DYNAMIC Study (DoxycYcliNe AMbulatoIre COVID-19)

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to compare a treatment with doxycycline vs a placebo as soon as the patient is confirmed COVID-19 + and before the onset of oxygen dependence with the aim of reducing or even abolishing the cytokine explosion and thus the evolution towards a serious form of the disease which can lead to death. Three criteria support the rational use of tetrcycline in COVI-19 (1) The coronaviruses is known to bind to metalloproteases (MMPs) of the host, in particular to ensure viral survival. Tetracyclines are known to chelate zinc from MMPs. Their chelating activity may help inhibit COVID19 infection by limiting its ability to replicate in the host. (2) Tetracyclines may also be able to inhibit the replication of positive-polarity single-stranded RNA viruses, such as COVID19 (demonstrated on the dengue virus). (3) In addition, tetracyclines are modulators of innate immunity (anti-inflammatory activity), a property used in the treatment of inflammatory skin diseases for many years. These modulating effects are noted on several targets of innate immunity: They can decrease the expression of NFKB, the release of inflammatory cytokines such as TNF-α, IL-1β and IL-6, inhibit granulomas inflammatory and free radical release. Tetracyclines could therefore participate in limiting the cytokine release induced by COVID19. Their lipophilic nature and their strong pulmonary penetration could allow them to inhibit viral replication.

Official Title
-----------------
Doxycycline Versus Placebo in COVID-19 + Patients Without Hospitalization Criteria: Prospective, Multicenter, Randomized, Double-blind Study

Conditions
-----------------
COVID19

Intervention / Treatment
-----------------
* Drug: Doxycycline
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Man or woman > 45 years old. Patient with a positive SARS-CoV-2 PCR Patient with ENT and / or respiratory symptoms, without hospitalization criteria (no dyspnea, respiratory rate <22 / min, SaO2 ≥ 94% in ambient air), or digestive signs. Patient with at least one of the following risk factors for unfavorable outcome: 70 years, BMI> 30, cardiovascular history (stroke, coronary artery disease, complicated hypertension, cardiac surgery, NYHA III or IV heart failure), respiratory pathology likely to decompensate during viral infection respiratory failure, unbalanced and / or complicated diabètes, respiratory pathology likely to decompensate in the event of of viral infection, patients with renal insufficiency chronic dialysis, .cancer patients under treatment. Exclusion Criteria: Lactose-intolerant patients Patient needing immediate hospitalization for any medical reason Patient having more than 5 days of clinical symptoms at the inclusion visit Patients with a history of allergy to tetracyclines Pregnant or lactating women Patients participating in another clinical trial Patients with photosensitive skin pathology Patients treated with anticoagulant Patients treated with oral retinoids: isotretinoin, alitretinoin, acitretin Patients treated with vitamin A Patients treated with systemic antibiotics for the duration of treatment Patients treated with barbiturates, carbamazepine or phenytoin Patients with treatment that may have an effect on COVID-19 infection: chloroquine, hydroxychloroquine, remdesivir, ganciclovir, acyclovir, ribavirin, lopinavir-ritonavir Patients under guardianship or trusteeship or in safeguard of justice

Ages Eligible for Study
-----------------
Minimum Age: 46 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline 100mg<br>Doxycycline capsule containing 2 tablets doxycycline 100mg over-encapsulated. Doxycycline is given at 200 mg once a day and administered per os during 2 weeks | Drug: Doxycycline<br>* comparison of doxycycline 200 mg/day to placebo<br>|
| Placebo Comparator: Doxycycline placebo<br>Doxycycline Placebo capsule 200 mg, containing 1 capsule of a marketed placebo = RODAEL placebo ( lactose, 380 mg / capsule). Doxycycline placebo is given once a day and administered per os during 2 weeks | Drug: Placebo<br>* Placebo : lactose, 380 mg/gélule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients with Clinical Respiratory Aggravation | Percentage of patients with clinical worsening (SaO2 ≤ 93%) after at least 48 hours of treatment | after at least 48 hours of treatment | 
| Percentage of patients hospitalized | Percentage of patients hospitalized after at least 48 hours of experimental treatment | after at least 48 hours of experimental treatment | 
| Percentage of patients requiring ventilatory assistance | Percentage of patients requiring ventilatory assistance | Day 0 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive SARS-CoV-2 PCR Test | Number of positive SARS-CoV-2 PCR tests on D-1 / D0 and D7 (+/- 2 days) | Day -1 or day 0 AND Day 7 | 
| Duration of symptoms | Duration of symptoms (fever, painful symptoms: headache, sore throat, dyspnea) | Day 0 to Day 28 | 
| Duration of hospitalization | Total duration of hospitalization | From day 0 until to the end of hospitalization or date of death for any cause, whichever came first, assessed up to 3 months after Day0 | 
| Hospitalization intensive care or reanimation | Duration of hospitalization in intensive care or reanimation | From day 0 until to the end of hospitalization or date of death for any cause, whichever came first, assessed up to 3 months after Day0 | 
| Duration of mechanical ventilatory assistance | Duration of mechanical ventilatory assistance | to the end of mechanical ventilatory assistance if any, assessed up to 3 months after Day0 | 
| Percentage of deaths related to SARS-CoV-2 | Percentage of deaths related to SARS-CoV-2 infection | Day 28, or end of hospitalization if any (assessed up to 3 months after Day0) | 
| AE / SAE in both arms | Number of AE / SAE in both arms | Day 28, or end of hospitalization if any (assessed up to 3 months after Day0) |