InfluenzaPhase 4NCT01891084
The Benefit and Harm of Fever Suppression by Antipyretics in Influenza
A Phase 4 study testing Paracetamol and Backup NSAID ibuprofen in people with Influenza, run by The University of Hong Kong at 1 site in China.
Trial summary
The purpose of this study is to investigate the potential benefits and risks of antipyretics use in naturally occurring influenza virus infections in humans. Read more about this study
- Who is it for?
- Ages 18 to 30 yearsHealthy volunteers can take part
- Conditions the study is for
- Influenza
- What is being tested?
- Paracetamol and Backup NSAID ibuprofen
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 300 participants
- Where
- 1 siteChina
- Study dates
- Jul 2013to Dec 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 30 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Adults aged between 18-30
- Presenting with symptoms of acute URTI (at least two among the following symptoms: body temperature ≥37.8°C, cough, rhinorrhea, sore throat, headache, myalgia/arthralgia) within 48 hours of illness onset
- being tested positive with a QuickVue rapid influenza test
Who cannot join
- Allergic to paracetamol or any other antipyretics
- Have any underlying immunocompromized condition or be receiving immunosuppressive agents.
- Have any history of chronic liver disease, or any active lung, heart or renal diseases requiring regular medication.
Trial locations and contacts
1 site in 1 country.
China1 site
University Health Service, The Hong Kong Polytechnic University
Hong Kong, Hksar
About this study
Official title: A Randomized Controlled Trial on the Effect of Fever Suppression by Antipyretics on Influenza
The purpose of this study is to investigate the potential benefits and risks of antipyretics use in naturally occurring influenza virus infections in humans.
Read the detailed description
Background:
Being one of the commonest conditions encountered in modern medical practice, fever is commonly regarded as an illness that has to be treated, both by medical professionals and patients. However, objective and convincing evidence is lacking that naturally occurring fever is harmful, and there is growing evidence that fever may serve an important host defense mechanism in infections and the risks of its suppression may far outweigh its apparent benefits. In acute respiratory infections including influenza, antipyretics are commonly being prescribed as a symptomatic treatment. Evidence from different randomized controlled trials, however, had challenged the actual amount of clinical benefit achievable by fever suppression for improving the patients' comfort and behavior. On the other hand, evidence from animal and human challenge studies has suggested that antipyretic therapy may actually prolong the duration of illness, suppress humoral antibody response, and increase the level and duration of viral shedding.
The knowledge gap:
Most of the currently available evidence on the harms and benefits of antipyretic treatment of upper respiratory tract infections (URTIs) are from either experimental animal studies, or human challenge studies with various respiratory viruses, or from randomized controlled trials (RCTs) on patients with fever of presumed viral origin. There has yet been no RCT that has investigated on the effect of antipyretics on the clinical course, disease duration, and the pattern of viral shedding in naturally occurring acute URTIs of viral origin in humans. Whereas acute URTIs can be caused by a range of viral and non-viral causes, influenza virus infection is one of its leading cause, and its pathogenesis is relatively well understood compared to some other respiratory viruses.
Aim:
To investigate the potential benefits and risks of antipyretic use in naturally occurring influenza virus infections in humans.
Design and subjects:
The study is a double-blind, randomized controlled trial. Four hundred young adults aged 18-30 years will be recruited when they present with symptoms of acute respiratory infection within 48 hours of symptoms onset to university health clinics, and being tested positive with a QuickVue rapid influenza test. They will receive their clinical consultation and prescriptions as indicated as usual, and being randomized to receive either paracetamol or placebo, and given back-up NSAID for intolerable fever when required. Blood specimen, nasal and throat swabs will be collected on the same day (day 1). They will be followed-up on day 4, day 7 and day 10 for further collection of nasal and throat swabs, and on day 28 for a final blood taking. A symptom diary will be kept by each participant for 10 days for monitoring the clinical course of the infection.
Potential significance:
This will be the first RCT to investigate the effect of antipyretics on the clinical course, disease duration, and the pattern of viral shedding in naturally occurring influenza virus infection in humans. Findings from this study will have important contribution to our understanding on the role of fever as a host defense mechanism, and help to inform the appropriate clinical management approach in human influenza virus infection.
- Conditions
- Influenza
- Being tested
- Paracetamol, Placebo, Backup NSAID ibuprofen
- Keywords
- Influenza, Antipyretics, Fever
- Medical subject headings
- Influenza, Human, Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ParacetamolDrug
Also called Acetaminophen
Paracetamol 1 tablet (500mg) four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets (1gm) in each dose.
PlaceboDrug
(Identical-looking) Placebo 1 tablet four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets in each dose.
Backup NSAID ibuprofenDrug
Also called ibuprofen
Backup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable.
| Study group | Role | What they receive |
|---|---|---|
| Paracetamol | Active comparator | Paracetamol 1 tablet (500mg) four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets (1gm) in each dose. Precautionary statement (Do not exceed 8 tablets daily) will be printed on the dispensary label to avoid overdose.
Backup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable. Receives: Drug: Paracetamol; Drug: Backup NSAID ibuprofen |
| Placebo | Placebo comparator | (Identical-looking) Placebo 1 tablet four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets in each dose. Precautionary statement (Do not exceed 8 tablets daily) will be printed on the dispensary label to avoid overdose.
Backup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable Receives: Drug: Placebo; Drug: Backup NSAID ibuprofen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time from recruitment to illness resolution, defined as the time when fever and at least nine out of the ten influenza symptoms had subsided (graded as 0 by the patient) for a period of 24 hours.
Self-recording of temperature twice daily for ten days (D1-D10) will be performed and recorded using a standard tympanic thermometer provided for free to each participant. Participants will also keep symptom diary twice daily for 10 days (from D1-D10), using 4-point scale of 0, 1, 2, or 3 for absent, mild, moderate, or severe symptoms respectively. Mild symptoms are easily tolerated and do not interfere with any usual activities; moderate symptoms interfere with usual activities; Severe symptoms are such that the individual cannot carry out usual activities. Ten common influenza symptoms (including feverishness, chills, cough, rhinorrhea, sore throat, general fatigue, headache, myalgia/arthralgia, vomiting, and diarrhea) will be recorded.
Measured: 10 days
Time from recruitment to cessation of viral shedding, defined as the time when no virus is detected by RT-PCR from both nasal and throat swabs.
Nasal and throat swabs will be collected on D1, D4, D7 and D10 for viral identification and subtyping by viral culture, and viral load detection and quantification by quantitative RT-PCR.
Measured: 10 days
Secondary outcomes (7)
Time to cessation of illness and viral shedding from illness onset
Nasal and throat swabs will be collected on D1, D4, D7 and D10 for viral identification and subtyping by viral culture, and viral load detection and quantification by quantitative RT-PCR.
Measured: 10 days
The duration of individual symptoms
Participants will keep symptom diary twice daily for 10 days (from D1-D10), using 4-point scale of 0, 1, 2, or 3 for absent, mild, moderate, or severe symptoms respectively. Mild symptoms are easily tolerated and do not interfere with any usual activities; moderate symptoms interfere with usual activities; Severe symptoms are such that the individual cannot carry out usual activities. Ten common influenza symptoms (including feverishness, chills, cough, rhinorrhea, sore throat, general fatigue, headache, myalgia/arthralgia, vomiting, and diarrhea) will be recorded for ten days (D1-D10) and the duration of individual symptoms will be assessed.
Measured: 10 days
The incidence of secondary complications
The symptom diary will be checked on each follow-up (D4, D7, and D10) and collected on D10 by our research staff when the patient returns for follow-up. Symptoms of possible side effects related to treatment (including skin rashes, nausea, vomiting, jaundice, dark urine) will be recorded. The occurrence of any complications including otitis media, bronchitis, sinusitis, and pneumonia will be enquired during all follow-up sessions and recorded, and cross checking with the attending doctor will be done where necessary.
Measured: 10 days
The use of backup NSAID provided
Compliance on the trial medication (paracetamol/ placebo) and the use of the backup NSAID prescribed on a PRN basis will also be recorded in the symptom diary.
Measured: 10 days
Quality of life
A simple quality of life (QOL) assessment based on two simple validated 11- point visual analog scales will also be done daily by all participants form D1 - D10, one to rate their own ability for performing normal daily activities (0 = unable to perform normal activity to 10 = fully able to perform normal activity) , and the other for a self-perceived overall health status over a 24-hour (0 = worst health to 10 = best possible health), both of which will be compared to an initial assessment of their normal pre-influenza state reported on the D1 baseline. All participants will also be required to complete the Acute Form of the Short Form-36, version 2 (SF-36), in D1, D10 and D28, for a more details assessment on the changes of Health-related quality of life (HRQL) related to the episode of the influenza infection.
Measured: 10 days
Geometric mean rise in antibody titre against the infecting type or subtype of influenza virus
Paired sera will be collected on D1 and D28 for measuring the humoral antibody titres against the infecting type or subtype and other circulating strains of influenza viruses, and for evaluating the geometric mean titer rise from baseline to convalescence.
Measured: 28 days
The severity of individual symptoms
Participants will keep symptom diary twice daily for 10 days (from D1-D10), using 4-point scale of 0, 1, 2, or 3 for absent, mild, moderate, or severe symptoms respectively. Mild symptoms are easily tolerated and do not interfere with any usual activities; moderate symptoms interfere with usual activities; Severe symptoms are such that the individual cannot carry out usual activities. Ten common influenza symptoms (including feverishness, chills, cough, rhinorrhea, sore throat, general fatigue, headache, myalgia/arthralgia, vomiting, and diarrhea) will be recorded for ten days (D1-D10) and the severity of individual symptoms will be assessed.
Measured: 10 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2013 (estimated)
- Study startJul 2013
- Primary completionDec 2018
- Study completionDec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for InfluenzaStudies of the same condition, open and under way.
- More trials run by The University of Hong KongThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 300 participants (actual)
Sponsor and investigators
- Lead sponsor
- The University of Hong Kong
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Dennis Kai-Ming Ip, The University of Hong Kong
- Investigators
- Dennis KM Ip, MBBS, Principal investigator, The University of Hong Kong
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01891084
- Sponsor's protocol ID
- DKMI003.4
- Status last verified
- Jan 2019
- First submitted
- 19 Jun 2013
- Last updated
- 31 Jan 2019
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Controlled Trial on the Effect of Fever Suppression by Antipyretics on Influenza
- ClinicalTrials.gov ID
- NCT01891084
- Acronym / sponsor ID
- DKMI003.4
- Conditions
- Influenza
- Keywords
- Influenza, Antipyretics, Fever
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 300 participants (actual)
- Lead sponsor
- The University of Hong KongUniversity, hospital or other
- Study start
- Jul 2013 (actual)
- Primary completion
- Dec 2018 (actual)
- Study completion
- Dec 2018 (actual)
- First posted
- 2 Jul 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to investigate the potential benefits and risks of antipyretics use in naturally occurring influenza virus infections in humans.
Detailed description
Background:
Being one of the commonest conditions encountered in modern medical practice, fever is commonly regarded as an illness that has to be treated, both by medical professionals and patients. However, objective and convincing evidence is lacking that naturally occurring fever is harmful, and there is growing evidence that fever may serve an important host defense mechanism in infections and the risks of its suppression may far outweigh its apparent benefits. In acute respiratory infections including influenza, antipyretics are commonly being prescribed as a symptomatic treatment. Evidence from different randomized controlled trials, however, had challenged the actual amount of clinical benefit achievable by fever suppression for improving the patients' comfort and behavior. On the other hand, evidence from animal and human challenge studies has suggested that antipyretic therapy may actually prolong the duration of illness, suppress humoral antibody response, and increase the level and duration of viral shedding.
The knowledge gap:
Most of the currently available evidence on the harms and benefits of antipyretic treatment of upper respiratory tract infections (URTIs) are from either experimental animal studies, or human challenge studies with various respiratory viruses, or from randomized controlled trials (RCTs) on patients with fever of presumed viral origin. There has yet been no RCT that has investigated on the effect of antipyretics on the clinical course, disease duration, and the pattern of viral shedding in naturally occurring acute URTIs of viral origin in humans. Whereas acute URTIs can be caused by a range of viral and non-viral causes, influenza virus infection is one of its leading cause, and its pathogenesis is relatively well understood compared to some other respiratory viruses.
Aim:
To investigate the potential benefits and risks of antipyretic use in naturally occurring influenza virus infections in humans.
Design and subjects:
The study is a double-blind, randomized controlled trial. Four hundred young adults aged 18-30 years will be recruited when they present with symptoms of acute respiratory infection within 48 hours of symptoms onset to university health clinics, and being tested positive with a QuickVue rapid influenza test. They will receive their clinical consultation and prescriptions as indicated as usual, and being randomized to receive either paracetamol or placebo, and given back-up NSAID for intolerable fever when required. Blood specimen, nasal and throat swabs will be collected on the same day (day 1). They will be followed-up on day 4, day 7 and day 10 for further collection of nasal and throat swabs, and on day 28 for a final blood taking. A symptom diary will be kept by each participant for 10 days for monitoring the clinical course of the infection.
Potential significance:
This will be the first RCT to investigate the effect of antipyretics on the clinical course, disease duration, and the pattern of viral shedding in naturally occurring influenza virus infection in humans. Findings from this study will have important contribution to our understanding on the role of fever as a host defense mechanism, and help to inform the appropriate clinical management approach in human influenza virus infection.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Paracetamol | Active comparator | Drug: Paracetamol, Drug: Backup NSAID ibuprofenParacetamol 1 tablet (500mg) four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets (1gm) in each dose. Precautionary statement (Do not exceed 8 tablets daily) will be printed on the dispensary label to avoid overdose. Backup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable. |
| Placebo | Placebo comparator | Drug: Placebo, Drug: Backup NSAID ibuprofen(Identical-looking) Placebo 1 tablet four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets in each dose. Precautionary statement (Do not exceed 8 tablets daily) will be printed on the dispensary label to avoid overdose. Backup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable |
Who may qualify
- Ages
- 18 to 30 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Adults aged between 18-30
- Presenting with symptoms of acute URTI (at least two among the following symptoms: body temperature ≥37.8°C, cough, rhinorrhea, sore throat, headache, myalgia/arthralgia) within 48 hours of illness onset
- being tested positive with a QuickVue rapid influenza test
Key exclusion criteria (3 listed)
- Allergic to paracetamol or any other antipyretics
- Have any underlying immunocompromized condition or be receiving immunosuppressive agents.
- Have any history of chronic liver disease, or any active lung, heart or renal diseases requiring regular medication.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ParacetamolAlso: AcetaminophenParacetamol 1 tablet (500mg) four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets (1gm) in each dose. | Drug | Paracetamol |
| Placebo(Identical-looking) Placebo 1 tablet four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets in each dose. | Drug | Placebo |
| Backup NSAID ibuprofenAlso: ibuprofenBackup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable. | Drug | Paracetamol, Placebo |
Primary outcome
Time from recruitment to illness resolution, defined as the time when fever and at least nine out of the ten influenza symptoms had subsided (graded as 0 by the patient) for a period of 24 hours.
Time frame: 10 days
Self-recording of temperature twice daily for ten days (D1-D10) will be performed and recorded using a standard tympanic thermometer provided for free to each participant. Participants will also keep symptom diary twice daily for 10 days (from D1-D10), using 4-point scale of 0, 1, 2, or 3 for absent, mild, moderate, or severe symptoms respectively. Mild symptoms are easily tolerated and do not interfere with any usual activities; moderate symptoms interfere with usual activities; Severe symptoms are such that the individual cannot carry out usual activities. Ten common influenza symptoms (including feverishness, chills, cough, rhinorrhea, sore throat, general fatigue, headache, myalgia/arthralgia, vomiting, and diarrhea) will be recorded.
Time from recruitment to cessation of viral shedding, defined as the time when no virus is detected by RT-PCR from both nasal and throat swabs.
Time frame: 10 days
Nasal and throat swabs will be collected on D1, D4, D7 and D10 for viral identification and subtyping by viral culture, and viral load detection and quantification by quantitative RT-PCR.
7 secondary outcomes
Time to cessation of illness and viral shedding from illness onset
Time frame: 10 days
The duration of individual symptoms
Time frame: 10 days
The incidence of secondary complications
Time frame: 10 days
The use of backup NSAID provided
Time frame: 10 days
Quality of life
Time frame: 10 days
Geometric mean rise in antibody titre against the infecting type or subtype of influenza virus
Time frame: 28 days
The severity of individual symptoms
Time frame: 10 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2019.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dennis KM Ip, MBBS principal investigator
The University of Hong Kong
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Paracetamol and Backup NSAID ibuprofen in people with Influenza, run by The University of Hong Kong at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time from recruitment to illness resolution, defined as the time when fever and at least nine out of the ten influenza symptoms had subsided (graded as 0 by the patient) for a period of 24 hours. (time frame: 10 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2019.