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Hydroxychloroquine in Combination With Azithromycin or Sirolimus for Treating COVID-19 Patients (COVID19-HOPE)

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ClinicalTrials.gov Identifier: NCT04374903
Recruitment Status : Not yet recruiting
First Posted : May 5, 2020
Last Update Posted : May 5, 2020
Sponsor:
Information provided by (Responsible Party):
Iyad Sultan, King Hussein Cancer Center

Brief Summary:
COVID-19 caused an unprecedented international crisis. There is an urgent need for an effective regimen to cure this illness. Anecdotal data and some prospective results suggested a role of antimalarial drugs (chloroquine and hydroxychloroquine) in the treatment of this disease with best available data showing value of adding azithromycin. Based on drug repurposing studies done by our team and others, we identified the autophagy/apoptosis pathway as a major target for intervention. Based on in-silico and in-vitro models, sirolimus was identified as the drug that deserves urgent prioritization. The rational for combining sirolimus and hydroxychloroquine is explained in details in the study background below and a short video prepared by study PI (https://youtu.be/-zlOMXJp2hg). The evidence for using sirolimus for influenza is emphasized by a RCT that showed reduction of mechanical ventilation time by 50% (7 days on sirolimus arm vs 15 days on oseltamivir/steroids arm). Safe administration in human subjects is illustrated by multiple phase I/II clinical trials, performed in patients with cancer. COVID19-HOPE trial will randomize patients to 2 arms: HCQ/AZ (Arm A) and HCQ/SIR (Arm B). The main inclusion criteria is an RT-PCR test confirming infection with SARS-CoV-2 along with objective clinical criteria of disease (fever, tachypnea and/or hypoxemia). The primary endpoint of study will be Time To Clinical Improvement (TTCI), defined as time from randomization to resolution of the clinical features mentioned above (no fever, no tachypnea and no hypoxemia). In addition, secondary endpoints will include clinical failure by day 28 (need for intubation and/or death), QT interval prolongation, and adverse events. The estimated NNT based on Wilcoxon Mann Whitney comparison of TTCI in study arms is 58 patients (29 each arm). The study includes an adaptive plan, meaning that after different time points the study results will be evaluated and the NNT and randomization scheme (1:1 vs. others) will be evaluated and submitted to the IRB. Also, if one arm proves to be of no value, another regimen might be introduced based on available data. The study will recruit patients for a year and once approved by IRB and JFDA attempts to recruit other centers will be made (including national and regional centers).

Condition or disease Intervention/treatment Phase
COVID-19 Patients Drug: HCQ & AZ vs HCQ+SIR Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Subjects who are enrolled in the study will be randomly assigned to any of the study arms, A or B

Study Arm A (HCQ & AZ): Subjects will receive HCQ 600mg PO X 10 days and AZ PO 250mg DAILY X 10 days.

Study Arm B (HCQ+SIR): Subjects will receive HCQ 600mg PO X 10 days and SIR 4mg PO X 1 day then 2mg PO DAILY X 9 days

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hydroxychloroquine in Combination With Azithromycin or Sirolimus for Treating COVID-19 Patients: A Pilot, Multicenter Randomized Open-Label Trial
Estimated Study Start Date : May 1, 2020
Estimated Primary Completion Date : August 1, 2020
Estimated Study Completion Date : September 1, 2020


Arm Intervention/treatment
Experimental: Study Arm A (HCQ & AZ)
Subjects will receive HCQ 600mg PO X 10 days and AZ PO 250mg DAILY X 10 days.
Drug: HCQ & AZ vs HCQ+SIR
Subjects will receive either Hydroxychloroquine with Azithromycin or Hydroxychloroquine with Sirolimus
Other Names:
  • Hydroxychloroquine+Azithromycin
  • Hydroxychloroquine+Sirolimus

Experimental: Study Arm B (HCQ+SIR)
Subjects will receive HCQ 600mg PO X 10 days and SIR 4mg PO X 1 day then 2mg PO DAILY X 9 days
Drug: HCQ & AZ vs HCQ+SIR
Subjects will receive either Hydroxychloroquine with Azithromycin or Hydroxychloroquine with Sirolimus
Other Names:
  • Hydroxychloroquine+Azithromycin
  • Hydroxychloroquine+Sirolimus




Primary Outcome Measures :
  1. Time to Clinical improvement (TTCI) [ Time Frame: 28 Days ]
    Time to clinical improvement (TTCI), defined as time from randomization to clinical improvement, defined as resolution of fever (oral T<38), respiratory rate(<24/min) and normalization of oxygen saturation (persistent pO2 ≥95% on RA). Assessment of clinical improvement should be confirmed on 2 consecutive days in patients who do not develop clinical failure. This outcome will be analyzed separately from clinical failure (i.e. patients with clinical failure will be excluded from TTCI calculation).


Secondary Outcome Measures :
  1. Clinical failure defined as death or need for Intubation and mechanical ventilation [ Time Frame: 28 Days ]
    Proportion of patients who develop clinical failure, defined as death or need for mechanical ventilation within 28 days of enrollment or until discharge (whichever later).

  2. Adverse effects [ Time Frame: 28 Days ]
    Safety and tolerability, as assessed by the occurrence of adverse events in any of the study arms.

  3. QT interval prolongation [ Time Frame: 28 Days ]
    Any clinically significant increase of QT, defined as increased to over 500, or increase by 60 msec (putting the patient in over 450 msec). Proportion of patients with clinically significant increase will be used as an Outcome.

  4. Failure to continue assigned therapy [ Time Frame: 28 Days ]
    Proportion of patients who do not continue on assigned therapy will be calculated. Causes of failure to continue (drop-out) will be captured as well.

  5. Time to viral clearance [ Time Frame: 28 Days ]
    Viral RT-PCR will be performed per institutional guidelines. The time from randomization to first negative test (Which is not followed by a positive test) will be recorded.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and non-pregnant female patients 18 years of age or older
  • Positive RT-PCR for SARS-CoV-2.
  • Fever (oral T≥39 C within 24 hours of enrollment), Tachypnea (resting respiratory rate ≥ 28/min) and/or Oxygen saturation (Sao2) ≤ 93% on room air.
  • Ability to read, understand and sign IRB approved informed consent
  • Patients on HCQ or HCQ/AZ already are eligible for randomization.

Exclusion Criteria:

  • Weight < 40 kg.
  • Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at the screening.
  • Subjects with a history of retinopathy, sickle cell disease or trait, psoriasis, porphyria, history of splenectomy, mental illness or uncontrolled seizures disorder, liver cirrhosis, end-stage renal disease or need for renal replacement therapy, Decompensated heart failure, known active tuberculosis or history of incompletely treated tuberculosis, uncontrolled systemic bacterial or fungal infections, active viral infection other than COVID-19, Patients on chronic immunosuppression for other medical conditions such as rheumatological disorders, inflammatory bowel disease, or in patients with organ transplants.
  • Allergy to any of the study medications.
  • Drug-Drug interaction (after consulting with study PI). For example:

    • Drugs that may interact and alter HCQ level: ampicillin, cimetidine, digoxin, statins, cyclosporine, warfarin, fluconazole, within 2 weeks of dosing start, and during the duration of the study.
    • Drugs that may interact and alter SIR level: rifampicin, azole antifungals, phenytoin, diltiazem, verapamil, nicardipine, phenobarbital, carbamazepine, within 2 weeks of dosing start, and during the duration of the study.
  • Any abnormal baseline laboratory screening tests listed below (Exceptions by study PI may apply if reason explained)
  • Liver Child-Pugh grade C (table is included in the study)
  • Creatinine >1.5 mg/dl.
  • Hemoglobin for males <12 g/dl and females <10 g/dl.
  • Platelet count of <100 X 103/L.
  • Cardiac assessment:
  • Patients with baseline corrected QT >450 msec.
  • Patients with decompensated heart failure or acute myocardial infarction within the past 30 days of infection.
  • Patients with HypoKalemia (<3.5 mg/dl), HypoCalcemia (<8.0 mg/dl), HypoMagnesemia (<1.6mg/dl) will be included after correction.
  • Advanced respiratory support (high flow oxygen ≥ 15 L/min, CPAP, non-invasive or invasive mechanical ventilation)
  • Any other significant finding based on the judgment of the PI would increase the risk of having an adverse outcome from participating in this study.
  • Patients that lack decision-making capacity will not be approached to participate in this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04374903


Contacts
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Contact: Iyad Sultan, MD +96265300460 ext 1857 isultan@khcc.jo
Contact: Nedal Al-Rawashdeh, MPH +9627777724198 na.08085@khcc.jo

Locations
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Jordan
King Hussein Cancer Center
Amman, Jordan
Contact: Iyad Sultan, MD       isultan@khcc.jo   
Contact: Nedal Al-Rawashdeh, MPH    +962777724198    na.08085@khcc.jo   
Principal Investigator: Iyad Sultan, MD         
Sub-Investigator: Hikmat Abdel-Razeq, MD         
Sub-Investigator: Amal Al Omari, PhD         
Sub-Investigator: Osama Abu Ata, MD         
Sub-Investigator: Rana Damsees, MPH         
Sub-Investigator: Nedal Al-Rawashdeh, MPH         
Sub-Investigator: Dalia Al Rimawi, MDS         
Sub-Investigator: Mayada Abu Shanap, MD         
Sub-Investigator: Anwar Alnassan, MD         
Sub-Investigator: Abdelghani Tbakhi, PhD         
Sub-Investigator: Iyad Ammouri, MD         
Sub-Investigator: Mohammed Abufaraj, Prof.         
Sub-Investigator: Rula Najjar, Pharm. D         
Sub-Investigator: Feras Hawari, MD         
Sponsors and Collaborators
King Hussein Cancer Center
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Responsible Party: Iyad Sultan, Chairman- Department of Pediatrics, Pediatrics Administration, King Hussein Cancer Center
ClinicalTrials.gov Identifier: NCT04374903    
Other Study ID Numbers: 20 KHCC 74
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: May 5, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Iyad Sultan, King Hussein Cancer Center:
COVID-19
Hydroxychloroquine
Sirolimus
Azithromycin
HOPE
Additional relevant MeSH terms:
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Sirolimus
Azithromycin
Hydroxychloroquine
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents