed to unblind study medication electronically through the specific procedure within 
the eCRF (GENIUS IWRS). Additionally, a copy of the individual envelopes identified with the subject 
assignment number/ kit number will be also provided to the Dompé Drug Safety before study start, 
together with access to the GENIUS IWRS. The identity of the treatments will remain unknown to the 
subject, Investigator, site staff, CRO and Dompé Development personnel until the study completion and 
formal unmasking. 
The randomization code will be broken when the last enrolled patient has completed therapy, and once 
the database has been locked. 
 


 
 
 
 
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9. 
STATISTICS 
9.1. 
SAMPLE SIZE 
The sample size of the study is calculated based on the following assumptions: 
• 
Virologic assumption: Early treatment with antivirals increases the proportion of patients with 
undetectable SARS-CoV-2 in upper respiratory tract at day 7 after therapy from 25% to 50%; 
• 
Clinical assumption: Early treatment with antivirals increases the proportion of participants who 
recover without need of mechanical ventilation and/or supplemental oxygen therapy by the day 
14 after therapy from 50% to 75%. 
Based on these assumptions and considering a randomization ratio 1:1:1, the sample size will be 
adaptively determined to achieve a power greater than 80% to show superiority of raloxifene vs placebo 
in terms of either one primary endpoint (section 7.1.1) and controlling the one-sided alpha below 0.025. 
Sample size will be determined throught the following steps: 
• 
an interim analysis will take place when 50 participants per arm (N=150) have reached their 
primary enpdoints (i.e. assessments available).  
o In case of efficacy of at least one treatment arm or futily of both arms (see criteria in 
section 9.3) the study enrollement will be stopped,  
o otherwise the actual number of new participants in each arm may be blindly reassessed 
according to observed efficacy of the best favourable and promising arm; 
• 
in case of continuation of the study to the final stage, it is expected to randomize on average 
additional 174 patients, depending on sample size reassessment and possible dropping of an 
uneffective treatment arm. Expected sample size will be between 250 and 450 randomized 
participants; 
• 
drop-outs of randomized subjects will not be replaced. 
This approach allows either to minimize the number of enrolled participants if the experimental 
assumptions are too conservative or to have a good power level if they are too optimistic. 
Pocock’s spending functions and conditional power (CP) will be used to control the type I and II errors, 
considering that interim analysis will be performed when half of the initial planned patients have been 
reached the primary endpoints (i.e. assessments available). 
Bonferroni method is used to adjust for multiple endpoint vs treatment comparisons. 
Sample size calculation has been performed through simulation (100000 replications). The statistical 
software used for simulation was SAS®, Version 9.4. 
9.2. 
RANDOMIZATION 
Eligible Patient will be randomized in a 1:1:1 fashion to either:  
• 
Group 1: 1 capsule of raloxifene 60 mg and 1 capsule of placebo. 
• 
Group 2: 2 capsules of raloxifene 60 mg.  


 
 
 
 
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• 
Group 3: 2 capsules of placebo. 
Randomization will be performed through IRS. Each Patient Kit number will be randomly associated 
with a treatment group. The randomization list will be provided to the facility responsible for IMP 
packaging/labelling for the purpose of IMP preparation. Each randomized patient will be allocated with 
randomization number according to the stratified randomization list. Dropouts after randomization will 
not be replaced.  
Randomization will be stratified by site and gender to ensure balanced assignment across treatment 
groups. The stratified permuted block randomization list will be generated with a computer procedure 
by an independent statistician not involved in the conduct of the study.  
Access to individual patient treatment code will be allowed only in the event of a medical emergency 
where the knowledge of patient treatment is required to provide the patient with appropriate care. The 
investigator will be provided with a protected access to the randomization system to allow opening of 
the treatment allocation for a specific patient in case of a medical emergency.  
Dompé Pharmacovigilance contact person will be provided with a protected access to the randomization 
information in case of unblinding for safety procedures. 
Unblinding events will be recorded and reported in the final study report. 
The randomization codes will be accessible to the independent statistician who will perform the interim 
analysis. The treatment assignment information will be kept confidential and will not be disclosed to 
any other person than those ones involved in these intermediate analysis. 
The randomization code will be broken according to study procedures after the last enrolled patient has 
completed his/her follow-up visit. 
9.3. 
STATISTICAL METHODOLOGY 
An interim analysis is planned when half of the planned evaluable patients has reached the primary 
endpoints at 7 and 14 days (i.e. assessments available). The intent of the interim analysis is either for 
identification of early superiority of raloxifene (early efficacy), or for an early stop of one or both 
treatment arms for futility, or for blind sample size reassessement. 
Pocock’s spending functions and CP will be used to control the type I and II errors for analyses of 
primary endpoints. Pocock’s boundaries (on standardized Z scale) for efficacy and futility at interim and 
final analyses are reported in Table 1. 
Table 1: Pocock spending functions boundaries for primary endpoints 
Analysis 
Sample 
Size 
Standardized Z Scaleboundaries for primary endpoints 
Alpha 
Beta 
Interim 
50% 
2.69640 
1.59184 
Final 
100% 
2.69640 
2.69640 
 


 
 
 
 
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The analysis will be conducted by an independent statistician who will communicate to the Sponsor the 
result of the interim analysis and the consequent decisions on the continuation of the study, drop of an 
unefficacious treatment arm and on the reassessment of sample size, if required.  
On the basis of Pocock’s boundaries and CP at interim analysis, each treatment arm will be classified 
and ranked as “Effective”, “Favorable”, “Promising”, or “Unfavorable”. According to the most effective 
up-ranked arm, a decisions on the continuation of the study and on the reassessment of sample size will 
taken. 
In case only one treatment arm is defined as “Unfavorable” at the interim analysis, this arm will be 
dropped from the continuation of study and no additional subjects will allocated to it. Already 
randomized subjects will continue the follow-up as planned. 
Criteria for classification and ranking of treatment arms and possible consequent actions are reported in 
Table 2. 
Table 2: Criteria for classification of treatment arms and actions post-interim analysis 
Arm 
Classification 
Criteria 
Action based on the most 
up-ranked treatment arm 
Pocock’s Alpha 
Higher Conditional Power 
between Virologic and 
Clinical endpoint 
1 - Effective 
Z > 2.69640    AND    CP>90% 
Stop for efficacy 
2 - Favorable 
- 
CP>80% 
No sample size reassessment 
3 - Promising 
- 
35%<CP≤80% 
Sample size reassessment 
4 - Unfavorable 
Z ≤ 1.59184      OR      CP≤35% 
Stop for futility 
9.4. 
PATIENT POPULATION 
The following population will be defined: 
• 
The Safety (SAF) population will consist of all randomized patients who received at least one 
dose of the investigational product. Safety population will be analyzed according to the actual 
treatment received. The SAF population will be used to present results on safety data. 
• 
The Full Analysis Set (FAS) population will consist of all randomized patients who received at 
least one dose of the investigational product. FAS population will be analyzed according to ITT 
principle, i.e. by treatment allocation regardless happening of intercurrent events. The FAS 
population will be used for the primary analyses of the study and to present results on efficacy 
data. 
The Per Protocol (PP) population will consist of all randomized patients who received at least one dose 
of the investigational product and do not have Major Protocol Deviations. The PP population will be 
used for sensitivity analyses. 


 
 
 
 
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9.5. 
STATISTICAL METHODOLOGY 
All patient data collected on the eCRF will be listed by patient and center.  
Appropriate descriptive statistics will be produced, according to the variable: 
• 
for continuous data n, mean, standard deviation (SD), median and range (minimum and 
maximum) will be presented; 
• 
for categorical data, frequency distributions and percentages will be presented; 
• 
for time-to-event variables, cumulative freedom from event will be evaluated using Kaplan-
Meier method. The degree of uncertainty will be expressed with 95% confidence limits 
(calculated per the method proposed by Greenwood). Comparison of curves among arms will 
be performed with the log-rank test. Kaplan-Meier graphs will be presented along with the 
number of patient-at-risk at exact time points. Subjects ongoing and who are free from event at 
the time of DB lock will be censored at the DB lock date. Subjects who have discontinued 
without an event will be censored at the date of discontinuation. 
Unless otherwise specified, the significance level used for statistical testing will be 0.05 and two-sided 
tests will be used.  
9.5.1. 
Demographic and baseline characteristics 
Demographic and baseline characteristics will be summarized for all patients in the FAS population, by 
treatment group. 
9.5.2. 
Analysis of efficacy variables 
9.5.2.1. 
Primary analyses 
The proportion of subjects with undetectable SARS-CoV-2 at PCR at day 7 after randomization 
(virologic endpoint) and the proportion of subjects who not requires supplemental oxygen therapy 
(NEWS ≤2) and/or mechanical ventilation at day 14 after randomization (clinical endpoint) will be 
separately analyzed by means of logistic regression models adjusting by pre-defined factors as center, 
age, gender and post-menopausal status. Additional covariates may be defined in the SAP. Each 
treatment arm will be compared independently with the placebo. 
The null hypothesis for the virologic endpoint is that proportion of treated subjects with undetectable 
SARS-CoV-2 at PCR at day 7 after randomization is lower or equal the placebo one (PLACEBO). Two 
sets of null and alternative hypotheses are provided, one for each treatment dosage: 
H01-60mg: RALOXIFENE-60mg ≤ PLACEBO 
H11-60mg: RALOXIFENE-60mg>PLACEBO 
H01-120mg: RALOXIFENE-120mg ≤ PLACEBO 
H11-120mg: RALOXIFENE-120mg>PLACEBO 
The null hypothesis for the clinical endpoint is that proportion of treated subjects who not requires 
supplemental oxygen therapy (NEWS ≤2) and/or mechanical ventilation at day 14 after randomization 
is lower or equal the placebo one (TPLACEBO). Two sets of null and alternative hypotheses are provided, 
one for each treatment dosage: 


 
 
 
 
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H02-60mg: TRALOXIFENE-60mg ≤ PLACEBO 
H12-60mg: TRALOXIFENE-60mg>PLACEBO 
H02-120mg: TRALOXIFENE-120mg ≤ PLACEBO 
H12-120mg: TRALOXIFENE-120mg>PLACEBO 
Superiority of raloxifene will be claimed if at least one null hypothesis is rejected, at interim or at final 
analysis according to criteria shown in section 9.3. 
Sensitivity analyses will be defined in the SAP to assess the robustness of results on primary endpoints 
versus the presence of missing data (unexpected) and the presence of protocol deviations. 
9.5.2.2. 
Secondary analyses 
All secondary endpoints will be analyzed at each available timepoints by means of descriptive statistics 
and by appropriate parametric tests depending on the nature of the variable and its distribution. Data 
transformation might be used in order to satisfy the assumption of normality requested by parametric 
statistical tests. In case such assumptions are not met, non-parametric counterpart tests will be used. 
Change from baseline value (for continuous variables) and shift tables versus baseline (for categorical 
variables) will also be summarized for all post-baseline visits. 
The incidence of participants with undetectable SARS-CoV-2 at PCR, the incidence of participants who 
requires supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation, and mortality will be 
analyzed as proportion at each time point and as time-to-event. 
Details will be provided in the SAP.  
9.5.3. 
Analysis of exploratory variables 
In addition to descriptive statistics at each available timepoint, explorative variables will be analyzed by 
means of inferential tests depending on their nature and distribution (all confidence intervals and 
statistical tests on explorative endpoints are of descriptive nature). Change from baseline value (for 
continuous variables) and shift tables versus baseline (for categorical variables) might be reported for 
all post-baseline visits. 
9.5.4. 
Analysis of safety variables 
TEAEs, ADRs and TESAE will be presented by treatment arms in terms of number of AEs and incidence 
by System Organ Class (SOC) and Preferred Terms (PT) using MedDRA. Analyses will be provided 
also by severity and relationship to the study drug. In addition, time-to-event methods will be used to 
summarize the overall survival. 
Vital signs and laboratory tests will be presented using descriptive statistics at each available visit. 
Additionally, the frequency of subjects reporting an abnormal or abnormal clinically significant 
laboratory value will be presented for each laboratory parameter. Shift tables versus baseline will 
compare abnormal laboratory findings at each post-baseline visit. 


 
 
 
 
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9.5.5. 
Missing data 
All reasonable efforts will be made to reduce the rate of missing data. Investigators will be trained about 
the importance of patient retention and full data capture. Also, any reasonable attempts should be made 
by the Investigators to emphasize continued subject’s participation for the full duration of the trial. 
9.5.6. 
Specification of subgroups for analysis 
Statistical tests for interaction (between subgroup and treatment arm) will be performed to decide about 
the need to further investigate subgroups of the trial population based on the following variables: age 
group, gender and Country.  
Subgroup analysis will be performed if interaction tests are statistically significant at 15% nominal level. 
Statistical details and potential new subgroups definitions will be reported in the SAP. 
9.5.7. 
Study termination 
The End of Study (EOS) is defined as the last day the last patient completes the last study assessment in 
the hospital, or retracts the consent to participate in the study, or withdraws from the study, or is deceased 
or otherwise lost to follow-up. 
9.5.8. 
Changes to the statistical plan 
The Statistical Analysis Plan will be issued before the interim analysis with more technical and detailed 
elaboration of the principal features of statistical analyses. Additional post-hoc analysis may be 
produced to further allow comparison between treatment and placebo, according to the results obtained.   
Any deviations from the original statistical plan (including unplanned analyses) will be clearly 
documented in the Clinical Study Report. 


 
 
 
 
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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INSTITUTIONAL 
REVIEW 
BOARD 
AND 
INDEPENDENT 
ETHICS 
COMMITTEE 
This study will be carried out in full compliance with the guidelines of ethics committee (EC) and 
government agencies of each respective country as well as the European Union (EU) Clinical Trial 
Directive (Directive 2001/20/EC)and any subsequent applicable law, where applicable. Before the study 
begins, the study centers will require approval from an EC and Regulatory agency. During the course of 
the study, the Sponsor or authorized contract research organization (CRO) representative will provide 
timely and accurate reports to the EC on the progress of the study, at intervals not exceeding 1 year (or 
as appropriate), and will notify the EC of SAEs or other significant safety findings. The study protocol, 
ICF, information sheet advertisements, and amendments (if any) will be approved by the EC at the study 
centers in conformance with the EU Clinical trial directive (Directive 2001/20/EC), and any subsequent 
applicable law and local regulations.  
10.2. 
ETHICAL CONDUCT OF THE STUDY 
The procedures outlined in this clinical trial protocol are designed to ensure that the Sponsor and the 
Investigators from the Clinical Sites perform their activities throughout the set-up, conduct, evaluation, 
documentation and analysis of the study, in accordance to the principles of the Good Clinical Practice 
(GCP) guidelines of the International Conference on Harmonization (ICH) and the Declaration of 
Helsinki. The study will be carried out adhering to local legal requirements and the applicable national 
laws, whichever represents the greater protection for the individuals. 
Study protocol, patient information and supportive materials for  the electronic informed consent will 
be submitted to the appropriate Ethics Committee for approval. The Sponsor will be responsible to 
inform in a timely manner the appropriate Ethics Committee about any changes in the study protocol 
which could interfere with the patient’s safety. 
10.3. 
PATIENT INFORMATION AND CONSENT 
 
The investigators, sub-investigators and General Practitioner(GP) involved in this clinical trial who are 
responsible for treating the patient for COVID-19 are responsible for providing all necessary 
information about the participation in the study to their patients, and consequently to obtain the 
signature of the Informed Consent. 
Since patients can’t go to clinical sites for discussing their participation to the study and eventually 
sign the informed consent, the consent procedure will be managed remotely (Genius remote 
ENGAGE) through an electronic application that allows the interaction between investigator and 
patient as well as the electronic signature of the consent form in the full respect of the enforced legal 
and regulatory requirements. 
The same procedure applies to the information of the patient and providing of consent to the processing 
of personal data according to the European Regulation n. 679/2016 on the Protection of Personal Data, 


 
 
 
 
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the Personal Data Protection Code (Legislative Decree 196/03) and subsequent amendments and 
additions, and to the provisions, guidelines and general authorizations of the National Guarantor for 
personal Data Protection. 
10.4. 
CONFIDENTIALITY AND DATA PROTECTION 
By signing this protocol, the investigator agrees to keep all the information provided by the sponsor in 
strict confidentiality and to request the same confidentiality from his/her staff. Study documents 
provided by the sponsor (protocols and other materials) will be stored appropriately to ensure 
confidentiality. The information provided by the sponsor to the investigator cannot be disclosed to others 
without direct written authorisation from the sponsor, except for the extent necessary to obtain the 
electronic informed consent from the subjects wishing to participate in the study.  
Data on subjects collected in the source documents during the study will be transferred to the Sponsor 
in an anonymized way. If, as an exception, for safety or regulatory reasons identification of a subject 
becomes necessary, the sponsor and the investigator will be bound to keep this information confidential. 
On the eCRF(andpatient diaries), patients will be identified ONLY by the assigned patient number. If 
patient names are included on copies of documents submitted to Sponsor or its delegate, the names will 
be obliterated or masked and the assigned patient number added to the document. 
The Investigator should keep a separate log (Patient Master List) of patient’s codes, names and 
addresses. 
10.5. 
ADMINISTRATIVE ASPECTS 
The investigational medicinal products required for the conduct of this study will be provided free of 
charge by the Sponsor to the participating clinical sites.  
Coverage for any damage resulting from the participation of the subjects in the clinical trial is warrented. 
In addition to the general insurance of the individual participating clinical centers, an insurance cover 
will be issued in favour of the subjects participating in this clinical study. The insurance is in compliance 
with the local regulation and with the requirements of the Health Authorities. 
 


 
 
 
 
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11. 
DATA HANDLING AND RECORD KEEPING 
11.1. 
CASE REPORT FORMS 
An eCRF customized for the trial will be provided by the CRO in compliance with EU regulations.  
An eCRF is required and should be completed for each patient enrolled. Entry in the eCRF will 
be progressed as soon as the data are available. The Investigator will be responsible for the 
accuracy and timeliness of the data entered in the eCRFs. All “free field” comments must be 
entered in ENGLISH.   
Source documents are the originals of any documents used by the Investigator or 
hospital/institution that allow verification of the existence of the patient and substantiate the 
integrity of the data collected during the trial. Source documents should be available to support 
all the data recorded in the eCRF; location of source documents, including those for which the 
eCRF might be accepted as being the sole source document, will be specified and listed in the 
“Source Document Location” log at the Site Initiation Visit. The Investigator is responsible for 
ensuring that data are reliably and correctly generated, recorded, processed and reported, in 
agreement with the ALCOAC principles (Attributable-Legible-Contemporaneous-Original-
Accurate-Complete). 
The data are the sole property of Dompé farmaceutici s.p.a. and should not be made available in 
any form to third parties, except for authorized representatives of the CRO, or appropriate 
Health/Regulatory Authorities, without written permission from Dompé farmaceutici s.p.a. 
11.2. 
PATIENT DIARY 
An eDiary (will be supplied to each randomized patient by the CRO on a pre-programmed 
electronic device (e.g. smartphone or tablet) directly connected to the eCRF. The eDiary must be 
used for the purpose of trial RLX0120 and should not be used or made available in any form to 
third parties, except for authorized Dompé designee or representatives of appropriate 
Health/Regulatory Authorities. 
The patient will report in the eDiary the details (date, time, number of capsules) of each 
administration of the IMP and vital signs self-monitored, AEs, CMs. It is responsibility of the 
Investigator/Nurse to explain to each patient how to enter the data in the eDiary; similarly, it is 
responsibility of the Investigator to check in a timely manner administration data. 
11.3. 
PROTOCOL DEVIATION 
Any deviations from the protocol procedures described in relevant sections will be reported in 
the study-specific PD form. The form will provide a detailed self-explaining narrative of the PD 
to include identification of the procedure that has been deviated, the reason why the deviation 
occurred and measures taken to prevent recurrence of the deviation, as appropriate.     


 
 
 
 
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11.4. 
DATA MANAGEMENT 
Data management of the eCRFs, eDiaries and PD forms will be performed by the CRO appointed 
by Dompé. The PD will be recorded during the study and the final list of PDs will be available 
before database lock. 
All data will be verified in a timely manner for missing information, inconsistencies, and for any 
necessary medical clarifications. Queries arising from the edit checks (either programmed or 
manual) will be sent to the Investigator for response.     
Once all data queries have been resolved, and comments/changes arisen from the Data Review 
Meeting incorporated, the study data will be declared to be “clean”, and the study database will 
be locked ready for analysis. 
A Data Management Plan will be issued, detailing the flow of data handling from entry in to the 
eCRF to final database audit. 
11.5. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING 
THE STUDY 
The following will be required from the Investigator prior to the initiation visit: 
- 
Current, signed and dated Curriculum Vitae of Principal Investigator and any 
Sub-Investigators/co-workers. Updates should be provided at least every two years. 
- 
Normal ranges of all laboratory tests to be performed at the study site and a recent 
certification or accreditation of established quality control (or other documentation of 
established quality control or external quality assessment or other validation). Updates 
should be provided as soon as any reference value has changed. 
- 
A signed page of the final protocol and any amendments. 
- 
A signed copy of the study Financial Agreement/Clinical Study Agreement with Sponsor 
or its delegate, including all study specific costs. 
- 
List and any updates of delegated responsibility (Study Team Signature List / Delegation 
of Responsibilities form).  
- 
A financial disclosure agreement completed and signed by the PI and all Sub-
Investigators. If applicable, the PI will provide an updated financial disclosure agreement 
to the Sponsor 1 year after the completion of the study 
11.6. 
ESSENTIAL DOCUMENT RETENTION 
The investigator must ensure that the clinical data required by the study protocol are carefully 


 
 
 
 
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reported in the subject’s source documents detailing the unique identification number and the 
date and time of the study procedures performed. Any correction to the source data entries must 
be carried out by the investigator or a designated member of staff. Incorrect entries must not be 
covered with correcting fluid, or obliterated, or made illegible in any way. A single stroke must 
be drawn through the original entry. Corrections have to be dated and initialled. The investigator 
must provide a reasonable explanation for all missing data. The source documents will be 
completed, signed by the investigator, the sensitive data will be obscured (i.e. only randomization 
number will be clearly legible) and the source document will be made available to the Sponsor 
for data management procedures. 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP) until 
at least 2 years after the last approval of a marketing application in an ICH region, and until there 
are no pending or contemplated marketing applications in an ICH region, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the Investigational Product. 
These documents should be retained for a longer period however if required by the applicable 
regulatory requirements. The Investigator should take measures to prevent accidental or 
premature destruction of these documents. 
The essential documents include at least: the signed protocol, copies of the completed CRFs, 
signed electronic Informed Consent Forms from all patients who consented, hospital records and 
other source documents, and all other documentation included in the Investigator Site File and 
Pharmacy/Dispensing File. 
The Investigator will inform Sponsor representative or its delegate of the storage location of these 
essential documents and must contact Sponsor representative or its delegates before disposing of 
any. If the Investigator wishes to assign the files to someone else or to remove them to another 
location, he/she should consult with Sponsor representative or its delegates about this change. 
Sponsor representative or its delegates will inform the Investigator in writing when these 
documents no longer need to be retained. 


 
 
 
 
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12. 
STUDY MANAGEMENT 
The study will be performed in accordance with the protocol, the Declaration of Helsinki. 
The approval and/or the acknowledgment of the study protocol, the SmPC and all other relevant 
documentation by the National Competent Authority and local EthicsCommittee competent for the study 
site will be obtained before the start of the study,according to the current regulations. 
The present clinical study will be carried out according to the current revision of GoodClinical 
Practice (GCP), ICH topic E6 (R2), and the applicable local law requirements. 
12.1. 
MONITORING 
Monitoring will be carried out by appropriate staff of the CRO appointed by Dompé.  
If for healthy or logistics reasons on-site monitoring visits will not be possible at the planned time 
intervals, such visits will be conducted in a virtual mode. A purpose-built source document workspace 
(Genius SITE VAULT) under the full and unique control of the site staff and completely separated from 
the study database will be implemented. Site staff will upload certified electronic copies of the source 
documents and will allow the study monitor to conduct the verification of the source data against the 
eCRF data. Encription protocols as well audit trails assure  full security and regulatory compliance. 
The purpose of the monitoring visit is to verify that the rights and the wellbeing of the patient are 
protected, that the reported data are accurate, complete and verifiable from source documents and that 
the conduct of the trial complies with the currently approved protocol and any amendments, with ICH 
GCP (E6-R2), and with regulatory requirements.  
Monitoring will also include support to site for handling of samples for the laboratories and electronic 
device for patients’ self-monitoring, IMP accountability and reconciliation, as well as follow-up with 
site as to SAEs. The CRA will also follow-up resolution of clinical/safety queries. Specific monitoring 
activities will be detailed in the Monitoring Plan. 
Prior to study start, the Investigator will be informed of the anticipated frequency of the monitoring 
visits.  (S)He will also receive a notification prior to each monitoring visit during the course of the study. 
It is expected that the Investigator and/or his/her sub-Investigator(s) and other appropriate staff, 
including the pharmacist(s) and responsible of the local laboratory, will be available on the day of the 
visit to discuss study conduct and to cooperate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 
Before any patient enters the study, a representative of Sponsor or its delegate, will meet with the PI and 
his or her staff to review the procedures to be followed during the study and to train them on recording 
the data in the eCRF using the electronic data capture (EDC) system. After the first patient is enrolled, 
the Sponsor/CRO representative, a monitor, will periodically monitor the progress of the study by 
conducting on-site visits. This CRA will also be able to review query statuses remotely, possibly 
warranting more frequent communication with the PI and his or her staff. The PI will make available to 
the CRA the eCRF, source documents, signed consent forms, and all other study-related documents. 
The PI and his or her staff will be responsible for reviewing eCRF, resolving data queries generated by 
the CRA via the system, providing missing or corrected data, approving all changes performed on his 


 
 
 
 
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or her data, and endorsing the patient data within theeCRF.This approval method will include applying 
an electronic signature, a uniquely assigned username and password that together will represent a 
traditional handwritten signature.  
12.2. 
ACCESS TO RECORDS 
The Investigator will allow designated Dompefarmaceutici S.p.A. representatives, including staff from 
the appointed CRO, and regulatory/ethics bodies to have direct access to the source documents to verify 
the data reported in the eCRF. Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and substantiate 
the integrity of the data collected during the trial. 
12.3. 
AUDIT AND INSPECTION 
The study site may be audited by Sponsor representativeor its delegate or inspected by a regulatory 
agency on one or more occasions The Investigator may be informed in advance of such a visit.  
12.4. 
PROTOCOL AMENDMENTS 
Any amendment to this protocol will be provided to the PI in writing by Dompé farmaceutici s.p.a. No 
protocol amendment may be implemented (with the exceptions noted below) before it has been approved 
by the IRB/IEC and the signature page, signed by the PI, has been received by Dompé farmaceutici 
s.p.a. If the protocol is amended to eliminate or reduce the risk to patients, the amendment may be 
implemented before IRB/IEC review and approval. However, the IRB/EC must be informed in writing 
of such an amendment, and approval must be obtained within reasonable time limits. Deviating from 
the protocol is permitted only if absolutely necessary for the safety or clinical management of the 
patients and must immediately be reported to Dompé farmaceutici s.p.a. 
12.5. 
DISCONTINUATION OF THE STUDY 
Dompé farmaceutici s.p.a. reserves the right to terminate the study in its entirety or at a specific study 
center at any timeon the basis of new information regarding safety or efficacy, or if study progress is 
unsatisfactory, or for other valid administrative reasons. 
12.6. 
PUBLICATIONS 
Study results will be communicated in full to the competent Health Authorities by the submission of a 
complete clinical study report.  
The sponsor agrees that the study results may be published by the investigator, and the investigator 
agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor before any public 
disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, accurate and 
balanced manner. The sponsor reviews the proposed manuscripts, before submission, within a 
reasonable period of time (30-90 days in relation with the complexity of the work).  


 
 
 
 
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The investigator will also be provided by the sponsor with the clinical study report and the results of 
any additional analysis, tables, figures, etc. undertaken for the purposes of the article, in order to take 
responsibility for the content of the publication(s). On an exceptional basis, the sponsor may temporarily 
delay registration of certain data elements (e.g. compound, name, outcome, measures, etc.) to seek 
necessary intellectual property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 






 
 
 
 
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13.3. 
APPENDIX 3 - COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) VERSION 5.0 
 
The CTCAE version 5.0 can be accessed via the following link: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_8.5x11.pdf 
 
 
 


 
 
 
 
CONFORMED COPY TO THE ORIGINAL 
 
 
 
 
 
Page 78 of 79 
 
Version No. 3.0 FINAL 22/DEC/2020 
CONFIDENTIAL  
CONFIDENTIAL 
14. 
REFERENCES 
 
1 European Centre for Disease Prevention and Control. Outbreak of novel coronavirus disease 2019 (COVID-
19): increased transmission globally – fifth update, 2 March 2020. ECDC: Stockholm; 2020; Guan WJ et al., N 
Engl J Med. 2020 doi: 10.1056/NEJMoa2002032 
2 Scientific Discussion held for the approval of Evista (EPAR), 1 October 2003. 
3 Summary of Product Characteristics (Annex 1) of Evista – 60mg. 
4 Doran PM et al., Journal of Bone and Mineral Research 2001; 6: 2118-2125. 
5 Duschek EJ et al., European Journal of Endocrinology 2004; 150: 539–546. 
6 Furusyo N et al., Journal of Hepatology. 2012; 57: 1186-1192. 
7 Breart G et al., Osteoporosis International 2020; 21: 1181-1187. 
8 COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. 
National Institutes of Health. 
9 Pereira, H et al., 1989 Coronaviridae. Andrewes ’Viruses of Vertebrates, 5th ed.pp. 42-57; Holmes, K.V. et al., 
1996 Virology 1, 1075-1093. 
10 Anand K et al., Science 2003; 300: 1763-7. 
11 Strope JD et al., Are sex discordant outcomes in COVID-19 related to sex hormones? Sem. Oncol.  2020. 
12 Ding T et al., A Multi-hospital Study in Wuhan, China：Protective Effects of Non-menopause and Female 
Hormones on SARS-CoV-2 infection, preprint 2020. 
13 Hussain A et al., COVID-19 and diabetes: Knowledge in progress, Diabetes Res. Clin. Pract. 2020. 
14 Finucane FM et al., Coronavirus and Obesity: Could Insulin Resistance Mediate the Severity of Covid-19 
Infection?, Front. Public Health 2020; 8:184. 
15 Rudragouda et al., Journal of Immunology 2017; 198: 4049-4053. 
16 Breithaupt-Faloppa AC et al., 17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection, Clinics 2020. 
17 Dyall J et al., Antimicrob Agents Chemother 2014; 58: 4885-4893; Channappanavar R et al., J Immunol 2017; 
198: 4046–4053. 
18 Montoya MC et al., Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease, 
mBio 2018;9:e02272-18; Laurence J et al. Blood 1990; 75: 696-703; Watashi K et al. J BiolChem 2007; 282: 
32765-32772. 
 
 


 
 
 
 
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Version No. 3.0 FINAL 22/DEC/2020 
CONFIDENTIAL  
CONFIDENTIAL 
 
19 Johansen LM et al., FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection, 
Science Translational Medicine 2013;5:190ra79.  
20 Zhao Y et al., Toremifene interacts with and destabilizes the Ebola virus glycoprotein, Nature 2016;535:169-
172. 
21 Jeffrey A et al., Journal of Steroid Biochemistry and Molecular Biology 1997;61:97-106. 
22 Murthy AN et al., American Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2012. 
23 Sun D, American Association of Pharmaceutical Scientists Journal 2020 26;22-77. 
24 Barker RO et al., Distribution of the National Early Warning Score (NEWS) in care home residents, Age and 
Ageing. 2019 Dec 1;49(1):141-145. 

SAP_001.pdf: 
 
Agati Clinical Informatics 
 
Statistical Analysis Plan (Final 1.0) 
 
 
Statistical Analysis Plan  
 
Multicenter, adaptive, randomized, placebo-controlled, double blind, 
parallel-group Phase 2/3 trial, to study efficacy and safety of two 
doses of raloxifene in adult paucisymptomatic COVID-19 patients. 
 
 
 
Statistical Analysis Plan: Version (Final 1.0), Date: 07 Jul 2021 
 
 
 
 
Protocol Number: Version No. 3.0 – FINAL, Date: 22 Dec 2020 
 
Name of the Drug: Raloxifene (RLX) 
 
 
 
 
 
Sponsor Company: Dompé farmaceutici s.p.a. [Dompé] 
Via Santa Lucia 6; 20122 Milan, Italy 
 
 
 
 
 
Confidentiality Statement 
Confidentiality Notice: This document contains confidential or legally privileged information that 
is intended only for the use of Agati Clinical Informatics.  You are hereby notified that any 
disclosure, copying, or distribution of the contents of this document is strictly prohibited. 
 
 
 
 
 
 


 
Agati Clinical Informatics 
 
Statistical Analysis Plan (Final 1.0) 
 
 
TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 4 
2 
INTRODUCTION ........................................................................................................ 5 
3 
STUDY OBJECTIVES AND ENDPOINTS ................................................................. 5 
3.1 
STUDY OBJECTIVES ................................................................................................ 5 
3.1.1 PRIMARY OBJECTIVES ........................................................................................... 5 
3.1.2 SECONDARY OBJECTIVES ..................................................................................... 5 
3.2 
STUDY ENDPOINTS ................................................................................................. 5 
3.2.1 PRIMARY ENDPOINTS ............................................................................................. 5 
3.2.2 SECONDARY ENDPOINTS ....................................................................................... 5 
4 
STUDY DESIGN AND SCHEDULE OF EVENTS ...................................................... 6 
4.1 
STUDY DESIGN ........................................................................................................ 6 
4.1.1 DESCRIPTION OF THE STUDY ................................................................................ 6 
4.1.2 SAMPLE SIZE ........................................................................................................... 6 
4.1.3 DESCRIPTION OF TREATMENTS ............................................................................ 7 
4.1.4 DESCRIPTION OF THE STUDY FLOW ..................................................................... 8 
4.1.5 SCHEDULE OF ASSESMENTS ................................................................................ 8 
4.2 
PLANNED ANALYSES .............................................................................................. 8 
4.3 
INTERIM ANALYSIS .................................................................................................. 9 
4.4 
OVERALL ANALYSIS ............................................................................................... 9 
5 
ANALYSES POPULATION ...................................................................................... 10 
5.1 
ALL PATIENTS ENROLLED [ENR] ........................................................................ 10 
5.2 
RANDOMIZED POPULATION [RND] ...................................................................... 10 
5.3 
FULL ANALYSIS SET [FAS] ................................................................................... 10 
5.4 
SAFETY POPULATION [SAF] ................................................................................ 10 
5.5 
PER PROTOCOL POPULATION [PP]..................................................................... 10 
6 
PROTOCOL DEVIATIONS ...................................................................................... 10 
7 
GENERAL CONSIDERATIONS ............................................................................... 11 
7.1 
REFERENCE START DATE AND STUDY DAY ...................................................... 11 
7.2 
STUDY BASELINE AND POST BASELINE ............................................................ 11 
7.2.1 BASELINE ............................................................................................................... 11 
7.2.2 POST-BASELINE .................................................................................................... 11 
7.2.3 CHANGE FROM BASELINE ................................................................................... 11 
7.3 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT AND END OF 
STUDY ............................................................................................................................... 11 
7.3.1 EARLY TRIAL DISCONTINUATION VISIT AND UNSCHEDULED VISITS ............. 11 
7.3.2 PREMATURE DISCONTINUATION ......................................................................... 12 
7.3.3 END OF STUDY (EOS) ............................................................................................ 12 
7.4 
ALL LISTINGS ......................................................................................................... 12 
7.5 
SOFTWARE VERSION ............................................................................................ 13 
8 
STATISTICAL METHODOLOGY AND CONSIDERATIONS ................................... 13 
8.1 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES ........................................................................................................................ 13 
8.2 
MULTICENTRE STUDIES ....................................................................................... 13 
8.3 
SENSITIVITY AND SUPPORTIVE ANLYSES ......................................................... 13 
8.4 
MULTIPLE COMPARISONS/ MULTIPLICITY ......................................................... 13 
8.5 
EXAMINATION OF SUBGROUPS ........................................................................... 13 
9 
OUTPUT PRESENTATIONS ................................................................................... 14 
10 
PATIENT DISPOSITION, WITHDRAWALS AND PROTOCOL DEVIATIONS ......... 14 
11 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................... 14 
11.1 
MEDICAL HISTORY ................................................................................................ 15 
12 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................ 15 
13 
STUDY MEDICATION EXPOSURE AND COMPLIANCE ........................................ 16 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 3 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
13.1 
DURATION OF EXPOSURE AND TREATMENT COMPLIANCE ............................ 16 
14 
ANALYSES OF EFFICACY VARIABLES ................................................................ 17 
14.1 
EFFICACY ANALYSES ........................................................................................... 17 
14.1.1 PRIMARY EFFICACY ENDPOINTS AND ANALYSES ............................................ 17 
14.1.2 SECONDARY EFFICACY ENDPOINTS AND ANALYSES ..................................... 19 
14.1.3 DERIVATION ........................................................................................................... 21 
15 
ANALYSIS OF SAFETY VARIABLES ..................................................................... 22 
15.1 
ADVERSE EVENTS (AE) ASSESSMENT ............................................................... 22 
15.1.1 DERIVATION ........................................................................................................... 22 
15.1.2 ADVERSE EVENT ANALYSIS ................................................................................ 22 
15.2 
VITAL SIGNS ........................................................................................................... 24 
15.3 
LABORATORY PARAMETERS: BLOOD (HEMATOLOGY & BIOCHEMISTRY), 
COAGULATION, VIROLOGY AND OTHER MARKER ...................................................... 24 
16 
PREGNANCY TEST OVER THE STUDY ................................................................ 26 
17 
GENERAL PROGRAMMING SPECIFICATIONS .................................................... 26 
18 
CHANGES FROM PROTOCOL ............................................................................... 27 
19 
REFERENCES ......................................................................................................... 27 
20 
REVISION HISTORY ............................................................................................... 28 
21 
APPENDIX 1: PROGRAMMING CONVENTIONS FOR OUTPUTS ......................... 28 
22 
APPENDIX 2: PARTIAL DATE CONVENTIONS ..................................................... 29 
22.1 
ALGORITHM FOR ADVERSE EVENTS .................................................................. 29 
22.1.1 ADVERSE EVENT END DATE IMPUTATION ......................................................... 29 
22.1.2 ADVERSE EVENT START DATE IMPUTATION ..................................................... 29 
22.2 
ALGORITHM FOR CONCOMITANT MEDICATIONS: ............................................. 30 
22.2.1 CONCOMITANT TREATMENT END DATE IMPUTATION ...................................... 30 
22.2.2 CONCOMITANT TREATMENT START DATE IMPUTATION ................................. 30 
23 
APPENDIX 3:NEWS SCORE ................................................................................... 32 
24 
SIGNATURE PAGE ................................................................................................. 33 
 
 
 
 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 4 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI 
Adverse Event of Special Interest
ATC 
Anatomic Therapeutic Chemical
BMI
Body Mass Index
BP
Blood Pressure
BT
Body Temperature
CI
Confidence Interval
CP 
Conditional Power
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DB
Data Base
ENR
Enrolled Analysis Set
EOS
End of Study
ETDV
Early Trial Discontinuation Visit
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IP/IMP
Investigational Product/ Investigational Medicinal Product
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not Applicable
NEWS 
National Early Warning Score
PCR
Polymerase Chain Reaction
PD
Protocol Deviation
PI
Principal Investigator
PP
Per Protocol
PR
Pulse Rate 
PT
Preferred Term 
QC
Quality Control
RTF
Rich Text Format
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan 
SD
Standard Deviation
SOC
System Organ Class 
SpO2
Oxygen Saturation
TEAE
Treatment Emergent Adverse Event 
TESAE
Treatment Emergent Serious Adverse Event 
TLF
Tables Listings Figures
WHODD
World Health Organization Drug Dictionary


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 5 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
2 
INTRODUCTION 
This document describes the rules and conventions to be used in the presentation 
and analysis of efficacy and safety data for Protocol RLX0120. It describes the 
data to be derived, summarized and the statistical analyses to be performed.  
This Statistical Analysis Plan (SAP) is based on study protocol version 3.0, dated 
22 Dec 2020.  
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 STUDY OBJECTIVES 
The objective of this study is to evaluate the efficacy and safety of two different 
doses of raloxifene orally administered compared to placebo in patients with early 
diagnosis of paucisymptomatic COVID-19 
3.1.1 PRIMARY OBJECTIVES 
- 
Evaluation of the effectiveness of therapy in reducing the proportion of patients 
who still have viruses in the upper airways after 7 days of therapy. 
- 
Evaluation of the effectiveness of therapy in reducing the proportion of patients 
who requires supplemental oxygen therapy and/or mechanical ventilation 
within 14 days of starting therapy. 
3.1.2 SECONDARY OBJECTIVES 
- 
Evaluation of the effectiveness of therapy in reducing the proportion of patients 
who still have viruses in the upper airways after 14 and 28 days of therapy. 
- 
Evaluation of the effectiveness of therapy in reducing the proportion of patients 
who requires supplemental oxygen therapy and/or mechanical ventilation 
within 7 or 28 days of starting therapy. 
- 
7, 14 and 28 days drug safety and tolerability profile. 
- 
Assessment of body temperature, blood and biochemical parameters between 
T0 and T28. 
3.2 STUDY ENDPOINTS 
3.2.1 PRIMARY ENDPOINTS 
- 
Virologic outcome - Proportion of patients with undetectable SARS-CoV-2 at 
PCR at day 7 after randomization. 
- 
Clinical outcome - Proportion of patients who does not require supplemental 
oxygen therapy (NEWS ≤2) and/or mechanical ventilation at day 14 after 
randomization. 
3.2.2 SECONDARY ENDPOINTS 
- 
Proportion of patients with undetectable SARS-CoV-2 at PCR at day 14 after 
randomization at day 28 after randomization. 
- 
Proportion of patients who does not require supplemental oxygen therapy 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 6 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
(NEWS ≤2) and/or mechanical ventilation at day 7 and 28 after randomization. 
- 
Proportion of patients in each NEWS category at time 7, 14 and 28 after 
randomization. 
- 
Mean value of NEWS category at time 7,14 and 28 after randomization. 
- 
Proportion of patients with any adverse event with grade ≤ 2 according to 
CTCAE at day 7, 14 and 28 after randomization. 
- 
Proportion of patients with any severe adverse events (grade ≥ 3 according to 
CTCAE) at day 7, 14 and 28 after randomization. 
- 
Proportion of hospitalized patients who at the beginning of the study were at 
domicile isolation at day 7, 14 and 28 after randomization. 
- 
Proportion of patients admitted to intensive care at day 7, 14 and 28 after 
randomization. 
- 
Proportion of survivors at day 7, 14 and 28 after randomization. 
- 
Mean variation of value of the following biomarker parameters, from baseline 
to day 7, 14, 21 and 28 after randomization: 
 Complete blood cell counts. 
 Hepatic function (ALT, AST and bilirubin). 
 Coagulation (PT, aPTT and INR). 
 Other marker including (D-dimer, CPK, LDH). 
- 
Quality of life questionnaire 3 months after the randomization. 
4 
STUDY DESIGN AND SCHEDULE OF EVENTS 
4.1 STUDY DESIGN 
4.1.1 DESCRIPTION OF THE STUDY 
This is a Multicenter, adaptive, double blind, randomized, placebo controlled, 
parallel group, to study efficacy and safety, with the following adaptive 
components: 
 Parallel multi-arms (2 interventional arms and 1 placebo control arm). 
 A 2-stage sequential design (1 interim analysis + 1 final analysis). 
 Sample size re-calculation at interim stage. 
 Stopping rule for efficacy or futility at interim stage. 
4.1.2 SAMPLE SIZE 
The sample size of the study has been based on the following assumptions: 
- 
Virologic assumption: Early treatment with antivirals increases the proportion 
of patients with undetectable SARS-CoV-2 in upper respiratory tract at day 7 
after therapy from 25% to 50%. 
- 
Clinical assumption: Early treatment with antivirals increases the proportion of 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 7 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
patients who recover without need of mechanical ventilation and/or 
supplemental oxygen therapy by the day 14 after therapy from 50% to 75%. 
Based on these assumptions and considering a randomization ratio 1:1:1, the 
sample size will be adaptively determined to achieve a power greater than 80% to 
show superiority of raloxifene vs placebo in terms of either one of primary endpoint 
and controlling the one-sided alpha below 0.025. 
Sample size will be determined through the following steps:  
 an interim analysis will take place when 50 patients per arm (N=150) have 
reached their primary endpoints (i.e. assessments available). 
o In case of efficacy of at least one treatment arm or futility of both 
arms (see criteria in protocol section 9.3) the study enrollment will 
be stopped, 
o otherwise the actual number of new patients in each arm may be 
blindly reassessed according to observed efficacy of the best 
favourable and promising arm;  
 in case of continuation of the study to the final stage, it is expected to 
randomize on average additional 174 patients, depending on sample size 
reassessment and possible dropping of an ineffective treatment arm. 
Expected sample size will be between 250 and 450 randomized patients;  
 drop-outs of randomized subjects will not be replaced.  
This approach allows either to minimize the number of enrolled patients if the 
experimental assumptions are too conservative or to have a good power level if 
they are too optimistic.  
Pocock’s spending functions and conditional power (CP) will be used to control 
the type I and II errors, considering that interim analysis will be performed when 
half of the initial planned patients have been reached the primary endpoints (i.e. 
assessments available).  
Bonferroni method is used to adjust for multiple endpoint vs treatment 
comparisons. Sample size calculation has been performed through simulation 
(100000 replications). The statistical software used for simulation was SAS®, 
Version 9.4. 
4.1.3 DESCRIPTION OF TREATMENTS 
After an administration of two oral doses in the first day of treatment (one dose in 
the morning and one dose in the evening, each dose administered with 2 capsules 
containing 60 mg of the active substance or placebo), a single daily oral dose of 
raloxifene (60 mg Group 1, 120 mg Group 2 – treatment groups) or placebo (Group 
3 - control group) will be taken on by the patients for two weeks.  
The patients will be randomly (1:1:1) assigned to receive either raloxifene 
treatment or placebo: 
 Treatment groups: 
o Group 1: will receive one capsule of raloxifene 60 mg and one 
capsule of placebo. 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 8 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
o Group 2: will receive two capsules of raloxifene 60 mg. 
 Control group: 
o Group 3: will receive two capsules of placebo. 
4.1.4 DESCRIPTION OF THE STUDY FLOW 
This study will be performed in clinical centers located in Europe. At each study 
center, the Principal Investigator (PI) will be responsible for ensuring that the 
investigation is conducted according to the signed Investigator agreement, the 
protocol, GCP guidelines, and local regulations.  
Screening investigations on patient will be done only after signing of informed 
consent.  
At the end of the screening period, patients meeting the entry criteria for this study 
will be randomized (1:1:1) to 1 of 3 treatment groups (group 1, group 2 or group 
3) and instructed by a physician on the correct self-administration of the treatment 
and completion of the patient diaries. 
The study will be a total of 5 weeks in duration: 
Screening Period
10 days
Treatment Period
2 weeks (14 days)
Follow-up Period
2 weeks (14 days)
 
A quality of life questionnaire will be submitted at 3 months after the 
randomization.  
4.1.5 SCHEDULE OF ASSESMENTS 
Assessment of efficacy and safety will be done periodically during the study as 
given in the schedule of assessment table in protocol section 2. 
4.2 PLANNED ANALYSES 
Statistical analysis and reporting will be performed by Agati Clinical Informatics, 
India for this study. 
SAS source (raw) data will be transferred as SAS dataset (.sas7bdat), together 
with laboratory reference range, and any support datasets. Transfer will occur via 
secured EXOM Group Share Point Portal with limited and restricted access.  
The statistical analysis will be based on validated analysis datasets prepared by 
Agati Clinical Informatics, India. 
Production SAS programmers will create derived datasets from the Source (Raw) 
datasets as per the mapping instructions given in the analysis mapping 
specifications. Simultaneously, the Validation (QC) SAS programmer will create 
the same derived datasets independently and will do a comparison with production 
datasets to validate them.  
Validated draft derived datasets will be sent to the Study Lead Biostatistician for 
review and approval. When the final source data transfer is made available (after 
database lock), the production and validation programs will be re-run to create the 
final derived datasets deliverable to be used for the final statistical analysis. 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 9 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
The statistical SAS output generated after running SAS programs will be copied 
in a Word file and paginated as specified in the Section 18 of this SAP. 
Tables, Listings and Figures will be presented according to TFL Shells document 
created and finalized based on approved version of the SAP. 
4.3 INTERIM ANALYSIS 
An interim analysis was planned for this study when half (i.e 50 participants per 
arm (N=150)) of the planned evaluable patients would have reached the primary 
endpoints at 7 and 14 days (i.e., assessments available). 
The intent of the interim analysis was either for identification of early superiority of 
raloxifene (early efficacy), or for an early stop of one or both treatment arms for 
futility, or for blind sample size reassessment. 
Due to the premature interruption of the enrolment (with 68 patients included in 
the study), no interim analysis will be done.  
4.4 OVERALL ANALYSIS 
Final analyses identified in this SAP will be performed by Agati Clinical Informatics 
following Sponsor Authorization of this Statistical Analysis Plan, Database Lock, 
Sponsor Authorization of Analysis Population and Unblinding of Study Treatment. 
For primary and secondary efficacy endpoints, p-value, lower and upper 95% 
Confidence Limits (CL) will be also presented based on the statistical analysis 
performed. 
The default summary statistics for quantitative variables will be the number of 
observations (n), mean, standard deviation (SD), median, minimum (min) and 
maximum (max).  
For qualitative variables, the number (n) and percentage (%) of patients with non-
missing data per variable of interest will be the default summary presentation, if 
appropriate and wherever required the number of missing values will be presented 
as a “Missing” category. If appropriate, 95% confidence intervals around the 
percentage will be presented. 
Time-to-event endpoints will be assessed by the Kaplan-Meier (K-M) method. 
Time to event curves will be compared (i.e comparisons of each active treatment 
group versus placebo) using log-rank test and estimates of hazard ratio will be 
obtained using Cox proportional hazards model after performing diagnostics of 
proportional hazard assumption (investigated with a time dependent exploratory 
variable treatment*{log[time to event ]}; if the p-value from the Wald Chi-squared 
statistic for this variable is less than 5% there is evidence of a departure from the 
adjusted model assumptions.). K-M estimates of median survival time associated 
with each treatment group will be provided along with 25th and 75th percentiles 
and their 2-sided 95% CIs (based on Greenwood’s method). K-M estimates will 
be presented at Day 7, 14 and 28 for each treatment group. K-M curves will be 
plotted comparing treatment groups with the number of patient-at-risk in each 
treatment group at exact time points. Patients who are ongoing and who are free 
from event at the time of DB lock will be censored at the DB lock date. Patients 
who have discontinued without an event will be censored at the date of 
discontinuation. Patients who are died will be considered as censored with death 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 10 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
date as date of censored. 
5 
ANALYSES POPULATION 
Agreement and authorization of patients included/excluded from each analysis 
Population will be performed on a case-by-case basis before the database 
lock/un-blinding.  
5.1 ALL PATIENTS ENROLLED [ENR] 
The Enrolled (ENR) population will contain all patients who provided informed 
consent for this study. 
The Enrolled (ENR) population will be used for the Patient disposition Table and 
Listings. And it will be analysed according to the randomized treatment, if 
applicable.  
5.2 RANDOMIZED POPULATION [RND] 
The Randomized (RND) population will contain all patients in the ENR Population 
who were randomized to the study, regardless of whether they received study 
medication or not. Patients will be analysed according to the treatment they were 
randomized. 
5.3 FULL ANALYSIS SET [FAS] 
The Full Analysis Set (FAS) population will consist of all randomized patients who 
received at least one dose of the study medication (either Raloxifene or Placebo).  
The Full Analysis Set (FAS) population will be used for Primary and secondary 
efficacy analyses, all the demographics and baseline characteristics Tables and 
Figures. Patients will be analysed according to the treatment they were 
randomized. 
5.4 SAFETY POPULATION [SAF] 
The Safety (SAF) population will consist of all randomized patients who received 
at least one dose of the study medication.  
The Safety (SAF) population will be used to present results on safety data. Safety 
data will be analysed according to the treatment which patients have received. 
5.5 PER PROTOCOL POPULATION [PP] 
The Per Protocol (PP) population will consist of all randomized patients who 
received at least one dose of the study medication and do not have any Major 
Protocol Deviations.  
The Per Protocol (PP) population will be used for sensitivity analyses of the 
efficacy endpoints. Patients will be analysed according to the treatment they were 
randomized. 
6 
PROTOCOL DEVIATIONS 
All the protocol deviations will be discussed on a case by case basis by the clinical 
team prior to database lock. Any significant deviation from the protocol will be 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 11 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
reviewed and a decision taken regarding evaluation for each analysis population. 
7 
GENERAL CONSIDERATIONS 
7.1 REFERENCE START DATE AND STUDY DAY 
In general, reference start date is defined as the day of the first dose of study 
medication (Study Day 1: first day) and will appear in every listing where an 
assessment date or event date appears.  
Study Day will be calculated from the reference start date and will be used to show 
start / stop day of assessments and events. 
If the date of the assessment/event is on or after the reference start date, then:  
Study Day = (date of assessment/event – reference start date) + 1 
If the date of the assessment/event is prior to the reference start date, then:  
Study Day = (date of assessment/event – reference start date) 
In the situation where the assessment/event date is partial or missing, the date 
will appear partial or missing in the listings, and Study Day and any corresponding 
duration will be presented based on the imputations specified in Appendix 2 
(Partial Date Conventions). 
7.2 STUDY BASELINE AND POST BASELINE 
7.2.1 BASELINE 
Unless otherwise specified, study baseline is defined as the last non-missing 
measurement taken prior to first IMP administration. 
7.2.2 POST-BASELINE 
Post-Baseline is defined as the measurement taken after the first IMP 
administration.  
7.2.3 CHANGE FROM BASELINE 
For some quantitative measurements, change from baseline will be calculated as: 
      Change from baseline = Value at Post-Baseline Visit – Baseline Value 
7.3 EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT AND 
END OF STUDY 
7.3.1 EARLY TRIAL DISCONTINUATION VISIT AND UNSCHEDULED 
VISITS 
In general, for by-visit summaries, data recorded at the nominal visit will be 
presented. 
Unscheduled measurements will not be included in by-visit summaries. Listings 
will include scheduled, unscheduled, and early trial discontinuation visit (ETDV). 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 12 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
7.3.2 PREMATURE DISCONTINUATION 
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of 
the study protocol procedures. Patients can be prematurely discontinued from the 
study for one of the following reasons: 
Primary Reason for treatment discontinuation: 
 Failure to meet inclusion/exclusion criteria or severe protocol violations 
 Negative Nasopharyngeal swab 
 Withdrawal of consent 
 Lost to follow-up 
 Study terminated by the Sponsor 
 Documented disease progression 
 Development of AE or unacceptable toxicity, precluding further therapy with 
the study drug 
 Pregnancy 
 Hypoalbuminemia at a level considered clinically relevant by the 
investigator 
 Other reasons 
Primary Reason for study discontinuation: 
 Failure to meet inclusion/exclusion criteria or severe protocol violations 
 Withdrawal of consent 
 Lost to follow-up (Every effort must be made to contact the patient; a 
registered letter must be sent) 
 Study terminated by the Sponsor 
 Development of AE or unacceptable toxicity, precluding further therapy with 
the study drug 
 Pregnancy 
 Other reasons 
In case of discontinuation, patients will undergo a remote Early Trial 
Discontinuation Visit aimed to assess physical abnormalities, vital signs and 
transdermal oxygen saturation measurement. 
7.3.3 END OF STUDY (EOS) 
The EOS is defined as the last day the last patient completes the last study 
assessment, or retracts the consent to participate in the study, or withdraws from 
the study, or is deceased or otherwise lost to follow-up. 
7.4 ALL LISTINGS 
All data will be listed by the patient. 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 13 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
7.5 SOFTWARE VERSION 
All statistical analyses will be conducted using the SAS® System version 9.1.3 or 
higher. 
8 
STATISTICAL METHODOLOGY AND CONSIDERATIONS 
8.1 ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
In the analysis of primary endpoints and secondary endpoints, the following 
factors/covariates will be considered in the Binary Logistic regression and 
Repeated Measures Logistic regression model as described in the SAP section 
14.1 
 Treatment group; 
 Center; 
 Age group; 
 Status (Male, Female pre-menopausal status, Female post-menopausal 
status); 
 For Clinical outcome: Baseline NEWS value. 
8.2 MULTICENTRE STUDIES 
This study will be conducted by multiple investigators at multiple centres and 
randomization will be stratified by site and gender. Both stratification factors will 
be included in the primary efficacy analysis model. 
8.3 SENSITIVITY AND SUPPORTIVE ANALYSES 
The virologic and clinical primary efficacy endpoints will be analysed using the 
same Binary Logistic regression procedure given in SAP section 14.1.1 on PP 
Population using observed data only; these analyses will be performed to explore 
the robustness of the primary results versus protocol adherence.  
8.4 MULTIPLE COMPARISONS/ MULTIPLICITY 
Bonferroni method is used to adjust for multiple endpoints and treatment 
comparisons. 
8.5 EXAMINATION OF SUBGROUPS 
Statistical tests for interaction (between subgroup and treatment arm) will be 
performed to decide about the need to further investigate subgroups of the trial 
population based on the following variables:  
 age group (< median vs ≥ median, where median is calculated based on 
ENR population) 
 gender (Male vs Female) 
 Status (Male, Female pre-menopausal status, Female post-menopausal 
status); 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 14 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
Subgroup analysis will be performed if interaction effects are statistically 
significant at 0.15 level of significance.  
Subgroup analysis will be performed for the primary efficacy endpoints. 
Descriptive and appropriate inferential statistical tests will be used. All subgroups 
will be analysed using FAS population. 
9 
OUTPUT PRESENTATIONS 
SAP Section 17 and Appendix 1 includes conventions for presentation of data in 
outputs.  
The templates provided with this SAP describe the presentations shell for this 
study and therefore the format and content of the summary tables, figures and 
listings to be provided. 
The reference analysis population of each table and line listing will be reported in 
the corresponding table, listing and figures. 
10 PATIENT DISPOSITION, WITHDRAWALS AND PROTOCOL 
DEVIATIONS 
A detailed description of the patient disposition will be provided. The number of 
patients screened, screen failures, randomized, randomized but not dosed, 
completed, as well as the number of dropouts, with reasons for treatment 
discontinuation, study discontinuation and major protocol deviations. The 
summary of analysis populations, a summary of reasons for exclusion from 
analysis populations will be presented. 
Patient disposition details will be presented in listing. 
Furthermore, Summary of Protocol Deviations table and an individual data listing 
of protocol deviations will be produced.  
The Enrolled (ENR) population will be considered for this analysis. And data will 
be summarized by randomized treatment group. 
11 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Summary of demographic data and other baseline characteristics will be tabulated 
for the Full analysis set (FAS) population and will be summarized by randomized 
treatment group. 
No statistical testing will be carried out for demographic or other baseline 
characteristics. 
The following demographic and baseline characteristics will be reported by 
treatment for this study: 
 Demographic variables: 
o Age (years) 
o Sex (Male, Female) 
o Race (White, Black or African American, Asian, American Indian or 
Alaska native, Native Hawaiian or other pacific islander, NA, Other) 
o Height (cm) 
o Weight (Kg) 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 15 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
o BMI 
o Smoking habits  
o Status (Male, Female pre-menopausal status and Female post-
menopausal status) 
 Female Patient childbearing potential (Yes/No) 
Default frequency tabulations will be provided for categorical variables and 
descriptive statistics will be provided for quantitative parameters. 
11.1 MEDICAL HISTORY 
Medical history information will be tabulated for both FAS and SAF analysis 
populations and will be summarized accordingly (see SAP section 5).  
All verbatim terms will be assigned to a Preferred Term (PT) and will be classified 
by primary System Organ Class (SOC) according to MedDRA dictionary 
September 2020, version 23.1 
Medical conditions which are not ongoing at Screening visit will be considered as 
previous diseases while those reported as “ongoing” in CRF will be considered as 
concomitant diseases. 
Medical History of special interest as per collected in CRF will be listed for ENR 
population. 
12 PRIOR AND CONCOMITANT MEDICATIONS 
All medications taken by the patients during the Screening will be recorded by the 
Investigator in the CRF. 
Prior and concomitant medications will be tabulated for both the FAS and SAF 
analysis populations and will be summarized accordingly. Prior and concomitant 
medications will be coded using WHODD Global September2020 version. 
See Appendix 2 for handling of partial dates for medications, in the case where it 
is not possible to define a medication as prior or concomitant, the medication will 
be classified by the worst case, i.e., concomitant.  
Prior medications are those which stopped prior to the date of first study 
medication administration. 
Concomitant medications are those which 
 started prior to, on or after the date of first study medication administration 
and started no later than end date of the study, and 
 ended on or after the date of first study medication administration or were 
ongoing at the end of the study. 
The following tables will be presented: 
 A frequency tables of prior medications by primary therapeutic subgroup 
(ATC level subgroup) and generic name. 
 A frequency tables of concomitant medications by primary therapeutic 
subgroup (ATC level subgroup) and generic name. 
Listing of prior/concomitant medication will be provided.  


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 16 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
13 STUDY MEDICATION EXPOSURE AND COMPLIANCE 
13.1 DURATION OF EXPOSURE AND TREATMENT COMPLIANCE 
Data will be summarized by actual treatment groups for Safety (SAF) population 
with descriptive statistics. 
Total duration of study medication exposure considered in days and will be 
summarized using descriptive statistics. 
Study medication taken (# of capsules) will be summarized using descriptive 
statistics. 
Descriptive statistics will be presented separately by treatment group for the 
overall compliance to study medication. The overall compliance categories 
 <= 80%, 
 >80 – <= 100%, and 
 >100% 
will be summarized using frequency and percent by treatment. 
Additionally, the individual table will be provided for  
 study medication taken (capsules)and overall compliance on Day 1 i.e., two 
oral doses in the first day of treatment.  
 study medication taken (capsules) and overall compliance after Day 1  i.e., a 
single daily oral dose of patients for two weeks. 
All the patient’s data will be listed. 
The following derivation rules will be applied: 
Total duration of exposure (days) = (Treatment end date – Treatment start date) 
+ 1. 
 Overall Compliance (%)= (number of capsules taken / expected number of 
capsules to be taken during the study (i.e.,30)) *100 
 Overall Compliance on Day 1 (%) = (number of capsules taken in first day / 
expected number of capsules taken in first day intake (i.e., 4)) *100  
 Overall Compliance after Day 1 (%) = (number of capsules taken after the 
first day / expected number of capsules to be taken after the first day (i.e., 
26) *100 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 17 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
14 ANALYSES OF EFFICACY VARIABLES 
14.1 EFFICACY ANALYSES 
 
NEWS score evaluation will be performed at T0, T7, T14 and T28. NEWS score and 
NEWS score parameters as per collected in CRF will be provided in Listing for FAS 
population. Refer Appendix 3 for NEWS score. 
 
Table 3: Summary of Analyses Strategies for efficacy endpoints: 
Endpoint 
Analysis 
set 
Statistical 
method 
Factors/Co
variates 
Missing 
data 
Handling
Analyses 
type 
Virologic outcome -
Proportion of patients with 
undetectable SARS-CoV-2 
at PCR at day 7 after 
randomization.
FAS 
Binary 
Logistic 
regression 
Treatment, 
center, age 
and status 
Missing 
data will 
not be 
imputed 
Primary 
analysis 
Virologic outcome -
Proportion of patients with 
undetectable SARS-CoV-2 
at PCR at day 7 after 
randomization.
PP 
Binary 
Logistic 
regression 
Treatment, 
center, age 
and status 
Missing 
data will 
not be 
imputed 
Sensitivity 
analysis 
Clinical outcome -
Proportion of patients who 
does not require 
supplemental oxygen 
therapy (NEWS ≤2) and/or 
mechanical ventilation at day 
14 after randomization.
FAS 
Binary 
Logistic 
regression 
Treatment, 
center, 
age, status 
and 
baseline 
NEWS 
Missing 
data will 
not be 
imputed 
Primary 
analysis 
Clinical outcome -
Proportion of patients who 
does not require 
supplemental oxygen 
therapy (NEWS ≤2) and/or 
mechanical ventilation at day 
14 after randomization. 
PP 
Binary 
Logistic 
regression 
Treatment, 
center, 
age, status 
and 
baseline 
NEWS 
Missing 
data will 
not be 
imputed 
Sensitivity 
analysis 
14.1.1 
PRIMARY EFFICACY ENDPOINTS AND ANALYSES 
1. Proportion of patients with undetectable SARS-CoV-2 at PCR at day 7 after 
randomization (virologic endpoint). This endpoint will be derived as below. 
 Based on Approved molecular test (PCR) result at day 7, the responses 
will be considered as “detectable” if PCR result is “Positive” otherwise 
“undetectable” if PCR result is “Negative” (Missing PCR result will be 
considered as missing in the main analysis). 
The response (detectable / undetectable) at day 7 will be analysed using Binary 
logistic regression model with treatment group and pre-defined baseline factors 
(center, age, status and their interaction effects with treatment group). Odds ratio 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 18 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
will be computed for comparisons of each active treatment group versus placebo. 
i.e., raloxifene (60 mg) versus placebo and raloxifene (120 mg) versus placebo. 
2. The proportion of patients who does not require supplemental oxygen therapy 
(NEWS ≤2) and mechanical ventilation at day 14 after randomization (clinical 
endpoint). This endpoint will be derived as below. 
 
 If collected NEWS score >2 or mechanical ventilation at day 14 result 
“Yes” then the response will be considered as “Required”. If collected 
NEWS score ≤ 2 and mechanical ventilation with result “No” then the 
response will be considered as “Not Required” (if both NEWS score and 
mechanical ventilation are missing, patient will be considered as 
missing). 
The response (Required/ Not required) at day 14 will be analysed using Binary 
logistic regression model with treatment group and pre-defined baseline factors 
(center, age, status, baseline NEWS and their interaction effects with treatment 
group). Odds ratio will be computed for comparisons of each active treatment 
group versus placebo. i.e., raloxifene (60 mg) versus placebo; and raloxifene (120 
mg) versus placebo. 
For both virologic and clinical endpoint, Binary Logistic regression will be 
performed using PROC GENMOD in SAS® on the observed data only to estimate 
difference in proportions between each active treatment versus placebo and its 
corresponding 95% (2-sided) confidence intervals. Exponential transformation will 
be used to obtain the odds ratio and corresponding 95% confidence interval. P-
values will be reported based on the Wald tests from Type III analyses. Bonferroni 
method will be considered to handle multiple treatment comparisons. 
In the SAS® procedure PROC GENMOD, a Type III analysis will be performed by 
adding the model options: TYPE3, DIST=BIN and LINK=LOGIT.  
If the model does not converge then the following steps will be performed 
subsequently: 
 PROC GENMOD with EXACT statement will be used.  
 If the model still does not converge, then remove the factors/covariates 
from the model one by one (according to statistical significance) until 
convergence reached. 
 If the model still does not converge, then perform the Fisher’s exact using 
the SAS procedure PROC FREQ without adjusting for any pre-defined 
factor and covariates. 
The following hypotheses will be tested: 
- 
The null hypothesis for the virologic endpoint is that proportion of treated 
patients with undetectable SARS-CoV-2 at PCR at day 7 after randomization 
(πRALOXIFENE) is lower or equal the placebo one (πPLACEBO). Two sets of null and 
alternative hypotheses are provided, one for each treatment dosage: 
H01-60mg: πRALOXIFENE-60mg ≤ πPLACEBO 
H11-60mg: πRALOXIFENE-60mg> πPLACEBO 
H01-120mg: πRALOXIFENE-120mg ≤ πPLACEBO
H11-120mg: πRALOXIFENE-120mg> πPLACEBO 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 19 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
- 
The null hypothesis for the clinical endpoint is that proportion of treated patients 
who does not require supplemental oxygen therapy (NEWS ≤2) and/or 
mechanical ventilation at day 14 after randomization (TRALOXIFENE) is lower or 
equal the placebo one (TPLACEBO). Two sets of null and alternative hypotheses 
are provided, one for each treatment dosage: 
H02-60mg: TRALOXIFENE-60mg ≤ TPLACEBO 
H12-60mg: TRALOXIFENE-60mg> TPLACEBO 
H02-120mg: TRALOXIFENE-120mg ≤ TPLACEBO 
H12-120mg: TRALOXIFENE-120mg> TPLACEBO 
Superiority of raloxifene will be established if at least one null hypothesis is 
rejected. 
The frequency and percent will be presented by treatment and visit for both 
primary endpoints results. 
The following figures will be produced for both primary endpoints results: 
 Bar chart for Proportion of Patients with undetectable SARS-CoV-2 at PCR 
by treatment and visit 
 Bar chart for Proportion of Patients who does not require supplemental 
oxygen therapy (NEWS ≤2) and/or mechanical ventilation by treatment and 
visit 
The following listings will be presented: 
 Listing for the Nasopharyngeal Swab Test (PCR) results 
 Listing for the supplemental oxygen therapy (NEWS ≤2) and/or mechanical 
ventilation 
Refer the Appendix 3 for NEWS score. 
14.1.2 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
1. Proportion of patients with undetectable SARS-CoV-2 at PCR at day 14 after 
randomization at day 28 after randomization. Analyses will be performed on 
FAS population. This endpoint will be derived as below 
 Based on Approved molecular test (PCR) result, the responses will be 
considered as “detectable” if PCR result is “Positive” otherwise 
“undetectable” if PCR result is “Negative” (Missing PCR result will be 
considered as missing). 
The response (detectable / undetectable) at day 14 and day 28 will be analysed 
using repeated measures logistic regression model with treatment group, visit and 
pre-defined baseline factors (center, age and status). Odds ratio will be computed 
for comparisons of each active treatment group versus placebo at each 
assessment day i.e., raloxifene (60 mg) versus placebo; and raloxifene (120 mg) 
versus placebo. Analyses will be performed on FAS population using observed 
data only. 
2. Proportion of patients who does not require supplemental oxygen therapy 
(NEWS ≤2) and mechanical ventilation at day 7 and 28 after randomization. 
This endpoint will be derived as below 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 20 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
 If collected NEWS score > 2 or mechanical ventilation with result “Yes” 
then the response will be considered as “Required”. If collected NEWS 
score ≤ 2 and mechanical ventilation with result “No” then the response 
will be considered as “Not Required” (if both NEWS score and 
mechanical ventilation are missing, patient will be considered as 
missing). 
 
The response (Required / Not Required) at day 7 and day 28 will be analysed 
using repeated measures logistic regression model with treatment group, visit 
and pre-defined baseline factors (center, age, status and baseline NEWS). 
Odds ratio will be computed for comparisons of each active treatment group 
versus placebo at each assessment day. i.e., raloxifene (60 mg) versus 
placebo; and raloxifene (120 mg) versus placebo. Analyses will be performed 
on FAS population using observed data only. 
For the above two secondary endpoints, Repeated Measures Logistic regression 
will be performed using PROC GENMOD in SAS® on the observed data only to 
estimate difference in proportions between each active treatment versus placebo 
and its corresponding 95% (2-sided) confidence intervals. Exponential 
transformation will be used to obtain the odds ratio and corresponding 95% 
confidence interval. P-values will be reported based on the Wald tests from Type 
III analyses.  
In the SAS® procedure PROC GENMOD, a Type III analysis will be performed by 
adding the model options: TYPE3, DIST=BIN and LINK=LOGIT. REPEATED 
statement will be used to consider visit and TYPE=UN option used for correlation-
matrix. If the model does not converge then appropriate TYPE would be applied 
for correlation-matrix. 
The following time-to-event endpoints will be analysed according to SAP section 
4.4 methods. 
i. 
Time to reach undetectable SARS-CoV-2 at PCR 
ii. 
Time to get relieved from supplemental oxygen therapy (NEWS ≤ 2) 
and/or mechanical ventilation 
iii. 
Overall survival 
Analyses will be performed on FAS population. 
3. Proportion of patients in each NEWS category at Day 7, 14 and 28 after 
randomization will be summarized by frequency and percent by treatment and 
visit for FAS population. 
 
4. NEWS score at Day 7, 14 and 28 after randomization will also be summarized 
using descriptive statistics by treatment and visit for FAS population. 
 
5. Proportion of hospitalized patients who at the beginning of the study were at 
domicile isolation at day 7, 14 and 28 after randomization will be analysed 
using comparison of proportions (i.e comparisons of each active treatment 
group versus placebo at each assessment day) through Fisher’s exact test and 
will be summarized using frequency and percent by treatment and visit. 
Analyses will be performed on FAS population. 
 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 21 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
6. Proportion of patients admitted to intensive care at Day 7, 14 and 28 after 
randomization will be analysed using comparison of proportions (i.e 
comparisons of each active treatment group versus placebo at each 
assessment day) through Z-test and will be summarized using frequency and 
percent by treatment and visit. Analyses will be performed on FAS population. 
 
7. Overall survival will be analysed according to time-to-event methods described 
in SAP section 4.4. 
 
8. Quality of life questionnaire (EQ-5D-5L) at 3 months after the randomization 
will be summarized using appropriate descriptive statistics by treatment. The 
number and proportion of subjects of each level (1 - no problems, 2 - slight 
problems, 3 - moderate problems, 4 - severe problems, 5 - extreme problems) 
for each dimension (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) will be reported. 
Analyses will be performed on FAS population. 
 
Patient’s data will be listed for all secondary endpoints. 
Additionally, conformed SARS-COV-2 infection listing will be provided for ENR 
population. Confirmation of SARS-CoV-2 infection must be available before the 
screening visit i.e Pre-screening. Only diagnosed COVID-19 paucisymptomatic 
patients will be evaluated for the trial participation. 
14.1.3 
DERIVATION 
Pre-menopausal status – Female patients with child-bearing potential will be 
considered. 
Post-menopausal status – Female patients with non-child-bearing potential will be 
considered. 
Status – Male, Female with pre-menopausal status and Female with post-
menopausal status will be considered for “Status” variable derivation for the 
Analysis. 
Time to reach undetectable SARS-CoV-2 at PCR: 
Patients who have experienced the event (undetectable SARS-CoV-2 at PCR), 
their date of PCR result confirmation will be used for time duration calculation. 
Time to reach undetectable SARS-CoV-2 at PCR = (Date of undetectable SARS-
CoV-2 at PCR / Censored date – Treatment Start date) + 1 
Time to get relieved from supplemental oxygen therapy (NEWS ≤ 2) and/or 
mechanical ventilation: 
Patients who have experienced the event (relieved from supplemental oxygen 
therapy (NEWS ≤ 2) and/or mechanical ventilation), their date of confirmation will 
be used for time duration calculation. 
Time to get relieved from supplemental oxygen therapy (NEWS ≤ 2) and/or 
mechanical ventilation = (Date of relieved from supplemental oxygen therapy 
(NEWS ≤ 2) and/or mechanical ventilation / Censored date - Treatment Start date) 
+ 1 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 22 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
Overall Survival: 
Overall Survival = (Date of Death / Censored date - Treatment Start date) + 1 
15 ANALYSIS OF SAFETY VARIABLES 
For the safety analysis, the SAF population will be used.  
Parameters for Assessment of Safety as follows:  
 Adverse Events (AE) assessment 
 Vital signs 
 Laboratory parameters: Blood (haematology & biochemistry), Coagulation, 
Virology and Other marker 
15.1 ADVERSE EVENTS (AE) ASSESSMENT 
15.1.1 
DERIVATION 
AEs started before administration of study treatment will be considered as Pre-
treatment AEs. Any AE started on or after the date of the first dose of study 
medication or started prior to first dose and worsened in severity after the first 
dose will be considered as Treatment-Emergent Adverse Event (TEAE). If the 
start date is missing for an AE, the AE will be considered as treatment emergent. 
15.1.2 
ADVERSE EVENT ANALYSIS 
All AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) 
according to The Medical Dictionary for Regulatory Activities (MedDRA) 
September 2020, version 23.1. 
Pre-treatment AEs will be presented in the listings only. 
 
 Proportion of patients with any adverse event (grade ≤ 2 according to 
CTCAE) within Day 7, 14 and 28 after randomization will be analysed using 
comparison of proportions (i.e comparisons of each active treatment group 
versus placebo at each assessment day) through Fisher’s exact test and 
will be summarized using frequency and percent by treatment and visit. 
Analyses will be performed on FAS population. 
 
 Proportion of patients with severe adverse events (grade ≥ 3 according to 
CTCAE) within Day 7, 14 and 28 after randomization will be analysed using 
comparison of proportions (i.e comparisons of each active treatment group 
versus placebo at each assessment day) through Fisher’s exact test and 
will be summarized using frequency and percent by treatment and visit. 
Analyses will be performed on FAS population. 
 
TEAE summaries will be presented, displaying frequencies and Percentages of 
patients reporting AEs within each SOC in decreasing order of total frequency 
according to the number of patients reporting the SOC and the AE within the SOC 
by treatment.  Along with AEs, incidence will be reported. On each of these 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 23 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
summaries, patients will be counted only once per SOC, even if they experience 
multiple AEs within the same SOC. Patients will be counted only once per 
preferred term, even if they experienced the same adverse event more than once. 
For the summary by severity (Mild, Moderate, Severe, Life-threatening or 
disabling, Death), patients will be classified by the most severe level of the adverse 
event experienced when they experienced the same adverse event (or AE within 
SOC) more than once. 
The severity of AEs and SAEs will be graded using the CTCAE version 5.0. Any 
AE not listed in the CTCAE will be graded as follows: 
1. Mild 
2. Moderate 
3. Severe 
4. Life-threatening or disabling 
5. Death 
For summaries, the drug-event relationship will be assessed as “None”, “Unlikely”, 
“Possible” “Probable” or “Highly probable”. Any AE reported in the study having a 
possible, probable or highly probable relationship to study drug will be defined as 
“Adverse Drug Reaction” (ADR). 
The following events will be considered adverse events of special interest: 
 Venous thromboembolic events (including deep vein thrombosis) 
o pulmonary embolism 
o retinal vein thrombosis 
o superficial vein thrombophlebitis 
 Arterial thromboembolic reactions 
 Thrombocytopenia 
TEAEs will be reported on a per-patient basis: even if a patient reported the same 
event repeatedly (i.e., events mapped to the preferred term) the event will be 
counted only once.  
The following tables will be provided separately for all TEAEs by treatment. 
1) An overview of TEAEs including, 
 at least one TEAE 
 at least one TESAE 
 at least one non-serious TEAE 
 at least one ADR 
 at least one serious ADR 
 number of TEAEs 
 number of TESAEs 
 number of non-serious TEAEs 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 24 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
 number of ADRs 
 number of serious ADRs 
 number of deaths 
 number of patients who discontinued study drug due to a TEAE 
2) Summary of TEAEs by Primary System Organ Class and Preferred Term 
3) Summary of TEAEs by Primary System Organ Class, Preferred Term and 
Severity 
4) Summary of TESAEs by Primary System Organ Class and Preferred Term 
5) Summary of ADRs by Primary System Organ Class and Preferred Term 
6) Summary of TEAEs leading to Study Drug Discontinuation by Primary System 
Organ Class and Preferred Term 
7) Summary of TEAEs leading to Death by Primary System Organ Class and 
Preferred Term 
8) Summary of Adverse Event of Special Interest (AESI) by Primary System 
Organ Class and Preferred Term 
9) Listing of all AEs by Patient 
10) Listing of SAEs by Patient 
11) Listing of Adverse Drug Reactions by Patient 
12) Listing of Deaths 
13) Listing of AESI 
15.2 VITAL SIGNS 
The following vital signs (blood pressure [BP], pulse rate [PR], body temperature 
[BT]), transdermal oxygen saturation (SpO2) will be collected for patients.  
Vital signs measurements will be summarized by treatment using descriptive 
statistics for each available visit, including change from baseline. 
All vital signs findings will be listed, including data from the unscheduled visits. 
15.3 LABORATORY PARAMETERS: BLOOD (HEMATOLOGY & 
BIOCHEMISTRY), COAGULATION, VIROLOGY AND OTHER 
MARKER 
The following biomarker parameters at Day 7, 14, 21 and 28 after randomization 
will be summarized using descriptive statistics by visit and treatment: 
 Complete blood cell counts 
 Hepatic function (ALT, AST and bilirubin) 
 Coagulation (PT, aPTT and INR) 
 Other marker including (D-dimer, CPK, LDH) 
 
Depending on the nature of the variable (continuous or categorical) the change 
from baseline values or shift tables comparing baseline and each post-baseline 
qualitative results of laboratory findings will be presented. 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 25 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
 
Mean (+/-) Standard Error Plot will be plotted for the change from baseline results 
of the above-mentioned laboratory parameters by visit and treatment. Analyses 
will be performed on SAF population. 
Actual results and change from baseline for quantitative laboratory parameters will 
be summarised descriptively by treatment and visits. In addition, shift tables for 
laboratory parameters comparing values (Low, Normal and High) using the 
standard reference ranges will be presented for the baseline laboratory 
measurements vs. each post-baseline visit measurements.  
Additionally, the frequency of patients reporting an abnormal or abnormal clinically 
significant laboratory value will be presented for each laboratory parameter. 
For any Patient, if more than 1 results per visit and per lab parameters are 
available then the latest one will be considered based the date and time.   
All laboratory results will be listed. 
The below list of lab parameters results will be collected for patients. 
Table 4: List of Lab parameters 
Biochemistry (T0, T7, 
T14, T21, T28)
Haematology (T0, T7, T14, 
T21, T28)
Coagulation (T0, T7, T14, 
T21, T28) 
Sodium 
Potassium 
Chloride 
Urea 
Uric acid 
Creatinine 
Calcium 
Inorganic phosphorus 
Total and direct bilirubin 
Total protein 
Albumin 
Alpha-1 Globulins 
Alpha-2 Globulins 
Beta Globulins 
Alkaline phosphatase 
AST 
ALT 
Gamma glutamyl 
transferase 
Total Cholesterol 
Triglycerides
Haemoglobin 
Red cell count 
Packed cell volume 
Mean cell volume 
Mean cell haemoglobin 
Mean cell haemoglobin 
concentration 
Platelet count 
White cell count 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Prothrombin time 
Activated partial 
thromboplastin time 
INR 
Virology (T7, T14, T28) 
Other markers (T0, T7, T14, 
T21, T28) 
 
PCR 
D-dimer 
Creatine phosphokinase 
(CPK) 
Lactate dehydrogenase(LDH)


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 26 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
16 PREGNANCY TEST OVER THE STUDY 
Data will be summarized for the SAF population. Pregnancy tests will be 
performed at T0, T7 and T14 visits.  
A summary table showing test results (Negative/Positive) over the study will be 
produced by treatment group. 
17 GENERAL PROGRAMMING SPECIFICATIONS 
Tables, Figures and Listings will be generated as per the shells template.  
All statistical analysis and output will be generated using SAS, all the reports will 
be printed in RTF format. All output will be in landscape orientation.  
 
Table Format Specification: 
a. In summary tables of quantitative variables, the minimum and maximum 
statistics will be presented to the same number of decimal places as the raw 
(observed) data. The estimated mean and median for a set of values will be 
reported to one more decimal place than the raw (observed) data and rounded 
appropriately. The standard errors (or standard deviations [SD]) and the 
confidence intervals will be reported to two additional decimal places than the 
raw (observed) data and rounded appropriately.  
 
b. Data in columns of a table will be formatted as follows: 
i. 
Alphanumeric values will be left-justified (in mixed and upper- and lower-
case) 
ii. 
Whole numbers (e.g. counts) will be right justified 
iii. 
Numbers containing fractional portions will be decimal aligned 
 
c. All fractional numeric values will be reported with a zero to the left of the decimal 
point (e.g. 0.12-0.3). 
d. In summary tables of qualitative variables, counts and percentages will be used. 
The denominator for each percentage will be the number of patients within the 
population under respective treatment group unless otherwise specified. 
Percentages will be reported to one decimal places 
 
e. When no data are available for a table or Listings or figures, an empty page 
with the title will be produced with suitable text. Example:  THERE WERE NO 
SERIOUS ADVERSE EVENTS. 
 
f. The default tables, figures and listings (TFL) layout will be as follows 
 
Orientation
Landscape
Paper Size
A4
Margins 
 
Top: 2.5 cm 
Bottom: 2.5 cm 
Left: 2 cm 
Right: 2 cm
Font
Courier new8-point


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 27 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
Headers 
 
1. The header will appear on the top left corner of each page 
of the output, containing the protocol number (RLX0120) 
and sponsor name (Dompé). The page number, in the 
format of “Page x of y”, will appear on the top right corner of 
the output, where y = last page of corresponding output. 
Table status (draft or final). 
2. Any TFLs generated prior to database lock or completion 
of TFL validation will be marked “Draft”.
Footers 
For Tables 
The SAS program name, Reference Listings and the date 
and time of the creation of the output (run date and time) will 
appear on the bottom left corner as follows:  
1. Reference Listings: listing Number 
2. Source:[program name].sas, Run on : 
DDMMMYYY:hh:mm:ss
Footers 
For Listings 
and 
Graphs/Figures
The SAS program name, and the date of the creation of the 
output (run date) and CRF Source will appear on the bottom 
left corner as follows:  
1.CRF Source: 
2.Source: [program name]. sas, Run on DDMMMYYYY
18 CHANGES FROM PROTOCOL 
Following are the changes from the protocol: 
a. Specification of additional populations-All Patient Enrolled (ENR) and 
Randomized Population (RND). 
b. Text “Subjects”, “Participants” changed to “Patients”. 
c. Baseline characteristics “gender” and “Child-bearing potential status” are 
combined and derived a new categorical variable with categories Male, Female 
pre-menopausal status and Female post-menopausal status to be included as 
factor “Status” in the statistical model of analysis of efficacy endpoints. 
d. Due to the premature interruption of the enrolment, no interim analysis will be 
done. 
19 REFERENCES 
1. FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Pandemic. 
2. Protocol No. RLX0120, Version No.: 3.0, dated 22 Dec 2020 and RLX0120 
eCRF Final v.2.0, dated 20 Jan 2021 
3. ICH-E3. (December 1995). Structure and content of clinical study reports. 
Step 4 Guideline. 
4. ICH-E6. (17 July 1996). Guideline for good clinical practice. Step 5 Guideline. 
5. ICH-E9. (5 February 1998). Statistical principles for clinical trials. Step 4 
guideline. 
6. Support SAS® - https://support.sas.com/kb/42/728.html 
7. SAS EXAMPLES - http://users.stat.ufl.edu/~aa/cda/Sas_web.pdf 
8. PROC GENMOD with GEE to Analyze Correlated Outcomes Data Using SAS 
https://stats.idre.ucla.edu/unlinked/sas-logistic/proc-logistic-and-logistic-
regression-models/ 
9. https://www.lexjansen.com/wuss/2006/tutorials/TUT-Smith.pdf 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 28 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
10. Survival Analysis 
https://sphweb.bumc.bu.edu/otlt/mph 
modules/bs/bs704_survival/BS704_Survival5.html 
11. PharmaSUG 2013 - Paper SP03 , Combining Analysis Results from Multiply 
Imputed Categorical Data 
12. https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-
SP03.pdf 
 
20 REVISION HISTORY 
Revision
Date
Description
 
 
 
 
 
 
 
21 APPENDIX 1: PROGRAMMING CONVENTIONS FOR OUTPUTS 
Dates & Times: 
Depending on data available, dates and times will take the form 
ddmmmyyyyhh:mm:ss (i.e. 01MAR2019 10:20:15) 
Listings: 
All listings will be ordered by the following (unless otherwise indicated in the 
template): 
 Randomized treatment group (or treatment received if it’s a safety output)  
 Patient ID 
 Date, Visit (where applicable) 
 For listings where non-randomized patients are included, these will appear 
in a category after the randomized treatment groups labeled ‘Not 
Randomized’ 
In all listings missing data will be reported, according to the variable type as 
follows: 
- 
Character variables and dates will be presented as empty fields 
- 
Numerical variables will be presented with a “- “ 
For Tables:  
If any of the tables has missing summary statistics or estimate, then report it as 
“NE” and add a note in the bottom of the table as NE = Not Estimable, not enough 
data to estimate the parameter 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 29 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
22 APPENDIX 2: PARTIAL DATE CONVENTIONS 
22.1 ALGORITHM FOR ADVERSE EVENTS 
22.1.1 
ADVERSE EVENT END DATE IMPUTATION 
If the AE end date “Month” is missing, then the imputed end date “Month” should 
be set to the earliest of the (Cutoff date, End of study date, 31DECYYYY).  
If the AE end date “Day” is missing, the imputed end date “Day” should be set to 
the earliest of the (Cutoff date, End of study date, last day of the month).  
If AE “Year” is missing or AE is “Ongoing”, the end date will not be imputed.  
If the imputed AE end date is before the corresponding AE start date, then the AE 
end date will be set to the AE start date. 
22.1.2 
ADVERSE EVENT START DATE IMPUTATION 
Adverse events with partially missing onset dates will also be included as 
treatment emergent when the month (if it exists) and the year occur on or after the 
month and year of the initial study treatment date. 
Partial AE start dates are imputed with reference to the treatment start date 
(TRTSDT) as outlined in the Imputation table below.  
 
First find the AE start reference date, before imputing the AE start date.  
1.  If the (imputed) AE end date is complete and the (imputed) AE end date < 
treatment start date then AE start reference date = minimum (informed 
consent date, earliest visit date).  
2.  Else AE start reference date = treatment start date 
Completely missing, start dates will not be imputed. As a conservative approach, 
such adverse events will be defined as treatment emergent.  
The date value is split into Day, 
month, year sections and 
referenced in the imputation table as 
outlined below 
Day 
Month 
Year 
Partial AE Start Date
01 or 15
MMM
YYYY
Treatment Start Date (TRTSDT) 
Not considered
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation:  
MMM Missing
MMM < TRTM
MMM = TRTM
MMM> TRTM
YYYY 
Missing
NI 
NI 
NI 
NI 
 
YYYY < 
TRTY 
 
(D)= 
01JULYYYY 
 
(C) = 
15MMMYYYY 
 
(C) = 
15MMMYYYY 
 
(C) = 
15MMMYYYY
YYYY = 
TRTY 
(B) = AE start 
reference date 
+ 1 day
 
(C) = 
15MMMYYYY
 
(A) = TRTSDT 
+1
 
(A) = 
01MMMYYYY


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 30 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
YYYY > 
TRTY 
(E) = 
01JANYYYY 
 
(A) = 
01MMMYYYY 
 
(A) = 
01MMMYYYY 
 
(A) = 
01MMMYYYY
 
The following table is the legend to the logic matrix 
Relationship
Before Treatment Start 
Partial date indicates AE start date prior to 
Treatment Start Date
After Treatment Start 
Partial date indicates AE start date after 
Treatment Start Date
Uncertain 
Partial date insufficient to determine 
relationship of AE start date to Treatment 
Start Date
Imputation Calculation
NI
No Imputation
(A) After Treatment Start or Uncertain
MAX(01MMMYYYY, TRTSDT+1 )
(B) Uncertain
AE start reference date+1
(C) Before Treatment Start
15MMMYYYY
(D) Before Treatment Start
01JULYYYY
(E) After Treatment Start
01JANYYYY
If complete (imputed) AE end date is available and the imputed AE start date is 
greater than the (imputed) AE end date, then imputed AE start date should be set 
to the (imputed) AE end date. 
22.2 ALGORITHM FOR CONCOMITANT MEDICATIONS: 
22.2.1 
CONCOMITANT TREATMENT END DATE IMPUTATION 
If the concomitant treatment end date year value is missing, the date uncertainty 
is too high to impute a reliable date. Therefore, if the concomitant treatment end 
year value is missing or ongoing, the imputed concomitant treatment end date is 
set to NULL. 
 
Else, if the concomitant treatment end date month is missing, the imputed end 
date should be set to the earliest of the (treatment follow up period 
date31DECYYYY).  
 
If the concomitant treatment end date day is missing, the imputed end date should 
be set to the earliest of the (treatment follow up period date, last day of the month). 
 
If the imputed concomitant treatment end date is before the existing concomitant 
treatment start date, use the concomitant treatment start date as the imputed 
concomitant treatment end date. 
22.2.2 
CONCOMITANT TREATMENT START DATE IMPUTATION 
In order to classify a medication as prior and prior/concomitant, it may be 
necessary to impute the start date. Completely missing start dates will be set to 
one day prior to treatment start date.  


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 31 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
 
As a conservative approach, such treatments will be classified as prior and 
concomitant (and summarized for each output). Concomitant treatments with 
partial start dates will have the date or dates imputed.  
 
Partial concomitant treatment start dates are imputed with reference to the 
treatment start date (TRTSDT) in accordance with the rules outlined below 
The date value is split into day, month, 
year sections and referenced in the 
imputation table as outlined below  
Day  
Month 
Year 
Partial CMD Start Date
01 or 15
MMM
YYYY
Treatment Start Date (TRTSDT) 
TRTD 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation:  
 
MMM Missing 
MMM < TRTM 
MMM = TRTM 
MMM > TRTM 
 
YYYY 
Missing 
 
(C) Uncertain 
 
(C) Uncertain 
 
(C) Uncertain 
 
(C) Uncertain 
YYYY < 
TRTY
 (D) = 
01JULYYYY
(A) = 
15MMMYYYY
(A) = 
15MMMYYYY
(A) = 
15MMMYYYY
YYYY = 
TRTY
(C) Uncertain 
(A) = 
15MMMYYYY
(C) Uncertain 
(B) = 
01MMMYYYY
YYYY > 
TRTY
(E) = 
01JANYYYY
(B) = 
01MMMYYYY
(B) = 
01MMMYYYY
(B) = 
01MMMYYYY
 
The following table is the legend to the logic matrix 
Relationship 
Before Treatment Start 
Partial date indicates CMD start date prior to Treatment 
Start Date 
After Treatment Start 
Partial date indicates CMD start date after Treatment Start 
Date 
Uncertain 
Partial date insufficient to determine relationship of CMD 
start date to Treatment Start Date 
Imputation Calculation
NI
No Imputation
(A) Before Treatment Start 
15MMMYYYY 
((B) After Treatment Start
MAX( 01MMMYYYY, TRTSDT+1 )
(C) Uncertain 
TRTSDT-1 
(D) Before Treatment Start
01JULYYYY
(E) After Treatment Start 
01JANYYYY 
 
If complete (imputed) CM end date is available and the imputed CM start date is 
greater than the (imputed) CM end date, then imputed CM start date should be 
set to the (imputed) CM end date. 
 
 


 
 
 
 
Raloxifene (RLX)- Protocol No.:RLX0120                                                                                         Page 32 of 33 
 
Agati Clinical Informatics                                                                                 Statistical Analysis Plan (Final 1.0) 
23 APPENDIX 3: NEWS SCORE 
Element 
Score
3 
2 
1 
0 
1 
2 
3 
Respiratory rate
≤ 8 
9-11
12-20 
21-24 
≥ 25 
SpO2 
≤ 91 
92-93 
94-95
≥ 96 
Oxygen 
Yes 
NO 
Systolic Blood 
Pressure 
≤ 90  
91-
100
101-
110
111-
219 
 
 
≥ 220  
Pulse  
≤ 40  
 
41-50 
51-90  
91-
110
111-
130 
≥ 131  
ACVPU 
A 
C,V,P,U 
Temperature, oC 
≤ 35.0 
 
35.1-
36.0 
36.1-
38.0 
38.1-
39.0 
≥ 39.1 
 
 
ACVPU: Alert, Confusion, Voice, Pain, Unresponsive