ProPAC-COVID: Proactive Protection With Azithromycin and hydroxyChloroquine in Hospitalized Patients With COVID-19

• Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark (Other)
• Overall Status: Terminated
• CT.gov ID: NCT04322396
• Collaborator: (none)
• Enrollment: 117
• Locations: 8
• Arms: 2
• Actual Duration (Months): 9.9
• Patients Per Site: 14.6
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

This study explores whether patients acutely hospitalized may have shorter hospitalization and fewer admittances at Intensive Care Units by treatment with azithromycin and hydroxychloroquine.

Condition or Disease	Intervention/Treatment	Phase
Virus Diseases; Infection Viral; Corona Virus Infection	Drug: Azithromycin; Drug: Hydroxychloroquine; Drug: Placebo oral tablet; Drug: Placebo oral tablet	Phase 2

Detailed Description

In the ongoing coronavirus pandemic, COVID-19, that arose in Wuhan China, there is still sparse data in the course, risk of various complications, and in particular how patients who are hospitalized are best treated to ensure high survival and short hospitalization. Despite the rapid spread of the disease globally, there is no solid data yet to recommend any specific treatments, which is why symptomatic, organ supportive therapy including respiratory therapy in acute pulmonary failure is recommended. There has been reported a high incidence of bacterial super-infections in patients with COVID-19. Patients with COVID-19 also have a higher risk of dying because of septic shock. Thus, there is an urgent need for treatment that can improve the patient's chance of the shortest hospitalization possible, and treatment that can lower the risk of secondary infection and death.

This is a randomized, placebo-controlled, double-blinded multi-center trial evaluating the effect of azithromycin and hydroxychloroquine treatment in patients with COVID-19 during hospitalization. The aim of the study is to investigate whether the treatment can shorten hospitalization, reduce the risk of non-invasive ventilation, admittance to Intensive Care Units and death.

Study Design

• Study Type: Interventional
• Actual Enrollment: 117 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Proactive Protection With Azithromycin and Hydroxychloroquine in Hospitalized Patients With COVID: A Randomized, Placebo-controlled Double-blinded Trial Evaluating Treatment With Azithromycin and Hydroxychloroquine to Patients With COVID-19
• Actual Study Start Date: Apr 6, 2020
• Actual Primary Completion Date: Feb 2, 2021
• Actual Study Completion Date: Feb 2, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Control This arm will receive standard care and placebo in 15 days. Azithromycin placebo: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 Hydroxychloroquine placebo: Day 1-15: 200 mg x 2	Drug: Placebo oral tablet; Placebo Azithromycin; Drug: Placebo oral tablet; Placebo Hydroxychloroquine
Active Comparator: Intervention This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 Hydroxychloroquine: Day 1-15: 200 mg x 2	Drug: Azithromycin; Azithromycin; Drug: Hydroxychloroquine; Hydroxychloroquine

Outcome Measures

Primary Outcome Measures

1. Number of Days Alive and Discharged From Hospital Within 14 Days [14 days]

Secondary Outcome Measures

1. Categorization of Hospitalization Status [14 days]

   The patient will be categorized into one of the following 8 categories depending on status of their hospitalization: Dead (yes/no) Hospitalized and receiving mechanical ventilation or ExtraCorporalMembraneOxygenation (ECMO) (yes/no) Hospitalized and receiving Non-invasive ventilation or "high-flow oxygen device" (yes/no) Hospitalized and given oxygen supplements different from (2) and (3) (yes/no) Hospitalized and without oxygen treatment, but receiving other treatment (both related to COVID-19 or other) (yes/no) Hospitalized for observation (yes/no) Discharged from hospital with restriction of activity level (yes/no) Discharged from hospital without any restrictions of activity level (yes/no) Only one category can be "yes".

2. Length of Stay in ICU [14 days]

   Length of stay in intensive care unit.

3. Number of Participants on Non-invasive Ventilation (NIV) During Hospitalization [14 days]

4. Mortality [30 days]

5. Length of Hospitalization [14 days]

6. Days Alive and Discharged From Hospital [30 days]

7. Mortality [90 days]

8. Mortality [365 days]

9. Number of Readmissions (All Causes) [30 days]

10. Number of Days Using Non-invasive Ventilation (NIV) [14 days]

    Number of days using non-invasive ventilation (NIV) if on NIV during hospitalization.

11. Change in Patient's Oxygen Partial Pressure [4 days]

    PaO2 measured in arterial puncture at baseline and 4 days.

12. Change in Patient's Carbondioxide Partial Pressure [4 days]

    PaCO2 measured in arterial puncture at baseline and 4 days.

13. Change of pH in Blood [4 days]

    pH measured in arterial puncture at baseline and 4 days.

14. Time for no Oxygen Supplement (or Regular Oxygen Supplement "LTOT") [14 days]

    Time for no oxygen supplement (or regular oxygen supplement "LTOT") if on oxygen during admission.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient admitted to a Danish emergency department, lung medical department or medical department

• Age >18 years

• Hospitalized <48 hours

• Positive COVID-19 test/diagnosis during the hospitalization

• Signs informed consent

Exclusion Criteria:

• If the patient uses > 5 LO2/min at time of recruitment

• Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinolinderivates

• Pregnancy

• Breastfeeding

• Neurogenic hearing loss

• Psoriasis

• Retinopathy

• Maculopathy

• Changes in vision field

• Severe liver disease other than amoebiases

• Severe gastrointestinal, neurological or haematological disorders

• eGFR < 45 ml/min/1.73m2

• Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval

• Myasthenia Gravis

• Uses Digoxin

• Glucose-6-phosphate dehydrogenase deficiency

• Porphyria

• Hypoglycemia at any time since hospitalization

• Severe mental illness which significantly impedes cooperation

• Severe linguistic problems that significantly impedes cooperation

• Treatment with sickle alkaloids

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aalborg Sygehus	Aalborg		Denmark
2	Bispebjerg Hospital	Copenhagen		Denmark
3	Herlev-Gentofte Hospital	Copenhagen		Denmark
4	Hvidovre Hospital	Copenhagen		Denmark
5	Nordsjællands Hospital	Hillerød		Denmark
6	Odense Universitetshospital	Odense		Denmark
7	Roskilde Sygehus	Roskilde		Denmark
8	Slagelse Sygehus	Slagelse		Denmark

Sponsors and Collaborators

• Chronic Obstructive Pulmonary Disease Trial Network, Denmark

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 16, 2020
• Statistical Analysis Plan - May 19, 2020

More Information

Publications

None provided.

• Responsible Party: Chronic Obstructive Pulmonary Disease Trial Network, Denmark
• ClinicalTrials.gov Identifier: NCT04322396
• Other Study ID Numbers: KronLungesyg_COVID_19_protokol
• First Posted: Mar 26, 2020
• Last Update Posted: Jun 29, 2021
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Infections; Communicable Diseases; Virus Diseases; Coronavirus Infections; Azithromycin; Hydroxychloroquine

Study Results

Participant Flow

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Period Title: Overall Study
STARTED	56	61
COMPLETED	56	61
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Control	Intervention	Total
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine	Total of all reporting groups
Overall Participants	56	61	117
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	63	68	65
Sex: Female, Male (Count of Participants)
Female	27 48.2%	25 41%	52 44.4%
Male	29 51.8%	36 59%	65 55.6%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	45 80.4%	53 86.9%	98 83.8%
African	1 1.8%	0 0%	1 0.9%
Asian	6 10.7%	6 9.8%	12 10.3%
Unknown/other	4 7.1%	2 3.3%	6 5.1%
Region of Enrollment (Count of Participants)
Denmark	56 100%	61 100%	117 100%

Outcome Measures

1. Primary Outcome

Title	Number of Days Alive and Discharged From Hospital Within 14 Days
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Median (Inter-Quartile Range) [days]	9	9

2. Secondary Outcome

Title	Categorization of Hospitalization Status
Description	The patient will be categorized into one of the following 8 categories depending on status of their hospitalization: Dead (yes/no) Hospitalized and receiving mechanical ventilation or ExtraCorporalMembraneOxygenation (ECMO) (yes/no) Hospitalized and receiving Non-invasive ventilation or "high-flow oxygen device" (yes/no) Hospitalized and given oxygen supplements different from (2) and (3) (yes/no) Hospitalized and without oxygen treatment, but receiving other treatment (both related to COVID-19 or other) (yes/no) Hospitalized for observation (yes/no) Discharged from hospital with restriction of activity level (yes/no) Discharged from hospital without any restrictions of activity level (yes/no) Only one category can be "yes".
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Dead	2 3.6%	1 1.6%
Hospitalized and receiving mechanical ventilation or ExtraCorporalMembraneOxygenation (ECMO)	1 1.8%	3 4.9%
Hospitalized and receiving Non-invasive ventilation or "high-flow oxygen device"	0 0%	1 1.6%
Hospitalized and given oxygen supplements different from (2) and (3)	2 3.6%	2 3.3%
Hospitalized and without oxygen, but receiving other treatment (both related to COVID-19 or other)	2 3.6%	1 1.6%
Hospitalized for observation	0 0%	1 1.6%
Discharged from hospital with restriction of activity level	27 48.2%	26 42.6%
Discharged from hospital without any restrictions of activity level	22 39.3%	26 42.6%

3. Secondary Outcome

Title	Length of Stay in ICU
Description	Length of stay in intensive care unit.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Median (Inter-Quartile Range) [days]	11	14

4. Secondary Outcome

Title	Number of Participants on Non-invasive Ventilation (NIV) During Hospitalization
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Count of Participants [Participants]	1 1.8%	3 4.9%

5. Secondary Outcome

Title	Mortality
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Count of Participants [Participants]	2 3.6%	1 1.6%

6. Secondary Outcome

Title	Length of Hospitalization
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Median (Inter-Quartile Range) [days]	4	4

7. Secondary Outcome

Title	Days Alive and Discharged From Hospital
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Median (Inter-Quartile Range) [days]	26	26

8. Secondary Outcome

Title	Mortality
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Mortality
Time Frame	365 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Number of Readmissions (All Causes)
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Count of Participants [Participants]	6 10.7%	9 14.8%

11. Secondary Outcome

Title	Number of Days Using Non-invasive Ventilation (NIV)
Description	Number of days using non-invasive ventilation (NIV) if on NIV during hospitalization.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed represents the number of participants with available data.

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	1	3
Mean (95% Confidence Interval) [days]	9.0	6.7

12. Secondary Outcome

Title	Change in Patient's Oxygen Partial Pressure
Description	PaO2 measured in arterial puncture at baseline and 4 days.
Time Frame	4 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Mean (95% Confidence Interval) [mmHg]	-0.2	-3.0

13. Secondary Outcome

Title	Change in Patient's Carbondioxide Partial Pressure
Description	PaCO2 measured in arterial puncture at baseline and 4 days.
Time Frame	4 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Mean (95% Confidence Interval) [mmHg]	1.4	-3.0

14. Secondary Outcome

Title	Change of pH in Blood
Description	pH measured in arterial puncture at baseline and 4 days.
Time Frame	4 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	56	61
Mean (95% Confidence Interval) [pH]	0.0	0.0

15. Secondary Outcome

Title	Time for no Oxygen Supplement (or Regular Oxygen Supplement "LTOT")
Description	Time for no oxygen supplement (or regular oxygen supplement "LTOT") if on oxygen during admission.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed represents the number of participants with available data

Arm/Group Title	Control	Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine	This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
Measure Participants	27	25
Median (Inter-Quartile Range) [hours]	72	72

Adverse Events

Time Frame	Adverse events were recorded during the period beginning when the patient received their first dose of trial medication up to and including day 15. All-Cause Mortality was assessed up to 30 days.
Adverse Event Reporting Description	A serious adverse event (SAE) was defined as an event or adverse event that, regardless of dose, was life-threatening, resulted in significant or persistent disability or incapacity, or led to a congenital anomaly or malformation. Because comorbidities and mortality are common in this patient group, prolonged admission, re-admission, non-invasive ventilation, invasive respiratory treatment and death were not considered SAEs.
Arm/Group Title	Control		Intervention
Arm/Group Description	This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine		This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
All Cause Mortality
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/56 (3.6%)		1/61 (1.6%)
Serious Adverse Events
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/56 (3.6%)		0/61 (0%)
Cardiac disorders
Ventricular arrhythmia	1/56 (1.8%)		0/61 (0%)
Myocardial infarction	0/56 (0%)		0/61 (0%)
Nervous system disorders
Hearing loss	1/56 (1.8%)		0/61 (0%)
Seizure	0/56 (0%)		0/61 (0%)
Stroke	0/56 (0%)		0/61 (0%)
Other (Not Including Serious) Adverse Events
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/56 (44.6%)		31/61 (50.8%)
Cardiac disorders
Prolonged QTc	7/56 (12.5%)		4/61 (6.6%)
Chest pain	4/56 (7.1%)		3/61 (4.9%)
Endocrine disorders
Hypoglycaemia	0/56 (0%)		0/61 (0%)
Gastrointestinal disorders
Diarrhoea	3/56 (5.4%)		12/61 (19.7%)
Vomiting	2/56 (3.6%)		2/61 (3.3%)
Nausea	6/56 (10.7%)		11/61 (18%)
Abdominal pain	7/56 (12.5%)		7/61 (11.5%)
Nervous system disorders
Headache	5/56 (8.9%)		3/61 (4.9%)
Photophobia	0/56 (0%)		0/61 (0%)
Dizziness	3/56 (5.4%)		10/61 (16.4%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	2/56 (3.6%)		3/61 (4.9%)
Skin and subcutaneous tissue disorders
Itching/Rash	0/56 (0%)		3/61 (4.9%)
Vascular disorders
Bleeding	0/56 (0%)		2/61 (3.3%)

Limitations/Caveats

Early termination based on recommendations from the DSMB leading to small numbers of subjects analyzed.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.