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Trial registered on ANZCTR


Registration number
ACTRN12618001672246
Ethics application status
Approved
Date submitted
13/09/2018
Date registered
10/10/2018
Date last updated
20/01/2023
Date data sharing statement initially provided
1/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
'The effect of two treatment regimens: weekly rifapentine and isoniazid (3HP), compared to 4 months of daily rifampicin (4RIF) on adherence to treatment for latent tuberculosis
Scientific title
The effect of weekly rifapentine and isoniazid (3HP), compared to 4 months of daily rifampicin (4RIF) upon adherence with treatment for latent TB infection
Secondary ID [1] 295764 0
nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tuberculosis infection 309163 0
Latent tuberculosis infection 309164 0
Condition category
Condition code
Respiratory 308042 308042 0 0
Other respiratory disorders / diseases
Infection 308662 308662 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Combination therapy (‘3HP’) (intervention arm): 3 months of self-monitored once-weekly isoniazid (oral 900 mg) and weekly rifapentine (oral 900mg). Adherence will be monitored through once-weekly SMS or phone call sent by clinic staff. Patients will also attend the clinic at the end of the first month of treatment, to monitor for adverse events.
Intervention code [1] 312091 0
Treatment: Drugs
Comparator / control treatment
Rifampicin only therapy (‘4RIF’) (control arm): 4 months of daily rifampicin (oral up to 600 mg) (120-dose), with clinic visits and assessment by medical staff at baseline, at least once during treatment and at the end of treatment.

Rifampicin dosing (daily)
• 10 mg/kg (600 mg max) daily.

Source: Menzies et al, Ann Int Med 2008
Control group
Active

Outcomes
Primary outcome [1] 307032 0
To evaluate the proportion of patients completing treatment with a three-month (12-dose) regimen of weekly rifapentine and isoniazid (intervention arm), supported by SMS, compared to the 120 dose regimen of daily self-administered rifampicin (control arm) to treat LTBI.

Primary outcome:
Treatment completion. Treatment completion is defined as taking at least 90% of the doses within the treatment period plus one month, based upon monthly pill count by healthcare workers. i.e. for the 3HP arm, this comprises greater than or equal to 11 doses taken within 16 weeks of enrolment for the 3HP arm, For the 4RIF arm, this comprises at least 108 of 120 doses taken within 5 months.
Timepoint [1] 307032 0
Treatment completion will be accessed within the treatment period plus one month
Secondary outcome [1] 350447 0
To compare the incidence of adverse events, grade 3 or above, among patients in each arm.

Adverse events will be graded according to the National Cancer Institutes (US) Common Terminology Criteria for Adverse Events (CTCA) v4.03, June 2010. Hepatotoxicity will be managed according to American Thoracic Society (ATS) criteria for the management of hepatotoxicity due to TB medications.

The following procedures will be undertaken to monitor for adverse events in both groups:
At baseline :
o Baseline liver function tests and full blood count, to assess for underlying liver disease. If AST or ALT are above three times the upper limit of normal, then treatment will be suspended. Participants may be randomised prior to the receipt of the liver function test results, given the low proportion of abnormal liver function tests in this population. Abnormalities in haemoglobin, white cell count and platelets will be assessed by the treating physician. If patients have abnormal results, they will be managed by the treating physician.
o Baseline pregnancy test (BHCG) will be performed for women aged 15-45 years. If women of this age do not believe they are currently pregnant, then they may still be randomised. If patients are subsequently found to be pregnant, then they will be excluded from a modified intention to treat analysis.
If a woman becomes pregnant on study medication then the treatment will be ceased. She will then be offered serial symptom and chest radiographic monitoring every six months for the development of incident TB. For study subjects who were treated for LTBI following contact investigation, this will be for a total of 24 months after the last date of exposure to the infectious index patient.

At 1 month
o Patients will have a clinic visit and assessment by a physician. This will include a clinical assesment and blood tests, as follows.
o Liver function tests and full blood count will be undertaken routinely at the one month visit. Abnormalities will be managed by the treating physician. If AST or ALT are above 3 times the upper limit of normal and symptoms are present, or above 5 times the upper limit of normal without symptoms then the drug will be stopped.
o Pregnancy test (BHCG) will be performed for women aged 15-45 years
o Clinical assessment by treating physician: to identify any immunological, haematological, cardiac or other adverse events.

At end of treatment
o Patients will have a clinic visit and assessment by a physician. This will include a clinical assesment.
o Clinical assessment by the treating physician to identify the presence of any symptoms of toxicity.
o Patients aged 15-45 years who are female will be asked to perform a urinary pregnancy test for BHCG, or a blood test for BHCG

Unscheduled visit:
o If patients develop symptoms of an immunological reaction during treatment, they will be asked to suspend treatment.
Timepoint [1] 350447 0
12 months post-enrolment
Secondary outcome [2] 352442 0
To compare the cost-effectiveness of each regimen from health system and patient perspectives as a composite end point

Costs will be established from a societal and health care perspective
a. Patient perspective: Patient costs will be captured using a standardised questionnaire at the completion of treatment, based upon the WHO Patient Cost Survey 2017
b. Health system perspective: A health system questionnaire based upon the WHO Patient Cost Survey 2017 will be completed to determine the cost of treatment in each arm, including drug and treatment costs.
Timepoint [2] 352442 0
12 months post-enrolment
Secondary outcome [3] 352443 0
To compare patient acceptability of with these two reigmens, using standardised questionnaires.

Patient acceptability will be measured using standardised questionnaire adapted from the Program Acceptability questionnaire published from the Charles P. Felton National Tuberculosis Center looking at the Adherence to treatment for LTBI.
Timepoint [3] 352443 0
12 months post-enrolment

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Patients aged greater than or equal to 2 years old.
2. Eligible for treatment for LTBI, by either:
a. A TST of 10mm or greater, or
b. A positive Interferon Gamma Release Assay (IGRA), or
c. A negative TST in the presence of HIV infection in a contact of a person with confirmed tuberculosis infection.
3. Access to EITHER a mobile phone OR landline telephone (people who cannot use phone will be called instead of SMS).
Minimum age
2 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. Presumptive tuberculosis in which TB has not been excluded
2. Confirmed tuberculosis.
3. Treatment for active tuberculosis.
4. History of isoniazid and/or rifampicin resistant tuberculosis.
5. Tuberculosis in the source case (i.e. ‘index’ case) known to be resistant to either isoniazid or rifampicin at the time of enrolment.
6. History of hypersensitivity to isoniazid, rifapentine, or rifamycins.
7. Medical conditions requiring the use of medication interacting with study medication
8. Weight of the participant < 10.0 kg
9. Currently pregnant, planning to become pregnant, or breastfeeding.
10. Consideration for solid organ transplantation.
11. Unable to give informed consent
12. AST over 3 times the upper limit of normal.
13. Known porphyria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Logistic regression will be used to measure differences in the proportion of patients completing therapy. Multivariable logistic regression will be performed to establish the effect of patient and clinic characteristics upon the t the completion rates and presence and severity of adverse events. Statistical significance will be defined as P < 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/10/2018
Actual
25/07/2019
Date of last participant enrolment
Anticipated
30/11/2023
Actual
Date of last data collection
Anticipated
30/04/2024
Actual
Sample size
Target
210
Accrual to date
139
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11616 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 11617 0
Canterbury Hospital - Campsie
Recruitment hospital [3] 11618 0
Concord Repatriation Hospital - Concord
Recruitment hospital [4] 11619 0
Liverpool Hospital - Liverpool
Recruitment hospital [5] 11620 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [6] 11621 0
St George Hospital - Kogarah
Recruitment hospital [7] 11622 0
Prince of Wales Hospital - Randwick
Recruitment hospital [8] 11623 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 23661 0
2050 - Camperdown
Recruitment postcode(s) [2] 23662 0
2194 - Campsie
Recruitment postcode(s) [3] 23663 0
2139 - Concord
Recruitment postcode(s) [4] 23664 0
2170 - Liverpool
Recruitment postcode(s) [5] 23665 0
2010 - Darlinghurst
Recruitment postcode(s) [6] 23666 0
2217 - Kogarah
Recruitment postcode(s) [7] 23667 0
2031 - Randwick
Recruitment postcode(s) [8] 23668 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 300352 0
University
Name [1] 300352 0
University of Sydney
Country [1] 300352 0
Australia
Funding source category [2] 300830 0
Commercial sector/Industry
Name [2] 300830 0
Sanofi Aventis Australia Pty Ltd (Sanofi).
Country [2] 300830 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred Hospital, Sydney Local Health District
Address
Level 11, Kgv Building, Missenden Road, Camperdown New South Wales 2050
Country
Australia
Secondary sponsor category [1] 300234 0
None
Name [1] 300234 0
Address [1] 300234 0
Country [1] 300234 0
Other collaborator category [1] 280320 0
Commercial sector/Industry
Name [1] 280320 0
Sanofi Aventis Australia Pty Ltd (Sanofi).
Address [1] 280320 0
12-24 Talavera Road, Macquarie Park New South Wales 2113
Country [1] 280320 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301167 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 301167 0
Ethics committee country [1] 301167 0
Australia
Date submitted for ethics approval [1] 301167 0
02/07/2018
Approval date [1] 301167 0
01/04/2019
Ethics approval number [1] 301167 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86074 0
A/Prof Greg Fox
Address 86074 0
Central Clinical School
The Medical Foundation Building
The University of Sydney
92-94 Parramatta Road
Camperdown NSW 2050
Country 86074 0
Australia
Phone 86074 0
+61-2-90363123
Fax 86074 0
Email 86074 0
gregory.fox@sydney.edu.au
Contact person for public queries
Name 86075 0
Greg Fox
Address 86075 0
Central Clinical School
The Medical Foundation Building
The University of Sydney
92-94 Parramatta Road
Camperdown NSW 2050
Country 86075 0
Australia
Phone 86075 0
+61-2-90363123
Fax 86075 0
Email 86075 0
gregory.fox@sydney.edu.au
Contact person for scientific queries
Name 86076 0
Greg Fox
Address 86076 0
Central Clinical School
The Medical Foundation Building
The University of Sydney
92-94 Parramatta Road
Camperdown NSW 2050
Country 86076 0
Australia
Phone 86076 0
+61-2-90363123
Fax 86076 0
Email 86076 0
gregory.fox@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There is risk of patient being identified if IPD data of the trial is available.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.