Safety and Efficacy Study of Nitazoxanide in the Treatment of Acute Uncomplicated Influenza

• Sponsor: Romark Laboratories L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01227421
• Collaborator: (none)
• Enrollment: 624
• Location: 1
• Arms: 3
• Duration (Months): 5
• Patients Per Site Per Month: 125.8

Study Details

Study Description

Brief Summary

This is a randomized clinical trial designed to evaluate the safety/efficacy of two dosing regimens of oral nitazoxanide compared to placebo in the treatment of acute uncomplicated influenza in adults and adolescents. The investigators hypothesize that treatment with Nitazoxanide will reduce the duration of symptoms in patients with confirmed influenza infection. Secondarily, the investigators hypothesize that treatment with nitazoxanide will reduce the complications of influenza, severity of symptoms, time lost from work, time to return to normal daily activities.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Nitazoxanide; Drug: Nitazoxanide; Drug: Placebo	Phase 2/Phase 3

Detailed Description

A Randomized, Double-Blind, Placebo Controlled Study of Nitazoxanide in Adults and Adolescents with Acute Uncomplicated Influenza. The primary objectives of this study are to demonstrate the efficacy of nitazoxanide administered 300 mg two times per day for 5 days or 600 mg two times per day for 5 days in reducing the time to resolution of all clinical symptoms of influenza.

The study will also evaluate pharmacokinetics of nitazoxanide in a subset of 24 patients and the safety of the nitazoxanide regimen compared to a placebo via analysis of adverse events and laboratory safety tests.

Blood samples will be collected for all patients at baseline, day 7 and day 28, and for a subset of 24 patients aged 18-65 years (pharmacokinetics subset) on day 2. Urine samples will be collected at baseline and day 7. Nasal swabs will be collected at baseline and day 7 for all patients and on days 2, 3, 4 and 5 for a subset of patients (approximately 20% of patients).

Study Design

• Study Type: Interventional
• Actual Enrollment: 624 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled Study of Nitazoxanide in Adults and Adolescents With Acute Uncomplicated Influenza
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nitazoxanide, Placebo 300 mg nitazoxanide tablet and 1 placebo tablet twice daily for 5 days	Drug: Nitazoxanide; Tablets, 300 mg (one 300 mg tablet + 1 placebo tablet) with food twice daily for 5 days; Other Names: Alinia, NTZ
Active Comparator: Nitazoxanide, Nitazoxanide Two 300 mg nitazoxanide tablets(600mg) twice daily for 5 days	Drug: Nitazoxanide; Tablets, 600 mg (two 300 mg tablets) with food twice daily for 5 days; Other Names: Alinia, NTZ
Placebo Comparator: Placebo 2 placebo tablets twice daily for 5 days	Drug: Placebo; Tablets, (2 tablets) twice daily with food for 5 days; Other Names: Sugar pill

Outcome Measures

Primary Outcome Measures

1. Time to Resolution of All Clinical Symptoms of Influenza as Reported by the Subjects [Up to 28 days]

   The primary efficacy analysis for this study was to demonstrate the efficacy of Nitazoxanide (NTZ) administered as 300 mg b.i.d. for 5 days or 600 mg b.i.d. for 5 days in reducing the time to resolution of all clinical symptoms of influenza in patients with laboratory confirmed influenza infection

Secondary Outcome Measures

1. Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects [at least 28 days]

   Time in hours (Median and Interquartile range)

2. Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline [7 days]

   Change in viral titer presented as logarithm with base 10 (log10) 50% Tissue Culture Infective Dose (TCID50)

3. Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline [7 days]

   Change in viral titer logarithm with base 10 (log10) Ribonucleic Acid (RNA)copies

4. Time to Cessation of Viral Shedding Measure by 50% Tissue Culture Infective Dose (TCID50) [28 days]

   Median time in hours

5. Time to Return to Normal Daily Activities [28 days]

   Time in hours as reported by patient

6. Symptom Severity Score Hours [28 days]

   Sum of the symptom severity score hours from first dose to resolution of symptoms. Patients rated each symptom's severity on a score from 0 to 3 (0=absent, 1=mild, 2=moderate, 3=severe). Total symptom severity score hours were calculated by multiplying the sum of the severity scores by duration of symptoms.

7. Time Loss From Work [28 days]

   Time loss from work

8. Complications of Influenza [28 days]

   Proportion of patients with a complication of influenza during the course of the study

9. Influenza Antibody Response Titer Change: Influenza A 2009 H1N1 [28 days]

   change in influenza antibody titer for Influenza A 2009 H1N1

10. Influenza Antibody Response: Influenza A H3N2 [28 days]

    Change in antibody titer for Influenza A H3N2

11. Influenza Antibody Response: Influenza B [28 days]

    Change in antibody titer for Influenza B

12. Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A 2009 H1N1 [28 days]

    Proportion of patients seroprotected or seroconverted at day 28

13. Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A H3N2 [28 days]

    Proportion of patients seroprotected and seroconverted at day 28

14. Influenza Antibody Response: Seroprotection and Seroconversion for Influenza B [28 days]

    Proportion of patients seroprotected and seroconverted at day 28

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA

• age 12 to 65 years

• Presence of clinical signs, respiratory symptoms and constitutional symptoms compatible with influenza infection:

1. fever,

2. at least one of the following respiratory symptoms: cough, sore throat, nasal discharge, nasal congestion, sneezing.

3. At least one of the following constitutional symptoms: headache, myalgia, seats, chills, fatigue of any severity (mild, moderate, severe)

• Confirmation of Influenza A or B infection in the local community

• Onset of illness no more than 48 hours before presentation. 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 patient experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom.

• willing and able to comply with protocol requirements and provide informed consent

EXCLUSION CRITERIA:

• severity of illness requiring or anticipated to require in-hospital care

• High risk of complications from influenza as follows:

1. persons with asthma or other chronic pulmonary diseases

2. persons with hemodynamically significant cardiac disease

3. persons who have immunosuppressive disorders or receiving immunosuppressive therapy

4. persons infected with Human Immunodeficiency Virus (HIV)

5. persons with sickle cell anemia or other hemoglobinopathies

6. persons with diseases requiring long-term aspirin therapy

7. persons with chronic renal dysfunction

8. persons with liver disorders

9. Persons with cancer

10. Persons with chronic metabolic disease such as diabetes and inherited mitochondrial disorders

11. Persons with neuromuscular disorders, seizure disorders, or cognitive dysfunction

12. Residents of any age of nursing homes or long-term institutions.

• Females of child bearing age who are pregnant, breastfeeding or sexually active without birth control

• vaccination for influenza or H1N1 (Swine Flu) on or after August 1, 2010

• treatment with antiviral medication such as oseltamivir, zanamivir, amantadine, or rimantadine within 30 days of screening.

• Prior treatment with nitazoxanide within 30 days prior to screening.

• subjects with active respiratory allergies or expected to require anti-allergy medications during the study period.

• known sensitivity to nitazoxanide

• subjects unable to take oral medication

• subjects with chronic kidney or liver disease

• Presence of any other pre-existing chronic infection that is undergoing or requiring medical therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Health Sciences Research Center	Elmira	New York	United States	14901

Sponsors and Collaborators

• Romark Laboratories L.C.

Investigators

• Study Director: Jean-Francois Rossignol, M.D., Ph.D., Romark Laboratories L.C.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Romark Laboratories L.C.
• ClinicalTrials.gov Identifier: NCT01227421
• Other Study ID Numbers: RM08-3001
• First Posted: Oct 25, 2010
• Last Update Posted: Feb 7, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by Romark Laboratories L.C.: influenza
• Additional relevant MeSH terms: Influenza, Human; Nitazoxanide

Study Results

Participant Flow

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Period Title: Overall Study
STARTED	201	212	211
COMPLETED	190	194	201
NOT COMPLETED	11	18	10

Baseline Characteristics

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide	Total
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days	Total of all reporting groups
Overall Participants	201	212	211	624
Age (Count of Participants)
<=18 years	25 12.4%	21 9.9%	20 9.5%	66 10.6%
Between 18 and 65 years	176 87.6%	189 89.2%	188 89.1%	553 88.6%
>=65 years	0 0%	2 0.9%	3 1.4%	5 0.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31 (12.6)	31 (13.3)	32 (13.2)	31 (13.0)
Sex: Female, Male (Count of Participants)
Female	104 51.7%	122 57.5%	129 61.1%	355 56.9%
Male	97 48.3%	90 42.5%	82 38.9%	269 43.1%
Region of Enrollment (participants) [Number]
United States	201 100%	212 100%	211 100%	624 100%

Outcome Measures

1. Primary Outcome

Title	Time to Resolution of All Clinical Symptoms of Influenza as Reported by the Subjects
Description	The primary efficacy analysis for this study was to demonstrate the efficacy of Nitazoxanide (NTZ) administered as 300 mg b.i.d. for 5 days or 600 mg b.i.d. for 5 days in reducing the time to resolution of all clinical symptoms of influenza in patients with laboratory confirmed influenza infection
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

624 patients were enrolled based on inclusion/exclusion criteria. The primary efficacy analysis was conducted on the 257 patients with laboratory confirmed influenza.

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	89	89	79
Median (Inter-Quartile Range) [Hours]	109.1	116.7	95.5

2. Secondary Outcome

Title	Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects
Description	Time in hours (Median and Interquartile range)
Time Frame	at least 28 days

Outcome Measure Data

Analysis Population Description

624 patients were enrolled based on inclusion/exclusion criteria. Secondary efficacy analyses were conducted on the 257 patients with laboratory confirmed influenza.

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	89	89	79
Nasal Congestion	84	81	60
Runny Nose	48	42	43
Sore Throat	63	52	50
Cough	96	104	84
Headache	42	48	39
Myalgia	46	46	42
Fatigue	65	69	60
Sweats / Chills	36	36	36
Fever	36	31	36

3. Secondary Outcome

Title	Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline
Description	Change in viral titer presented as logarithm with base 10 (log10) 50% Tissue Culture Infective Dose (TCID50)
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Analysis conducted on 113 patients from intensive virologic follow up group with laboratory confirmed influenza

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	33	41	39
Day 2	-0.58 (1.4)	-0.03 (1.7)	-1.11 (1.7)
Day 3	-1.26 (1.8)	-1.21 (2.2)	-1.84 (1.7)
Day 4	-1.86 (1.9)	-1.65 (1.9)	-2.58 (1.3)
Day 5	-2.46 (1.8)	-2.41 (1.8)	-2.55 (1.4)
Day 7	-2.82 (1.6)	-2.79 (1.8)	-3.01 (1.4)

4. Secondary Outcome

Title	Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline
Description	Change in viral titer logarithm with base 10 (log10) Ribonucleic Acid (RNA)copies
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Analysis conducted on 113 patients from the intensive virologic follow up group with laboratory confirmed influenza

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	33	41	39
Day 2	-0.63 (1.4)	-0.22 (1.7)	-0.73 (1.5)
Day 3	-1.34 (1.4)	-0.92 (2.0)	-1.64 (1.7)
Day 4	-1.75 (1.5)	-1.63 (1.8)	-2.21 (1.4)
Day 5	-2.42 (1.5)	-2.49 (1.7)	-2.44 (1.4)
Day 7	-2.97 (1.3)	-2.82 (1.6)	-3.08 (1.3)

5. Secondary Outcome

Title	Time to Cessation of Viral Shedding Measure by 50% Tissue Culture Infective Dose (TCID50)
Description	Median time in hours
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Analysis performed on 107 patients from the intensive virologic follow up population with laboratory confirmed influenza

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	31	39	37
Median (Inter-Quartile Range) [Hours]	77.0	91.3	71.8

6. Secondary Outcome

Title	Time to Return to Normal Daily Activities
Description	Time in hours as reported by patient
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Analysis conducted on 257 patients with laboratory confirmed influenza

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	89	89	79
Median (Inter-Quartile Range) [Hours]	84.2	82.1	84.0

7. Secondary Outcome

Title	Symptom Severity Score Hours
Description	Sum of the symptom severity score hours from first dose to resolution of symptoms. Patients rated each symptom's severity on a score from 0 to 3 (0=absent, 1=mild, 2=moderate, 3=severe). Total symptom severity score hours were calculated by multiplying the sum of the severity scores by duration of symptoms.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Analysis conducted for 257 patients with laboratory confirmed influenza

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	89	89	79
Mean (Standard Deviation) [symptom score *hour]	1035.1 (765)	1220.9 (592)	1125.2 (681)

8. Secondary Outcome

Title	Time Loss From Work
Description	Time loss from work
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Analysis conducted on 241 patients with laboratory confirmed influenza excluding those who are unemployed

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	84	82	75
Mean (95% Confidence Interval) [days]	2.6	3.0	3.3

9. Secondary Outcome

Title	Complications of Influenza
Description	Proportion of patients with a complication of influenza during the course of the study
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study medication

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	201	212	211
Bronchitis	10 5%	3 1.4%	7 3.3%
Sinusitis	6 3%	6 2.8%	2 0.9%
Pneumonia	1 0.5%	2 0.9%	1 0.5%
Pleurisy	0 0%	1 0.5%	0 0%
Otitis	3 1.5%	3 1.4%	1 0.5%

10. Secondary Outcome

Title	Influenza Antibody Response Titer Change: Influenza A 2009 H1N1
Description	change in influenza antibody titer for Influenza A 2009 H1N1
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Member of the intensive virologic follow up group with laboratory confirmed Influenza A 2009 H1N1

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	26	34	36
Median (Inter-Quartile Range) [Fold change in antibody titer]	2	2	2

11. Secondary Outcome

Title	Influenza Antibody Response: Influenza A H3N2
Description	Change in antibody titer for Influenza A H3N2
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Members of the intensive virologic follow up group with laboratory confirmed influenza A H3N2

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	15	16	12
Median (Inter-Quartile Range) [Fold change in antibody titer]	8	16	16

12. Secondary Outcome

Title	Influenza Antibody Response: Influenza B
Description	Change in antibody titer for Influenza B
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Members of intensive virologic follow up group with laboratory confirmed Influenza B

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	21	20	17
Median (Inter-Quartile Range) [Fold change in antibody titer]	4	3	4

13. Secondary Outcome

Title	Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A 2009 H1N1
Description	Proportion of patients seroprotected or seroconverted at day 28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Members of intensive virologic follow up group with laboratory confirmed Influenza A 2009 H1N1

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	26	34	36
Seroprotected at day 28	11 5.5%	14 6.6%	12 5.7%
Seroconverted at day 28	11 5.5%	12 5.7%	11 5.2%

14. Secondary Outcome

Title	Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A H3N2
Description	Proportion of patients seroprotected and seroconverted at day 28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Members of intensive virologic follow up group with laboratory confirmed Influenza A H3N2

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	15	16	12
Seroprotected at day 28	14 7%	12 5.7%	12 5.7%
Seroconverted at day 28	13 6.5%	12 5.7%	12 5.7%

15. Secondary Outcome

Title	Influenza Antibody Response: Seroprotection and Seroconversion for Influenza B
Description	Proportion of patients seroprotected and seroconverted at day 28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Members of intensive virologic follow up group with laboratory confirmed Influenza B

Arm/Group Title	Nitazoxanide	Placebo	Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days	placebo tablet twice daily with food for 5 days	2X 300 mg controlled release tablet twice daily with food for five days
Measure Participants	21	20	17
Seroprotected at day 28	14 7%	13 6.1%	13 6.2%
Seroconverted at day 28	12 6%	10 4.7%	13 6.2%

Adverse Events

Arm/Group Title	Nitazoxanide		Placebo		Nitazoxanide
Arm/Group Description	300 mg nitazoxanide twice daily with food for 5 days		placebo tablet twice daily with food for 5 days		2X 300 mg controlled release tablet twice daily with food for five days
All Cause Mortality
	Nitazoxanide		Placebo		Nitazoxanide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Nitazoxanide		Placebo		Nitazoxanide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/201 (0%)		1/212 (0.5%)		1/211 (0.5%)
Respiratory, thoracic and mediastinal disorders
moderate pneumonia	0/201 (0%)	0	0/212 (0%)	0	1/211 (0.5%)	1
respiratory syncytial virus type A	0/201 (0%)	0	1/212 (0.5%)	1	0/211 (0%)	0
Other (Not Including Serious) Adverse Events
	Nitazoxanide		Placebo		Nitazoxanide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/201 (5%)		7/212 (3.3%)		25/211 (11.8%)
Gastrointestinal disorders
Mild Diarrhea	4/201 (2%)	4	7/212 (3.3%)	7	17/211 (8.1%)	17
Renal and urinary disorders
Chromaturia	6/201 (3%)	6	0/212 (0%)	0	8/211 (3.8%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Presentation and/or publication is encouraged provided the Sponsor is notified in advance and given the opportunity to review the manuscript or abstract 30 days prior to its submission for presentation at a scientific meeting or for publication in a scientific journal. The investigators will have complete autonomy regarding the content and wording including the decision of whether or not to publish.