Typhoid FeverPhase 4NCT02224040
Typhoid Fever: Combined vs. Single Antibiotic Therapy
A Phase 4 study testing ceftriaxone, ceftriaxone and azithromycin and azithromycin in people with Typhoid Fever, run by Sheba Medical Center at 1 site in Nepal.
Trial summary
The current study goal is to examine the effect of Cephalosporins, Azithromycin and the combination of both on typhoid fever therapy in endemic population. The investigator's hypothesize that the combination of azithromycin and ceftriaxone may prove superior to each drug, ceftriaxone or azithromycin, alone. Read more about this study
- Who is it for?
- Ages 2 to 80 years
- Conditions the study is for
- Typhoid Fever
- What is being tested?
- ceftriaxone, ceftriaxone and azithromycin and azithromycin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 1 siteNepal
- Study dates
- Aug 2013to Aug 2015
- 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 2 to 80 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Blood culture-proven typhoid fever (S. typhi or S. paratyphi)
- Signed informed consent to participate in the study.
Who cannot join
- Allergy to ceftriaxone or macrolides
- Major typhoid fever-associated complications
- Inability to swallow oral medication
- Underlying illness
- Pregnancy
- Lactation
- Treatment within the past 4 days with an antibiotic that may be effective against typhoid fever
Trial locations and contacts
1 site in 1 country.
Nepal1 site, 1 recruiting
- Recruiting
Dhulikhel hospital
Dhulikhel, 11008
Sudeep Shrestha, M.D, itsactionpotential@gmail.com
About this study
Official title: Typhoid Fever: Combined vs. Single Antibiotic Therapy. A Prospective Randomized Controlled Study in Nepal.
The current study goal is to examine the effect of Cephalosporins, Azithromycin and the combination of both on typhoid fever therapy in endemic population.
The investigator's hypothesize that the combination of azithromycin and ceftriaxone may prove superior to each drug, ceftriaxone or azithromycin, alone.
Read the detailed description
Typhoid Fever is a highly prevalent infection in the Indian subcontinent. Due to multidrug resistant strains in these areas, third generation cephalosporins, such as ceftriaxone, are the treatment of choice. However, the latter regimen exhibits a slow response with mean time of 5 to 7 days or even longer to defervescence, which could be attributed to poor penetration capability of the drug into cells, and thus difficulty to eradicate the bacteria from the intracellular niche.
Attempts have been made to overcome this setback by introducing alternative antibiotic regimens, such as azithromycin. However studies comparing between azithromycin and a third-generation cephalosporin for the treatment of typhoid fever in adult population in the Indian subcontinent are lacking.
Over the last few years our approach towards non-immunized travelers, who acquired typhoid fever in the Indian subcontinent, was to administer a combination therapy of intravenous ceftriaxone with oral azithromycin. The rationale of this dual regimen was its pharmacokinetic profile, which suggests a complimentary action of the two agents - ceftriaxone on the extracellular compartment and azithromycin on the intracellular compartment. Moreover, in our clinical experience, preliminary published data has proven combination therapy significantly superior to ceftriaxone alone albeit in a small group of travelers.
In the current study the investigators intend to compare the efficacy of ceftriaxone vs. azithromycin and vs. combined therapy of both agents for the treatment of uncomplicated typhoid fever in terms of time to defervescence.
4 different treatment strategies will be examined (as mentioned in the arm section). All participants will be checked for vital signs, will undergo physical examination, ECG, laboratory testing, blood, urine and stool culture and tests for susceptibility to antibiotics.
- Conditions
- Typhoid Fever
- Being tested
- ceftriaxone, ceftriaxone and azithromycin, azithromycin, azithromycin and cefixime
- Medical subject headings
- Typhoid Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ceftriaxoneDrug
ceftriaxone and azithromycinDrug
azithromycinDrug
azithromycin and cefiximeDrug
| Study group | Role | What they receive |
|---|---|---|
| Ceftriaxone I.V | Experimental | The participants in this arm will receive the following drug and dosage: adult: Ceftriaxone intravenous 2 gr once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day (maximum dose 2.5 g/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period). Receives: Drug: ceftriaxone |
| Ceftriaxone I.V+Azithromycin P.O | Experimental | The participants in this arm will receive the following drugs and dosages: adult: 2 g intravenous ceftriaxone and 500 mg oral azithromycin once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day and oral 20 mg/kg azithromycin suspension once a day. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period). Receives: Drug: ceftriaxone and azithromycin |
| Azithromycin P.O | Experimental | The participants in this arm will receive the following drug and dosage: adult: azithromycin oral 500 mg once a day. Pediatric: oral 20 mg/kg azithromycin suspension once a day (maximum dose 1000 mg/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Receives: Drug: azithromycin |
| Azithromycin P.O+Cefixime P.O | Experimental | The participants in this arm will receive the following drugs and dosages: adult: 500 mg azithromycin and 400 mg cefixime. Pediatric: oral 20 mg/kg azithromycin suspension once a day and oral 10 mg/kg cefixime. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Receives: Drug: azithromycin and cefixime |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fever clearance time
Time to fever clearance will be measured and will be defined as an oral temperature that is below 37.50 C
Measured: One month
Secondary outcomes (1)
Treatment failure
Secondary endpoints will be treatment failure (defined as the need to switch antibiotic treatment according to physician's decision such as high grade fever after 5 days of treatment, appearance of typhoid complications under the treatment), clearance of bacteremia, development of typhoid-related complications, late relapse, fecal carriage and adverse drug reactions.
Measured: One month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2014 (estimated)
- Study startAug 2013
- Primary completionDec 2014 (estimated)
- Study completionAug 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Typhoid FeverStudies of the same condition, open and under way.
- More trials run by Sheba Medical CenterThe 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
- None (open label)
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sheba Medical Center
- Sponsor type
- Other government
- Responsible party
- Principal investigator, Prof. Eli Schwartz MD, DTMH, Sheba Medical Center
- Investigators
- Eli Schwartz, MD, DTMH, Principal investigator, Sheba Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02224040
- Sponsor's protocol ID
- 64/12
- Status last verified
- Aug 2014
- First submitted
- 21 Aug 2014
- Last updated
- 27 Aug 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Zmora N, Shrestha S, Neuberger A, Paran Y, Tamrakar R, Shrestha A, Madhup SK, Bedi TRS, Koju R, Schwartz E. Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults. PLoS Negl Trop Dis. 2018 Apr 23;12(4):e0006380. doi: 10.1371/journal.pntd.0006380. eCollection 2018 Apr.
PubMed 29684022
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Typhoid Fever: Combined vs. Single Antibiotic Therapy. A Prospective Randomized Controlled Study in Nepal.
- ClinicalTrials.gov ID
- NCT02224040
- Acronym / sponsor ID
- 64/12
- Conditions
- Typhoid Fever
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 120 participants (estimated)
- Lead sponsor
- Sheba Medical CenterOther government
- Study start
- Aug 2013
- Primary completion
- Dec 2014 (estimated)
- Study completion
- Aug 2015 (estimated)
- First posted
- 22 Aug 2014 (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 current study goal is to examine the effect of Cephalosporins, Azithromycin and the combination of both on typhoid fever therapy in endemic population.
The investigator's hypothesize that the combination of azithromycin and ceftriaxone may prove superior to each drug, ceftriaxone or azithromycin, alone.
Detailed description
Typhoid Fever is a highly prevalent infection in the Indian subcontinent. Due to multidrug resistant strains in these areas, third generation cephalosporins, such as ceftriaxone, are the treatment of choice. However, the latter regimen exhibits a slow response with mean time of 5 to 7 days or even longer to defervescence, which could be attributed to poor penetration capability of the drug into cells, and thus difficulty to eradicate the bacteria from the intracellular niche.
Attempts have been made to overcome this setback by introducing alternative antibiotic regimens, such as azithromycin. However studies comparing between azithromycin and a third-generation cephalosporin for the treatment of typhoid fever in adult population in the Indian subcontinent are lacking.
Over the last few years our approach towards non-immunized travelers, who acquired typhoid fever in the Indian subcontinent, was to administer a combination therapy of intravenous ceftriaxone with oral azithromycin. The rationale of this dual regimen was its pharmacokinetic profile, which suggests a complimentary action of the two agents - ceftriaxone on the extracellular compartment and azithromycin on the intracellular compartment. Moreover, in our clinical experience, preliminary published data has proven combination therapy significantly superior to ceftriaxone alone albeit in a small group of travelers.
In the current study the investigators intend to compare the efficacy of ceftriaxone vs. azithromycin and vs. combined therapy of both agents for the treatment of uncomplicated typhoid fever in terms of time to defervescence.
4 different treatment strategies will be examined (as mentioned in the arm section). All participants will be checked for vital signs, will undergo physical examination, ECG, laboratory testing, blood, urine and stool culture and tests for susceptibility to antibiotics.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Ceftriaxone I.V | Experimental | Drug: ceftriaxoneThe participants in this arm will receive the following drug and dosage: adult: Ceftriaxone intravenous 2 gr once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day (maximum dose 2.5 g/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period). |
| Ceftriaxone I.V+Azithromycin P.O | Experimental | Drug: ceftriaxone and azithromycinThe participants in this arm will receive the following drugs and dosages: adult: 2 g intravenous ceftriaxone and 500 mg oral azithromycin once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day and oral 20 mg/kg azithromycin suspension once a day. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period). |
| Azithromycin P.O | Experimental | Drug: azithromycinThe participants in this arm will receive the following drug and dosage: adult: azithromycin oral 500 mg once a day. Pediatric: oral 20 mg/kg azithromycin suspension once a day (maximum dose 1000 mg/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. |
| Azithromycin P.O+Cefixime P.O | Experimental | Drug: azithromycin and cefiximeThe participants in this arm will receive the following drugs and dosages: adult: 500 mg azithromycin and 400 mg cefixime. Pediatric: oral 20 mg/kg azithromycin suspension once a day and oral 10 mg/kg cefixime. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. |
Who may qualify
- Ages
- 2 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- Blood culture-proven typhoid fever (S. typhi or S. paratyphi)
- Signed informed consent to participate in the study.
Key exclusion criteria (7 listed)
- Allergy to ceftriaxone or macrolides
- Major typhoid fever-associated complications
- Inability to swallow oral medication
- Underlying illness
- Pregnancy
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 |
|---|---|---|
| ceftriaxone | Drug | Ceftriaxone I.V |
| ceftriaxone and azithromycin | Drug | Ceftriaxone I.V+Azithromycin P.O |
| azithromycin | Drug | Azithromycin P.O |
| azithromycin and cefixime | Drug | Azithromycin P.O+Cefixime P.O |
Primary outcome
Fever clearance time
Time frame: One month
Time to fever clearance will be measured and will be defined as an oral temperature that is below 37.50 C
1 secondary outcome
Treatment failure
Time frame: One month
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2014.
- Derived from this study: PubMed 29684022Zmora N, Shrestha S, Neuberger A, Paran Y, Tamrakar R, Shrestha A, Madhup SK, Bedi TRS, Koju R, Schwartz E. Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults. PLoS Negl Trop Dis. 2018 Apr 23;12(4):e0006380. doi: 10.1371/journal.pntd.0006380. eCollection 2018 Apr.
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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.
Eli Schwartz, MD, DTMH principal investigator
Sheba Medical Center
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 ceftriaxone, ceftriaxone and azithromycin and azithromycin in people with Typhoid Fever, run by Sheba Medical Center at 1 site in Nepal.
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 2 inclusion and 7 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: status not confirmed, as of the sponsor's last update on 27 Aug 2014. 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 Nepal. 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. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Eli Schwartz, MD, DTMH (+97235308456, Eli.schwartz@sheba.health.gov.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fever clearance time (time frame: One month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02224040, which also lists 1 linked publication.
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 27 Aug 2014.