Clinical Trials Register

Summary
EudraCT Number:	2013-003933-14
Sponsor's Protocol Code Number:	RM08-3002
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-02
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2013-003933-14

A.3

Full title of the trial

A Phase III Randomized Double-Blind Placebo Controlled Trial to Evaluate the Efficacy and Safety of Nitazoxanide and Nitazoxanide plus Oseltamivir in the Treatment of Acute Uncomplicated Influenza

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

RM08-3002

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	Romark Laboratories L.C.
B.1.3.4	Country	United States
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	Romark Laboratories L.C.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Romark Laboratories L.C.
B.5.2	Functional name of contact point	Yelen Concepcion
B.5.3	Address:
B.5.3.1	Street Address	3000 Bayport Drive, Suite 200
B.5.3.2	Town/ city	Tampa, Florida
B.5.3.3	Post code	33607
B.5.3.4	Country	United States
B.5.4	Telephone number	+1813282 8544
B.5.5	Fax number	+1813282 1162
B.5.6	E-mail	Yelen.Concepcion@romark.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	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	Nitazoxanide
D.3.2	Product code	NTZ
D.3.4	Pharmaceutical form	Film-coated 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	NITAZOXANIDE
D.3.9.1	CAS number	55981-09-4
D.3.9.3	Other descriptive name	PH-5776, NTZ or Alinia®
D.3.9.4	EV Substance Code	SUB09311MIG
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	300
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.IMP: 2
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	Tamiflu®
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Oseltamivir
D.3.2	Product code	OST
D.3.4	Pharmaceutical form	Capsule, hard
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	OSELTAMIVIR
D.3.9.1	CAS number	196618-13-0
D.3.9.4	EV Substance Code	SUB03553MIG
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	75
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
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 uncomplicated influenza

E.1.1.1

Medical condition in easily understood language

flue

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10022000
E.1.2	Term	Influenza
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

- Evaluate the effect of NTZ administered 600 mg orally b.i.d. for 5 days on time to alleviation of symptoms of acute uncomplicated influenza compared to that of a placebo.
- Evaluate the effect of combination therapy with NTZ 600 mg plus OST 75 mg administered orally b.i.d. for 5 days on time to alleviation of symptoms of acute uncomplicated influenza compared to that of monotherapy with NTZ 600 mg b.i.d. for 5 days and monotherapy with OST 75 mg b.i.d. for 5 days

E.2.2

Secondary objectives of the trial

a) Change in influenza virus titer (by TCID50) and viral RNA titer (by RT-PCR) over time ;
b) Time to cessation of shedding of infectious virus (by TCID50) and of viral RNA (by RT-PCR);
c) Time to return to normal activity;
d) Time to alleviation of each individual symptom;
e) Severity of disease expressed as “score-hours” (symptom score multiplied by duration of symptom) using data collected from patient diaries;
f) Complications of influenza including physician-diagnosed secondary illnesses, antibiotic use and hospitalizations;
g) Time lost from work; and
h) Selection of drug-resistant influenza virus.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 13 to 65 years
2. Presence of clinical signs and/or symptoms consistent with an acute illness compatible with influenza infection (each of the following is required):
a) oral temperature of ≥100.4 °F or ≥38 °C (obtained in office or self-measured within 12 hours prior to screening – if self-measured, subject must also have taken an antipyretic within 4 hours prior to screening) AND
b) at least one of the following respiratory symptoms (cough, sore throat, nasal obstruction,) that is considered by the patient to be moderate or severe (greater than mild severity), AND
c) one of the following constitutional symptoms (fatigue, headache, myalgia, feverishness) that is considered by the patient to be moderate or severe (greater than mild severity).
3. Confirmation of influenza A or B infection in the local community by one of the following means: a) the institution's local laboratory, or b) the local public health system or c) the national public health system or d) a laboratory of a recognized national or multinational influenza surveillance scheme.
4. Onset of illness no more than 48 hours before enrollment in the trial.
Note: Time of onset of illness is defined as either the earlier of:
(1) the time when the temperature was first measured as elevated, OR
(2) the time when the subject experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom.
5. Willing and able to provide written informed consent (including assent by legal guardian if under 18 years of age) and comply with the requirements of the protocol, including completion of the patient diary.

E.4

Principal exclusion criteria

1. Severity of illness requiring or anticipated to require in-hospital care or subject defined as being at high risk of complications from influenza infection according to the IDSA guidelines for seasonal influenza in adults and children (CID 2009:48) or current CDC criteria.
Current criteria for persons 12-65 years of age who are at risk of influenza complications include (list to be reviewed and updated as required prior to initiation of the study and at least monthly during the study):
 Persons with asthma or other chronic pulmonary diseases, such as cystic fibrosis in children or chronic obstructive pulmonary disease in adults.
 Persons with hemodynamically significant cardiac disease.
 Persons who have immunosuppressive disorders or who are receiving immunosuppressive therapy.
 HIV-infected persons.
 Persons with sickle cell anemia or other hemoglobinopathies.
 Persons with diseases requiring long-term aspirin therapy, such as rheumatoid arthritis or Kawasaki disease.
Persons with chronic renal dysfunction.
 Persons with liver disorders.
 Persons with cancer.
 Persons with chronic metabolic disease, such as diabetes mellitus, inherited metabolic disorders and mitochondrial disorders.
 Persons with neuromuscular disorders, seizure disorders or cognitive dysfunction that may compromise the handling of respiratory secretions.
 Residents of any age of nursing homes or other long-term care institutions.
 Persons who are morbidly obese (Body Mass Index ≥40)
 American Indians (seemed to be at higher risk of complications last flu season)
 Alaskan natives (seemed to be at higher risk of complications last flu season)
2. Females of childbearing potential who are either pregnant, breast-feeding or are sexually active without the use of birth control. Female patients of child-bearing potential that are sexually active must have a negative baseline pregnancy test and must agree to continue an acceptable method of birth control for the duration of the study and for 1 month post-treatment. A double barrier method, oral birth control pills administered for at least 2 monthly cycles prior to study drug administration, an IUD, or medroxyprogesterone acetate administered intramuscularly for a minimum of one month prior to study drug administration are acceptable methods of birth control for inclusion into the study. Female subjects are considered of childbearing potential unless they are postmenopausal (absence of menstrual bleeding for 1 year - or 6 months if laboratory confirmation of hormonal status), or have had a hysterectomy, bilateral tubular ligation or bilateral ovariectomy.
3. Vaccination for seasonal influenza on or after (i) August 1, 2012 in the case of subjects enrolled during the 2012/2013 flu season in the United States, (ii) February 1, 2013 in the case of subjects enrolled during the 2013 flu season in Australia or New Zealand, (iii) August 1, 2013 in the case of subjects enrolled during the 2013/2014 flu season in the United States, Canada, Europe, or other countries in the Northern Hemisphere, or
February 1, 2014 in the case of subjects enrolled during the 2014 flu season in Australia or
New Zealand.
4. Receipt of any dose of NTZ, OST, zanamivir, amantadine or rimantadine within 30 days prior to screening.
5. Prior treatment with any investigational drug therapy within 30 days prior to screening.
6. Subjects with active respiratory allergies or subjects expected to require anti-allergy medications during the study period for respiratory allergies.
7. Known sensitivity to NTZ or any of the excipients comprising the NTZ tablets.
8. Known sensitivity to OST or any of the excipients comprising the OST capsules.
9. Subjects unable to take oral medications.
10. Subject has chronic kidney or liver disease (including Hepatitis A, B or C) or known impaired hepatic and/or renal function.
11. Presence of any other pre-existing chronic infection that is undergoing or requiring medical therapy.

E.5 End points

E.5.1

Primary end point(s)

Time to alleviation of all clinical symptoms of influenza as reported by the subjects.

E.5.1.1

Timepoint(s) of evaluation of this end point

Blood samples will be collected for all subjects at baseline, day 7 and day 28. Urine samples will be collected at baseline and day 7. Nasopharyngeal swabs will be collected at baseline, days 7, 14 and 28 for all subjects and on days 2, 3, 4 and 5 for a subset of subjects (≥20%). A blood sample will be collected on days 3 and 5 for the same subset of subjects for pharmacokinetics.

E.5.2

Secondary end point(s)

i. Change in influenza virus titer (TCID50)
ii. Time to cessation of viral shedding
iii. Time to return to normal activity
iv. Time to alleviation of each individual symptom
v. Severity of disease expressed in “score-hours” (symptom scores multiplied by duration of symptoms)
vi. Complications of influenza including physician-diagnosed secondary illnesses, antibiotic use and hospitalizations
vii. Time lost from work
viii. Selection of oseltamivir or tizoxanide-resistant influenza virus

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

Yes

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

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

New Zealand

Australia

United States

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

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

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	40
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	20
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	60
F.4.2	For a multinational trial
F.4.2.1	In the EEA	60
F.4.2.2	In the whole clinical trial	1800

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

2013-11-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-09

P. End of Trial
P.	End of Trial Status	Completed

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