Hydroxychloroquine Monotherapy and in Combination With Azithromycin in Patients With Moderate and Severe COVID-19 Disease

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04358081
• Collaborator: (none)
• Enrollment: 20
• Locations: 7
• Arms: 3
• Actual Duration (Months): 2.9
• Patients Per Site: 2.9
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Two recent studies have suggested that in patients with Covid19, treatment with hydroxychloroquine may shorten the duration of symptoms and improve viral clearance, an effect that appears most pronounced when combined with azithromycin. Hydroxychloroquine treatment may inhibit viral nucleic acid-mediated activation of various innate immune pathways, as well as blockade of lysosomal functions in cell types relevant for viral entry and antigen presentation.

The purpose of the study was to determine if oral hydroxychloroquine monotherapy, or in combination with azithromycin results in clinical benefit in patients hospitalized with COVID19 pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Covid-19	Drug: HCQ; Drug: HCQ+AZT; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Safety and Efficacy of Hydroxychloroquine Monotherapy and in Combination With Azithromycin in Patients With Moderate and Severe COVID-19 Disease
• Actual Study Start Date: May 1, 2020
• Actual Primary Completion Date: Jul 27, 2020
• Actual Study Completion Date: Jul 27, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: hydroxychloroquine + aithromycin placebo Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin (AZT) placebo o.d.	Drug: HCQ; Hydroxychloroquine Monotherapy; Other Names: JWT629
Experimental: Arm 2: hydroxychloroquine + azithromycin Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Drug: HCQ+AZT; Hydroxychloroquine with azithromycin; Other Names: JWT629 + AZT
Placebo Comparator: Arm 3: hydroxychloroquine placebo + azithromycin placebo Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Achieved Clinical Response by Day 15 [15 days]

   Clinical response was defined as a) discharged alive; or b) No need for mechanical ventilation in any participants and no need for supplemental oxygen requirement (SpO2) in participants without pre-morbid O2 requirement.

Secondary Outcome Measures

1. Number of Participants Who Achieved Viral Clearance [6 days and 10 Days]

   Number and percentage of participants with negative or below LLOQ SARS-COV-2 based on polymerase chain reaction (PCR) test

2. Number of Participants Discharged or Ready for Discharge [15 days]

   Number of participants who received hydrochloroquine plus azithromycin relative to placebo who were discharged from hospital

3. Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo [15 days]

   Number of participants requiring supplemental oxygen at the time of randomization who returned to pre-morbid supplemental oxygen

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Informed consent must be obtained prior to participation in the study

2. Adult patient ≥ 18 years old

3. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test from respiratory tract specimen (e.g nasopharyngeal swab)

4. Onset of signs and symptoms of COVID19 illness ≤ 7 days prior to randomization (including but not limited to fever, cough, myalgias, fatigue, abnormal chest imaging)

5. Currently hospitalized or requiring hospitalization due to COVID-19 disease

Exclusion Criteria:

1. Use of other investigational drugs or newly approved COVID-19 treatments within 5-half lives or 30 days of enrolment

2. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes

3. Participation in any other clinical trial of an experimental treatment for COVID-19

4. Expectation of concurrent treatment with any other agents or potential direct acting antiviral activity against SARS-Co V-2 during study drug dosing

5. Requires, in the judgement of the investigator, admission to the intensive care unit (ICU) or mechanical ventilatory support (invasive or non-invasive) prior to first dose of study drug (There might be a patient who cannot be admitted to the ICU, even if the patient's condition is severe enough, due to administrative reasons under the current circumstances. This case is also considered under admission to the ICU judged by the investigator)

6. Evidence of cytokine storm syndrome or multi-organ system failure

7. Confirmed co-infection with influenza

8. Creatinine clearance < 45 mL/min or requiring acute renal replacement therapy

9. History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study

10. Any other condition which in the opinion of the investigator, would put the safety of the participant at risk, impede compliance or hinder completion of the study

11. Pregnant or nursing (lactating) women

12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use basic methods of contraception during dosing of study treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Fullerton	California	United States	92835
2	Novartis Investigative Site	Los Angeles	California	United States	90095-1793
3	Novartis Investigative Site	Chicago	Illinois	United States	60612
4	Novartis Investigative Site	Baton Rouge	Louisiana	United States	70809
5	Novartis Investigative Site	Baltimore	Maryland	United States	21287
6	Novartis Investigative Site	Chapel Hill	North Carolina	United States	27599
7	Novartis Investigative Site	Seattle	Washington	United States	98104

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 8, 2020
• Statistical Analysis Plan - Aug 13, 2020

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04358081
• Other Study ID Numbers: CJWT629A12301
• First Posted: Apr 22, 2020
• Last Update Posted: Oct 11, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: covid19; covid 19; covid-19; coronavirus; SARS-CoV; SARS-CoV-2; novel coronavirus; adult; JWT629; acute respiratory syndrome coronavirus
• Additional relevant MeSH terms: COVID-19

Study Results

Participant Flow

Recruitment Details	Study was conducted in 9 centers in the United States. A total of 20 participants were randomized, of whom 19 were treated.
Pre-assignment Detail	One patient was mis-randomized and never received any treatment. This patient has creatine clearance level <45 mL/min or required acute renal replacement therapy and therefore was not eligible for inclusion in the study.

Arm/Group Title	Arm 1: Hydroxychloroquine + Aithromycin Placebo	Arm 2: Hydroxychloroquine + Azithromycin	Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo
Arm/Group Description	Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin placebo o.d.	Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.
Period Title: Treatment Phase of Study
STARTED	7	7	5
COMPLETED	3	6	2
NOT COMPLETED	4	1	3
Period Title: Treatment Phase of Study
STARTED	7	7	5
COMPLETED	6	7	3
NOT COMPLETED	1	0	2

Baseline Characteristics

Arm/Group Title	Arm 1: Hydroxychloroquine + Aithromycin Placebo	Arm 2: Hydroxychloroquine + Azithromycin	Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo	Total
Arm/Group Description	Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin placebo o.d.	Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.	Total of all reporting groups
Overall Participants	7	7	5	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	4 57.1%	5 100%	16 84.2%
>=65 years	0 0%	3 42.9%	0 0%	3 15.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.9 (10.6)	60.9 (12.5)	55.2 (11.1)	53.8 (12.7)
Sex: Female, Male (Count of Participants)
Female	3 42.9%	1 14.3%	3 60%	7 36.8%
Male	4 57.1%	6 85.7%	2 40%	12 63.2%
Race/Ethnicity, Customized (Count of Participants)
White	1 14.3%	3 42.9%	3 60%	7 36.8%
Black or African American	2 28.6%	1 14.3%	0 0%	3 15.8%
Asian	1 14.3%	0 0%	0 0%	1 5.3%
Native Hawaiian or Other Pacific Islander	1 14.3%	0 0%	0 0%	1 5.3%
Unknown	2 28.6%	3 42.9%	2 40%	7 36.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Achieved Clinical Response by Day 15
Description	Clinical response was defined as a) discharged alive; or b) No need for mechanical ventilation in any participants and no need for supplemental oxygen requirement (SpO2) in participants without pre-morbid O2 requirement.
Time Frame	15 days

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) was comprised of all participants to whom study treatment had been assigned by randomization excluding one mis-randomized participant.

Arm/Group Title	Arm 1: Hydroxychloroquine + Aithromycin Placebo	Arm 2: Hydroxychloroquine + Azithromycin	Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo
Arm/Group Description	Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin placebo o.d.	Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.
Measure Participants	7	7	5
Count of Participants [Participants]	7 100%	7 100%	4 80%

2. Secondary Outcome

Title	Number of Participants Who Achieved Viral Clearance
Description	Number and percentage of participants with negative or below LLOQ SARS-COV-2 based on polymerase chain reaction (PCR) test
Time Frame	6 days and 10 Days

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Arm 1: Hydroxychloroquine + Aithromycin Placebo	Arm 2: Hydroxychloroquine + Azithromycin	Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo
Arm/Group Description	Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin (AZI) placebo o.d.	Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.
Measure Participants	7	7	5
by 6 days	2 28.6%	3 42.9%	3 60%
by 10 days	2 28.6%	3 42.9%	3 60%

3. Secondary Outcome

Title	Number of Participants Discharged or Ready for Discharge
Description	Number of participants who received hydrochloroquine plus azithromycin relative to placebo who were discharged from hospital
Time Frame	15 days

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Arm 1: Hydroxychloroquine + Aithromycin Placebo	Arm 2: Hydroxychloroquine + Azithromycin	Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo
Arm/Group Description	Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin (AZI) placebo o.d.	Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.
Measure Participants	7	7	5
Number [participants]	7 100%	7 100%	4 80%

4. Secondary Outcome

Title	Time to Return to Pre-morbid Supplemental Oxygen Requirement in Participants Receiving Hydrochloroquine or Hydrochloroquine Plus Azithromycin Relative to Placebo
Description	Number of participants requiring supplemental oxygen at the time of randomization who returned to pre-morbid supplemental oxygen
Time Frame	15 days

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Arm 1: Hydroxychloroquine + Aithromycin Placebo	Arm 2: Hydroxychloroquine + Azithromycin	Arm 3: Hydroxychloroquine Placebo + Azithromycin Placebo
Arm/Group Description	Hydroxychloroquine 600mg o.d. as loading dose (Day 1) +followed by 200mg t.i.d was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin (AZI) placebo o.d.	Hydroxychloroquine 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d. was initiated within 8-12 hours of the loading dose (not to exceed 12 hours) Azithromycin: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 - Day 5	Hydroxychloroquine placebo o.d. (day 1) followed by hydroxychloroquine placebo t.i.d Azythromycin placebo o.d.
Measure Participants	7	7	5
Number [participants]	7 100%	6 85.7%	4 80%

Adverse Events

Time Frame	at day 15
Adverse Event Reporting Description	Adverse Events (AEs) are any untoward sign or symptom that occured during the study treatment period of 15 days
Arm/Group Title	Hydroxychloroquine + Aithromycin Placebo		Hydroxychloroquine + Azithromycin		Hydroxychloroquine Placebo + Azithromycin Placebo		Total
Arm/Group Description	HCQ		HCQ + AZI		HCG + AZI + Placebo		Total
All Cause Mortality
	Hydroxychloroquine + Aithromycin Placebo		Hydroxychloroquine + Azithromycin		Hydroxychloroquine Placebo + Azithromycin Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		1/5 (20%)		1/19 (5.3%)
Serious Adverse Events
	Hydroxychloroquine + Aithromycin Placebo		Hydroxychloroquine + Azithromycin		Hydroxychloroquine Placebo + Azithromycin Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)		0/7 (0%)		2/5 (40%)		3/19 (15.8%)
Cardiac disorders
Cardiac arrest	0/7 (0%)		0/7 (0%)		1/5 (20%)		1/19 (5.3%)
Renal and urinary disorders
Acute kidney injury	0/7 (0%)		0/7 (0%)		1/5 (20%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Tachypnoea	0/7 (0%)		0/7 (0%)		1/5 (20%)		1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Hydroxychloroquine + Aithromycin Placebo		Hydroxychloroquine + Azithromycin		Hydroxychloroquine Placebo + Azithromycin Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		5/7 (71.4%)		2/5 (40%)		11/19 (57.9%)
Cardiac disorders
Intracardiac mass	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Gastrointestinal disorders
Constipation	1/7 (14.3%)		1/7 (14.3%)		0/5 (0%)		2/19 (10.5%)
Diarrhoea	0/7 (0%)		3/7 (42.9%)		0/5 (0%)		3/19 (15.8%)
Gastrooesophageal reflux disease	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Nausea	0/7 (0%)		2/7 (28.6%)		0/5 (0%)		2/19 (10.5%)
Vomiting	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
General disorders
Chest discomfort	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Chest pain	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Chills	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Fatigue	1/7 (14.3%)		1/7 (14.3%)		1/5 (20%)		3/19 (15.8%)
Pain	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Pyrexia	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Investigations
Alanine aminotransferase increased	0/7 (0%)		2/7 (28.6%)		1/5 (20%)		3/19 (15.8%)
Aspartate aminotransferase increased	0/7 (0%)		2/7 (28.6%)		1/5 (20%)		3/19 (15.8%)
Blood bilirubin increased	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Blood lactate dehydrogenase increased	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Blood triglycerides increased	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Electrocardiogram QT prolonged	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Hepatic enzyme increased	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Neutrophil percentage increased	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Urine analysis abnormal	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Metabolism and nutrition disorders
Decreased appetite	0/7 (0%)		2/7 (28.6%)		0/5 (0%)		2/19 (10.5%)
Hypercholesterolaemia	0/7 (0%)		0/7 (0%)		1/5 (20%)		1/19 (5.3%)
Hyperkalaemia	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Vitamin B12 deficiency	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Myalgia	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Nervous system disorders
Dizziness	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Dysgeusia	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Headache	0/7 (0%)		2/7 (28.6%)		0/5 (0%)		2/19 (10.5%)
Psychiatric disorders
Feeling of despair	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Insomnia	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Renal and urinary disorders
Acute kidney injury	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)		2/7 (28.6%)		0/5 (0%)		3/19 (15.8%)
Dyspnoea	1/7 (14.3%)		1/7 (14.3%)		0/5 (0%)		2/19 (10.5%)
Hypoxia	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Pleuritic pain	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Night sweats	0/7 (0%)		1/7 (14.3%)		0/5 (0%)		1/19 (5.3%)
Vascular disorders
Hypotension	1/7 (14.3%)		0/7 (0%)		0/5 (0%)		1/19 (5.3%)

Limitations/Caveats

Only 20 participants of the initially planned 444 were randomized; and one of those was mis-randomized (so total of 19 participants). Due to this limited number of participants, study objectives could not be evaluated as planned. Results for select efficacy and for safety were summarized based in the information collected up to the eCRF database lock on 13-Aug-2020.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.