FROM CLINICAL TRIAL TO CLINICAL
PRACTICE: THE SOUTH AFRICAN
BEDAQUILINE STORY
Dr. Francesca Conradie
Technical Advisor for MDR-TB
Investigator, Clinical HIV Research Unit (CHRU), Helen Joseph
Hospital, Johannesburg, South Africa
Investigator, Sizwe Hospital, Johannesburg, South Africa
Thursday
March 19, 2015
10:00 a.m. EST
(GMT -5:00)
www.drtbnetwork.org
- Phase 2b trial, randomly assigned 160 patients with newly
diagnosed MDR-TB
C208 Stage 2: Follow-up
• Subjects were to be followed for 96 weeks after
end of treatment. Total study duration was 120
weeks (24+96)
• Study visits were weekly to biweekly in the first
24 weeks and every 4-12 weeks afterwards
• In the data sets, all subjects completed Week 72
or discontinued earlier
Source: U.S. Food and Drug Administration. www.fda.gov
Study C208 Stage 2: Timeline
24-week investigational treatment (beqailine/placebo)
72-to-96-week background regimen
120-Week Study Duration
Week 24
Primary analysis
72
Data cut-point
96
120
Final Analysis
10
Source: U.S. Food and Drug Administration. www.fda.gov
C208 Stage 2: Enrollment
• 282 subjects were enrolled from 15 sites,
each site with 2 to 58 subjects
• South Africa 1 and 2 enrolled 58 and 57
• 161 were randomized
Source: U.S. Food and Drug Administration. www.fda.gov
Diacon AH, et al. N Engl J Med 2014;371:723-32.
Bedaquiline Clinical Access Programme
• Goals of a compassionate use/early access
program for new tuberculosis drugs:
– To protect patients
– To minimize the risk of treatment failure and
emergence of resistance
– To exercise fairness
– To comply with regulatory guidance.
Horsburgh C.R., et al. Compassionate use of and expanded access to 2012 Dec 4;
17(January):146–52.
Patient Protection
• Ability and capacity to make autonomous
decisions.
• Informed consent.
• Approved by the sites’ Research Ethics
committees (REC).
•
Department of Health, 2006 Guidelines for Good Practice in the Conduct of Clinical Trials with Human
Participants in South Africa Department of Health: Pretoria, South Africa.
To minimize the risk of treatment
failure and emergence of resistance
“Never adding a single drug to a failing regimen”
To minimize the risk of treatment
failure and emergence of resistance
• South African Clinical Advisory committee was
thus established, comprising a number of experts
in the treatment of M/XDR TB.
• This virtual committee operates by e-mail
consensus
• Once approval from the local team is obtained, a
patient summary is sent to the Janssen Global
Programme Manager
• In parallel to this, approval is obtained from the
MCC on a Section 21 or named patient basis.
Regulatory guidance
• Research Sites involved in the phase 2 clinical
trials were approached first to conduct a
compassionate use program for bedaquiline.
• In November 2011, the protocol for
compassion access was presented to the MCC
by the National Department of Health.
• Requested a clinical trial to monitor safety
with the TB directorate of NDoH being the
sponsor.
Regulatory guidance
• In collaboration with Right to Care and MSF,
assisted by the local Janssen Pharmaceutica, a
clinical access program was drafted by
National Department of Health based on the
Clinical Use program.
• In December 2012, the Clinical access program
was approved by the MCC.
THE NATIONAL BEDAQUILINE
CLINICAL ACCESS PROGRAMME
IN SOUTH AFRICA
13
Inclusion & Exclusion criteria
INCLUSION
•
•
Laboratory confirmed pre-XDR
and XDR-TB
Specific inclusion criteria:
– Adult male or female patient
≥18 years of age
– The BR should be
constructed with at least 3
anti-tuberculosis drugs to
which the Patient’s
infection is known to be
susceptible on DST or likely
to be susceptible, based on
known treatment history
– Negative urine pregnancy
test prior to starting
treatment with bedaquiline
– Contraceptive methods
prescribed
EXCLUSION
•
•
•
Pregnant or breast-feeding
female.
Unstable medical conditions,
known allergy to bedaquiline
Patients with the following
laboratory abnormalities
– Serum creatinine grade 1 or
greater (> 1.0 x ULN);
– Lipase grade 2 (with no
signs or symptoms of
pancreatitis) or greater (>
1.5 x ULN);
– AST or ALT grade 2 or
greater (≥ 2.0 - < 3.0 x ULN);
– Total bilirubin grade 1 or
greater (> 1.0 x ULN).
14
BCAP
• All patients will receive
– bedaquiline 400 mg q.d. (once daily) for 2 weeks then
– 200 mg t.i.w (three times a week) for 22 weeks in
combination with a background regimen (BR) of
selected 2nd line drugs used to treat pre- XDR or
XDR
• BR will be continued beyond the 22 weeks of
bedaquiline administration
• BR will be supplied via National TB program at
each site.
• BDQ provided by Janssen for 200 patients
15
National BCAP
• To date there were 12 approved sites in South
Africa
• However ,Pre-XDR and XDR- TB patients presented
in this report are from five approved sites
• Up to 227 patients have been started on BDQ
• Analysis presented here for 91 patients enrolled by
15 July 2014
• Data censored on 30 August 2014
13
Enrolling sites
14
Bq in SAR. Results-Baseline
Characteristics
•
•
•
•
•
•
Median Age :34,1 years ( IQR 25.7, 40.9)
Sex M: 56 (61.5%)
HIV infected : 55 (60.5%)
Median CD4+ : 249 (IQR 134; 356)
On LPV/r: 19 (34.5%)
On NVP 36 (65.5%)
18
Bq in SAR. Results-Baseline
Characteristics
• Drug-resistance patterns:
– XDR in 33 (36.3%)
– pre-XDR TB (fluoroquinolone) in 41 (45.1%)
– pre-XDRTB (injectable) in 1(18.1%)
• OBR included:
– Clofazimine for 68 (74.5%)
– Linezolid for 64 (70%)
– Levofloxacin 76 (83.5%)
Figure 1. Interim outcomes for XDR and pre XDR TB patients enrolled in National Bedaquiline Clinical
Access Programme in South Africa
Died
n=2
Completed 24
weeks BDQ
n=58
>24 weeks since
treatment start
n=60
Enrolled, started on BDQ
and included in the
analysis
Did not complete
BDQ
n=2
n=91
33 XDR-TB
41 pre XDR (FLQ)
17 pre XDR (injectable)
<25 weeks since
treatment start
n=31
Still on treatment
n=31
Transferred out
n=1
Defaulted n=1
Culture negative
at start
n=15
On continuation
treatment
n=54
Culture
converted
n=33
Died
n=1
Still culture
positive
n=6
Defaulted
n=1
Culture negative
at start
n=6
Culture
converted
n=10
Culture pending
n=15
BDQ: bedaquiline; XDR TB: extensively drug resistant TB; FLQ: fluoroquinolone
11
Culture Conversion by Resistance
pattern
21
Culture Conversion by HIV status
13
BCAP– QTc
• One patient developed atrial fibrillation on BDQ and
was withdrawn from BDQ treatment
• At BDQ start, median QTcF was 408ms (IQR 390-426):
 Median increase of 8ms (IQR -12-31) at 2 months
 14 patients had increases of >40ms
 2 had QTc >500ms (BDQ temporarily withdrawn in one and
the other resolved in 24 hours)
Overview of SAEs in the global Safety Database in S.
Africa June 2013-2014ⱡ
Review of 15 patients with SAE. ⫛
The general pattern and frequency of reported events including
deaths and events of QT prolongation are in line with the known safety
profile of BDQ
•3 reports of death; none related to BDQ per the investigator
•3 reports of QT prolongation with causality of probable or possible
per the investigator. All 3 resolved.
•3 reports of psychosis/mood disorder/delusion; none related to
BDQ per the investigator. All 3 were receiving Terizidone (prodrug of
cycloserine with known ADR of mood disorder)
⫛SAEs by Dr Dannemann, Sirturo Medical Leader showed:
ⱡOnly SAEs required to be reported; no site monitoring done
18
Conclusion
• The programme has allowed access to better
treatment hence the good interim outcomes for
(pre-)XDR patients with otherwise limited options
and poor prognosis
• Access has already been extended to other sites
bringing the total of sites to 12
• Bedaquiline was registered in South Africa in
October 2014
19
Introduction of New Drugs
Policy framework
The WHO recommends the following as prerequisite for the introduction of new or repurposed
TB drugs:
– National implementation plan for introduction of new
TB drugs and/or regimens
– Monitoring and evaluation of new drugs and
regimens, including pharmacovigilance and drug
resistance surveillance
– Private sector engagement
– Systems approach for ensuring uninterrupted supply
of quality-assured drugs
– Operational research
Objectives for the introduction of new drugs, regimens
and management for DR-TB within the SA NTP
• To ensure the appropriate selection of DR-TB
patients for new drugs, regimens and
management.
• To ensure the effective management of patients
currently or previously treated for DR TB.
• To ensure appropriate monitoring and managing
of adverse events during DR-TB treatment and
effective pharmacovigilance
• To ensure oversight and management from the
national level and implementation at provincial
and district levels
Who is eligible for BDQ in the SA
NTP?
• Patients ≥18 years of age
and
• Laboratory-confirmed RR-TB (at least resistance
to RIF) by culture-based phenotypic drug
sensitivity testing or genotypic line probe assay or
PCR testing (Xpert MTB/RIF ) from both
pulmonary and/or extrapulmonary sites
and
• No history or family history of QT prolongation or
baseline QTcF> 450 msec; and
Who is eligible for BDQ in the SA
NTP?
• Drug resistance in addition to RR TB:
– XDR TB; or pre-XDR TB (resistant to either
fluoroquinolone or second line injectable drug); or
– inhA and katG mutations;
OR
• Documented / recorded intolerance to 2nd line
anti-TB treatment at baseline (prior to treatment
initiation) or during RR TB treatment, e.g. hearing
loss, renal dysfunction, or other ADRs
Which cases should be reviewed prior
to prescribing BDQ?
When bedaquiline should NOT be approved at a
hospital/provincial level and rather needs
national committee review:
• Patients has already had > 3 months of preXDR or XDR treatment;
OR
• Patient has fewer than 2 of the following 4
drugs counted to be effective in regimen
Which cases should be reviewed prior
to prescribing BDQ?
Which cases should be reviewed by the
National committee prior to prescribing BDQ?
• Patients does not have at least one other drug to which
their TB is susceptible or predicted susceptible
(because not previously exposed)
OR
• Age < 18 years
OR
• Pregnant
OR
• Patients with MDR treatment failure (smear or culture
positive at 8 months on MDR treatment) without
proven 2nd line resistance.
Contraindications
Absolute contraindications:
• Patient refuses consent.
• High risk for cardiac complications
• History of severe allergic reaction to
bedaquiline
Toxicity
If ototoxicity hearing loss occurs,
20dB decrease at any one frequency
10dB decrease at any two adjacent frequencies
Loss of response at three consecutive test frequencies
where responses were previously obtained
the SLD should be stopped and changed to
another agent e.g. bedaquiline or linezolid
Relative contraindication
• For relative contraindications, BDQ could be used in
situations where the options of treatment are
extremely limited and the benefit outweighs the
potential risks after PCAC or the National Clinical
Advisory Committee.
• No concomitant QTc prolonging medications :
• Breastfeeding females
• For HIV-infected patients on ART:
–
–
–
–
NVP
Raltegravir
LPV/r
Rilviripine
Effective management of patients
Additional safety investigations
• Inpatient or outpatient
• All standard safety investigations as per the
national guidelines
• Additional safety investigations required for BDQ:
– ECG prior to starting BDQ (baseline)
– Monthly thereafter unless clofazimine or moxifloxacin
is used. In this case, weekly ECGs should be done for
the first month.
Management of HIV-infected patients
• HIV infected patients who are ART naïve or currently
on ART may be started on BDQ. As per national ART
guidelines, HIV-infected patients not yet on ART should
be initiated on ART.
• For patients requiring ART the following are options
– NVP and two appropriate NRTIs if the CD4 is <250 in
women and <350 in men
– LPV/r-containing regimen with two appropriate NRTI for
patients that require second line therapy or have CD4 is
greater than 250 in women and 350 in men
– Rilpivirine and raltegravir can be considered if available.
Monitoring for resistance to BDQ
• Surveillance to monitor the emergence of drug
resistance to BDQ is essential component
– BDQ DST by the MIC methods has been validated
– However, not yet available in NHLS network.
– Initial testing would be performed at the NTBRL
• All DR-TB patients receiving the BDQ should have BDQ
DST performed on baseline sputum culture isolates.
• In addition post-baseline isolates, after week 24 (6
months), indicative of treatment failure should be tested
in parallel with the corresponding baseline isolate.
Monitoring for resistance to BDQ
• After this period, these selected referral laboratories will
test BDQ at three concentrations ranging from 0.12 – 0.5
µg/ml (as supplied by the NTBRL).
• Any isolates with an MIC of ≥ 0.25 mg/ml would be sent to
the NTBRL for confirmation and testing over a wider
concentration range (0.06 – 2.0 µg/ml).
• A review of MIC data should be performed on a quarterly
basis and any cases where the MIC increased 4 fold from
baseline or has an MIC ≥ 0.25 mg/ml will be notified
immediately to the attending clinician and the National
Clinical Advisory Committee.
• BDQ should not be prematurely discontinued before 24
weeks except for safety reasons.
Conclusion
• South African patients were given access to
BDQ prior to registration safely
• National framework aims to continue this until
RCT data is available in best MDR regimen
Learn more:
www.drtbnetwork.org
This presentation has been supported by the TB CARE II project
and is made possible by the generous support of the American people through the United
States Agency for International Development.
The contents of this presentation are the responsibility of the lecturers and do not necessarily reflect the views of USAID or the United States Government.