Clinical Trials Register

Summary
EudraCT Number:	2014-001863-11
Sponsor's Protocol Code Number:	EWO-ISO-2014/1
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:	2014-06-30
Trial results	View 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

2014-001863-11

A.3

Full title of the trial

A Phase 4, Randomised, Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate Efficacy of Isoprinosine® in Comparison With Placebo in Subjects With Confirmed Acute Respiratory Viral Infections due to Influenza A or B Virus, Respiratory Syncytial Virus, Adenovirus, or Parainfluenza Virus 1 or 3.

Randomizované, dvojitě zaslepené, placebem kontrolované multicentrické klinické hodnocení fáze 4, hodnotící účinnost přípravku Isoprinosine® v porovnání s placebem u pacientů s potvrzenou akutní respirační virovou infekcí způsobenou chřipkovým virem A nebo B, respiračním syncyciálním virem, adenovirem, nebo virem parainfluenzy 1 nebo 3

A.3.1

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

Phase 4 study evaluate the efficacy of Isoprinosine in patients with infections due to influenza or parainfluenza virus.

A.4.1

Sponsor's protocol code number

EWO-ISO-2014/1

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	Ewopharma AG.
B.1.3.4	Country	Switzerland
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	Ewopharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ewopharma International, s.r.o.
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	Hlavna 13
B.5.3.2	Town/ city	Bratislava
B.5.3.3	Post code	SK-831 01
B.5.3.4	Country	Slovakia
B.5.4	Telephone number	+4212594 298 25
B.5.5	Fax number	+4212547 930 85
B.5.6	E-mail	e.salpova@ewopharma.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	Isoprinosine
D.2.1.1.2	Name of the Marketing Authorisation holder	Ewopharma International, s.r.o.
D.2.1.2	Country which granted the Marketing Authorisation	Bulgaria
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	Isoprinosine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Inosine Acedoben Dimepranol (IAD)
D.3.9.1	CAS number	36703-88-5
D.3.9.2	Current sponsor code	Isoprinosine
D.3.9.4	EV Substance Code	SUB14214MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Respiratory Viral Infections due to influenza A or B virus, RSV, adenovirus, or parainfluenza virus 1 or 3

E.1.1.1

Medical condition in easily understood language

Infections due to influenza

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	17.1
E.1.2	Level	HLT
E.1.2	Classification code	10022005
E.1.2	Term	Influenza viral 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

To evaluate the clinical efficacy of Isoprinosine compared with placebo in subjects with laboratory confirmed acute respiratory viral infections due to influenza A or B virus, RSV, adenovirus, or parainfluenza virus 1 or 3.

E.2.2

Secondary objectives of the trial

• To evaluate the clinical efficacy of Isoprinosine compared with placebo in subjects with clinically diagnosed influenza-like illnesses.
• To evaluate the effect of Isoprinosine compared with placebo:
- on ability to perform activities of daily living in subjects with laboratory confirmed acute respiratory viral infections due to influenza A or B virus, RSV, adenovirus, or parainfluenza virus 1 or 3.
- on the ability to perform activities of daily living in subjects with clinically diagnosed influenza-like illnesses.
- on the incidence of complications of influenza-like illness and laboratory confirmed acute respiratory viral infections due to influenza A or B virus, RSV, adenovirus, or parainfluenza virus 1 or 3.
• To assess the safety of Isoprinosine compared with placebo in the treatment of influenza-like illnesses.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or nonpregnant female subjects aged 18 to 75 years.
Female subjects must be either surgically sterile, postmenopausal (no menses during the previous 12 months), or must be practicing an effective method of birth control as determined by the investigator (eg, oral contraceptives, double barrier methods, injectable or implanted hormonal contraceptives, tubal ligation, or male partner with vasectomy or complete abstinence).
2. Has an influenza-like illness defined as:
• oral temperature of ≥38°C obtained at study site. If oral temperature measured at screening is <38°C, then the subject will still be eligible if the self-measured temperature at home within 12 hours prior to screening is either an oral temperature of ≥38°C or an axillary temperature of > 37.5°C and the subject has taken an antipyretic within 4 hours prior to screening
• at least 1 of the following respiratory symptoms: cough, sore throat, or nasal obstruction that is considered by the subject to be moderate or severe in intensity (a score of more than 1 on a 4-point scale [Table S2]) , and
• at least 1 of the following constitutional symptoms: fatigue, headache, myalgia, or feverishness that is considered by the subject to be moderate or severe in intensity (rated greater than “mild” on a 4-point scale ).
3. Has onset of influenza-like illness no more than 36 hours prior to screening, defined as when the subject experienced fever and at least 1 respiratory symptom and at least 1 constitutional symptom.
4. Is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements, including completion of the subject diary.

E.4

Principal exclusion criteria

1. Has immunosuppressive disorder or who is receiving immunosuppressive therapy (eg, immunosuppressants, antitumour agents).
2. Is receiving treatment with xanthine oxidase inhibitors (allopurinol) or uricosuric agents, or treatment with thiazide diuretics (eg, hydrochlorothiazide, chlorthalidone, and indapamide) or loop diuretics (eg, furosemide, torsemide, and ethacrynic acid).
3. Has chronic renal dysfunction (creatinine clearance <50 mL/min).
4. Has liver disorder (severe liver function impairment; aspartate aminotransferase and alanine aminotransferase values greater than 3 times the upper limit of normal).
5. Is lactose intolerant.
6. Has cancer in a nonremission stage (subject with nonmetastatic basal cell or squamous cell skin cancer or other early cancer for which surgical resection is considered to be completely curative is eligible for enrolment).
7. Is a resident of a nursing home or other long-term care institution.
8. Is receiving treatment with zidovudine.
9. Is pregnant or lactating/breastfeeding female.
10. Has received any dose of Isoprinosine, oseltamivir, zanamivir, amantadine, or rimantadine during this period of influenza-like illness.
11. Has received prior treatment with any investigational drug or vaccine within 30 days prior to screening.
12. Has known hypersensitivity to inosine acedoben dimepranol or any of the excipients comprising Isoprinosine from the 500 mg Isoprinosine tablets.
13. Has a medical history of hyperuricaemia or gout.
14. Is unable to take oral medications.
15. Has any preexisting illness that, in the opinion of the investigator, would place the subject at an increased risk through participation in this study.
16. Is a subject who, in the judgment of the investigator, will be unlikely to comply with the requirements of this protocol.

E.5 End points

E.5.1

Primary end point(s)

Time to resolution of all influenza-like symptoms present at baseline to none (ie, score of 0 on influenza-like symptoms assessment scale)

E.5.1.1

Timepoint(s) of evaluation of this end point

Subjects will be instructed to record the presence of influenza like illness respiratory and constitutional symptoms once daily in the evening using the 4 point scale on subject diary cards.

E.5.2

Secondary end point(s)

• Time to resolution of all constitutional symptoms present at baseline to none (ie, score of 0 on influenza-like symptoms assessment scale)
• Time to resolution of cough present at baseline to none (ie, score of 0 on influenza-like symptoms assessment scale)
• Time to resolution of sore throat present at baseline to none (ie, score of 0 on influenza-like symptoms assessment scale)
• Time to resolution of nasal obstruction present at baseline to none (ie, score of 0 on influenza-like symptoms assessment scale)
• Time to absence of fever (oral temperature of ≤37.5°C for at least 2 consecutive readings at least 12 hours apart)
• Time to resumption of normal activity (ie, score of 0 on daily activities assessment scale)
• Frequency of viral respiratory infection complications of hospitalisation, death due to influenza-like illness or complications of influenza-like illness, and requirement for antibiotics to treat secondary bacterial infections

E.5.2.1

Timepoint(s) of evaluation of this end point

Subjects will be instructed to measure oral temperature using a digital thermometer 3 times daily and record these readings in the subject diary cards starting from Day 1 after the first dose of study drug until the EOT Visit.

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

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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)

E.8.2.2

Placebo

Yes

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Last Patient Last Visit (LPLV)

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

E.8.9.2

In all countries concerned by the trial months

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:

430

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

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

215

F.4.2

For a multinational trial

F.4.2.1

In the EEA

430

F.4.2.2

In the whole clinical trial

430

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)

Standard of Care, there are no plans for future treatment by the sponsor.

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

2014-09-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-05-14

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