Multicenter Double Blind, Parallel-group Phase 2/3 Trial, to Study Raloxifene in Adult COVID-19 Patients.

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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SARS CoV 2 Infection

Intervention / Treatment
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* Drug: Raloxifene
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject autonomously provides informed consent prior to initiation of any study procedures Males and females ≥ 40 years old 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 Agrees to the collection of nasopharyngeal swabs and venous blood samples per protocol Has laboratory-confirmed SARS-CoV-2 infection as determined by an approved molecular test (PCR) in Europe within 10 days at the screening time 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 No need of supplemental oxygen therapy, mechanical ventilation 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: Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit until 30 days after final visit 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 A male sexual partner who agrees to use a male condom with spermicide 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: Being totally asymptomatic at the screening time Requires supplemental oxygen therapy or mechanical ventilation Being already under raloxifene or other SERM treatment for another medical condition at the time of randomization 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) Clinically significant abnormal physical findings which could interfere with the objectives of the study Diseases: history of stroke and/or venous thromboembolism; known moderate / severe renal impairment: Chronic Kidney Disease (CKD) stage 3 or higher; known liver disease (Child-Pugh Class A or higher); presence of known hypoalbuminemia; endometrial bleeding; signs or symptoms of endometrial cancer Autoimmune diseases receiving therapy at the time of randomization Risk of venous thrombosis or any condition/disease that could bring to an extended period of immobilization 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 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 coadministered with the experimental compound Pregnancy: positive or missing pregnancy test before first drug intake or day 1; pregnant or lactating women; 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.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, adaptive, double-blind, randomized, placebo controlled, double blind, parallelgroup, 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Raloxifene 60 mg<br>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. | Drug: Raloxifene<br>* 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.<br>|
| Experimental: Group 2: Raloxifene 120 mg<br>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. | Drug: Raloxifene<br>* 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.<br>|
| Placebo Comparator: Group 3: Placebo.<br>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. | Other: Placebo<br>* Placebo was administered orally once a day as 2 capsules (for maintaining the blinding design)<br>* Other names: control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Undetectable SARS-CoV-2 at PCR at Day 7 After Randomization in the FAS | Number of participants who, after an approved molecular test (PCR), were not detected as SARS-CoV2 positive. Based on Approved molecular test (PCR) result at day 7, the responses were considered as detectable if PCR result was Positive otherwise undetectable if PCR result was Negative . | At Day 7 | 
| Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 14 After Randomization in the FAS | Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. NEWS uses six physiological measurements. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. If collected NEWS score > 2 or mechanical ventilation with result Yes then the response was considered as Required. If collected NEWS score ≤ 2 and mechanical ventilation with result No then the response was considered as Not Required (if both NEWS score and mechanical ventilation were missing, patient was considered as missing). | At Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Undetectable SARS-CoV-2 at PCR at Days 14 and 28 After Randomization in the FAS | Number of participants with undetectable SARS-CoV-2 at PCR at day 14 after randomization, and at day 28 after randomization. Based on Approved molecular test (PCR) result at days 14 and 28 after randomization, the responses were considered as detectable if PCR result was Positive otherwise undetectable if PCR result was Negative. | At days 14 and 28 after randomization | 
| Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 7 an d at Day 28 in the FAS | Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation after randomization; | At days 7 and 28 | 
| Number of Patients in Each National Early Warning Score (NEWS) Category in the FAS | Proportion of patients in each National Early Warning Score (NEWS) category after randomization. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. NEWS uses six physiological measurements: respiratory rate; oxygen saturation; temperature; systolic blood pressure; heart rate and level of consciousness. Each scores 0-3 and individual scores are added together for an overall score. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. The higher the score, the worse the outcome. | At days 7, 14, 28 | 
| Mean Value of National Early Warning Score (NEWS) Category in the FAS | Mean value of National Early Warning Score (NEWS) category after randomization. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk. Higher scores indicate the need for escalation, medical review and possible clinical intervention and more intensive monitoring | At days 7, 14, 28 after randomization | 
| Number of Hospitalized Participants Who at the Beginning of the Study Were at Domicile Isolation After Randomization in the FAS | Proportion of hospitalized participants at Day 7, Day 14 and Day 28 after randomization among subjects who at the beginning of the study were at domicile isolation. | At days 7, 14, 28 | 
| Number of Participants Admitted to Intensive Care After Randomization in the FAS | Proportion of participants admitted to intensive care. Intensive care is a special medical treatment in which a patient who is dangerously ill is kept under constant observation, typically in a dedicated department of a hospital. | At days 7,14 ,28 | 
| Number of Survivors in the FAS | Proportion of survivors after randomization. There were no events (i.e. deaths) in any treatment groups and thus the median overall survival could not be estimated. Overall survival was analysed according to the Kaplan-Meier method. Time to event curves were compared (i.e. comparisons of each active treatment group versus placebo) using log-rank test and estimates of hazard ratio were obtained using Cox proportional hazards model. | At days 7, 14, 28 | 
| Quality of Life Questionnaire (EQ-5D-5L) at 3 Months After Randomization - EQ-5D Descriptive System | The EQ-5D-5L consists of: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number describing the patient's health state. In the EQ VAS - quantitative measure of health outcome - the patient records a self-rates health on a vertical visual analogue scale (numbered from 0 to 100) which goes from 'Best imaginable health state' (100) to 'Worst imaginable health state' (0). | At month 3 After Randomization | 
| Quality of Life Questionnaire (EQ-5D-5L) at 3 Months After Randomization - EQ VAS | The EQ-5D-5L consists of: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number describing the patient's health state. In the EQ VAS - quantitative measure of health outcome - the patient records a self-rates health on a vertical visual analogue scale (numbered from 0 to 100) which goes from 'Best imaginable health state' (100) to 'Worst imaginable health state' (0). | At month 3 After Randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, severe pneumonia, pneumonia