Overview of publications reporting active drug safety monitoring and management (aDSM) data or otherwise prospectively collected data in programmatic settings

First author [ref.]LocationSettingPatient enrolment periodPatients nPatient age yearsPatient typeDrug or regimenPatients receiving ND&R nPatients with SAEPatients with drug(s) interrupted or withdrawnPatients with any type of AE
Bastard [67]Maputo, MozambiqueProspective data collection from MSF-supported projectNov 2015–May 201819NRPulmonary MDR-TBSTR with Km shifted to Bdq after a median of 2.8 months because of ototoxicity (n=17), nephrotoxicity or hypokalaemia19 STR with Bdq instead of KmNR0% after shifting from Km to Bdq“No grade 3/4 QT prolongation or AST/ALT increase”
Other AEs NR
Hafkin [68]GlobalProspective data collection from compassionate use programme for Dlm (Otsuka with ERS, WHO, MSF and PiH)Feb 2014–Jun 2016788–59Pulmonary MDR-TB: MDR (8), pre-XDR (26), XDR (44)Individualised regimens with Dlm78 Dlm with#
Lzd (60/66)
Cfz (50/66)
carbapenems (33/66)
Bdq (12/66)
10.3% died during Dlm course, none attributed to Dlm
Dlm: 2.6% temporary, 1.3% permanently (all QT prolongation)QTcF>500 ms: 3.8% attributable to Dlm, Cfz (and Bdq in 1/3, or hypokalaemia in 2/3)
Other AEs NR
Hafkin [23]GlobalProspective data collection from compassionate use programme for Dlm (Otsuka with ERS, WHO, MSF and PiH)Feb 2014–Feb 201884≥6MDR (4), pre-XDR (18), XDR (62)Individualised regimens with Dlm and Bdq84 Bdq+Dlm with:
Lzd (77)
Cfz (66)
carbapenems (33/66 on Cfz)
12% died not related to Dlm/Bdq
Bdq: 1% interrupted then Cfz withdrawn due to QTcF>500 msQT prolongation: 6%
QTcF>500 ms: 1%
Other AEs NR
Ndjeka [14]5 sites across South AfricaProspective programmatic data collection including SAE; interim analyses after ≥1 month of treatmentMar 2013–Aug 201491≥18(Pre-)XDR-TB: MDR+FQ-R (41), MDR+SLID-R (16), XDR (34)Individualised regimens with Bdq91 Bdq with:
Lfx (76)
Lzd (64)
Cfz (68)
10% ≥1 SAE
1% atrial fibrillation (attributed to Bdq)
3% severe psychosis, mood disorder and delusion
3% died
Bdq: 1% due to atrial fibrillationQTcF>500 ms: 3% (attributed to Bdq)
QTcF>50 ms from BL: 26%
Other AEs NR
Ndjeka [17]7 sites across South AfricaProspective programmatic data collection including SAE; analysis of final treatment outcomesMar 2013–Mar 2015200≥18(Pre)-XDR-TB: MDR+FQ-R (87), MDR+SLID-R (33), XDR (78), unknown (2)Individualised regimens with Bdq200 Bdq with:
Lfx (166)
Lzd (128)
Cfz (164)
32% ≥1 SAE;
Attributed to Bdq: 5% of all 87 SAE (QTcF>500 ms),
Anaemia: n=12 (14% of SAE)
Peripheral neuropathy: n=9 (10%)
Ototoxicity: n=7 (8%)
12.5% died
11% Bdq interrupted, in only one case due to AE other than QT- prolongationAny: 86%
Attributed to Bdq: 3.2% (n=19) of all 603 AEs:
QTcF>500 ms: n=5, 0.6% overall
QTcF>50 ms from BL: n=8 (1.3%)
Atrial flutter: n=1 (0.2%)
Olayanju [18]1 site in South AfricaProspective cohort of patients on programmatic treatment with/without BdqJan 2008–Sep 2014 (non-Bdq);
Nov 2013–Apr 2016 (Bdq)
272NRLab-confirmed XDR-TBIndividualised regimens with/without Bdq68 Bdq with:
Lzd (55)
Cfz (67)
Mer (1)
204 no Bdq with:
Cfz (2)
15% died on Bdq vs 13% on non-Bdq regimens (p<0.05)
≥1 drug withdrawn due to AE: 59% Bdq vs 38% non-Bdq (p<0.05)
Bdq withdrawn: 0%
Lzd withdrawn: 33%
PAS withdrawn: 16%
Cm withdrawn: 86%
Cs withdrawn: 13%
Any AE: 96% Bdq (vs 70% non-Bdq group)
AE in Bdq group occurring at >10% frequency:
QT prolongation: 10% (all <500 ms)
Peripheral neuropathy: 22%
Dizziness/disorientation: 16%
Hearing impairment: 43% (vs 15%),
Abdominal pain: 22%
Vomiting: 24%
Nausea: 24%
Skin reaction: 29%
Arthralgia: 19%
Body pains: 28%
Anaemia: 21% (vs 1%)
Nephrotoxicity: 21%
Sarin [69]IndiaProspective programmatic data collection in the National Institute of TB and Respiratory DiseasesUnclear290≥18MDR-TB: MDR (2), MDR+FQ-R (214), MDR+SLID-R (14), XDR (60)Semi-standardised regimens with Bdq290 Bdq with:
MfxHd (116)
Lzd (261)
Cfz (249)
22% died
Bdq interrupted: 16% (due to QT prolongation)
Bdq withdrawn: 1% (due to QT prolongation)
Any AE: 38%
QTcF 480–500 ms: 13%
QTcF >500 ms: 4%
AEs occurring at >10% frequency:
Peripheral neuropathy: 14%+
Dermatological: 10%+
Haematological: 10%+
Sarin [70]IndiaProspective programmatic data collection for patients on Bdq+Dlm salvage regimens in the National Institute of TB and Respiratory DiseasesMar 2017– Nov 201853≥17 yearsMDR-TB: MDR (35), pre-XDR (1), XDR (17)Individualised regimens with Bdq+DlmBdq+Dlm: 53
Exposure to MfxHd, Imp, Lzd and Cfz cannot be calculated
32% ≥1 SAE
19% or 21% died§
All drugs: 2% due to cardiac arrhythmiaQTcF>60 ms above BL: 14%
QTcF>480 ms: 21%
Skrahina [66]BelarusaDSM data from patients receiving BdqJune 2015–June 2016? (end of observation NR)197NRMDR-TB: MDR (10), MDR+FQ-R (34), MDR+SLID-R (25), XDR (128)NR (regimens with Bdq)Bdq: 197NR
“1 death possibly related to MDR-TB treatment”
NRDisorder (most commonly reported AE):
Metabolism and nutrition: 68% (hyperuricaemia)
Hepatobiliary: 64% (hepatic functions abnormality)
Electrolyte: 47% (hypomagnaesemia)
Cardiac: 41% (abnormal ECG/arrhythmias)
GI system: 35% (nausea, vomiting, abdominal pain)
Blood/lymphatic system: 27% (low platelet counts)
Renal and urinary: 21% (creatinine increased)
Nervous system: 20% (headache, dizziness, paraesthesia)
Skin and subcutaneous tissue: 18% (rash, pruritis)
Ear and labyrinth: 17% (tinnitus, hearing loss)
Psychiatric: 15% (insomnia)
Infections and infestations: 14% (candidiasis)
Skrahina [65]BelarusaDSM data for patients on regimens with Lzd and BdqJun 2014–Jun 2016? (end of observation NR)214NRMDR-TB (BL resistance unknown)NR; regimens with Lzd and/or BdqLzd: 205
Bdq: 133
(Lzd+Bdq: 124)
Lzd: 5% any SAE requiring withdrawal or dosage reduction of TB medicines (not specified which)
Bdq: 4% any SAE requiring withdrawal or dosage reduction of TB medicines (not specified which)
0% died due to SAE caused by Lzd or Bdq
Lzd: any ADR 78%
Bdq: any ADR 72%

ND&R: new drugs and regimens; SAE: serious adverse event; AE: adverse event; MSF: Médecins Sans Frontières; NR: not reported; MDR: multidrug-resistant; TB: tuberculosis; STR: shorter (9-month) treatment regimen; Km: kanamycin; Bdq: bedaquiline; AST: aspartate transaminase; ALT: alanine transaminase; Dlm: delamanid; ERS: European Respiratory Society; WHO: World Health Organization; PiH: Partners in Health; XDR: extensively drug-resistant; Lzd: linezolid; Cfz: clofazimine; QTcF: Fridericia-corrected QT interval; FQ-R: fluoroquinolone resistance; SLID-R: second-line injectable drug resistance; ADR: adverse drug reaction; Lfx: levofloxacin; BL: baseline; Mer: meropenem; PAS: para-aminosalicylic acid; Cm: capreomycin; Cs: cycloserine; MfxHD: high-dose moxifloxacin (dose not specified in paper); Imp: imipenem; GI: gastrointestinal. #: only reported for those who completed Dlm treatment of 6 months (n=66); : only those percentages being different in the group not receiving Bdq are displayed, the proportion of ototoxicity in the Bdq group versus the non-Bdq group is striking because fewer patients in the Bdq group received aminoglycosides/capreomycin than in the non-Bdq group (authors attributed this difference to the effect of previous treatment and not to the current regimen, it is likely some of the patients in the Bdq group had been given Bdq because of a pre-existing hearing impairment); +: out of all AEs (not per patient); §: conflicting data between table (n=10 deaths) and text (n=11 deaths).