Clinical Trials Register

Summary
EudraCT Number:	2020-003770-50
Sponsor's Protocol Code Number:	20200403
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-09-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2020-003770-50

A.3

Full title of the trial

An Open-Label, Single/Multiple Ascending Dose Study to Assess the Pharmacokinetics, Efficacy, Safety and Tolerability of Inhalation Delivery of Hydroxychloroquine Sulfate (HCQ) in Healthy Volunteers and patients with COVID-19

Otevřená studie jednorázové/vícenásobné vzestupné dávky k posouzení farmakokinetiky, účinnosti, bezpečnosti a snášenlivosti inhalačního podání hydroxychlorochin sulfátu (HCQ) u zdravých dobrovolníků a pacientů s COVID-19.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

20200403

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Všeobecná fakultní nemocnice v Praze
B.1.3.4	Country	Czechia
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	IOCB
B.4.2	Country	Czechia
B.4.1	Name of organisation providing support	Cadore INV s.r.o.
B.4.2	Country	Czechia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	General University Hospital in Prague
B.5.2	Functional name of contact point	Ondřej Slanař
B.5.3	Address:
B.5.3.1	Street Address	Albertov 4
B.5.3.2	Town/ city	Praha 2
B.5.3.3	Post code	12000
B.5.3.4	Country	Czechia
B.5.4	Telephone number	+420224968146

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Hydroxychloroquine Sulfate Solution for Nebulization
D.3.4	Pharmaceutical form	Inhalation solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydroxychloroquine
D.3.9.1	CAS number	118-42-3
D.3.9.4	EV Substance Code	SUB08077MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.33 to 0.67
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Healthy volunteers and patients with COVID - 19

E.1.1.1

Medical condition in easily understood language

Healthy volunteers and patients with COVID - 19

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	HLT
E.1.2	Classification code	10084510
E.1.2	Term	Coronavirus infections
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• Assessment of pharmacokinetics of single dose hydroxychloroquine sulfate following inhalation delivery in an ascending dosing scheme.
• Population pharmacokinetics after multiple dose administration

E.2.2

Secondary objectives of the trial

• Evaluation of efficacy, safety and tolerability of multiple dose hydroxychloroquine sulfate following inhalation delivery of HCQ combined with standard of care versus standard of care only using oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) considering:
• Change in SpO2/FiO2 ratio from baseline versus Day 7 or at release
• Time to saturation ≥92% on room air
• Duration of supplemental oxygen use
• Time to fever resolution
• Number of days without fever
• X ray lungs – prior to the start of the therapy and at release (number of affected segments)
• Change in quantitative SARS-CoV-2 virus evaluation prior start of the therapy orand Day 1, and at release (nasal swab/BAL/ELF and blood)
• Time to progression to noninvasive or invasive mechanical ventilation or ECMO in patients on oxygen or high flow nasal oxygen (HFNO)
• Time to weaning from noninvasive or invasive mechanical ventilation or ECMO in the patients on MV or ECMO
• Time to release from the hospital
• Mortality

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria healthy subjects
1. Healthy male volunteers ≥ 18 and ≤ 55 years old (date of ICF signature is decisive).
2. Non-smoker or past-smoker (who has stopped smoking at least 6 months before the first dosing).
3. Body Mass Index at screening ≥ 18.5 and ≤ 30.0 kg/m2.
4. Subject is available for the whole study and has provided his written informed consent.
5. With clinical history and physical examination results within normality.
6. All laboratory screening results within the normal range or deemed clinically insignificant by Investigator.
7. Acceptance of use of effective contraceptive measures during the whole study.
8. Screening Vital signs and ECG without significant deviations.
9. Czech citizenship.

Inclusion criteria COVID-19 patients
1. Study subjects must be ≥18 years inclusive (male or female)
2. Hospitalized or admitted patients to hospital with COVID-19 pneumonia or respiratory symptoms confirmed with positive PCR or antigen test for SARS-CoV-2 virus
3. Moderate to severe disease with or without supplemental oxygen administration by nasal cannula, face mask and or noninvasive or mechanical ventilation (for the purpose of the study the patient conditions and treatment will be considered, please see the protocol section Study population specific information and procedures) etc
4. Capable of giving sSigned informed consent prior to performing study procedures (please see the protocol section Study population specific information and procedures)
5. For woman of childbearing potential use of contraceptive measures during the study up to follow-up call day 30 after the end of treatment and or later discharge from the hospital

E.4

Principal exclusion criteria

Exclusion Criteria healthy subjects
1. Known hypersensitivity to 4-aminoquinoline compounds and contraindication of HCQ use.
2. Medical history of retinal or visual field changes of any etiology.
3. Acute or chronic diseases and/or clinical findings e.g. several renal or liver impairment, which may interfere with the aims of the study or with the bioavailability and/or pharmacokinetics of the IMP.
4. Medical history of asthma bronchiale or bronchospasms or any allergies deemed clinically significant by Investigator.
5. Clinically significant illness within 4 weeks before the first dosing, including major surgery.
6. Vaccination with live vaccines less than 14 days prior to the first administration of IMP.
7. Use of an investigational drug within 2 months prior to dosing in this study.
8. Use of HCQ within 3 months prior to dosing in this study.
9. Any clinically significant laboratory abnormality, including positive results of HBsAg and/or HCV and/or HIV test during screening procedure.
10. Prolonged QT interval at baseline or at increased risk for arrhythmia.
11. Positive alcohol breath test.
12. Positive urinary drug screen test at check-in.
13. Serious mental disease or inability to cooperate with clinical team.
14. Sitting blood pressure is out of the range of 90 - 140 mmHg for systolic BP and/or 60-90 mmHg for diastolic BP and/or heart rate out of the range of 50-100 bpm at screening.
15. Body temperature <35.7 and/or >37.2°C at screening or baseline.
16. History of substance abuse including alcohol.
17. Donation or loss of ≥ 500 mL of blood within 90 days prior to the first dosing.
18. Donation of plasma or platelets within 14 days prior to the first dosing.
19. Haemoglobin below 120 g/L for women and 130 g/L for men at Screening.
20. Leukocytosis, level of leukocytes above 9.00 * 109/L at Screening.
21. All prescription, over-the-counter and herbal medications are prohibited within 10 days prior to study dosing (with exception of paracetamol ≤1000 mg/day at the discretion of the Investigator).
22. Subject is not willing to keep contraceptive requirements (set in Inclusion criteria).
23. Employees of the Study Centers, Study personnel and relatives of study personnel

Exclusion Criteria COVID-19 patients
1. Presence of retinal or visual field changes of any etiology
2. Known hypersensitivity to 4-aminoquinoline compounds and contraindication of HCQ or present peroral HCQ use
3. Prolonged QT interval at baseline or at increased risk for arrythmia
4. Use of HCQ contraindicated medications (e.g. citalopram)
5. Multi-organ system dysfunction as judged by the investigator to be of clinical relevance
6. Elevated liver enzymes or judged by the investigator to be of clinical relevance
7. Exclusion of patients with hypokalemia/hypomagnesemia
8. Sever renal impairment as judged by the investigator to be of clinical relevance
9. Medical history of asthma bronchiale or bronchospasms or any allergies deemed clinically significant by Investigator
10. Participation of study subject in any concurrently ongoing clinical investigation for COVID-19 treatment which could interfere with the study outcome
11. Pregnancy and breast feeding.
12. Employees of the Study Centers, Study personnel and relatives of study personnel

E.5 End points

E.5.1

Primary end point(s)

Healthy: pharmacokinetics of hydroxychloroquine sulfate following inhalation delivery in an ascending dosing scheme
Patients: Evaluation of efficacy, safety and tolerability of hydroxychloroquine sulfate following inhalation delivery of HCQ combined with standard of care versus standard of care only using oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) considering:
• Change in SpO2/FiO2 ratio from baseline versus Day 7 or at release
• Time to saturation ≥92% on room air
• Duration of supplemental oxygen use
• Time to fever resolution
• Number of days without fever
• X ray lungs – prior to the start of the therapy and at release (number of affected segments)
• Change in quantitative SARS-CoV-2 virus evaluation prior start of the therapy or Day 1, and at release (nasal swab/BAL/ELF and blood)
• Time to progression to noninvasive or invasive mechanical ventilation or ECMO in patients on oxygen or high flow nasal oxygen (HFNO)
• Time to weaning from noninvasive or invasive mechanical ventilation or ECMO in the patients on MV or ECMO
• Time to release from the hospital
• Mortality
• Evaluation of complement plasma levels

E.5.1.1

Timepoint(s) of evaluation of this end point

Healthy subjects: 5 days
Patients: discharge from hospital

E.5.2

Secondary end point(s)

Healthy subjects
• Evaluation of safety and tolerability of hydroxychloroquine sulfate following inhalation delivery of HCQ

Patients
• Assessment of pharmacokinetics of hydroxychloroquine sulfate following inhalation delivery in an ascending dosing scheme.
• Population pharmacokinetics after multiple dose administration

E.5.2.1

Timepoint(s) of evaluation of this end point

Healthy subjects: 5 days
Patients: discharge from hospital

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetic dose escalation study

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

dose escalation study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Follow up day 30 phone call

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

137

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with moderate to severe COVID19 infection, on oxygen therapy.

Pacienti s těžkým průbhem COVID19 s potřebou oxygenoterapie.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

137

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Study exit procedures (healthy subjects ) include:
1) Physical examination.
2) 12-lead ECG.
3) Clinical chemistry – urea, creatinine, sodium, potassium, chloride, tot. bilirubin, ALT, AST, GGT, ALP, Total Protein, Albumin, Cholesterol, Glucose , C-Reactive Protein (CRP) and HCG.
4) Haematology – haemoglobin, haematocrit, RBC, MCV, MCH, MCHC, Platelets, WBC
5) Vital signs – heart rate, systolic and diastolic blood pressure in sitting position.
6) Body temperature.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-10-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-08-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-15

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