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.
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