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Trial registered on ANZCTR


Registration number
ACTRN12616000215426
Ethics application status
Approved
Date submitted
29/01/2016
Date registered
17/02/2016
Date last updated
Type of registration
Prospectively registered

Titles & IDs
Public title
The V-QUIN MDR TRIAL: A randomized controlled trial of six months of daily levofloxacin for the prevention of tuberculosis among household contacts of patients with multi-drug resistant tuberculosis
Scientific title
The V-QUIN MDR TRIAL: A randomized controlled trial of six months of daily levofloxacin for the prevention of tuberculosis among household contacts of patients with multi-drug resistant tuberculosis
Secondary ID [1] 288194 0
NHMRC APP#1081443
Universal Trial Number (UTN)
U1111-1177-9052
Trial acronym
The V-QUIN MDR Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
tuberculosis 297100 0
tuberculosis, multi-drug resistant 297101 0
Condition category
Condition code
Infection 297340 297340 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Six months of daily oral levofloxacin (dosing: 12.00-24.99kg: 250mg once daily; 25.00-49.99kg: 500mg once daily, 50kg and above: 750mg once daily).
Compliance monitoring is based on pill count and self-report
Screening for incident disease is performed for 30 months after enrollment, at 6, 12, 18, 24 and 30 months. Screening includes clinical assessment and chest radiography. Additional telephone-based symptom screening will be performed at 9, 15, 21 and 27 months, with clinical evaluation if symptoms are present (including new cough or sputum production for 2 weeks or more) .
No maximum duration of therapy. Patients will continue to receive treatment beyond 180 days, if they have not completed the requisite number of doses by that time.
Intervention code [1] 293497 0
Treatment: Drugs
Intervention code [2] 293781 0
Prevention
Intervention code [3] 293933 0
Early detection / Screening
Comparator / control treatment
Six months of daily oral placebo.
A matching placebo is used that is similar in size, colour and shape to the active drug.
Control group
Placebo

Outcomes
Primary outcome [1] 296900 0
The incidence ratio, that is, the ratio of the incidence rate of bacteriologically-confirmed TB among subjects in the active levofloxacin group to the incidence rate in the placebo control group.

In adults, aged 15 and above, bacteriologically-confirmed TB is defined as a positive identification of Mycobacterium tuberculosis by culture, Xpert or another PCR-based diagnostic test in a contact with clinical or radiological evidence of disease.

In adults, aged 15 and above, a result will be considered positive if: (a) at least one sample of sputum, or other body fluid or tissue is positive by culture, Xpert or another PCR-based diagnostic test; or (b) at least 2 samples of sputum or other body fluid or tissue are positive by smear)
* AFB-positive TB alone on a single smear (that is not positive on culture, Xpert or another PCR-based diagnostic test) would not be considered “bacteriologically confirmed”.
* If available cultures are contaminated or negative, then two samples that are both AFB-positive will satisfy the definition of “bacteriologically confirmed”.
* Extrapulmonary TB will be considered “bacteriologically confirmed” if based upon either: additional investigations seeking microbiological confirmation (e.g. lymph node aspirate, CSF) with either a positive culture, Xpert or another PCR-based diagnostic test; OR two or more samples that are AFB positive on smear.

Bacteriologically confirmed TB should be classified as pulmonary, extra-pulmonary or both.
Timepoint [1] 296900 0
Within 30 months of randomization
Secondary outcome [1] 319647 0
The incidence ratio of all forms of TB (bacteriologically confirmed or clinically probable) in the active levofloxacin group compared to that of the placebo group

The definition of bacteriological confirmation is given above.
Probable clinical TB: Known exposure to TB plus “Well-defined” clinical evidence AND supportive radiological or laboratory evidence of pulmonary or extra-pulmonary disease in a contact that is not bacteriologically-confirmed.

The End Point Review Panel will reach a conclusion about the diagnosis of clinically probable TB on the basis of the following, in adults:

* Well-defined clinical evidence of clinically probable TB would include any TB-related symptoms of over 14 days’ duration that was not improving (e.g. cough, fever, night sweats, lethargy) or sign (documented weight loss, moderate or severe malnutrition, neck swelling or other clinical features of EPTB).

* In contacts with no clinical evidence, chest radiography is consistent with intrathoracic disease due to Mycobacterium tuberculosis. In contacts with no clinical evidence, radiological evidence to support probable pulmonary TB would only include marked abnormality on CXR.

* AFB-positive alone on smear that is not culture or Xpert positive would be considered as supportive laboratory evidence.

* Probable EPTB will be based upon either additional investigations seeking microbiological confirmation (e.g. lymph node aspirate, CSF) or supportive clinical/radiological findings from laboratory investigation or imaging (e.g. pleural aspirate or ascitic tap, X-ray)

* Any form of EPTB with supportive evidence (see above) that is not also bacteriologically confirmed would be considered as Clinically Probable TB.

Clinical TB should be classified as pulmonary, extra-pulmonary or both.
Timepoint [1] 319647 0
Within 30 months of randomization
Secondary outcome [2] 319648 0
The incidence ratio of all forms of TB (bacteriologically confirmed or clinically probable) in the active levofloxacin group compared to that of the placebo group among subjects who completed therapy

The definitions of bacteriologically confirmed and clinically probable TB are given in the previous secondary outcome.

A contact will be defined to have completed the study therapy if they complete 80% or more of the total prescribed doses within a total period of 30 weeks after randomization. This will be confirmed by unused tablet return.
Timepoint [2] 319648 0
Within 30 months of randomization
Secondary outcome [3] 319649 0
The incidence ratio of bacteriologically confirmed TB in the active levofloxacin group, compared to that of the placebo group, among contacts of MDR-TB patients with fluoroquinolone susceptible disease.

Bacteriologically confirmed TB is defined above.
Timepoint [3] 319649 0
Within 30 months of randomization
Secondary outcome [4] 319650 0
The proportion of participants in each group discontinuing treatment owing to adverse events

This will be assessed by participant self-report, either by telephone or in person.
Timepoint [4] 319650 0
During treatment with levofloxacin or placebo.
Secondary outcome [5] 319651 0
The proportion of participants in each group completing six months (180 doses) of preventive therapy

Adherence will be assessed at the end of each month of treatment with pill counts. Standardized questionnaires developed for this study will also be used to assess compliance. Contacts will be considered non-adherent if they fail to complete 80% of the total prescribed doses (i.e. fail to complete 36 doses or more) within 270 days after commencing therapy.
Timepoint [5] 319651 0
270 days after randomization
Secondary outcome [6] 319652 0
The ratio of the incidence of grade 3 or 4 adverse events in the active levofloxacin group, compared to that of the placebo group.

These adverse events are classified as follows:
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. (for example, for QT prolongation, QTc >= 501 ms on at least two separate ECGs)
Grade 4 Life-threatening consequences; urgent intervention indicated. (for example, for QT prolongation QTc >= 501 or >60 ms change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs / symptoms of serious arrhythmia).
Grade 5 Death related to the adverse event.
Timepoint [6] 319652 0
During treatment with levofloxacin or placebo
Secondary outcome [7] 319653 0
Death from any cause (except for violent (e.g. homicide) or accidental (e.g. motor vehicle accident) causes) among the levofloxacin group compared to placebo
Timepoint [7] 319653 0
Within 30 months after randomization
Secondary outcome [8] 319654 0
Cost-effectiveness of therapy, expressed in the total cost per disability adjusted life year (DALY) averted, under programmatic conditions
Timepoint [8] 319654 0
Within 30 months after randomization
Secondary outcome [9] 319655 0
The proportion of contacts with incident TB with acquired fluoroquinolone resistance in comparison to bacterial isolates of the index patient, the levofloxacin group compared to the placebo group.

M. tuberculosis isolated from index patients will be archived at central laboratories to enable subsequent molecular comparison with the isolates from contacts. We will study isolates from contacts who develop culture positive TB, at baseline or after treatment, to determine whether acquired drug resistance has developed, based upon concordant phenotypic DST and whether they have matching Mycobacterial Interspersed Repetitive Unit - 24 loci (MIRU-24) patterns. For greater resolution, we will also apply Whole Genome Sequencing to index-contact pairs, with samples to be tested in a facility with appropriate quality assurance, meeting international standards.
Timepoint [9] 319655 0
Within 30 months after randomization
Secondary outcome [10] 319656 0
The difference in specific biomarkers (including microRNAs) between treatment initiation and treatment completion for compliant participants allocated to levofloxacin compared to the placebo group;

Biomarkers will be assessed based on a serum assay. Biomarker panels will be derived from published studies, including a microRNA profile. Further work is required to develop the precise biomarker panel.
Timepoint [10] 319656 0
During treatment with levofloxacin or placebo (no more than 30 months after randomization)

Biomarkers will be measured at baseline, then 6 months post-randomization (at the completion of treatment).
Secondary outcome [11] 319657 0
The difference in specific biomarkers (including microRNAs) for patients with microbiologically proven TB, compared with enrolled contacts with infection, and enrolled contacts that are uninfected.

Biomarkers will be assessed based on a serum assay. Biomarker panels will be derived from published studies, including a microRNA profile. Further work is required to develop the precise biomarker panel.
Timepoint [11] 319657 0
At baseline and 6 months

Eligibility
Key inclusion criteria
Eligibility for screening, prior to randomization, include:
1. Any age (note: only those age 15 and above will be eligible for randomization, but consenting children may be screened to detect active disease and latent TB infection).
2. Living in the same household** as the index patient within the previous 3 months

Eligibility for randomization include:
1. Living in the same household as the index patient within the previous 3 months
2. Age 15 years and above*
3. One of:
(a) Tuberculin skin test positive (a size of 10mm or greater at first reading); OR
(b) Any TST size if known to be HIV positive or severely malnourished; OR
(c) New TST conversion on the second reading

*Note that in the initial period of the study, we will enroll contacts <15 years, and conduct periodic screening for disease, however they will not be randomised to receive the intervention. After this initial period, and review of additional safety data, we intend to include contacts of all ages for randomisation to receive the intervention, subject to approval by the relevant institutional review boards / ethics committees.

**A household contact is defined as: “A person who shares (or has shared) the same enclosed living space for one or more nights each week, or for frequent or extended time periods during the day with the index case, during the 3 months before the commencement of the current treatment episode.
Minimum age
0 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for initial screening, prior to randomization:
1. Unwilling or unable to provide informed consent
2. Suffering from a condition likely to lead to uncooperative behaviour (e.g. severe psychiatric illness or alcoholism).


Exclusion criteria for randomization:
1. Unwilling or unable to provide informed consent
2. Suffering from a condition likely to lead to uncooperative behaviour (e.g. severe psychiatric illness or alcoholism)
3. A diagnosis of current active TB disease made during initial assessment
4. Known to be pregnant
5. Unable to take oral medication
6. Unwilling or unable to participate in follow-up for 30 months
7. Currently breast feeding
8. Known allergy to fluoroquinolone antibiotics, or history of severe tendinopathy related to fluoroquinolones
9. Currently taking another medication reported to increase the cardiac QTc interval
10. Documented previous treatment for MDR-TB
11. Documented treatment with antibiotics that are active against MDR-TB in the previous month (including fluoroquinolones).
12. Prior severe blistering reaction to tuberculin
13. End stage liver failure (class Child-Pugh C).
14. Dialysis-dependent chronic kidney disease

(Later in the study, pending additional ethical review, children <15 years may also be eligible to receive therapy. If this occurs, then a weight of <3kg will be an additional exclusion criterion for randomization).

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)
Allocation concealment present.

Allocation will be performed by central randomization, by computer and/or telephone. The holder of the allocation will be located off-site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomization, stratified by province
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
If another member of the household has already been randomized in the within a 90 day period, then additional household members will also be allocated to that same group. There will be no more than 90 days between the first and last contact that are allocated to the same group.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size estimate:
The intra-class correlation coefficients are 1.04 at the district level and 1.07 at the level of the household, with 2.1 contacts recruited per patient (data from the ACT2 contact screening study, previously conducted in VIetnam). An average of 21 index patients will be recruited per district (based on reported PMDT data). Hence, the overall design effect is 1.1. The prevalence of LTBI in household contacts of MDR-TB patients is expected to be at least 60%, and the incidence of TB among untreated MDR-TB contacts over a 2-year follow-up period will be 3.0%. We estimate levofloxacin will reduce incidence by 70% in the treatment group, based upon a mid-range estimate of the effectiveness of isoniazid treatment for LTBI in drug-susceptible disease. The prevalence of fluroquinolone resistance among MDR-TB patients in Vietnam was measured in the 4th National Drug Resistance Survey to be 16.7%. Hence we will increase the sample size to allow for a sub-group analysis of those contacts of patients with MDR-TB that is susceptible to fluroquinolones. We will allow for a 10% drop-out rate. We assume alpha = 0.05 and the power to detect superiority is 80%. Hence, we will randomize 2,006 infected contacts

Analytic methods:
Analysis will be by intention to treat. We plan to use a marginal Poisson regression model estimated via a generalised estimating equation (GEE) to test the effect of treatment group allocation on the incidence ratio of TB.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
22/02/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
2006
Accrual to date
Final
Recruitment outside Australia
Country [1] 7476 0
Viet Nam
State/province [1] 7476 0
Hanoi, Nam Dinh, Da Nang, Quang Nam, Thanh Hoa, Khanh Hoa, Ho Chi Minh City, Can Tho, Tien Giang, An Giang

Funding & Sponsors
Funding source category [1] 292588 0
Government body
Name [1] 292588 0
National Health and Medical Reserach Council
Country [1] 292588 0
Australia
Primary sponsor type
University
Name
Univerrsity of Sydney
Address
Woolcock Institute of Medical Research
431 Glebe Point Road
Glebe NSW 2037
Country
Australia
Secondary sponsor category [1] 291310 0
None
Name [1] 291310 0
N/A
Address [1] 291310 0
N/A
Country [1] 291310 0
Other collaborator category [1] 278747 0
Hospital
Name [1] 278747 0
Vietnam National Lung Hospital
Address [1] 278747 0
463 Hoang Hoa Tham, Ba Dinh, Ha Noi
Country [1] 278747 0
Viet Nam

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294072 0
Human Research Ethics Committee, University of Sydney
Ethics committee address [1] 294072 0
Ethics committee country [1] 294072 0
Australia
Date submitted for ethics approval [1] 294072 0
07/11/2014
Approval date [1] 294072 0
17/12/2015
Ethics approval number [1] 294072 0
2014/929
Ethics committee name [2] 294281 0
Institutional Review Board of the Vietnam Ministry of Health
Ethics committee address [2] 294281 0
Ethics committee country [2] 294281 0
Viet Nam
Date submitted for ethics approval [2] 294281 0
29/06/2015
Approval date [2] 294281 0
30/09/2015
Ethics approval number [2] 294281 0
4040/QD-BYT

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

Contacts
Principal investigator
Name 62326 0
Dr Greg Fox
Address 62326 0
Woolcock Institute of Medical Research, University of Sydney
431 Glebe Point Road, Glebe, NSW Australia 2037
Country 62326 0
Australia
Phone 62326 0
+61 2 9114 0000
Fax 62326 0
Email 62326 0
greg.fox@sydney.edu.au
Contact person for public queries
Name 62327 0
Greg Fox
Address 62327 0
Woolcock Institute of Medical Research, University of Sydney
431 Glebe Point Road, Glebe, NSW 2037
Country 62327 0
Australia
Phone 62327 0
+61 412 912 538
Fax 62327 0
Email 62327 0
greg.fox@sydney.edu.au
Contact person for scientific queries
Name 62328 0
Greg Fox
Address 62328 0
Woolcock Institute of Medical Research, University of Sydney
431 Glebe Point Road, Glebe, NSW 2037
Country 62328 0
Australia
Phone 62328 0
+61 2 9114 0000
Fax 62328 0
Email 62328 0
greg.fox@sydney.edu.au

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