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The use ofdelamanid in

the treatment ofmultidrug-resistanttuberculosisInterim policy guidance

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Interim policy guidance

The use ofdelamanid in

the treatment ofmultidrug-resistanttuberculosis

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WHO/HM/B2014.23

© World Health Organization 2014

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Contents

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iii

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2. Guideline purpose and target audience . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.1. Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.2 arget audience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3. Guideline development process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.1 Expert Group meeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.2 Management o conflicts o interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.3 Review o evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

3.4 Decision-making during the Expert Group meeting . . . . . . . . . . . . . . . . . . 16

3.5 External peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.6 Financial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

4. Evidence base or policy ormulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4.1 Evidence or the efficacy o delamanid in the treatment o MDR-B . . . . . . . . . 20

4.2 Evidence or the saety o delamanid in the treatment o MDR-B . . . . . . . . . . 24

4.3 Cost-effectiveness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

5. Expert Group recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

5.1 Summary o evidence or the recommendation . . . . . . . . . . . . . . . . . . . . . 27

5.2 Expert Group recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

6. WHO interim policy recommendations . . . . . . . . . . . . . . . . . . . . . . . . . 32

7. Further research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

8. Dissemination and implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

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A b b r e v i a t i o n s

Abbreviations

AIDS acquired immunodeficiency syndrome

AR antiretroviral therapy

BD twice daily

CEA cost effectiveness analysis

CEM cohort event monitoring

CI confidence interval

CHMP Committee or Medicinal Products or Human Use

DDI drug drug interaction

DoI declaration o interests

DO directly observed treatment

DOS basic package that underpins the WHO Stop B Strategy

DS drug-susceptibility testing

ECG electrocardiogram

EG Expert Group

ERP External Review Panel

EMA European Medicines Agency

GB WHO Global B Programme

GRADE Grading o Recommendations, Assessment, Development and Evaluation

GRC Guidelines Review Committee

HIV human immunodeficiency virus

I intention to treat

MDR-B multidrug-resistant tuberculosis

MIC minimal inhibitory concentrationMGI mycobacteria growth indicator tube liquid culture system

MI modified intention to treat

NP national tuberculosis programme

OBR optimized background regimen

PICO population, intervention, comparator, outcome

PLHIV people living with HIV

PMD programmatic management o drug-resistant tuberculosis

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A c k n o w l e d g e m e n t s

Acknowledgements

Tis document was prepared by Christian Lienhardt, Ernesto Jaramillo, Dennis Falzon,Fraser Wares, Karin Weyer, Diana Weil and Mario Raviglione (WHO Global BProgramme), on the basis o the recommendations o an international Expert GroupMeeting convened by WHO in Geneva on 15–16 April 2014.

WHO grateully acknowledges the contributions made by the Chair o the Expert Group(Holger Schünemann); the members o the Expert Group (Mauricio Barreto, ErlinaBurhan, Lucy Chesire, Kelly Dooley, Erica Lessem, Dick Menzies, Norbert Ndjeka,

Viet Nhung Nguyen, James Seddon, Alena Skrahina, Piret Viiklepp) who developedthe recommendations; consultants working on background analyses (Bernard Fourie,Anna Vassall, Ekaterina Kurbatova); and technical resource persons in the meeting(Frank Cobelens, Michael L. Rich, Francis Varaine).

WHO also acknowledges the contributions o the members o the External ReviewPanel (Jose A. Caminero, Richard E. Chaisson, Gavin Churchyard, Anna Marie CelinaGarfin, Giovanni Battista Migliori, Rohit Sarin, Maarten van Cleeff, Andrew Vernon), aswell as members o the WHO Strategic and echnical Advisory Group or uberculosis(SAG-B) 2014 (Draurio Barreira, Amy Bloom, Gavin Churchyard, Daniela Cirillo,

Frank Cobelens, Elizabeth Corbett, Michel Gasana, Stephen Graham, Akramul Islam,Michael Kimerling, Wang Lixia, Anshu Prakash, Ejaz Qadeer, Joseph Sitienei, AlenaSkrahina, Soumya Swaminanthan, Maarten van Cleeff, Irina Vasilyeva).

Tis document was finalized ollowing consideration o all comments and suggestionsrom the participants o the Expert Group, the External Review Panel and SAG-B.

USAID is acknowledged or its support in the development o these guidelines througha sub-agreement under Cooperative Agreement (CA) No. AID-OAA-A-10–00020 orthe B CARE I project awarded to KNCV by the USAID Office o Health. Te USCenter or Disease Control and Prevention (CDC) provided work pro bono on the use

o sputum culture conversion as a surrogate marker o MDR-B treatment outcome(carried out by Ekaterina Kurbatova and colleagues).

Declarations of interest

All Expert Group members, consultants, technical resource persons, members o theExternal Review Panel and SAG-B members submitted completed Declaration oInterest (DoI) orms. Tese were reviewed by the WHO Legal Department prior to theExpert Group meeting and preparation o the draf interim policy guidance, in keepingwith WHO rules.

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A c k n o w l e d g e m e n t s

wo Expert Group members (Daniela Cirillo, Erica Lessem) declared having receivedsupport rom pharmaceutical companies or work not related to the present guideline;

and Dalene van Delf declared receiving compassionate use access to bedaquiline –all o these declarations were deemed to be insignificant. Tree members (FrankCobelens, Michael L. Rich, Francis Varaine) declared current discussions with thecompany (Otsuka) on potential access to delamanid or uture studies on roll-outo new drugs under programmatic conditions (FC, MR) or or uture clinical trialo new regimens or MDR-B reatment (FV). Tese declarations were deemed tobe significant or a possible conflict o interest, and experts were requested not tocontribute to deliberations on the recommendations. Te other members o the ExpertGroup as well as the consultants and the members o the Expert Review Panel declaredno interest.

With respect to the SAG-B review, Chuck Daley declared serving as chair o thedata monitoring board or Otsuka delamanid trials, and Francis Varaine declaredparticipation in discussions between MSF and Otsuka to receive supplies o Delamanidor use in clinical trials along with other drugs. Tese two declarations were deemedsignificant or a possible conflict o interest and these SAG members did not participatein external review. Frank Cobelens, as a member o SAG-B, had a revised declarationo interest noting no current or uture planned work with Otsuka; he participated inthe external review.

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E x e c u t i v e s u m m a r y

Executive summary

Background

Drug resistance is a major threat to global tuberculosis (B) care and control. WHOestimates that around 480,000 new multidrug-resistant tuberculosis (MDR-B)a casesoccured in 2013. Current treatment regimens or drug-resistant B are complex, lengthy,toxic and expensive. Only about one hal o MDR-B patients started on treatmentglobally are reported to be treated successully, largely due to a high requency o death

and loss to ollow-up, commonly associated with adverse drug reactions and highcosts o treatment. In addition, it is estimated that up to a third o MDR-B cases mayhave strains with additional resistance to fluoroquinolones and/or injectable second-line drugs (aminoglycosides or capreomycin), rendering their treatment even moredifficult, with recourse only to highly toxic drugs.

Te landscape o drug development or treatment o B has evolved over the past tenyears and novel drugs are presently or soon entering Phase III trials or the treatmento MDR-B. Considering the global MDR-B crisis, the limited therapeutic optionsavailable or this lie-threatening condition, and the need to promote sae and

responsible use o B drugs, WHO convened an Expert Group in April 2014 to reviewthe available evidence on the efficacy, saety and effectiveness o delamanid, a new drugor the treatment o MDR-B, with the view to issue interim recommendations on itsuse in conjunction with WHO-recommended MDR-B treatment.

Evidence assessment

Data on the pre-clinical and clinical development o the drug provided by themanuacturer, as well as publicly available data were reviewed to assess efficacy, saetyand tolerability o the drug. In addition, modeling work to assess the potential cost-

effectiveness o programmatic implementation was commissioned to an independentexpert. Te comprehensive review o these data was conducted according to theGRADE process or evidence assessment, as required by WHO.

a Multidrug-resistant tuberculosis: tuberculosis with resistance to, at least, isoniazid and riampicin.

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Data on delamanid efficacy and saety resulted rom three studies:

• rial 204: A phase 2, multicentre, double-blind, randomized, placebo-controlledclinical trial conducted in nine countries.a A total o 481 patients aged 18 to 64 wererandomized to receive two months o treatment with either delamanid 100mg twicedaily (BD) on top o an optimized background regimen (OBR), delamanid 200mgtwice daily+OBR, or placebo+OBR;

• rial 208:a An open-label extension o rial 204 that allowed continued or first-time access to delamanid in combination with OBR or an additional six monthsor patients who completed rial 204 and consented to participate. A total o 213(44.2%) o the 481 patients rom rial 204 were enrolled in this study;

• Study 116:b An observational study which captured the long-term treatment

outcomes or patients who participated in rial 204 and rial 208. 421 patients whoinitially participated in rial 204 were included, and 390 completed the 24 monthsollow-up.

Summary of results

Short-term efficacy: Data or efficacy analysis was provided by the manuacturer or various time periods and rom a variety o patient populations. Te primary efficacyendpoint (short-term efficacy) was two-month sputum culture conversion (SCC) asderived rom rial 204. Efficacy analysis was based on a modified intention to treat

(MI) population (N=402/481 patients) and involved randomized patients whohad a positive sputum culture or B and drug-resistance to isoniazid and riampicinconfirmed phenotypically at baseline, using the mycobacteria growth indicator tube(MGI) liquid culture system. A higher proportion o patients treated with delamanid100mg BD (the dose recommended by the manuacturer)+OBR achieved SCC at twomonths (Day 57) than patients treated with placebo+OBR: 64/141 (45.4%) vs. 37/125(29.6%); p=0.008. Te hazard ratio or time to conversion to a negative sputum culturewas 0.58 (95% CI: 0.39 to 0.89) in the delamanid-100mg BD group.

Long-term efficacy: Data or efficacy beyond the first two months o treatment was

provided by the manuacturer through analysis o combined data using solid culturerom rial 204, rial 208 and Study 116, grouping patients according to the totalduration o delamanid received in the various trials, irrespective o the dose received(100mg BD or 200mg BD). By the end o treatment, 90.9% (130/143) o patients whoreceived delamanid+OBR or six months or more (≥6 months) achieved sustainedSCC compared to 70.9% (112/158) o patients who received delamanid+OBR or twomonths (≤2 months) or less.

a China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, Republic o Korea, and the United States oAmerica.

b rial 208 and Study 116 are extensions o rial 204. Tey are reerred to by the terminology used in the

published reerences and as provided by the manuacturer; it should be noted that these are not different/separate studies, but involved non-randomized and selected patients rom the original rial 204.

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Te proportion o patients reported with a favourable treatment outcome at the end othe 24-month treatment period (i.e. confirmed microbiological cure on solid culture

or treatment completion) was significantly higher in the ≥6 month group (74.5%, 95%CI: 67.7–80.5) than in the ≤2 month group (55.0%, 95% CI: 48.3–61.6) (p

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end o treatment (Study 116) perormed by the manuacturer had little value or theevaluation o effect, since this was a retrospective analysis relying on non-standardized

ollow-up procedures and conditions, and on artificial grouping o patients with wide variability o drug exposure in terms o timing, duration and doses o treatment.

Te Expert Group thereore requested re-analyses o data or the estimate o effectbeyond the two-month SCC, considering (i) only patients included in Study 116who received delamanid rom the start o treatment in rial 204 and continued toreceive delamanid during rial 208, as this was elt to be more consistent with themanuacturer’s instruction to use delamanid or 6 months (in addition to OBR) romthe start o treatment; and (ii) using as controls only those patients who did not receivedelamanid at all in either trial. Te revised analyses showed a 35% increase in cure(according to WHO definition) when delamanid was added to an OBR vs. OBR alone(RR 1.35; 95% CI 1.03 – 1.63).

O note, 4/205 patients seemed to have developed in vitro resistance to delamanidduring treatment, although no discernible reasons could be established.

Final conclusion on efficacy : Te Expert Group concluded that data on short-termor long-term efficacy o delamanid added to an OBR or MDR-B were o ‘very low’quality, i.e. the Expert Group had very low confidence in the estimate of effect of delamanid.

Final conclusion on safety : Te Expert Group noted that the risk o any adverse event

in the delamanid treatment arms in rial 204 was not significantly different than in theplacebo arm. Tey noted, however, that prolongation o the Q interval was the mostserious adverse event, with a significantly higher risk o Q prolongation relative tobaseline in the delamanid treatment arms compared to the placebo arm. Saety risksor patients receiving at least six months o treatment with delamanid+OBR comparedto OBR alone could not be assessed in rial 208 due to the absence o proper controls.Te Expert Group also noted that there was no inormation on the potential synergyo cardiotoxic effects i delamanid was used in combination with other drugs whichalso prolong the Q interval (such as moxifloxacin); thereore, the overall evidenceor saety was graded as ‘low’, despite the clear difference in mortality observed whendelamanid was added to an OBR .

Cost-effectiveness: Te Expert Group assessed the results o a cost-effectiveness analysis(CEA) conducted to model the incremental cost-effectiveness o adding delamanidto existing WHO-recommended MDR-B regimens. Tis CEA was undertaken or

various settings to allow or variation among countries in income level, the modelo care used or MDR-B treatment, and background patterns o drug resistance. Itocused on the direct benefits to patients, but did not attempt to assess the indirect(and acquired) transmission benefits, nor did it assess the broader economic benefits topatients or society. Since several analyses were conducted by the manuacturer to assessefficacy (see above), a sensitivity analysis was perormed on the cost-effectiveness

o delamanid applying the different trial data and respective assumptions. Using a

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conservative approach, delamanid was ound to be cost-effective in most settings, butthe quality o this evidence was considered ‘very low’, and the Expert Group concluded

that urther work was needed to evaluate cost-effectiveness once the final price o thedrug is made public by the manuacturer.

Overall, balancing the potential benefits and risks o adding delamanid to anoptimised MDR-B regimen, the Expert Group concluded that the anticipatedbenefits probably outweighed anticipated undesirable effects. Tereore, the ExpertGroup recommended that delamanid (100mg BD or 6 months) may be added to aWHO recommended regimen in MDR-B adult patients under specific conditions(conditional recommendation, very low confidence in estimates of effect ).

WHO interim policy recommendationsAvailable data on delamanid efficacy and saety is very limited as assessed by theGRADE process; however, the overall benefits o the inclusion o delamanid in a WHO-recommended MDR-B regimen appear to outweigh the observed harms. Tereore,considering the global MDR-B crisis, the limited therapeutic options available orthis lie-threatening condition, and the need to promote sae and responsible use o Bdrugs, WHO is making the ollowing interim policy recommendation or the use odelamanid in the treatment o MDR-B:

WHO recommends that delamanid may be added to a WHO-recommendedregimen in adult patients with pulmonary MDR-B (conditional recommendation;very low confidence in estimates of effect).

In view o the insufficient experience with the use o delamanid under the differentconditions that may be expected in treatment programmes, and the uncertainty aboutits overall added value in the treatment o MDR-B patients, WHO recommends thatthe use o delamanid in the treatment regimen o MDR-B be made subject to theollowing five conditions:

1. Proper patient inclusion

Te current recommendation or the use o delamanid applies to adults (≥18yrs) withpulmonary MDR-B disease, including people living with HIV. Special caution andproper clinical judgment should be applied when delamanid is used in persons 65 yearsand older, or in those with diabetes, hepatic or severe renal impairment, or those whouse alcohol or substances, given that data on efficacy and saety under such conditionsare extremely limited or unavailable.

Use o the drug in children and in pregnant and breasteeding women is not currentlyadvised due to a lack o evidence on saety, efficacy and proper dosing in these groups.

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Because delamanid is shown to cause prolongation o the Q interval, patients with aQcF>500ms should not receive the drug.

When an effective and reasonably well-tolerated MDR-B regimen can be composedwith conventional second-line drugs, the routine addition o delamanid may not bewarranted and the implications o additional health service costs should be considered.MDR-B patients in whom delamanid may have a particular role include those with:

• higher risk or poor outcomes (eg. drug intolerance or contraindication, extensiveor advanced disease);

• additional resistance to fluoroquinolones or injectable drugs;

• XDR-B (see 3.b or additional measures to apply when the drug is used in XDR-B patients).

While patients with exclusive extrapulmonary disease were not included in thedelamanid trials, there is no absolute contraindication or its use in such patients andinclusion may be considered where any potential harm that delamanid may cause isoffset by the benefit expected.

2. Adherence to the principles of designing a WHO-recommendedMDR-TB regimen

Delamanid is intended to be introduced alongside other anti-B drugs in composing aneffective second-line regimen based on WHO guidelines; the cardinal rules governing

the general composition and duration o MDR-B regimens remain the same:

a. Te WHO-recommended MDR-B treatment regimen (1) is typicallycomposed o at least pyrazinamide and our second-line drugs consideredto be effective (based on drug susceptibility testing (DS) and/or previoususe and/or drug resistance surveillance data): a fluoroquinolone (preerablylater-generation), a second-line injectable agent, and two bacteriostatic drugs,preerably prothionamide or ethionamide plus cycloserine or p-aminosalicylicacid.

b. MDR-B patients with confirmed resistance or intolerance to either

fluoroquinolones or the second-line injectable drugs represent a particulartreatment challenge. In such cases, delamanid may have a crucial role to play instrengthening a regimen, bringing the number o drugs likely to be effective toa minimum o our, and reducing the risk o acquisition o additional resistanceand progression towards XDR-B.

c. Tere is as yet no standardized DS method or delamanid, nor a commerciallyavailable test. DSs or second-line drugs other than fluoroquinolonesand injectables (kanamycin, amikacin, capreomycin) are not accurate orreproducible, and MDR-B patients may respond poorly to treatment orreasons other than drug resistance. A change in medication may, thereore,

have to be based on persistence o positive sputum culture, or reversion topositive ollowing initial culture conversion rather than DS.

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d. While experience in the use o delamanid in the management o XDR-Bis very limited, there may be a benefit given the limitations in designing an

effective regimen. In such patients, delamanid may lower the need to includeother drugs belonging to Group 5 which have unproven anti-tuberculosisactivity or a lower saety profile. However, special caution is necessary whendelamanid is used with a fluoroquinolone or a Group 5 drug given the potentialor synergistic drug-drug interactions effects, particularly on Q prolongation.a

e. Tere are currently no data on the simultaneous use o bedaquiline anddelamanid in the same patient. Until such data become available, norecommendation on the joint administration o these two medicines ispossible within the scope o this interim guidance.

. In line with general principles o B therapeutics, delamanid should not be

introduced into a regimen in which the other companion drugs are known orbelieved to be ineffective, or are ailing to show effectiveness. Tis means thatdelamanid should not be added alone to a ailing regimen. Given the emergenceo resistance to delamanid observed in the available data, all possible measuresshould be taken to protect the efficacy o the drug.

g. Te recommended dose o delamanid in adults is 100mg twice a day, irrespectiveo body-weight, or a period o six months. As bioavailability was higherwhen given afer a standard meal, delamanid should preerably be deliveredafer a meal. Tere was no evidence that delamanid 200mg twice a day wasmore effective than the 100mg dose and the higher dose was associated with

higher rates o adverse events including Q interval prolongation. It should beparticularly noted that supervision o delamanid intake should be adapted totwice a day.

3. Treatment is closely monitored

Adherence to best practices when administering treatment is imperative to ensureoptimal drug effectiveness and saety. It is thereore recommended that the ollowingmeasures are in place:

a. Sound treatment and management protocols, including clear patient eligibility

criteria, locally appropriate procedures or inormed consent (see 5), anddefined roles and responsibilities o all proessionals involved. Saety concernsare best addressed through active pharmacovigilance (2).

Te treatment protocols should allow or the prospective capture o data onkey variables or both effectiveness and saety, making sure that the goodpractices, such as those applied in the conduct o observational studies, areadhered to (3,4).

a A QcF value greater than 440ms is considered prolonged. A value greater than 480ms (or an increase o

greater than 60ms rom baseline) should trigger electrolyte testing and more requent ECG monitoring. AQcF interval o more than 500ms is considered dangerous and stopping Q-prolonging drugs is indicated.

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b. reatment protocols are preerably submitted to, and approved by the relevantnational ethics authority in the country prior to patient enrolment on treatment.

c. Preerably, oversight o treatment programmes is provided by an independentgroup o experts in clinical management and public health (e.g. a nationalMDR-B advisory group).

d. Te potential or emergence o delamanid resistance during the course otherapy requires that all measures to enable patient’s adherence are in placebeore starting treatment.

4. Active pharmacovigilance and proper management of adverse drugreactions and prevention of drug–drug interactions.

Alongside the measures in 3. above to monitor treatment adherence and effectiveness,

special vigilance is needed or adverse events, including potential reactions to delamanidwhich are as yet undescribed.

a. Given that the results o Phase III trials are expected in the next ew years, itis particularly important that the introduction o delamanid is accompaniedby an enhanced monitoring or adverse events. For this purpose, spontaneousreporting is not expected to represent an appropriate level o care and activepharmacovigilance techniques, such as ‘cohort event monitoring’ (CEM), willbe needed to improve the early detection o adverse drug reactions. Detailson the methodologies or mounting CEM, particularly when new drugs are

introduced, have already been published by WHO (2).b. Any adverse drug reaction attributed to delamanid should be reported to

the national pharmacovigilance centre. As or any other drug in an MDR-B regimen, the patient should be encouraged to report to the attendinghealth worker any adverse event that occurs during the time the drug is beingtaken. Such occurrences should also trigger a rapid response to manage theseuntoward effects in the patient.

c. When introducing delamanid into a regimen, there is also the potential or itsinteraction with other medications administered concurrently, with additiveor synergic adverse effects. Other second-line drugs that are likely to be

administered with delamanid, notably fluoroquinolones and cloazimine, maypotentially increase the risk o cardiotoxicity. Although there are data showingQ interval prolongation when delamanid is administered simultaneously withlevofloxacin, no data are available on concomitant use with moxifloxacin and/or cloazimine. Also, some antiretroviral medications can cause modest Qprolongation, especially ritonavir-containing regimens. Tereore, monitoringo patients or cardiac dysrhythmias or Q interval prolongation (i.e. using

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B a c k g r o u n d

INTERIM POLICY GUIDANCE

THE USE OF DELAMANID IN THE TREATMENT OFMULTIDRUG RESISTANT TUBERCULOSIS

Background

Te emergence o drug-resistant tuberculosis is a major threat to global tuberculosis

care and control. WHO estimates that around 480,000 new multidrug-resistanttuberculosis (MDR-B)a cases occurred in the world in 2013 (5). Current treatmentregimens or drug-resistant B are ar rom satisactory. Whereas most patients withdrug-susceptible B can usually be cured with a six-month course o treatment, inmost MDR-B cases a treatment length o 20 months or more is used, requiring thedaily administration o drugs that are more toxic, more expensive and less effectivethan those used to treat drug-susceptible B. Only about hal o MDR-B patientsstarted on treatment globally are treated successully, as a result o loss to ollow-up(28%), commonly associated with adverse drug reactions and high costs associated withtreatment, and high requency o death (15%). In addition, it is estimated that up to a

third o MDR-B cases may have strains with additional resistance to fluoroquinolonesand/or injectable second-line drugs (aminoglycosides or capreomycin), renderingtheir treatment even more difficult, with recourse only to highly toxic drugs. Finally,the global deployment o rapid diagnostics or drug resistance, such as the Xpert MB/RIF assay, has increased the demand or treatment o MDR-B patients, and this hasnot been matched by a similar expansion in the provision o appropriate treatmentor diagnosed cases. Te increased global scale-up o rapid tests to diagnose MDR-Bcases is bound to make this gap even wider in the coming years. Te lack o effectiveand affordable drugs or the treatment o MDR-B is a critical actor in the inabilityo programmes to scale-up their treatment efforts to meet national and global targets.

Te landscape o drug development or treatment o B has evolved dramaticallyover the last ten years, and novel drugs are presently or soon entering Phase III trialsor the treatment o MDR-B. Dossiers have been submitted to stringent regulatoryauthorities (SRAs) under procedures o “accelerated” or “conditional” approval ormarketing these new drugs. Among these, bedaquiline, a diarylquinoline, was approvedby the US Food and Drug Administration (FDA) in December 2012, and WHO issuedinterim guidance or its use in the treatment o MDR-B in June 2013(6). Delamanid,a nitro-imidazole, another new compound, has been granted a conditional marketingauthorisation by the European Medicines Agency (EMA) Committee or MedicinalProducts or Human Use (CHMP) on the 28th April 2014 (7). Dossiers are currently

a Multidrug-resistant tuberculosis: tuberculosis with resistance to, at least, isoniazid and riampicin.

1.

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B a c k g r o u n d

being submitted to several national regulatory authorities and are being evaluatedunder procedures o “accelerated” or “conditional” approval based on early (Phase IIb)

clinical data, and Member States have expressed the need or WHO to provide interimadvice on the use o delamanid in MDR-B treatment.

Considering the global MDR-B crisis, the limited therapeutic options available orthis lie-threatening condition, and the need to promote sae and responsible use oB drugs, WHO has evaluated the added value o delamanid within the context oexisting guidelines on programmatic management o MDR-B. An Expert GroupMeeting was convened in April 2014 in Geneva to review the available evidence on theefficacy, saety and effectiveness o this new drug or the treatment o MDR-B, and torecommend whether WHO interim guidance on the use o this drug in treatment oMDR-B is warranted. As in the case o bedaquiline (6), it is acknowledged that issuinginterim guidance carries the responsibility to ensure that this guidance provides specificrecommendations on the conditions or the use o the drug that reflect the limiteddata currently available. WHO will review, revise or update the interim guidance asadditional substantive data on efficacy and saety become available. Acceleration oPhase III trials and completion at the earliest opportunity is imperative, as is timelyanalysis o emerging operational data on the use o the drug. It should also be notedthat, in the absence o interim guidance rom WHO, uncontrolled and potentiallyirresponsible use o the new drug may adversely affect B care and control effortsoverall – with emergence o additional drug resistance and the possible loss o a newdrug or B chemotherapy.

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G u i d e l i n e p u r p o s e a n d t a r g e t a u d i e n c e

Guideline purpose and target audience

2.1. Purpose

Te aim o this guidance is to provide the interim principles that should guide theuse o delamanid in conjunction with WHO-recommended MDR-B treatment. Italso specifies the essential treatment and management conditions or use o this drug,in particular the patient’s eligibility criteria and saety conditions, and presents thenecessary caveats relevant to the use o this new drug or which Phase III clinical trial

data are not yet available.

Te interim guidance positions delamanid in the context o existing guidelines onMDR-B treatment, as the drug cannot be used on its own and should be added toMDR-B regimens designed according to WHO-recommended principles. Tisdocument should thereore be read in conjunction with the most recent documents onthe programmatic management o drug-resistant tuberculosis:

• Guidelines for the programmatic management of drug-resistant tuberculosis, 2011update. (GRC-approved) (1); and

• Companion handbook to the WHO guidelines for the programmatic management of

drug-resistant tuberculosis (3).It should also be read in conjunction with the detailed findings rom the ExpertGroup meeting and the delamanid implementation manual, part o the ‘Companionhandbook’ reerenced above.

Te planned date of review of this interim guidance is 2016, or earlier in case of significantdevelopment. It is expected that data emerging rom a currently on-going Phase IIIclinical trial o delamanid will inorm uture review and possible refinement o theinterim policy guidance.

2.2 Target audience

Te main target audience o this interim guidance is national B programmes(NP), other public health agencies, and other public and private partners involvedin planning, implementing and monitoring tuberculosis control activities. Teprinciples and recommendations are also relevant or specialist clinicians, technicaladvisors, laboratory technicians, drug procurement managers, other service providers,other relevant government officials, and implementing partners involved in country-level strengthening o drug-resistant B care and control. Individuals responsible orprogramme planning, budgeting, resource mobilization, and training activities or

drug-resistant B diagnostic services may also benefit rom using this document.

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G u i d e l i n e d e v e l o p m e n t p r o c e s s

Guideline development process

Te process developed by the Guideline Review Committee (GRC) o WHO wasstrictly ollowed. A WHO Guideline Steering Group was ormed (see Annex 1), whichidentified, together with the chair o the Expert Group (see below), the areas requiringevidence synthesis.

3.1 Expert Group meeting

An Expert Group (EG) was convened in Geneva by the Global B Programme o theWorld Health Organization (WHO) on 15–16 April 2014 to assess available data ondelamanid with a view towards developing interim policy recommendations on its use,i deemed appropriate. Te EG (Annex 2) consisted o researchers, epidemiologists,end-users (clinicians and national B and drug-resistant B programme managers),community representatives and evidence synthesis experts. Te meeting ollowed astructured agenda (Annex 3) and was chaired by a clinical epidemiologist/methodologistwith extensive experience in evidence synthesis and guideline development.

Te aim o this meeting was to evaluate the added benefit o delamanid or the treatmento MDR-B and, i appropriate, provide recommendations to WHO or interimguidance to countries on its use in conjunction with WHO-recommended MDR-Btreatment regimens.

Te specific objectives were:

• o evaluate the efficacy and saety o delamanid when given together with currentWHO recommended MDR-B treatment;

• o evaluate the balance between harms and benefits o the drug, its potential cost-effectiveness, patient and provider preerences and concerns, and the easibility ointroducing the drug in MDR-B programmes; and

• o provide, as appropriate, recommendations on the use o the drug as part o WHO-recommended MDR-B treatment regimens, including attention to concerns/constraints relevant to the use o a new drug or which Phase III clinical trial dataare not yet available.

3.2 Management of conflicts of interest

WHO policies on conflicts o interest were applied in consultation with the WHOLegal Department. All EG members were asked to complete the WHO Declaration oInterest (DoI) orm beore their invitation was confirmed and data shared with them

under non-disclosure agreements. All orms were reviewed by the WHO Guideline

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Steering Group in conjunction with the WHO Legal Department prior to the EGmeeting. Attention was given to potential conflicts o interest related to the appraisal o

evidence, the ormulation o recommendations and the external peer review process.Particular attention was also given to assessment o financial as well as intellectualDoIs. In addition, individuals were not considered or inclusion in the Expert Groupi they had been involved in clinical trials conducted by the company, or in any entityor committee related to the conduct o any trial conducted by the company (e.g. trialsteering committee, data monitoring committee, scientific advisory board), even i notremunerated, or i they had been involved in the development and testing o the newdrug or other, potentially competing, drugs.

DoI statements were summarized by the WHO/GB secretariat at the start o themeeting. A summary is attached in Annex 4.

echnical resource consultants participated in the meeting to provide specificinormation on technical issues, but were not involved in the deliberations andpreparation o the actual recommendations.

Just prior to the EG meeting, some participants updated their DoIs with ongoing talkswith the company or uture studies involving delamanid. Tis was considered to besignificant and possibly conflicting interest, so these participants were asked to serveas “technical resource persons” during the meeting – i.e. they provided technical inputduring discussions o the data but did not take part in the discussion and deliberations

leading to the development o the recommendations. All participants signed aconfidentiality agreement and were reminded o the need or confidentiality until theull WHO process was concluded.

3.3 Review of evidence

Published data on the pre-clinical and clinical development o the drug were assembledand reviewed to assess efficacy, saety and tolerability o the drug. In addition, a series odocuments were submitted to WHO by the manuacturer, ollowing the list o requireddata as stipulated in the “Inormation Note to developers o B drugs” (8). Tese data

included preclinical toxicity evaluations, dosing and pharmacokinetic studies, drug-drug interaction studies, early bactericidal activity studies, saety studies, Phase IIbstudies (including a Phase IIb randomized controlled trial (RC) using sputum cultureconversion (SCC) at two months as the primary endpoint, and an open-label Phase IIbtrial) and subsequent observational studies. An independent consultant was contractedto review and synthetize all available data into a synthesis document and prepare theGRADE evidence tables that were reviewed by the EG. Tis was complemented bymodeling work to assess the cost-effectiveness o implementation o the drug in MDR-B programmes. A ormal bibliographic search o inormation on the product wascarried out, and all publications in English were made available to the EG.

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o comply with current standards or evidence assessment in ormulation o policyrecommendations, the GRADE system (www.gradeworkinggroup.org), adopted by

WHO or all policy and guidelines development was used (9). Te GRADE evaluation,assessing both the quality o evidence and strength o recommendations, aims toprovide a comprehensive and transparent approach or developing policy guidance.It assesses the impact o a particular intervention on patient-important outcomes andthe generalizability o results to the target population, taking into consideration thecomparison used and whether this was direct or indirect.

A PICO (Population, Intervention, Comparator, Outcome) question was pre-definedin consultation with the WHO Expert Group: “In MDR-B patients, does the additionof delamanid to a background regimen based on WHO-recommendations safely improve

patient outcomes?”

PICO reers to our elements that should be in a question governing a systematic searcho the evidence, and was defined or delamanid as ollows:

• Population: targeted by the action/intervention: patients with MDR-B, includingnewly diagnosed patients, patients treated empirically or MDR-B, HIV-inectedpatients (+/- use o ARVs), and children;

• Intervention: addition o delamanid during the first 6 months o WHO-recommendedbackground MDR-B therapy;

• Comparator: addition o placebo to WHO-recommended MDR-B treatment;

• Outcome: efficacy (as demonstrated by sputum culture conversion during treatmentand final treatment outcomes based on WHO definitions), saety (toxicity, seriousadverse events, mortality).

In order to preserve consistency in the evaluation o drugs that are being considered orthe treatment o MDR-B, it was proposed that the EG use the same patient outcomesor the GRADE evaluation as those that were used or the evaluation o bedaquilineand determined to be most important or patients (6). Tese important outcomes wereapplied to the published results as well as data that were provided to WHO by the drugmanuacturer (Otsuka). Subsequently, the ollowing outcomes were evaluated or theevidence profile:

1. Sputum culture conversion at two months

2. ime to sputum culture conversion over the first two months o treatment

3. Sustained sputum culture conversion at 24 months

4. Cure at 24 months

5. Mortality at 24 months

6. Serious adverse events

7. Acquired resistance to delamanid.

Tese different outcomes were scored by the EG members on a scale rom 1 to 9 basedon their relative importance; all were considered “critical”.

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Te review o evidence took place in three successive stages.

At the first stage, prior to the in-person meeting o the Expert Group, experts reviewedthe evidence rom available studies o delamanid, including data rom a Phase IIb RCusing SCC at two months as the primary endpoint, an open-label Phase IIb trial andsubsequent observational study, together with the synthesis document prepared by theexternal independent consultant.

At the second stage, experts evaluated the available evidence using the GRADE systemor grading quality o evidence and assessing strength o recommendations, based onthe PICO question. For each o the agreed outcomes (above), the quality o evidence was evaluated according to the ollowing criteria:

• Overall study design: randomized trial(s), or consecutive selection o patients(observational), or selection o patients according to given reerence standard(case-control).

• Risk of bias or limitations in study design and execution

• Inconsistency: unexplained inconsistency in study endpoints or estimates.

• Indirectness: absence o direct evidence o impact on patient-important outcomesand generalisability.

• Imprecision: wide confidence intervals or treatment outcome estimates.

• Other considerations: possibility o publications bias, etc.

A glossary o the GRADE terms used can be ound in Annex 5.

In a third stage, as called or by GRADE and based on the PICO question, the EGdeveloped a recommendation and considered the strength o the recommendation(strong or conditional), based on the quality o available evidence, the balance o effects(benefits weighed against harms), as well as patient values and preerences, resourcesand equity.

3.4 Decision-making during the Expert Group meeting

Te EG meeting was chaired by a recognized methodologist/evidence synthesis expert.Decisions were based on consensus (preerred option). In one instance, consensuscould not be achieved among members and the EG proceeded to a vote (with simplemajority rule) – this decision related to the need or written inormed consent prior tostarting a delamanid-containing MDR-B treatment (see section 5.2).

Concerns and opinions by EG members during the meeting were noted and includedin the final meeting report. Te detailed meeting report was prepared by the WHOSecretariat Steering Group and was revised based upon input and sign-off by all EGmembers.

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3.5 External peer review

An External Review Panel (ERP) independently reviewed the draf interim guidanceprepared by the WHO Guideline Steering Group on the basis o the recommendationsby the EG. Te ERP was composed o eight reviewers external to the Expert Group,including content experts, end-users rom high B and HIV burden countries, andrepresentatives rom WHO’s Strategic and echnical Advisory Group or B (SAG-B). Te list o members o the ERP can be ound in Annex 6. Comments made by themembers o the ERP are reflected in the final version o the present interim guidancedocument.

3.6 Financial support

Financial support or the EG meeting and related analyses was provided under a Sub-agreement under Cooperative Agreement (CA) No. AID-OAA-A-10–00020 or theB CARE I project awarded to KNCV by the Office o Health o the US Agency orInternational Development (USAID). US Centers or Disease Control and Prevention(CDC) provided work pro bono on the evaluation o sputum culture conversion asa surrogate marker o MDRB treatment outcome (work carried out by EkaterinaKurbatova and colleagues).

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E v i d e n c e b a s e f o r p o l i c y f o r m u l a t i o n

Evidence base for policy formulation

Published data on the pre-clinical and clinical development o delamanid were reviewed.a

Additional data were provided to WHO by the manuacturer with the understandingthat these data would be available publically at the time that the interim policy guidancewas issued by WHO. An independent consultant was contracted to prepare a concisesynthesis report o the available evidence, and this report was circulated to the EGbeore the meeting. In addition, two technical resource consultants were requested todevelop specific documents to assist the EG in their evaluation o delamanid:

1. an assessment o the validity o sputum culture conversion at two and six months andtime to culture conversion as surrogate markers o MDR-B treatment outcomes;and

2. a cost-effectiveness analysis o introducing delamanid in MDR-B regimens basedon modeling.

Te overall clinical development programme or delamanid included, in addition to 12Phase I trials in healthy subjects, six trials conducted in patients with B. During 2008–2011, the manuacturer launched and completed two trials and one observational studyevaluating the efficacy and saety o delamanid or the treatment o MDR-B when usedin combination with an ‘optimized background regimen’ (OBR) designed according toWHO recommendations (1) – see Figure 1. o design an OBR, initial inormation wasrequired on susceptibility o the individual patient M.tuberculosis isolates, the patient’sprevious treatment history or B, drug resistance patterns o known MDR-B contacts,and HIV status. According to the manuacturer, such a strategy was believed to offerindividual patients the best opportunity or cure, irrespective o whether delamanidwas added to the regimen. While this approach to treatment would inevitably resultin greater variability in the regimens used in the delamanid and placebo arms, asopposed to a standardized regimen, the manuacturer considered that any benefit odelamanid observed in such heterogeneous population could be considered a closerapproximation o real-world conditions.

According to the manuacturer, the objectives o the clinical development programmeor delamanid were first to demonstrate increased SCC at two months o treatmentwhen delamanid was added to background MDR treatment and then to show continuedimproved microbiologic outcomes with prolonged treatment by extending treatmentor an additional six months (consistent with the WHO-recommended six to eightmonth initial intensive phase treatment or MDR-B). Results rom these two trialsand a urther observational study, were analysed together and served as the basis orsubmission o the Marketing Authorization Application or delamanid with the EMA.

a Reerences or documents available on delamanid can be ound at the website indicated in page 3 o thisGuidance document.

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A higher proportion o patients treated with delamanid + OBR achieved SCC by Day57 using the MGI culture system than patients treated with placebo + OBR: 64/141

(45.4%) [p=0.008] in the delamanid 100mg group, 57/136 (41.9%) [p=0.04] in thedelamanid 200mg BD + OBR group, and 37/125 (29.6%) in the placebo + OBR group –see Figure 2. Similar results were obtained when using solid culture (data not shown).

Figure 2: Proportion o patients with sputum-culture conversion by Day 57

0

10

20

30

4050

60

70

80

90

100

Placebo 100mg, Twice daily 200mg, Twice daily

Delamanid

P=0.04

P=0.008

29.6%

(37/125)

45.4%

(64/141)

41.9%

(57/136) P a t i e n t s ( % )

Source: Gler et al, 2012 (11).

A secondary efficacy endpoint was time to SCC . Although the median time to SCC(sustained SCC achieved by Day 57) could not be calculated because ewer than 50% opatients in each group met the criteria, the Kaplan-Meier curves or time to SCC usingthe MGI system showed clear separation between each delamanid BD + OBR groupand the placebo + OBR group rom Day 36 to Day 57 (Weeks five to eight). By theend o the two-month treatment period, the difference in SCC between the delamanidgroups (both doses) and the placebo group was significant (p=0.001). Te hazard ratioor increased time to conversion to a negative sputum culture as assessed with MGIwas 0.58 (95% CI: 0.39 to 0.89) in the 100mg BD group and 0.63 (95% CI: 0.42 to 0.96)in the 200mg BD group. When using solid medium, the hazard ratio or increased timeto conversion to a negative sputum culture was 0.54 (95% CI, 0.36 to 0.81) in the 100mgBD group and 0.44 (95% CI, 0.29 to 0.64) in the 200mg BD group.

o assess the long-term efficacy of delamanid for MDR-B beyond the first two monthsof treatment , the manuacturer combined data rom rial 204, rial 208 and Study 116to evaluate the proportion o patients who achieved sustained SCC and final treatmentoutcomes at 24 months (including mortality). In total, ollow-up could be assessedin 421 (87.5%) out o the 481 patients initially randomized in rial 204. o comparetreatment outcomes, patients were grouped as ollows:

• Patients treated with delamanid 100mg BD or 200mg BD (+ OBR) were groupedtogether. Te rationale or this was that short-term treatment results (two-monthSCC) were similar or those participants who received 100mg BD and 200mg BD;

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• Patients who participated in rial 208 and received six months o delamanid (anydose) were grouped together with those who had received placebo, delamanid 100mg

BID, or delamanid 200mg BD during rial 204 and designated as the “≥6month”administration group. Individuals in this group thus received six or eight monthso delamanid. Te manuacturer’s rationale or this was that treatment outcomesand sustained SCC results were similar among those who had received six vs. eightmonths o delamanid.

• Patients who only contributed to trial 204 and received delamanid or two months orwho received placebo were pooled to make a delamanid “≤2 month” administrationgroup, because o comparable demographics and baseline characteristics and similarfinal treatment outcome. Hence individuals in this group received two months odelamanid or no delamanid at all.

Analyses perormed by the manuacturer to evaluate the long-term efficacy odelamanid compared patients who received delamanid or ≥6 months with patientsreceiving delamanid or ≤2 months. Te key endpoints or assessing longer termefficacy included:

• Sustained SCC : By the end o treatment, 90.9% (130/143) o patients in the delamanid≥6months treatment group achieved sustained SCC compared to 70.9% (112/158) opatients in the delamanid ≤2months treatment group.

• Favourable outcome: Te proportion o patients who showed a avourable treatmentoutcome (i.e. confirmed microbiological cure by solid culture or treatment

completion) at the end o the 24-month treatment period was significantly higher inthe ≥6 month group (74.5%, 95% CI: 67.7–80.5) than in the ≤2 month group (55.0%,95% CI: 48.3–61.6) (p < 0.0001).

• Mortality : Te reported mortality rate was lower in the delamanid ≥6 monthstreatment group (two deaths, 1%) compared to the delamanid ≤2 months treatmentgroup (19 deaths, 8.3%) (p < 0.001).

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able 1: Favourable treatment outcome and mortality at 24 months or MDR-Bpatients treated with delamanid

Delamanidexposure

otal I patientsN

24 months outcome

avourable deaths

N (%) 95% CI N (%) 95% CI

≥ 6 months* 192 143 (74.5) 67.7–80.5 2 (1.0) 0.1–3.7

≤ 2 months** 229 126 (55.0) 48.3–61.6 19 (8.3) 5.1–12.7

*Patients participating in rial 208 and treated with delamanid or placebo in rial 204

**Patients not participating in rial 208 and treated with delamanid or placebo in rial 204

In order to clariy the participation o patients in the above analysis, WHO requested themanuacturer to provide treatment outcomes at 24 months (using WHO-recommendedtreatment outcome definitions) stratified by delamanid dose and duration o exposureor patients who had been ollowed up within Study 116. Te results are provided inable 2.

able 2: Outcome at 24 months or patients consenting to participate in Study116 who were treated with delamanid 100mg BD or 200mg BD + OBRor two, six or eight months or with OBR alone, using WHO treatment

outcome categories (N=421)

rial 204Assignment(2 monthsDLM+OBRor OBRalone)

rial 208Participation(6 monthsDLM+OBR orOBR alone)

Ipatientsin Study116 (N)

Cured Completed Failed DiedLost to

Follow-up

n % n % n % n % n %

100-BD

1 100-BD 38 24 63% 9 24% 2 5% 0 0% 3 8%

2 200-BD 21 13 62% 2 10% 2 10% 1 5% 3 14%

3 No 80 31 39% 17 21% 12 15% 9 11% 11 14%

200-BD

4 100-BD 45 25 56% 16 36% 3 7% 0 0% 1 2%

5 200-BD 22 15 68% 3 14% 4 18% 0 0% 0 0%

6 No 76 36 47% 14 18% 12 16% 4 5% 10 13%

Placebo

7 100-BD 39 27 69% 7 18% 3 8% 0 0% 2 5%

8 200-BD 27 18 67% 2 7% 4 15% 1 4% 2 7%

9 No 73 33 45% 12 16% 13 18% 6 8% 9 12%

otal 421 222 53% 82 19% 55 13% 21 5% 41 10%

Note: this table was used for the estimate of efficacy of delamanid on ultimate treatment outcomes in the GRADE table –i.e. cure and mortality (see table 4). In the test arms, patients receiving delamanid (irrespective of dose) from the start oftreatment only were considered, as a clearer proxy of the manufacturer’s recommendation for delamanid use of 6 months– i.e. groups 1, 2, 4 and 5. For controls, only patients who did not receive any delamanid (i.e. placebo only on top of OBRin rial 204 and 208) were considered (group 9). otal population is N=199.

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4.2 Evidence for the safety of delamanid in the

treatment of MDR-TBwelve phase I trials in healthy subjects have been conducted. Pooled data provided bythe manuacturer showed that treatment-emergent adverse effects (EAEs) with thehighest incidence in subjects who received delamanid were headache (20.9%, 88/422),nausea (11.6%, 49/422), and dizziness (8.8%, 37/422).

In total, 887 individuals have been exposed to delamanid in clinical trials. Overall,22.1% (196/887) o delamanid-treated patients had a cumulative exposure o longerthan six months (180 days). Most requent were headache, abdominal pain andinsomnia. Te incidence and distribution o EAEs occurring in 10% o patients in thetwo delamanid groups in rial 204 are shown in able 3. Te only clinically relevantEAE with a difference in incidence between the delamanid+OBR treatment groupscompared to the placebo+OBR group was Q prolongation.a Other EAEs varied inoccurrence but were present in similar proportions in the delamanid+OBR and theplacebo+OBR groups. Most requent were nausea, vomiting, and dizziness.

In rial 204 and rial 208, 74 patients experienced severe adverse events (SAEs),including death. Te only clinically relevant SAE with a difference in incidence amongtreatment groups was Q interval prolongation, which was significantly higher in thedelamanid 100mg BD + OBR group (4.3%, 7/161) and the delamanid 200mg BD +

OBR group (5.6%, 9/160) than the placebo + OBR group (1.9%, 3/160). In rial 204,the placebo-corrected, change-rom-baseline QcFb increased with duration o dosingand reached 11.3 to 13.1 msec in delamanid 100mg BID + OBR and 14.1 to 15.6 msecin delamanid 200mg BID + OBR over all time points on Day 56. In rial 208, our o131 patients treated with delamanid 100mg BID + OBR and our o 73 patients treatedwith delamanid 200mg BID + OBR) had a change rom baseline QcF exceeding 60msec. Only patients on delamanid exhibited QcF prolongation exceeding 60 msecrom baseline.

Delamanid is metabolized by cytochrome P450 enzymes like CYP3A4, and ormationo its main metabolite is regulated by plasma albumin. It is neither an inducer noran inhibitor o key drug metabolizing enzymes so is unlikely to have a significantimpact on concentrations o companion drugs. Studies in healthy subjects showed noclinically-significant interactions when delamanid was co-administered with tenoovir,eavirenz or lopinavir/ritonavir.

a Te heart’s electrical cycle can be measured on an electrocardiogram (ECG); the Q interval is a measure othe time between the start o the Q wave and the end o the wave representing the electrical depolarization

and repolarization o the ventricles. A lengthened Q interval is a marker or potential ventricular tachy-

arrhythmias (such as ‘torsades de pointes’) and a risk actor or sudden death. Concomitant use o drugs thatprolong the Q interval may cause additive Q prolongation, and should be avoided i possible. O note, some

o the other second-line anti-B drugs are known to prolong the Q interval.b QcF: Q interval corrected or heart rate according to the Fridericia method.

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4.3 Cost-effectiveness

Te EG assessed the results o a cost-effectiveness analysis (CEA) conducted tomodel the incremental cost-effectiveness o adding delamanid to existing WHO-recommended MDR-B regimens. Tis CEA was undertaken or different settings toallow or variation among countries across income level, the model o care used orMDR-B treatment, and background patterns o drug resistance. It ocused on thedirect benefits to patients, but did not attempt to assess the indirect (and acquired)transmission benefits, nor did it assess the broader economic benefits to patients orsociety.

Since several analyses were conducted by the manuacturer to assess efficacy (see

above), a sensitivity analysis was perormed on the cost-effectiveness o delamanidwhen different trial data and assumptions about the translation o trial results to currentpractice were applied. Results showed that delamanid would be cost-effective in mostenvironments studied. However, this interpretation needs to take into account thequality o clinical evidence as assessed by the EG (i.e. i the quality o clinical evidenceis viewed as low, then likewise the evidence supporting cost-effectiveness should beregarded as low), as well as all limitations related to the assumptions made above.O note, in settings where cure/treatment success rate is currently high, delamanidmay not be cost-effective, as it may result in limited additional benefit. However, theincremental cost o delamanid introduction will not only depend on price, but alsoon the cost savings or retreatment as a result o an expected reduction in treatment

ailures. Using a conservative approach, delamanid was thus ound to be cost-effectivein most settings, but the quality o this evidence was considered very low, and urtherwork would be needed to evaluate cost-effectiveness and to test the robustness o theassumptions in various settings.

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E x p e r t G r o u p r e c o m m e n d a t i o n s

Expert Group recommendations

5.1 Summary of evidence for the recommendation

Te GRADE process was used to evaluate the quality o evidence presented to the EGto determine whether delamanid should be added to WHO recommended backgroundMDR-B regimen. For each identified critical endpoint, the quality o evidencewas assessed based on the criteria o study limitations/risk o bias, inconsistency,indirectness, and imprecision.

Te EG members agreed that key data to consider or evaluation o efficacy were thosecollected in the pivotal rial 204, since this trial was using a randomized controlleddesign with proper selection o controls. Te experts took note that two months SCCand time to SCC were assessed as surrogates or cure, but they were not convinced othe prognostic adequacy or accuracy o these endpoints or MDR-B cure. Te expertsalso noted that the duration o comparison between delamanid and placebo in rial204 did not allow an assessment o the potential benefit o adding delamanid (at either100mg or 200mg BD dose) to OBR or six months duration without interruption (asrecommended by the manuacturer).

rial 208 investigated six months exposure to delamanid. Here, the experts noted anumber o problems in the design and conduct o this trial hampering the collectiono high quality data, including: absence o randomization; sel-selection o patients;absence o blinding or treatment allocation; a variable gap period between the endo rial 204 and the beginning o rial 208; and a lack o consistency in the allocationo drug dosages. As a result, there were wide variations in the doses, timing andduration o exposure to the drug or various subgroups o patients. Furthermore,the experts considered that there was a serious risk o bias or all data arising romthe observational Study 116 due to variability in ollow-up procedures as well asun-blinded assessment o outcome, and serious inconsistency due to the variability in

duration o drug exposure. Experts were also in agreement that the post hoc analysisperormed by the manuacturer o efficacy at the end o treatment in Study 116 hadlittle value or the evaluation o effect: this was a retrospective analysis relying on non-standardized ollow-up procedures and conditions, and the grouping o patients inthose who received ≥6 versus ≤2 months o delamanid was considered not appropriatedue to lack o randomization to the various treatment arms and the high variability oexposure (in terms o timing, duration and doses o treatment).

Te experts noted that the duration o exposure to delamanid in the pivotal RC wastoo short to be able to discern a benefit o adding delamanid (at either 100mg or 200mg

BD dose) to OBR or six months, and the subsequent enrolment o patients in rial 208and Study 116 did not allow or a controlled assessment o efficacy endpoints over the

5.

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proposed duration o use o delamanid (six months), nor a robust assessment o curerates by the end o treatment.

Experts also noted that the risk o any adverse event in the delamanid arms was notsignificantly different than in the placebo arm. Tey noted, however, that Q intervalprolongation was the most concerning serious adverse event, and were concerned aboutthe lack o inormation on the potential synergy o cardiotoxic effects i delamanidwas used in combination with other Q prolonging drugs, such as moxifloxacin orcloazimine. Te experts also noted that there was no evidence that delamanid 200mgtwice a day was more effective than 100mg twice a day and that the higher dose wasassociated with higher rates o adverse events, including Q prolongation.

Overall, the EG had a very low level o confidence in the short- or long-term efficacy

o delamanid given that the available evidence was very limited and o low or very lowquality (or efficacy and saety, respectively).

Te EG also discussed the potential to draw conclusions or different subcategories oMDR-B patients, such as patients with strains resistant to either fluoroquinolones orinjectable drugs or both. Limited evidence or use o the drug in XDR-B patients wasavailable, but members o the EG elt that delamanid in MDR-B patients with isolatesthat have additional resistance to fluoroquinolones or injectables or XDR-B couldpotentially benefit rom delamanid, given that treatment options or these patients areseverely limited. Te EG also expressed concern about the potential or emergence o

resistance ollowing exposure to delamanid.

In view o the shortcomings o the analyses o long-term efficacy perormed by themanuacturer and submitted to WHO (ables 1 and 2), the EG requested a re-analysiso the estimate o efficacy beyond the two-month SCC considering: (i) only patientsincluded in Study 116 who received delamanid rom the start o treatment in rial204 and continued to receive delamanid during rial 208 (as a clearer proxy o themanuacturer’s recommendation or delamanid use o 6 months), and (ii) using a stricterdefinition o the control group (restricted to patients who did not receive any delamanid– i.e. placebo only on top o OBR). Due to the uneven distribution o deaulters in therespective arms (able 2), the EG urther conducted a sensitivity analysis, including

and excluding patients who deaulted rom treatment. Te measured effects or curewere in the same direction irrespective o whether deaulters were included or excluded,and in the same direction as in the manuacturer’s analysis. However, when the analysiswas restricted to exclude deaulters (n=183), the relative risk o treatment success wassmaller and did not reach statistical significance (RR: 1.25; 95% CI: 0.96 – 1.65). Tereasons or this observation were not clear but the sensitivity analysis would suggestthat, as patients were not randomized during rial 208 and Study 116 and deault wasa non-random outcome, treatment outcomes may have been correlated with deault.For example, patients who deaulted could have been more likely to ail or die had theycompleted treatment, and the observed treatment success o 1.35 (95% CI: 1.03 to 1.63)

(able 4) could thereore be an over-estimation o effect.

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O note, 4/205 patients seemed to have developed in vitro resistance to delamanidduring treatment, although no discernible reasons could be established.

Overall, although the experts had very low confidence in the quality o evidenceavailable, they agreed that the anticipated benefit of adding the drug to OBR couldoutweigh the anticipated undesirable effects. Te experts considered that any potentialharm associated with using the drug would be offset by the benefits which can beexpected in most settings, given that clinicians treating MDR-B patients ofenace limited treatment options, that outcomes or MDR-B patients on second-linetreatment are very unsatisactory, and that ineffective regimens could increase thelikelihood o acquisition o additional resistance or chronicity.

Te EG elt that there were potentially large variations in patient values and preferences

or each outcome. Most members elt that patients would place high value on treatmentsuccess/cure, serious adverse events and mortality but that it was less clear that patientswould similarly value mycobacterial culture conversion. Te expert group assumedthat there was minimal variation or values related to death, but larger variation orother outcomes, in particular about how much value patients would place on the sideeffects (e.g. Q interval prolongation).

EG members expressed the view that patient acceptance of delamanid would depend onthe severity o their disease and the likelihood that an effective background regimencould be designed or them – e.g. XDR-B patient groups might be more likely to

accept the risk o taking a new drug with uncertain efficacy than patients with newlydiagnosed MDR-B without additional drug resistance. Te EG elt, however, that a dulyinormed decision making-process by patients should be ollowed; this would requirethat the intervention be presented as an option and that inormation be provided onuncertainty about the effects. Te decision about requesting signed inormed consentwas submitted to a vote (5:5 vote, 2 missing). Subsequently, as written inormed consentis mandatory or MDR treatment in some settings, the EG noted that local practiceshould be observed.

With respect to required resources, the EG took the cost perspective o a B programmeand ocused on direct benefits to patients. Te cost-effectiveness analysis showed that

while incremental cost varied relative to the net benefits, there were a number o sourceso uncertainty including the costs o the drug, related additional treatment costs, efficacyand long-term outcomes. Te EG noted that indirect transmission benefits were notconsidered, and that the analysis was based on drug cost parameters provided by themanuacturer. Te EG also noted that relative cost-effectiveness does not necessarilytranslate into affordability or country readiness to pay, given the potential high relativecost o adding delamanid. Resource implications related to training o health care staffand establishing pharmacovigilance systems were not considered but were elt to beimportant. Te EG concluded that the resource implications o introducing delamanidin addition to MDR-B treatment may be more substantial than those presented in the

cost-effectiveness study.

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Te EG elt that the direction or impact on equity was uncertain based on presentknowledge about resource requirements or the drug and companion regimen, and

additional resource requirements o the B programme. Experts recognized thatimplementation o any new intervention may be associated with trade-offs in theabsence o additional resource mobilization.

Te EG considered that treatment should be acceptable overall to the patient, giventhe likely benefits, tolerability and limited harms. Te EG pointed that, while the othercompanion drugs o the MDR-B regimen are administered in a single daily dose,delamanid should be given twice daily. Tis may affect acceptability and adherence,given the need or directly observed therapy to prevent acquisition o urther resistance.However, acceptability may be improved by the act that delamanid is only used or sixmonths.

Te EG elt that requirements or ECG beore and during treatment may reduceoperational feasibility , as the availability o ECG machines is not a given in all settingsand because interpretation o ECG results may require reerral to specialists orextension o ECG access (implying additional resources). wice-daily dosing may alsoaffect easibility, and would require additional resources to ensure drug administrationunder observation. However, oral (in comparison to injectable medication) use mayincrease easibility. On the whole, the EG estimated that the use o delamanid on top oOBR would be easible in most MDR-B treatment settings.

Based on the available evidence, the EG concluded that delamanid may only be given inaddition to a current WHO-recommended regimen, and not as a substitute or any o thecurrently recommended second-line drugs unless they are considered to be ineffectiveor cannot be used because o severe intolerance (3). Tere was no evidence at presentthat addition o delamanid could allow or any shortening o treatment duration.

5.2 Expert Group recommendations

Based on the available evidence, and recognizing the limits o available clinical data,the EG recommended that delamanid (100mg BD or six months) may be added to

a WHO recommended regimen in MDR-B adult patients under specific conditionsand taking into account the ollowing remarks (conditional recommendation, very lowconfidence in estimates of effects):

• Te population to whom this recommendation applies is MDR-B patients. Tismay also include those with additional resistance or intolerance to fluoroquinolonesor second line injectable drugs, those with extended lesions, advanced disease andothers deemed at higher baseline risk or poor outcomes, as well as patients withXDR-B.

• Te population excludes patients with Q prolongation.

• Adherence to principles o designing a WHO-recommended regimen is required. Aswith all B treatment regimens, delamanid should never be added as a single drug

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to an already ailing regimen. Rather, it should be part o a multi-drug regimen, inwhich the other companion drugs are selected based on WHO MDR-B treatment

recommendations.• Tis recommendation includes PLHIV, as individuals with HIV co-inection were

included in the RC.

• Delamanid has not been tested in pregnant and breasteeding women, children, andpatients with extra-pulmonary MDR-B, and there are limited or no data describingthe effects o substance abuse, advanced age and diabetes, on treatment outcomesor saety. Because o uncertainty regarding saety and efficacy in these patientpopulations, particular caution is suggested or use o delamanid in these situations.

• Te use o the drug in patients with extra-pulmonary MDR-B may be considered,extrapolating rom the data in patients with pulmonary B.

Implementation considerations:

• A duly inormed decision making-process by patients should be ollowed; thisincludes presenting the intervention as an option and providing inormation onuncertainty about the effects.

• With regard to Q prolongation, data were available or simultaneous use withlevofloxacin only. No evidence was available on the effect on Q prolongation whendelamanid was used in combination with other fluoroquinolones or cloazimine.Delamanid should be given under strict monitoring o Q intervals, particularly igiven in combination with other Q prolonging drugs. Active pharmacovigilance is

recommended.

• No data or the simultaneous use o bedaquiline and delamanid (that can bothprolong Q) were available. Without this data, no recommendation about thesimultaneous use o delamanid and bedaquiline can be made.

Monitoring and evaluation:

• Te EG recommends that Q and serum potassium levels be regularly monitoredduring treatment with delamanid

• Te risk o emergence o resistance to delamanid should be a key guiding principle

when the drug is being used, and appropriate DS should be in place, when available.

In addition, based on the available evidence, the EG considered that culture conversionat two months should not be used as a surrogate marker or treatment outcome inMDR-B patients.

Te Expert Group proposed that interim recommendations should be valid or amaximum o two years and be updated should additional data become available.

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W H O i n t e r i m

p o l i c y r e c o m m e n d a t i o n s

WHO interim policy recommendations

Available data on delamanid efficacy and saety is very limited as assessed by theGRADE process; however, the overall benefits o the inclusion o delamanid in a WHO-recommended MDR-B regimen appear to outweigh the observed harms. Tereore,considering the global MDR-B crisis, the limited therapeutic options available orthis lie-threatening condition, and the need to promote sae and responsible use o Bdrugs, WHO is making the ollowing interim policy recommendation or the use odelamanid in the treatment o MDR-B:

WHO recommends that delamanid may be added to a WHO-recommendedregimen in adult patients with pulmonary MDR-B (conditional recommendation;

very low confidence in estimates of effect).

In view o the insufficient experience with the use o delamanid under the differentconditions that may be expected in treatment programmes, and the uncertainty aboutits overall added value in the treatment o MDR-B patients, WHO recommends thatthe use o delamanid in the treatment regimen o MDR-B be made subject to theollowing five conditions:

1. Proper patient inclusionTe current recommendation or the use o delamanid applies to adults (≥18yrs) withpulmonary MDR-B disease, including people living with HIV. Special caution andproper clinical judgment should be applied when delamanid is used in persons 65 yearsand older, or in those with diabetes, hepatic or severe renal impairment, or those whouse alcohol or substances, given that data on efficacy and saety under such conditionsare extremely limited or unavailable.

Use o the drug in children and in pregnant and breasteeding women is not currentlyadvised due to a lack o evidence on saety, efficacy and proper dosing in these groups.

Because delamanid is shown to cause prolongation o the Q interval, patients with aQcF>500ms should not receive the drug.

When an effective and reasonably well-tolerated MDR-B regimen can be composedwith conventional second-line drugs, the routine addition o delamanid may not bewarranted and the implications o additional health service costs should be considered.MDR-B patients in whom delamanid may have a particular role include those with:

• higher risk or poor outcomes (eg. drug intolerance or contraindication, extensiveor advanced disease);

• additional resistance to fluoroquinolones or injectable drugs;

6.

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• XDR-B (see 3.b or additional measures to apply when the drug is used in XDR-B patients).

While patients with exclusive extrapulmonary disease were not included in thedelamanid trials, there is no absolute contraindication or its use in such patients andinclusion may be considered where any potential harm that delamanid may cause isoffset by the benefit expected.

2. Adherence to the principles of designing a WHO-recommendedMDR-TB regimen

Delamanid is intended to be introduced alongside other anti-B drugs in composing aneffective second-line regimen based on WHO guidelines; the cardinal rules governing

the general composition and duration o MDR-B regimens remain the same:

a. Te WHO-recommended MDR-B treatment regimen (1) is typicallycomposed o at least pyrazinamide and our second-line drugs consideredto be effective (based on DS and/or previous use and/or drug resistancesurveillance data): a fluoroquinolone (preerably later-generation), a second-line injectable agent, and two bacteriostatic drugs, preerably prothionamideor ethionamide plus cycloserine or p-aminosalicylic acid.

b. MDR-B patients with confirmed resistance or intolerance to eitherfluoroquinolones or the second-line injectable drugs represent a particulartreatment challenge. In such cases, delamanid may have a crucial role to play instre

who_htm_tb_2014.23_eng

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