Study Evaluating the Efficacy of Hydroxychloroquine and Azithromycine in Patients With COVID-19 and Hematological Malignancies (HYACINTHE)

Study Overview
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Brief Summary
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The primary objective of this phase 2, multicentric, placebo-controlled double-blind, randomized study is to evaluate the efficacy of the combination of hydroxychloroquine and azithromycine on the viral load drop at day 5 among patients with COVID-19 and hematological malignancies.

Detailed Description
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The study will evaluate the effect of the combination of hydroxychloroquine and azithromycine versus placebo among 114 patients with COVID-19 and hematologic malignancy. After randomization in 1:1 ratio, patients will receive either the study treatment or placebo : Patients enrolled in the experimental arm will receive hydroxychloroquine (200mgx3 tablets per day during 10 days) and azithromycine (500 mg at day 1 then 250mg per day during 4 days) Patients enrolled in the control arm will receive a placebo of hydroxychloroquine (3 tablets per day during 10 days) and a placebo of azithromycine (2 capsules at day 1, then 1 capsule per day during 4 days)

Official Title
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Randomised, Double-blind, Placebo-controlled Phase 2 Study Evaluating the Efficacy of Hydroxychloroquine and Azithromycine in Patients With COVID-19 and Hematological Malignancies

Conditions
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COVID19, Hematologic Malignancy

Intervention / Treatment
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* Drug: Hydroxychloroquine Sulfate 200 MG [Plaquenil]
* Drug: Azithromycin 250 MG Oral Capsule
* Drug: Placebo oral tablet
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older patients Patient with hematologic malignancy who received or not hematopoietic stem cell transplantation Non severe Covid-19 disease PCR-confirmed COVID-19 disease by a nasopharyngeal swab Life-expectancy related to the hematologic malignancy of at least 1 month Men or women of child-bearing potential accepting to use effective contraception during and until 8 months after the end of the study treatment Exclusion Criteria: Patients with severe form of COVID-19 infection defined as the presence of crackles observed during clinical exam, associated with less than 94% oxygen saturation or patients with respiratory insufficiency on oxygen therapy or mechanical ventilation Previous treatment with hydroxychloroquine or azithromycine for Covid-19 infection QTc interval greater than 480 ms Hypersensibility to hydroxychloroquine or azithromycine Retinopathy TGO or TGP geater than 5 x the normal upper limit Creatinine clearance lower than 30 ml/min Concomitant treatment that may lead to prolongation of the QT space Concomitant treatment with dihydroergotamine, ergotamine, cisapride or colchicine Known G6PD deficiency

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Patients enrolled in the experimental arm will receive hydroxychloroquine (200mgx3 tablets per day during 10 days) and azithromycine (500 mg at day 1 (2 capsules taken at the same time) then 250mg per day (1 capsule per day) during 4 days). | Drug: Hydroxychloroquine Sulfate 200 MG [Plaquenil]<br>* Hydroxychloroquine is an anti-malarial drug also used as anti-inflammatory treatment for systemic lupus erythematosus and rheumatic disorders. HCQ also inhibits pH-dependant replication stages of diverse types of viruses including flavivirus, retrovirus and coronaviruses.<br>Drug: Azithromycin 250 MG Oral Capsule<br>* Azithromycin is amacrolide antibiotic.<br>|
| Placebo Comparator: Control arm<br>Patients enrolled in the control arm will receive a placebo of hydroxychloroquine (3 tablets per day during 10 days) and a placebo of azithromycine (2 capsules taken at the same time at day 1, then 1 capsule per day during 4 days) | Drug: Placebo oral tablet<br>* Placebo of Hydroxychloroquine Sulfate 200 MG [Plaquenil].<br>Drug: Placebo oral capsule<br>* Placebo of Azithromycin capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the efficacy of hydroxychloroquine and azithromyncine on the viral load drop at day 5. | Locally evaluated rate of viral response. Favorable response is defined as (1) complete response : negative PCR (absence of detectable signal with a minimum of 40 cycles) or (2) major response : detectable signal but with an increased number of cycles > or egal to 10 compared to initial PCR. Response failure is defined as (1) minor response : detectable signal but with an increased number of cycles < 10 compared to initial PCR or (2) stabilisation or worsening of the viral load. | 5 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical evolution | Duration of fever - duration of respiratory symptoms (cough, dyspnea) - duration of other COVID-19 related symptoms (digestive symptoms, ageusia, anosmia) | up to 3 months | 
| Proportion of patients progressing to a severe form | Less or equal to 94% oxygen saturation - need to initiate oxygenotherapy - occurrence of respiratory distress - patient transfer in intensive care unit - need of mechanical ventilation - occurrence of non-respiratory organ failure - occurrence of septic shock | up to 3 months | 
| Mortality | Date and cause of death | up to 1 and 3 months | 
| Evaluation of viral load drop | SARS-CoV-2 viral load by PCR on nasopharyngeal swab at day 10 (if positive at day 5) : rate of negativation and comparison of number of cycles with previous samples | at day 10 | 
| Tolerance of study treatment | Frequence and causality of all-grade cardiac adverse events - frequence and causality of grade > 1 adverse events for other adverse events - frequence and causality of serious adverse events (CTCAE v5) | up to 3 months | 
| Evaluation of the seroconversion | Collection of serum to realize serological tests | at inclusion, day 10, day 30 and day 90 after treatment | 
| NK immunological study | Phenotypic and functional study of NK lymphocytes at inclusion, Retrospective analysis on frozen cells. | at day 10 and day 30 after treatment | 
| Hospitalisation duration | Duration of hospitalisation (conventional, intensive care, reanimation) | up to 3 months | 
| Impact of the study treatment on the treatment of the hematological disease | Patient follow-up during 3 months : hematological status and associated therapy | up to 3 months | 
| Monitoring of the QT space | ECG (using connected machine to allow monitoring at home) | at inclusion, day 2, day 5, day 10 | 
| Dosage of residual concentration of azithromycine and hydroxychloroquine. | Dosage of residual concentration of azithromycine and hydroxychloroquine. | at day 5 and day 10 | 
| T immunological study | Phenotypic and functional study of T lymphocytes at inclusion, Retrospective analysis on frozen cells. | at day 10 and day 30 after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Hematologic malignancy