Safety and Efficacy of Doxycycline and Rivaroxaban in COVID-19

Study Overview
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Brief Summary
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This is an exploratory study to evaluate the efficacy of Doxycycline (200mg on D1 to D7) and Rivaroxaban (15 mg daily on D1 to D7) versus the combination of Hydroxychloroquine (400 mg on D1 to D7) and Azithromycin (500 mg on D1 and 250mg on D2 to D5) as per national standard to treat ambulatory mild COVID-19 patients, with the aim to achieve early negativity of RT-PCR of SARS-CoV-2 from nasopharyngeal swab, and early clinical improvement and prevention of severe disease.

Detailed Description
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This is an exploratory study to evaluate the efficacy of Doxycycline (200mg on D1 to D7) and Rivaroxaban (15 mg on D1 to D7) versus combination of hydroxychloroquine (400 mg on D1 to D7) and azithromycin (500 mg on D1 and 250mg on D2 to D5) to treat ambulatory patients with mild COVID-19. We aim to demonstrate early improvement of a clinical core set of outcomes and prevention of clinical worsening, and early negativity of SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) among ambulatory patients with mild COVID-19 by treating them with Doxycycline and Rivaroxaban compared to patients who receive Hydroxychloroquine and Azithromycin as per National standard therapy of COVid-19. Ambulatory patients with mild symptoms and with confirmed diagnosis of COVID-19 will receive the treatment. The primary objective of the study is to evaluate the Safety and Efficacy of Doxycycline and Rivaroxaban versus National standard therapy of mild COVid-19. The primary endpoint is failure (i.e severe evolution) measured as PaO2 < 92% within 10 days after initiation of treatment. The secondary objectives of the study are to evaluate Safety of the different investigational therapies up to D10 days of follow-up per arm, Hospitalisation due to Covid 19 infection rate per arm, Time to hospitalisation due to Covid 19 infection, Cure rate by treatment arm and Death rate, Worsening as assessed by the need for additional concomitant medication, Efficacy in sub-groups of patients (with pre-existing conditions/co-morbidities and by age group).

Official Title
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Open-label, Randomized Trial of the Safety and Efficacy of Doxycycline and Rivaroxaban Therapy Versus National Standard Therapy in Ambulatory Patients With Mild Symptomatic COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Doxycycline Tablets
* Drug: Rivaroxaban 15Mg Tab
* Combination Product: Hydroxychloroquine and Azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COVID-19 infection confirmed by SARS-Cov2 - RT PCR - as per protocol Able to start the treatment within 24 hours from time of diagnosis Patient with mild symptoms as defined by WHO, with PaO2 > 93% Signed written consent of the patient Accepts and has the ability to be reached by phone during the study duration, plus a designated a contact person who can be contacted in case of emergency Exclusion Criteria: Blood pressure < 90/60mm Hg Respiratory rate ≥ 30/min Known cardiac condition Known G6PD deficiency Patients with < 45kg eGFR < 30 ml/min or ALT ≥ 3N or body temperature ≥ 38°C or any life-threatening comorbidity Any reason that makes it impossible to monitor the patient during the study period Baseline ECG prior to randomization showing QTc > 500 ms Ongoing treatment other than symptomatic history of retinopathy Absolute contra-indication to treatment with hydroxychloroquine (known hypersensitivity, concomitant treatment at risk of torsades de pointes) Contraindication to any study medication including allergy Ongoing treatment with high dose systemic chronic corticosteroid (> 40 mg) Patients treated by immunosuppressants treatment at the time of randomization Known Pregnant women and breastfeeding women

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycyclin and Rivaroxaban<br>Oral Doxycyclin 200 mg daily for 7 days with or without Rivaroxaban | Drug: Doxycycline Tablets<br>* Doxycycline 200 mg daily for 7 days<br>* Other names: Doxycycline;Drug: Rivaroxaban 15Mg Tab<br>* Rivaroxaban 15 mg tablets daily from day 1 to day 10<br>|
| Active Comparator: National Standard<br>Hydroxychloroquine 400 mg daily for 5 days in combination with Azithromycin 500 mg on day 1 and 250 mg daily from day 2 through day 5 | Combination Product: Hydroxychloroquine and Azithromycin<br>* Hydroxychloroquine 400mg daily from day 1 to day 5 in combination with Azithromycin 500mg on day 1 and 250 mg daily from day 2 to day 5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical | Change of Clinical stage of COVID-19 | Day 1 to 10 | 
| Virological | Time to negativity of SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) on nasopharyngeal swab. | Day 1 to 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom remission | Time to remission of symptoms in days | Day 1 to 10 | 
| Hospitalisation | Need for hospitalisation due to worsening | Day 1 to 10 | 
| Mortality | All-cause mortality | Day 1 to 10 | 
| Biological variables | Change from baseline of WBC count | Day 1 to Day 7 and Day 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Doxycycline, Rivaroxaban, Hydroxychloroquine