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

Sponsor

Dompé Farmaceutici S.p.A (Industry)

Overall Status

Completed

CT.gov ID

NCT05172050

Collaborator

(none)

Enrollment

Locations

Arms

4.6

Actual Duration (Months)

6.2

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
SARS CoV 2 Infection	Drug: Raloxifene Other: Placebo	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Participant, Investigator)

Masking Description:

Appearance, including packaging and labelling, of the investigational medicinal product (IMP, capsules, packaging) will not allow to recognize actual treatment (either raloxifene or placebo).

Primary Purpose:

Treatment

Official 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.

Actual Study Start Date :

Jan 22, 2021

Actual Primary Completion Date :

Jun 12, 2021

Actual Study Completion Date :

Jun 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: Raloxifene 60 mg 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 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.
Experimental: Group 2: Raloxifene 120 mg 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 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.
Placebo Comparator: Group 3: Placebo. 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 Placebo was administered orally once a day as 2 capsules (for maintaining the blinding design) Other Names: control

Arm

Intervention/Treatment

Experimental: Group 1: Raloxifene 60 mg

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

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.

Experimental: Group 2: Raloxifene 120 mg

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

Placebo Comparator: Group 3: Placebo.

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

Placebo was administered orally once a day as 2 capsules (for maintaining the blinding design)

Other Names:

control

Outcome Measures

Primary Outcome Measures

Proportion of participants with undetectable SARS-CoV-2 at PCR randomization [At Day 7]
Number of participants who, after a PCR test, were not detected as SARS-CoV2 positive
Proportion of participants not requiring oxygen therapy and/or mechanical ventilation [At Day 14]
Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation

Secondary Outcome Measures

Proportion of participants with undetectable SARS-CoV-2 at PCR [At days 14 and 28]
Proportion of participants with undetectable SARS-CoV-2 at PCR at day 14 after randomization, and at day 28 after randomization
Proportion of participants not requiring oxygen therapy and/or mechanical ventilation [At days 7 and 28]
Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation after randomization;
Proportion of patients in each National Early Warning Score (NEWS) category [At days 7, 14, 28]
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. The score can range from 0 to 19. The higher the score, the worse the outcome.
Mean value of National Early Warning Score (NEWS) category [At days 7, 14, 28]
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 score can range from 0 to 19. The higher the score, the worse the outcome.
Proportion of participants with any adverse event with grade ≤ 2 after randomization. [At days 7, 14, 28]
Proportion of participants with any adverse event with grade ≤ 2 according to Common Terminology Criteria for Adverse Events (CTCAE).
Proportion of participants with any severe adverse events (grade ≥ 3 according to CTCAE) after randomization [At days 7, 14, 28]
Proportion of participants with any severe adverse events (grade ≥ 3 according to CTCAE)
Proportion of hospitalized participants who at the beginning of the study were at domicile isolation after randomization. [At days 7, 14, 28]
Proportion of hospitalized patients who at the beginning of the study were at domicile isolation.
Proportion of participants admitted to intensive care after randomization. [At days 7,14 ,28]
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.
Proportion of survivors [At days 7, 14, 28]
Proportion of survivors after randomization.
Mean change from baseline to day 7, 14, 21 and 28 after randomization of value for biomarker parameters [At days 7, 14, 21 and 28]
biomarker parameters assessed have been: Complete blood cell counts; Hepatic function (alanine aminotransferase or ALT, aspartate aminotransferase or AST and bilirubin); Coagulation (prothrombin time or PT, activated partial thromboplastin time or aPTT and INR or PT); Other markers including (D-dimer, creatine phosphokinase or CPK, lactate dehydrogenase or LDH); Please note that multiple measurements will be aggregated to arrive at one reported value (e.g., weight and height will be combined to report BMI in kg/m^2).
Quality of life questionnaire [At month 3]
Quality of life questionnaire 3 months after the randomization. No specifications on the questionnaire structure are reported in the protocol.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject autonomously provides informed consent prior to initiation of any study procedures
Males and females > 40 years old at time of enrolment
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.

Contacts and Locations

Locations

	Site	City	Country
1	CHU Amiens	Amiens	France
2	Clinique de l'infirmerie protestante de Lyon	Caluire-et-Cuire	France
3	CH Emile Roux le Puy en Velay	Le Puy-en-Velay	France
4	Centre Hospitalier de Troyes	Troyes	France
5	Humanitas Gavazzeni	Bergamo	Italy
6	Ospedale San Salvatore	L'Aquila	Italy
7	AO dei Colli (Ospedale Monaldi)	Napoli	Italy
8	INMI Lazzaro Spallanzani	Roma	Italy
9	Istituto Clinico Humanitas	Rozzano	Italy
10	A.O.U. Città della Salute e della Scienza	Torino	Italy
11	Hospital Universitario Virgen de la Victoria	Málaga	Spain