Clinical Trials Register

Summary
EudraCT Number:	2021-000516-37
Sponsor's Protocol Code Number:	TS-020DESE
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-02-04
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2021-000516-37

A.3

Full title of the trial

A Phase I/II open-label study for Azacitidine, initiated with a lead-in dose escalation pharmacokinetic Phase I/b part in the 20–50 mg/m2 range to evaluate safety in Hospitalized COVID-19 Patients in Severe Infection with Risk of Progression as Add-on Therapy to Standard of Care, continued with a Randomized, Controlled, Open-Label Adaptive Phase II part to Determine Efficacy and Safety

Azacitidinnel végzett I/II. fázisú nyílt vizsgálat a 20-50 mg/m2 dózistartományban dóziskereső farmakokinetikai Fázis Ib vizsgálati résszel indítva, a kezelés mint „add-on” terápia biztonságosságának meghatározására a progresszió kockázatával kórházban kezelt, standard ellátásban részesülő, súlyos állapotú COVID-19 betegek körében; folytatva nyílt, randomizált, kontrollált, adaptív II. fázisú résszel a hatásosság és biztonságosság meghatározása érdekében

A.3.1

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

The efficacy and the safety of TS-020 in acute viral infection

A TS-020 hatásosságának és biztonságosságának vizsgálata akut vírusfertőzésben

A.3.2

Name or abbreviated title of the trial where available

The efficacy and the safety of TS-020 in acute viral infection

A TS-020 hatásosságának és biztonságosságának vizsgálata akut vírusfertőzésben

A.4.1

Sponsor's protocol code number

TS-020DESE

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	TurnSole Biologics Llc
B.1.3.4	Country	Hungary
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	EMMI
B.4.2	Country	Hungary
B.4.1	Name of organisation providing support	TurnSole Biologics Ltd
B.4.2	Country	Hungary
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TurnSole Biologics Llc
B.5.2	Functional name of contact point	Gabor Heltovics, CEO
B.5.3	Address:
B.5.3.1	Street Address	József street 10/a
B.5.3.2	Town/ city	Pécs
B.5.3.3	Post code	H-7621
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+36303310535
B.5.6	E-mail	info@turnsolebiologics.com

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	Yes
D.2.1.1.1	Trade name	AZACITIDIN SANDOZ 25 mg/ml por szuszpenziós injekcióhoz
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz Hungária
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	AZACITIDIN SANDOZ
D.3.4	Pharmaceutical form	Powder for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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

COVID-19 patients with confirmed sever viral infection of SARS-COV-2

súlyos állapotú igazolt virusfertőzéssel kórházban kezelt COVID-19 betegek

E.1.1.1

Medical condition in easily understood language

hospitalised COVID-19 patients with confirmed viral infection of SARS-COV-2 in sever conditions and risk of progression

súlyos állapotú igazolt virusfertőzéssel kórházban kezelt COVID-19 betegek a progresszió kockázatával

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10047461
E.1.2	Term	Viral infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To establish the tolerable maximal recommended Phase 2 dose (MRP2D) based on safety results
and continued in Phase 2:
To evaluate the responder rate out of subjects enrolled and completed the treatment period at day 10 of trial by the primary endpoint in each treatment group.
The state “Responder”/ “Non-Responder” to be evaluated by the composite outcome criteria as follows. Subject will be defined as “Responder” at the time point of evaluation in case one of the three outcome criteria below is fulfilled:
1) No further worsening of respiratory function as defined below:
a) Improvement of oxygen saturation >3 percentage points or >10%, with stable FiO2 or
b) with a possibility to reduce FiO2 to maintain adequate saturation with 100 points.
2) Significant reduction in number of viral replicas detected:-
3) Change in clinical state assessed by a 6-point ordinal scale (6-POC). at least 1 point from baseline on a six-point ordinal scale:

E.2.2

Secondary objectives of the trial

1. To evaluate the change in clinical state compared to control group –
2. To assess and demonstrate the efficacy on the virological status of SARS-CoV-2 patients by virion replicates
3. To assess changes of Disease Severity (DiS) by the proportion of patients:
4. To obtain information on changes in Symptoms Severity (WHO SyS):
5. To assess the risk reduction effect of study treatment on overall mortality by the 28-day survival:
6. Length of stay in hospital [Time Frame: Till hospital discharge, up to 28 days] measured as duration of days from baseline to hospital discharge.
7. To obtain safety information -
8. To evaluate the ratio of “Responders”/ “Non-Responders” after day 3, 5, 10 and 14 of randomisation.
9. Time (days) to clinical improvement
10. Routine laboratory parameters assessment: total blood count, routine chemistry, IL-6, D-dimer, ferritin, CRP, pro-BNP.
11. Evaluations of CT Image scan of the chest.
12. Evaluation of cytokine status

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacokinetic substudy in Phase 1b: incorprated to protocol:
A Phase I/II open-label study for Azacitidine, initiated with a lead-in dose escalation pharmacokinetic Phase I/b part in the 20–50 mg/m2 range to evaluate safety in Hospitalized COVID-19 Patients in Severe Infection with Risk of Progression as Add-on Therapy to Standard of Care
TS-020DESE

E.3

Principal inclusion criteria

1. Trial subjects are in 18-75 years of age.
2. Severe COVID-19 infected patient
(criteria applicable as one of the following):
- Respiratory rate >30 breaths/min or rapidly worsening respiratory gas exchange (PaO2 <80 Hgmm on room air) OR
- Evidence of rales/crackles on physical examination and SpO2 93% on room air, OR
- increasing need for O2 supplementation greater than >50% Venturi mask, including use of non-invasive mechanical ventilation (NIMV) or High Flow Nasal Cannula, OR
- Acute Lung Injury physiology confirmed by PaO2/FiO2 ratio of 300 Hgmm, OR
- CT scan of the chest: presence of bilateral pulmonary infiltrates or 50% progression within 48 hours OR
- COVID-19 infection associated secondary hemophagocytic lymphohistiocytosis (sHLH)/ macrophage activation syndrome (MAS)
- HS scores greater than 169
3. Confirmed SARS-CoV2 infection, by specific lab results at least one positive rt-PCR or IgA/IgM test (1x SARS-CoV-2 PCR positive or if SARS-CoV-2 PCR negative, within 48 hours must have the 2. test SARS-CoV-2 PCR positive)
4. Female subjects: with childbearing potential are under efficient contraception, or in post-menopause.
5. The trial subject has the willingness to comply with study procedures and to give voluntary written informed consent signed and dated prior to enrolment.

E.4

Principal exclusion criteria

1. Clinical signs of critical status:
a) SpO2  90%, while oxygen supply with FiO2 > 100%
b) PaO2/FiO2  200 mmHg
c) Respiratory failure which requiring mechanical ventilation
d) Shock
e) Combined with organ failure other than lung, need to be admitted to ICU
2. Known sensitivity/allergy to azacitidine or other class effect pyrimidine nucleoside analogues, or hypersensitivity to any of the excipients listed.
3. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) /alkaline phosphatase (ALP) ≥ 3x upper limit of normal (ULN) and Total Bilirubin (TBILI) ≥2x ULN; or Creatinine clearance <30 mL/min.
4. Neutrophil count (ANC) below 1500/mcl,
5. Haemoglobin (Hgb)<7.0 mmol/L
6. Platelet count below 100,000/mcl
7. Advanced malignant hepatic tumors / patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.
8. Cardial disorders by Echocardiography or by medical history (arrhythmia, atrialfibrillation or fluttern, sick sinus syndrome (SSS) ventricular arrhythmia, coronary disorders, AMI, EF 50% or valve disorders (excl. mitralis prolapsus). Severe heart failure/ with a history of severe congestive heart failure, (NYHA III-IV, or NYHA IV)
9. Severe chronic renal disorder, or renal impairment requiring dialysis (eGFR<30)
10. Ongoing/suspected sever bacterial infection
11. Acute cerebrovascular disease within 3 months prior to enrolment
12. Pregnancy or breast-feeding (latter can be stopped)
13. Has received other immunomodulatory drug in the past for the treatment of other medical conditions
14. Previously diagnosed with HIV (HIV-Ab test positive) or anti-HCV antibodies positive
15. Obesity of 35 BMI or above
16. Uncontrolled hypertension (RR >170/100 Hgmm) or above.
17. Dementia, or inability to give informed consent
18. Any serious medical condition or abnormal clinical laboratory tests which in the judgement of the investigator may compromise patient safety should he/she participates in the study.
19. Use of concomitant medication:
- Drugs with reported antiviral activity against SARS-CoV-2 included hydroxychloroquine sulfate, chloroquine phosphate, lopinavir-ritonavir combination, ciclesonide, nafamostat mesylate, camostat mesylate, etc. at baseline or within 7 days prior randomization unless a part of standard of care. With the exception of prior or ongoing treatment with antivirals of favipiravir, remdesivir (or generics of these products) are allowed.
- Concurrent immunomodulating biologics or use of Palifermin, Dipyrone, Deferiprone, interferon-alpha.
20. Individuals, in the opinion of the investigator, where progression to death is imminent and inevitable in the next 24 hours irrespective of treatment provision
21. Any medical condition, per opinion of PI that would affect subject safety and/or compliance

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint in the study is the responder rate at Day 10 in each treatment group.

The state “Responder”/ “Non-Responder” to be evaluated by the composite outcome criteria as follows. Subject will be defined as “Responder” at the time point of evaluation in case one of the three outcome criteria below is fulfilled:
1) No further worsening of respiratory function as defined below:
a) Improvement of oxygen saturation >3 percentage points or >10%, with stable FiO2 or
b) with a possibility to reduce FiO2 to maintain adequate saturation with 100 points.

2) Significant reduction in number of viral replicas detected: as below 5% of baseline in the case of quantitative PCR was performed; or the PCR test is turned out negative at Ct18 sensitivity limit in case of qualitative PCR test performed at baseline.

3) Change in clinical state assessed by a 6-point ordinal scale (6-POC). Clinical Improvement since start of treatment, defined as a decrease of at least 1 point from baseline on a six-point ordinal scale:
If none of the above three criteria is fulfilled, then the subject will be considered as “Non-Responder” at the time point of evaluation.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 10 in each treatment group.

E.5.2

Secondary end point(s)

Secondary Endpoints:
1) Ratio of subjects with no further worsening of respiratory function.
No further worsening of respiratory function as defined below:
a) Improvement of oxygen saturation >3 percentage points or >10%, with stable FiO2 or
b) with a possibility to reduce FiO2 to maintain adequate saturation with 100 points.

2) Ratio of subjects with significant reduction in number of viral replicas detected.
Significant reduction in number of viral replicas detected: as below 5% of baseline in the case of quantitative PCR was performed; or the PCR test is turned out negative at Ct18 sensitivity limit in case of qualitative PCR test performed at baseline.

3) Change in clinical state assessed by a 6-point ordinal scale (6-POC). Clinical improvement since start of treatment, defined as a decrease of at least 1 point from baseline on a six-point ordinal scale:
1. Not hospitalized/discharged;
2. Hospitalized, not requiring supplemental oxygen;
3. Hospitalized, requiring supplemental oxygen;
4. Hospitalized, requiring nasal high-flow oxygen therapy, non-invasive
mechanical ventilation, or both;
5. Hospitalized, requiring invasive mechanical ventilation, extra-corporeal
membrane oxygenation (ECMO), or both; and
6. Death.

4) Responder rate at Day 3, Day 5 and Day 7 in each treatment group. Responder rate is defined in the primary endpoint section.

5) Additional secondary endpoints:
(5a) Change in symptom severity assessed by the World Health Organization (WHO)Coronavirus Disease 2019 (COVID19) ordinal 8-point scale
(5b) Change in oxygenation index where OI is used to assess severity of hypoxic respiratory failure. OI is treated as a continuous variable.
(5c) The proportion of subjects with ICU admission (ratio)
(5d) The proportion of subjects requiring mechanical ventilation (ratio)
(5e) The proportion subjects with a need for intubation (ratio)
(5f) Duration of mechanical ventilation (days)
(5g) Overall 28-day survival ratio (ratio)
(5h) Time to clinical improvement (based on a 6-point ordinal scale) (days)
(5i) Length of stay in hospital (based on days from baseline to hospital discharge)

6) Percentage of “RESPONDERS” to TS020 or RESCUE therapy within 7/14 days of treatment by the treatment groups, respectively
Secondary endpoints (Safety):
1. Detection of adverse drug reaction profile during treatment periods, by frequency and distribution during the treatment and the follow-up in both groups,
2. Evaluation of adverse events/serious adverse events.
3. Number of patients with events of special interest [ Time Frame: Within 28 days after randomisation] Events of special interest are defined as elevated serum creatinine, secondary infections, acute kidney failure, hepatic, and cardiac failure, acute ANC failure
4. Number of patients with SAEs considered by the investigator to be at least probably related to the IMP [ Time Frame: Within 28 days after randomisation]
Additional secondary endpoints (QoL):
Changes in daily activities and in subjective signs of respiratory failure based on assessment of daily activities by questionnaire and VAS during and by the end of follow-up period

E.5.2.1

Timepoint(s) of evaluation of this end point

days 3, 5 7, 10, 14, 21, 28

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

Yes

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

dose escalation in dose range of 20-50 mg/m2 body surface

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

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

LVLS

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

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

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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)

none

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

2021-03-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-01-21

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