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V-QUIN MDR Trial Overview
RESIST TB Webinar | 3 November 2016
Q
UIN
V
MDR-TB prevention study
SYDNEY MEDICAL SCHOOL
Greg Fox, PI VQUIN MDR Trial
University of Sydney
Trial Registration: ACTRN12616000215426
(Australian and New Zealand Trials Registry)
Background
VQUIN
MDR-TB prevention study
Background: the global burden of MDR-TB
› MDR-TB affects 480,000 (360,000-600,000) people each
year1 and is responsible for 13% of all TB deaths2
› Second-line treatments are prolonged, complex, toxic and
costly compared to first-line therapies
› MDR-TB consumes 20% of TB control budgets in resourcelimited settings2
› New strategies are urgently needed to prevent MDR-TB
1WHO
Global TB Report 2015
2WHO Global TB Report 2014
3
Infection with M. tuberculosis
› Latent tuberculosis infection
TST/IGRA
4
Background: MDR-TB in contacts
› Contacts of patients with MDR-TB have a high risk of LTBI and TB
- Our study in Ho Chi Minh City, Vietnam, found 40.8% of 151 contacts of RR-TB
had TST ≥ 10mm or above (OR 2.0, 95% CI 1.3-3.2 compared to new TB)3
- 5% of contacts of MDR-TB patients in Peru developed TB within 3 years4
› Not all TB in MDR-TB contacts is MDR-TB
- 72% (36/50) of MDR-TB contacts in Peru developed MDR-TB4
- In our study 3/7 contacts with incident or prevalent MDR-TB had MDR-TB
(however 2/2 incident cases had MDR-TB.)3
1Marks
et al, AJRCCM 2000
et al, Chest 2016
3Fox et al, IJTLD 2016 (accepted for publication)
4Grandjean et al, 2011
2Trauer
5
Approach to preventive therapy for MDR-TB contacts
› Preventive therapy aims to:
- Reduce the risk of progression from LTBI  disease
- Reduce transmission
› In treating LTBI due to MDR-TB or XDR-TB, antibiotic selection is based
upon the confirmed or suspected drug resistance pattern of the
presumptive source case
› Decision to use preventive therapy must weigh the likely benefits and risks
of therapy
6
Preventive therapy for MDR-TB
› Randomized studies of 6-12 months of isoniazid preventive therapy (IPT)
for contacts of drug susceptible TB have been shown to reduce the
incident of TB by 40-90%1
› Fluoroquinolones are well tolerated and appear effective against M.
tuberculosis in vivo2
› Small observational studies have been promising:
- 110 MDR-TB contacts in Micronesia received 12 months (including FQ) – no
incident cases3
- 184 children received 6 months of therapy including FQ – well tolerated4
› No randomized trials of preventive therapy for MDR-TB contacts have
been conducted.
1Lobue
et al, Respirology 2010
2Gillespie et al, REMOX trial 2014
3Bamrah et al, 2010
4Seddon et al, 2013
7
Levofloxacin for treating TB
Levofloxacin for treating MDR-TB
› Levofloxacin (LFX) is a 3rd generation FQ
- FQNs inhibits DNA gyrase and are highly active against M. tuberculosis
- Batericidal and sterilising actions (murine models)
› LFX is commonly used in backbone of MDR-TB treatment regimen
› Levofloxacin has a long history of use and is generally well-tolerated
9
Fluoroquinolone and MDR-TB
10
“Moxifloxacin, gatifloxacin and high-dose levofloxacin have
excellent EBA, only slightly less than INH, and greater EBA”
(5 days)
Gatifloxacin 400mg / Moxifloxacin 400mg / levofloxacin 1000mg (5 days)
Gatifloxacin 400mg / Moxifloxacin 400mg / levofloxacin 1000mg (5 days)
14
Fluoroquinolones in treating LTBI
Prospective cohort study in the Federated
States of Micronesia
Setting:
› FSM is a Western Pacific nation affiliated with the USA
› TB incidence 127 / 100,000 in 2007
› Outbreaks of MDR-TB between 2007-2009
› 232 contacts identified  119 contacts with LTBI (5mm cut-off) offered
preventive therapy by DOT; regimens included:
- Monthly compensation ($5) provided to contacts completing 90% of doses
Source M.tb resistance
Age (y)
MDR LTBI regimen
INH, RIF, ETH
>12
MFX 400mg + EMB 15mg/kg daily for 12 mo.
≤12
LFX 20mg/kg + EMB 15/mg/kg for 12 mo.
>12
MFX 400mg daily for 12 mo.
≤12
LFX 20mg/kg daily for
12 mo.
Bamrah
et al, IJTLD 2014
INH, RIF, EMB, PZA, SM
16
Prospective cohort study in the Federated
States of Micronesia
Results
- 119 TST positive individuals offered treatment
- Contacts followed to February 2012
- Findings during follow-up
(a) 104 accepted treatment  93 completed treatment (89%), 0 MDR-TB
cases
(b) 15 refused MDR-TB treatment  3 developed MDR-TB
- Contacts who took treatment had a median age of 24, those who did not
had a median age of 32
- 56 (54%) of treated contacts reported at least one adverse effects, with 16
(15%) reporting adverse effects 3 times or more.
- No individuals tested positive for HIV
Bamrah et al, IJTLD 2014
17
Tolerability of regimens in FSM
18
Prospective cohort study: child contacts in
South Africa
› Small observational studies have been promising:
- 186 children (<5 or HIV+ <15 years), regardless of TST status
- Treated with OFX, EMB and high dosed INH for 6 months
- Treatment was were well tolerated1
- Adherence 141 / 186 (75.8%)
- 7 (3.7%) developed Grade 3 or Grade 4
- 1 death (0.5%), 6 (3.2%) cases of incident TB during 219 years follow-up
1Seddon
… Schaaf, 2013
19
Levofloxacin for LTBI
› Optimal duration of therapy?
› Optimal dose in LTBI?
20
Current guidelines for preventive therapy in MDR-TB
Institution (Year)
Recommended treatment for LTBI that is presumed multidrug resistant
WHO (2014)
Strict clinical observation for 2 years is preferred over provision
of preventative therapy. Benefits of preventive therapy may
outweigh harm for children <5 years. If preventive therapy is
given, monitor for acquired drug resistance.
US CDC (2000)
Not stated
UK NICE Guidelines (2016)
Not stated
European Union Standards
for TB care (2012)
Clinical monitoring and no preventive therapy.
Canadian TB Standards
(2013)
MDR-TB: 9LFX or 9MOX with close monitoring.
Harvard – UAE (2015)
At least 6 months LFX or MOX, following all exposed
individuals at least 18 months
21
Adverse events and levofloxacin
Common side effects
A decision about using prolonged antibiotics to treat LTBI requires an
evaluation of the likely risks vs benefits
Common side effects of levofloxacin include:
› nausea, diarrhea, headache, dizziness, lightheadedness, or trouble
sleeping.
US FDA July 2016
23
FDA Drug Safety Communication: FDA updates warnings for oral and injectable
fluoroquinolone antibiotics due to disabling side effects
Safety Announcement
[07-26-2016] The U.S. Food and Drug Administration (FDA) approved changes to the labels of
fluoroquinolone antibacterial drugs for systemic use (i.e., taken by mouth or by injection). These
medicines are associated with disabling and potentially permanent side effects of the tendons,
muscles, joints, nerves, and central nervous system that can occur together in the same patient.
As a result, we revised the Boxed Warning, FDA’s strongest warning, to address these serious
safety issues. We also added a new warning and updated other parts of the drug label, including
the patient Medication Guide.
We have determined that fluoroquinolones should be reserved for use in patients who have no
other treatment options for acute bacterial sinusitis (ABS), acute bacterial exacerbation of
chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) because the risk
of these serious side effects generally outweighs the benefits in these patients. For some serious
bacterial infections the benefits of fluoroquinolones outweigh the risks, and it is appropriate for
them to remain available as a therapeutic option.
Patients must contact your health care professional immediately if you experience any serious
side effects while taking your fluoroquinolone medicine. Some signs and symptoms of serious
side effects include unusual joint or tendon pain, muscle weakness, a “pins and needles” tingling
or pricking sensation, numbness in the arms or legs, confusion, and hallucinations. Talk with
your health care professional if you have any questions or concerns (see List of Serious Side
Effects from Fluoroquinolones).
1997-2015: 178
cases
of disabling
potentially
irreversible
Health
care professionals
should not and
prescribe
systemic fluoroquinolones
to patients who have
other treatment options for acute bacterial sinusitis (ABS), acute bacterial exacerbation of
adverse reaction
chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) because the risks
outweighpatients
the benefits in these
patients.
fluoroquinolone
immediately if
a patient
In 2014, 22 million
in the
USStopreceived
a treatment
prescription
for
reports serious side effects, and switch to a non-fluoroquinolone antibacterial drug to complete
the patient’s
treatment course
(see List of Currently Available FDA-approved
FQN (cipro, moxi,
ofloxacin,
gemifloxacin)
Fluoroquinolones for Systemic Use).
US FDA July 2016 Update to boxed warning on the labels24
Fluoroquinolones are antibiotic medicines that work by killing or stopping the growth of bacteria
25
Study setting
MDR-TB in Vietnam
VQUIN
MDR-TB prevention study
› Vietnam has approximately 5,000 cases of MDR-TB / year
- Notifications were approx. 1,500 (2013), 2,000 (2014), 2200 (2015)
- Global Fund has set target of 3,000 new patients treated by 2017.
- 16.7% of MDR-TB is FQ resistant (ofloxacin)1
› Treatment for MDR-TB is through District TB Units
- Diagnosis and initial treatment in inpatient facilities (e.g. Pham Ngoc Thach
Hospital in Ho Chi Minh City, or Hanoi Lung Hospital)
- Provided free of charge (PMDT program)
14th
National DR Survey, Nguyen VN et al 2015
27
VQUIN study objectives
VQUIN
MDR-TB prevention study
› Principal research question:
What is the effectiveness of levofloxacin given for 6 months, compared to
placebo, in the prevention of active TB among household contacts of
patients with MDR-TB who have latent tuberculosis infection?”
› Secondary objectives (1):
- Evaluate the tolerability, adherence, severe adverse events (Grade 3,
4 and 5) and cost-effectiveness of 6 months of levofloxacin therapy,
compared to placebo, in contacts of patients with MDR-TB
- Determine the rate of acquired fluoroquinolone resistance among
contacts taking six months of levofloxacin compared to placebo who
develop incident tuberculosis
28
VQUIN study objectives
VQUIN
MDR-TB prevention study
› Secondary objectives (continued):
- Determine the difference in specific biomarkers: (a) between infected
contacts from therapy initiation to six months later among compliant
contacts allocated to levofloxacin, compared to placebo, (b) between
tuberculosis infection and disease.
- Compare the effectiveness of levofloxacin compared to placebo among
contacts of patients with MDR-TB bacilli that are susceptible to
fluoroquinolones
- Evaluate the cost-effectiveness of 6 months of levofloxacin therapy,
compared to placebo, in contacts of patients with MDR-TB
29
Study design
› Double blind placebo controlled RCT
- Randomize 2,006 contacts over 30 month period
- Children <15 years screened for active TB, and LTBI, but not treated (due to
ethics committee concerns) – will aim to expand later
30
VQUIN
V-QUIN Trial design
6LEV
Active arm
Control arm
Placebo
Screening
Phase
Treatment
Phase
Months
0
1
Days
0
0
Visit
MDR-TB prevention study
1
2
12
18
24
30
30 60 90 120 150 180
365
540
720
900
1
7
8
9
10
2
3
Follow-up
Phase
3
4 5
4
5
6
6
6LEV = six months of daily oral levofloxacin
Q
UIN
V
Sample size: 2,006 contacts randomized
MDR-TB prevention study
TB incidence in 2
years
(in group taking
placebo)
Total infected
household
contacts to be
randomized
Estimated total
household
contacts to recruit
in 3 years if 60%
infected
Estimated MDRTB patients to
recruit within 3
years
2.5%
2414
4,023
1,915
3.0%
2,006
3,344
1,592
3.5%
1,711
2,852
1,358
32
Source: http://wikipedia.org
China
Hà Nội Capital
V
V-QUIN
MDR
QUIN
Trial candidate recruitment sites
Vietnam 2015 - 2020
MDR-TB prevention study
Nam Định Province
Laos
National
Tuberculosis
Program
Vietnam
Thanh Hóa Province
Đà Nẵng City
Quảng Nam Province
Cambodia
An Giang Province
Cần Thơ City
Khánh Hòa Province
Hồ Chí Minh City
Tiền Giang Province
Eligibility: index patients
VQUIN
MDR-TB prevention study
› Index patients with microbiologically confirmed MDR-TB, and enrolled
on treatment through the NTP, are eligible to enrol
Inclusion criteria for index patients
Exclusion criteria for index patients

Any age


A diagnosis of bacteriologically proven
pulmonary MDR-TB *

Commenced on treatment for MDR-TB
Unwilling or unable to provide informed
consent

Usual residence is outside of the
Provinces participating in the study
by the Vietnam National TB Program
within the past 90 days

Have at least one household contact
that is likely to be eligible for the study
*Definition of bacteriologically proven MDR-TB:
• Acid fast bacilli (AFB) smear positive, M. tuberculosis (MTB) culture positive, OR
MTB positive based on the PCR-based sputum test Xpert MTB/RIF; AND
• Rifampicin (RIF) resistant on Xpert, OR has phenotypic resistance to rifampicin
and isoniazid on DST, OR has rifampicin and isoniazid resistance on other
approved molecular assays.
Eligibility: household contacts
Inclusion criteria
Exclusion criteria

Any age


Living in the same household** as the
index patient within the previous 3 months
VQUIN
MDR-TB prevention study
Unwilling or unable to provide informed
consent

Suffering from a condition likely to lead to
uncooperative behaviour (e.g. severe
psychiatric illness or alcoholism).
35
Criteria for randomization of household contacts
Eligibility criteria for randomization

Age ≥15 years [to be reviewed in 2017, to extend to children]

Tuberculin skin test positive (a size of 10mm or greater at first
reading);
OR

Any TST size if known to be HIV positive or severely malnourished;
OR

New TST conversion on the second reading, defined as:

If the first test was <5mm
o a size of 10mm or greater at second reading; OR

If the first test was 5-9mm:
o an increase of 6mm or greater at the second reading
36
Criteria for randomization of household contacts
•
Exclusion criteria (1)
•
Diagnosis of current active TB disease made during initial assessment¶
•
Known to be pregnant*
•
Unable to take oral medication
•
Body weight < 3kg
•
Unwilling or unable to participate in follow-up for 30 months
•
Currently breast feeding**
•
Known allergy to fluoroquinolone antibiotics, or history of severe
tendinopathy related to fluoroquinolones
•
Currently taking another medication reported to increase the cardiac QTc
interval (e.g. amiodarone, sotalol, disopyramide, quinidine, procainamide,
terfenadine)
•
Documented previous treatment for MDR-TB
•
Documented treatment with antibiotics that are active against MDR-TB in
the previous month (including fluoroquinolones).
•
Prior severe blistering reaction to tuberculin
•
End stage liver failure (class Child-Pugh C).
•
Dialysis-dependent chronic kidney disease
37
Criteria for randomization of household contacts
•
Exclusion criteria (2)
•
For adults aged 15 and above only:
•
A baseline liver function test (AST, ALT or ALP) more than 3 times the
upper limit of normal
•
Baseline ECG shows the QT segment (corrected for the R-R interval)
is >450ms
•
Kidney tests show end stage kidney disease (defined as an EGFR <
20mL/min)
•
The platelet count is < 50x109 cells/L
38
Initial assessment of contacts
› Symptom screen (cough, sputum, haemoptysis, weight loss etc)
› Chest Xray
› Tuberculin skin test (RT23)
› Sputum Xpert (if can produce sputum)
Tuberculin skin test:
All contacts will have a Mantoux tuberculin skin test (2 tuberculin units of RT23) placed subcutaneously, with reading after 48-72 hours to establish LTBI
status.
39
Levofloxacin dosing and duration
Levofloxacin / Levofloxacin / Levofloxacin /
Weight
placebo
placebo
placebo
Daily dose
(mg)
250 mg tablets 500mg tablets 750mg tablets
12.0– 24.99 kg
1 tablet
--
--
250mg
25.0 – 49.99kg
--
1 tablet
--
500mg
1 tablet
750mg
50kg & above
• 180 doses of levofloxacin will be given (and treatment extended if patients do
not adhere to therapy).
• If the estimated creatinine clearance is <20mL/min then the subject will not be
eligible for therapy. If the creatinine clearance is <50mL/min then the dose will
be adjusted to half that of the normal adult dose (US FDA Levofloxacin
Product information). If the subject’s creatinine clearance is ≥ 50mL/min then
the usual dose will be given.
40
Investigation of suspected TB
In contacts aged ≥ 5 years
In child contacts aged < 5 years
Symptoms are defined as one or more
Symptoms are defined as one or more
of:
of:

Cough a for 2 weeks or more
•
Coughb

Sputum production for 2 weeks or
•
Fever
more
•
Night sweats

Night sweats
•
Lethargy

Haemoptysis
•
Failure to thrive

Documented weight loss
•
Documented weight loss
•
Moderate or severe malnutrition
41
Investigation of TB suspects
› The appropriate tests for suspected pulmonary TB in contacts aged 5 and
above will include:
- 2 sputum samples, both tested for sputum smear and culture and (if applicable)
DST
- 1 sputum sample, tested for Xpert (or equivalent PCR based diagnostic test)
› Sputum will be collected from suspects using sputum induction, where this
is available (not currently available).
42
Blinding
› Participants and staff are blinded to treatment allocation
› Unblinding can only occur on the basis of approval by the PI
- Unblinding will be restricted to the clinician involved in the case
43
Outcome definitions
Outcome definitions for subjects 15 years and over
Primary outcome (1)
› 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.
› 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)
45
Outcome definitions
Primary outcome (2)
› 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, extrapulmonary or both.
› Microbiologically confirmed MTB should be classified as:
- MDR-TB
- Rifampicin Resistant TB
- Not MDR-TB
- Drug susceptibility unknown
46
Outcome definitions
Probable Clinical TB
› Definition: Known exposure to TB plus “Well-defined” clinical evidence
AND supportive radiological or laboratory evidence of pulmonary or extrapulmonary disease in a contact that is not bacteriologically-confirmed.
› The diagnosis of clinically probable TB is equivalent to the secondary
outcome of “Clinical TB”. The End Point Review Panel will reach a
conclusion about the diagnosis of clinically probable TB
47
Outcome definitions: others
Possible clinical TB – Known exposure to TB plus clinical or radiological
evidence/abnormality that is not consistent with above definitions AND a
decision was made to treat for TB. Possible clinical TB should be classified
as pulmonary, extra-pulmonary or both.
48
Death
Death
› The secondary mortality outcome will be death from any cause except for
violent (e.g. homicide) or accidental (e.g. motor vehicle accident) causes.
› A TB death is a death where TB is considered by the IDMC to be the most
likely/major contributing cause of death.
49
Other outcomes
Acquired drug resistance
› Acquired antibiotic resistance will be deemed to have occurred when (a)
molecular testing of paired isolates (index patient and contact with incident
TB) demonstrates transmission has occurred (ie. the strain is the same)
and, (b) the isolate of the
Proportion of contacts successfully treated
› Contacts will be classified as successfully treated if they either achieve
outcomes of (a) treatment success, or (b) cure according to WHO
treatment definitions
50
Adverse event classification
Adverse events
› Adverse events will be graded according to a scale derived from the:
- American Thoracic Society Guidelines for hepatotoxicity, published criteria for
joint, muscle and bone complications
- National Cancer Institute Common Terminology Criteria for Adverse Events v4.0
› The Endpoint Review Panel will perform the grading of adverse events
and establishment of their cause, blinded to the study drug.
52
Process for adverse event reporting
Monitoring for AEs
› Subjects will be assessed frequently during the study:
- Once monthly on treatment
- Then every six months
› Routine blood tests:
- LFTs and EUC at baseline, 1 month and 2 months
› ECG
- Performed at baseline, 1 month
53
Definitions of AEs and SAEs
Definition of Severe Adverse Event
› Any adverse event that:
- results in death,
- is life-threatening,
- requires inpatient hospitalization or prolongation of existing hospitalization,
- results in persistent or significant disability/incapacity, or
- is a congenital anomaly/birth defect
Definition of USAE (Unexpected Serious Adverse Event)
› An event which is SERIOUS (SAE) AND UNEXPECTED.
Definition of SUSAR (Serious Unexpected Suspected Drug Reaction)
› An SAE for which there is some degree of probability that the event is an
adverse reaction to the administered drug, and the adverse reaction is
unexpected.
54
Interim analyses
Interim safety analysis
› The trial Independent Data Monitoring Committee (IDMC) will conduct an
interim analysis after 1/3 of participants (600 contacts) have completed 6
months of therapy for grade 3 and 4 adverse events.
Interim analysis for LFTs
› After 600 contacts with LFTs at 1 and 2 months; IDMC will review need to
continue for 1 and 2 month tests
55
Ethical issues
› Ethical approval from:
- the University of Sydney Human Research Ethics Committee and
- the Institutional Review Board of the Vietnam Ministry of Health
› Participants provide written informed consent
› Oversight by an Independent Data Monitoring Committee
56
Study timeline
› Recruitment at first site commenced 14/3/2016
› 8 Provinces currently recruiting, with 2 additional provinces to commence
by 31/12/2016
› Completion of study expected in late 2020
57
VQUIN investigators
NHMRC Project Grant #1081443 (2015-2019)
› Dr Greg Fox (Principal Investigator), University of Sydney, Australia
› Professor Guy Marks, University of New South Wales, Sydney, Australia
› Professor Dick Menzies, McGill University, Montreal, Canada
› A/Professor Nguyen Viet Nhung, National Lung Hospital, Hanoi, Vietnam
› Professor Steve Graham, Melbourne University, Melbourne, Australia
› A/Professor Ben Marais, Sydney University, Sydney, Australia
› Professor Marcel Behr, McGill University, Montreal, Canada
› A/Professor David Dowdy, Johns Hopkins University, BA, USA
› A/Professor Andrea Benedetti, McGill University, Montreal, Canada
58
Trial Governance
› Trial Steering Committee (Chair: Dr Greg Fox)
› Scientific Advisory Committee (Chair: Prof Bill Burman)
› Independent Data Monitoring Committee (Chair: Prof Andrew Nunn)
› Expert Clinical Panel (Chair: Dr Hazel Goldberg)
59
Questions
60