Conditions: Multidrug Resistant Tuberculosis
Keywords: Tuberculosis Tuberculosis, Multidrug-Resistant Mycobacterium Infections Actinomycetes Infections Gram-Positive Infections Bacterial Infections Pediatric
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
The purpose of this trial is to assess the safety, tolerability, pharmacokinetics, and efficacy of long-term (6-month) treatment with delamanid plus an optimized background regimen (OBR) of other anti-tuberculosis drugs in pediatric participants who completed Study 242-12-232 (NCT01856634).

Detailed description:
This study will assess the safety, tolerability, pharmacokinetics, and efficacy of delamanid plus an optimized background regimen in pediatric participants with MDR-TB over a 6-month treatment period. This long-term study, an extension of Study 242-12-232, will be conducted in participants who have completed Study 242-12-232.

Arms:
arm 1: Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) plus optimized background regimen (OBR) up to Day 182. Participants continued to receive OBR up to Day 365. arm 2: Participants 6 to 11 years old (inclusive) received adult formulation delamanid 50 mg (1x50 mg tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365. arm 3: Participants 3 to 5 years old (inclusive) received 25 mg pediatric formulation of delamanid (DPF - suspension prepared using dispersible tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365. arm 4: Participants from birth to 2 years old (inclusive) received DPF (suspension prepared using dispersible tablet) for 182 days plus OBR. Participants continued to receive OBR up to Day 365. The DPF dose was based on the participant's body weight during the baseline visit:

* Participants \>10 kilograms (kg) received DPF 10 mg BID plus OBR
* Participants \>8 kg and ≤10 kg received DPF 5 mg BID plus OBR
* Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) plus OBR

Delamanid dose was adjusted as needed for Group 4 participants based on the weight measurement at specified study visits \[Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)\].

Interventions: intervention 1: Delamanid intervention 2: Delamanid Pediatric Formulation (DPF) intervention 3: Optimized Background Regimen (OBR)
Intervention descriptions: intervention 1: Participants received adult formulation delamanid as per regimen specified in the arm description. Morning dose of the delamanid BID regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard dinner meal. intervention 2: Participants received delamanid as an extemporaneous suspension using the delamanid pediatric dispersible tablet formulation. Morning dose of the delamanid BID/once daily (QD) regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard meal. intervention 3: Selection and administration of the treatment medications (i.e. OBRs) was based on Search Results Web result with site links

World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines. Study Investigator could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Delamanid (OPC 67683) in Pediatric 
Multidrug-resistant Tuberculosis Patients on Therapy with an Optimized 
Background Regimen of Antituberculosis Drugs over a 6-Month Treatment 
Period 
 
NCT Number: 
NCT01859923 
 
Document Date: 
 
Protocol Version Amendment 5: 28 February 2019 
 
 
 
 
 
 
 
 


Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Delamanid (OPC 67683)
REVISED CLINICAL PROTOCOL
Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Delamanid (OPC 67683) in Pediatric 
Multidrug-resistant Tuberculosis Patients on Therapy with an Optimized Background 
Regimen of Antituberculosis Drugs over a 6-Month Treatment Period
Protocol No. 242-12-233
IND No. 76,728
CONFIDENTIAL – PROPRIETARY INFORMATION
Drug Development Phase:
2
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, MD 20850, United States
Sponsor Representatives:
, MD
2440 Research Boulevard
Rockville, MD 20850, United States
Phone:  
Fax:  
E-mail:  
, 
2440 Research Boulevard
Rockville, MD 20850, United States
Phone: 
Fax:  
E-mail:  


Protocol 242-12-233
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Amendment 5, 28 February 2019  
Immediately Reportable Event 
Otsuka Europe Development and 
Commercialisation Ltd (OEDC) 
Pharmacovigilance Region Europe (PVRE)
Grüneburgweg 102
60323 Frankfurt am Main
Germany
Fax:  
E-mail:  
Issue Date:
09 November 2012
Amendment 1 Issue Date:
11 March 2013
Amendment 2 Issue Date:
14 October 2014
Amendment 3 Issue Date:
29 June 2015
Amendment 4 Issue Date:
04 October 2016
Amendment 5 Issue Date:
28 February 2019


Protocol 242-12-233
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Amendment 5, 28 February 2019  
Protocol Synopsis
Name of Company:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  Delamanid 
Protocol # 242-12-233
Protocol Title:
Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of Delamanid 
(OPC 67683) in Pediatric Multidrug-resistant Tuberculosis 
Patients on Therapy with an Optimized Background Regimen 
of Antituberculosis Drugs Over a 6-Month Treatment Period 
Clinical Phase:
Phase 2
Treatment Indication: Pediatric patients with multidrug-resistant tuberculosis 
(MDR-TB) who are receiving an optimized background 
regimen (OBR) of antituberculosis drugs
Objective(s):
The primary objectives of this trial are:

To evaluate the long-term safety and tolerability of 
delamanid and its metabolites in combination with an
OBR during a 6-month treatment period in pediatric 
patients with MDR-TB

To report delamanid and metabolite plasma 
concentrations at each visit day by age groups and to 
conduct a population pharmacokinetics (POPPK)
analysis of delamanid when delamanid is administered 
in combination with an OBR during a 6-month 
treatment period in pediatric patients with MDR-TB
The secondary objectives are:

To conduct the pharmacokinetic 
(PK)/pharmacodynamic (PD) relationship analysis of
delamanid and its metabolite DM-6705 plasma 
concentrations and change in corrected QT interval 
(QTc) when delamanid is administered in combination 
with OBR during a 6-month treatment period in 
pediatric patients with MDR-TB

To evaluate the efficacy of delamanid when 
administered in combination with an OBR during a 
6-month treatment period in pediatric patients with 
MDR-TB

To determine the palatability of the delamanid pediatric 
formulation


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Amendment 5, 28 February 2019  
Trial Design:
This is a phase 2, open-label, multiple-dose, multicenter trial to 
assess the safety, tolerability, PK, and efficacy of delamanid in 
pediatric patients with MDR-TB over a 6-month treatment 
period. This long-term trial, an extension of Trial 242-12-232 
(Trial 232), will be conducted in patients who have completed 
Trial 232. The current Trial 242-12-233 (Trial 233) will be 
conducted sequentially in 4 groups of pediatric patients with 
MDR-TB. 
  

Group 1 (ages 12 - 17 years, inclusive) will receive 
adult formulation delamanid 100 mg BID + OBR (n = 
6)

Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive 
pediatric formulation delamanid 25 mg BID + OBR (n 
= 12)

Group 4 (ages birth - 2 years, inclusive) will 
receive the following delamanid pediatric formulation 
(DPF) dose based on patient’s body weight during 
baseline visit (n = 12):

Patients  > 10 kg will receive DPF 10 mg BID + 
OBR

Patients > 8 and ≤10 kg will receive DPF 5 mg 
BID + OBR

Patients  ≤8 kg will receive DPF 5 mg QD + OBR

Delamanid dose will be adjusted as needed for 
Group 4 patients based on the weight measurement   
at specified study visits (Visits 5, 7, 9, 11 and 12).
All groups will have assessments at screening and during the 
treatment period, the post-treatment period, and the follow-up 
period, as indicated in the schedule of assessments. All 
patients must have completed the pediatric PK Trial 232 prior 
to enrollment into Trial 233. Those patients who have 
completed Trial 232 and choose to enter Trial 233 must roll
over from within 30 days of completing Trial 232. If any 
patients terminate Trial 232 early or choose not to enter 
Trial 233, patients will be recruited to first enter and complete 
Trial 232, and then roll over into Trial 233. Patients who 
terminate Trial 233 early will not be replaced.


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Trial Design 
(continued):
The trial will comprise the following periods: 
Screening Period (Day −30 to −2): Study data will either be 
taken from screening or Day 10 of Trial 232 or will be 
performed during the 30-day period immediately after 
completion of Trial 232 as described in the Schedule 
of Assessments. 
Baseline (Day −1): Inclusion/exclusion criteria, physical 
examination, and safety assessments, including lab tests, signs 
and symptoms of tuberculosis (TB), audiometry and visual 
assessments, vital signs, height, weight, head circumference 
(Group 4 only), percentiles for age, body mass index (BMI), 
and electrocardiogram (ECG) as described in the Schedule of 
Assessments. OBR administration as prescribed by 
investigator, and recording of concomitant medications. 
Treatment Period (Days 1 to 182):  Morning and evening 
dosing of delamanid with meal. OBR administration as 
prescribed by investigator.  Sparse blood draws for PK as 
described in the Schedule of Assessments. Signs and 
symptoms of TB, physical examination, and other safety 
assessments, including safety lab tests. Audiometry and visual 
assessments, and ECG at weeks and times shown in the 
Schedule of Assessments. Vital signs, head circumference 
(Group 4 only), height, weight, and BMI beginning at Week 2, 
and collection of adverse events (AEs) and immediately 
reportable events (IREs), and concomitant medications.
Post-treatment Period (Days 183 to 238):  
Physical examination, vital signs, ECGs, safety labs, and 
sparse blood draws for PK at visits and times described in the 
Schedule of Assessments. Head circumference (Group 4 
only), height, weight, signs and symptoms of TB, audiometry 
and visual assessments, thyroid function tests (for patients 
taking ethionamide or para-aminosalicylic acid), 
OBR administration, and collection of AEs/IREs and 
concomitant medications.  
Follow-up Period (Days 239 to 365) Six Month Post Last 
Delamanid Dose: Physical examination, height and weight, 
BMI, percentiles for age, vital signs, head circumference 
(Group 4 only), height, weight, signs and symptoms of TB, 
chest radiograph, audiometry and visual assessments, safety 
labs, thyroid function tests (for patients taking ethionamide or
para-aminosalicylic acid), OBR administration, and collection 
of AEs/IREs and concomitant medications.  


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Amendment 5, 28 February 2019  
Treatment Outcome Follow-up (Day 730 [Month 24] + 2 
months): All patients will either visit the clinic or be 
contacted by telephone for clinical assessment.  Collection of 
treatment outcome information as routinely documented in the 
patient medical records or in  national TB program.
Subject Population:
At least 36 male and female MDR-TB patients ages birth to 
17 years, inclusive, who successfully completed Trial 232, and 
meet all of the inclusion criteria and none of the exclusion 
criteria, and are receiving OBR will be assigned to one of 4 
treatment groups based on age.  For Groups 1 and 2, a 
minimum of 6 patients will be included in each age group, and 
Group 1 (12 to 17 years, inclusive) must include at least 2 but 
no more than 5 females.  For Groups 3 and 4, a minimum of 12 
patients will be included in each age group.
Inclusion/Exclusion 
Criteria:
Key Inclusion Criteria:

Successfully completed Trial 232 

Male or female

Age birth to 17 years, inclusive

Confirmed diagnosis of MDR-TB, ie, culture positive 
for Mycobacterium tuberculosis (MTB) with isoniazid 
and rifampicin resistance on drug-susceptibility testing, 
or a positive rapid test demonstrating resistance to 
rifampicin alone or to rifampicin and isoniazid
OR
Presumptive diagnosis of pulmonary or extrapulmonary 
MDR-TB such that the treating physician has decided to 
treat for MDR-TB the patient who has one of the 
following:

Clinical specimen (eg, cerebral spinal fluid, pleural 
fluid, ascitic fluid, lymph node aspirate, or other tissue
specimen) suggestive of tuberculosis (TB) disease

Persistent cough lasting > 2 weeks

Fever, weight loss, and failure to thrive

Findings on recent chest radiograph or other imaging 
studies (prior to Visit 1) consistent with TB
AND

Household contact of a person with known MDR-TB 
or a person who died while appropriately taking drugs 
for drug-sensitive TB
OR


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Amendment 5, 28 February 2019  

On first-line TB treatment but with no clinical 
improvement

Negative urine pregnancy test for female patients who 
have reached menarche

Study-specific written informed consent/assent 
obtained from a parent(s) or guardian or legally 
acceptable representative, as applicable for local laws 
prior to the initiation of any protocol-required 
procedures.  In addition, for patients in Groups 1 and 2
and as required by local laws, the patient must provide 
informed assent at screening and must be able to fully 
understand that he or she can withdraw from the study 
at any time.   
Key Exclusion Criteria:

Patients who have not completed Trial 232

Children with laboratory evidence of active hepatitis B 
or C

Children with body weight < 5.5 kg 

For patients with HIV co-infection, CD4 cell count ≤
1000/mm3 for children 1-5 years old, and ≤
1500/mm3 for children less than 1 year old

History of allergy to metronidazole and any disease or 
condition in which metronidazole is required

Use of amiodarone within 12 months prior to the first 
dose of investigational medicinal product (IMP) or use 
of other predefined antiarrhythmic medications within 
30 days prior to the first dose of IMP

Serious concomitant conditions (cardiovascular 
disorders, severe respiratory disease, severe diarrheal 
disease, renal, hepatic, or neurological impairment)

Preexisting cardiac conditions including but not limited 
to structural cardiac disease including suspected TB 
involvement of the heart on clinical or radiographic 
grounds

Abnormalities in screening electrocardiogram (ECG)
(including atrioventricular block, bundle branch block
or hemi-block, QRS prolongation > 120 msec, or QT 
interval corrected using Fridericia’s method (QTcF)
> 450 msec in both males and females)

A concomitant condition such as renal impairment 


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characterized by serum creatinine levels > 1.5 mg/dL, 
hepatic impairment (alanine aminotransferase or 
aspartate aminotransferase > 3 times the upper limit of 
normal [ULN]), or hyperbilirubinemia characterized by 
total bilirubin > 2x ULN

Concurrent diagnosis of severe malnutrition or 
kwashiorkor

Positive urine drug screen (Groups 1 and 2 only)

Use of rifampicin and/or moxifloxacin within 1 week 
prior to the first dose of IMP and/or any prior or 
concurrent use of bedaquiline

Lansky Play Performance Score < 50 (not applicable 
for children < 1 year old) or Karnofsky Score < 50

Administered an IMP within 1 month prior to Visit 1 
other than delamanid given as IMP in Trial 232

Pregnant, breast-feeding, or planning to conceive or 
father a child within the timeframe described in the 
informed consent form (Groups 1 and 2 only)
Trial Site(s)
Multiple phase 2 sites
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of 
Administration:
Delamanid 50-mg adult formulation tablets administered orally 
for 6 months to Groups 1 and 2:

Group 1 (ages 12 to 17 years, inclusive) -
100 mg (2 x 50-mg tablet) BID

Group 2 (ages 6 to 11 years, inclusive) -
50 mg (1 x 50-mg tablet) BID 
Delamanid pediatric dispersible tablets admixed with water 
and administered orally as an extemporaneous suspension to 
Groups 3 and 4 for 6 months:

Group 3 (ages 3 to 5 years, inclusive) -
25 mg (1 x 25-mg tablet) BID

Group 4 (ages birth to 2 years, inclusive) -
will receive the following dose depending on patient’s 
weight: 

Patient > 10 kg will receive pediatric formulation 
delamanid 10 mg BID + OBR

Patient > 8 and ≤10 kg will receive pediatric 
formulation delamanid 5 mg BID + OBR

Patient ≤ 8 kg will receive pediatric formulation 
delamanid 5 mg QD + OBR


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Amendment 5, 28 February 2019  
OBR will be provided for all patients in the trial by the 
investigation site as per the World Health Organization 
Guidelines for the Programmatic Management of Drug-
Resistant Tuberculosis, relevant national guidelines for 
treating MDR-TB, and the investigator’s best clinical 
judgment. OBR generally comprises 4 or more classes of first-
line (other than isoniazid and rifampicin) and second-line anti-
TB medications to which the patient’s strain of MTB has 
suspected or documented susceptibility based on previous 
treatment history and epidemiologic and clinical factors. 
Whenever possible, 5 or more classes of drugs are preferred 
for use in treatment, particularly in the initial stage of 
treatment. The components of OBR include:
1) Any remaining first-line anti-TB medications to which 
the patient’s isolates are likely susceptible such as 
pyrazinamide
2) An anti-TB medication given by injection; preferred 
order of selection: amikacin > kanamycin > 
capreomycin
3) Fluoroquinolone class; preferred order of selection: 
moxifloxacin, levofloxacin, gatifloxacin > ofloxacin 
(gatifloxacin to be used with caution secondary to rare 
but severe side effect of dysglycemia; ciprofloxacin not
recommended for use). Moxifloxacin causes QT 
interval prolongation and should not be used in this 
trial
Other medications include (but are not limited to):
4) Ethionamide or prothionamide
5) Cycloserine
6) Para-aminosalicyclic acid


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Criteria for 
Evaluation 
(Variables):
The primary criteria for evaluation in this trial are:

Safety and Tolerability: assessed by physical 
examination, vital signs, treatment-emergent adverse 
events (TEAEs), ECGs, Holter monitoring (if 
applicable), and clinical laboratory tests

Pharmacokinetics: Delamanid and metabolite plasma 
concentrations at each visit day per age and dose group
The secondary criteria for evaluation in this trial are:

Pharmacokinetics/Pharmacodynamics: ECG and blood 
samples for PK/PD analysis for changes in QTc as a 
function of delamanid and DM-6705 plasma 
concentrations 

Efficacy: evaluated on the basis of results of chest 
radiography (for patients with pulmonary disease); 
change in body weight and height measurements; and 
evaluation of TB symptoms.  In addition, sputum 
culture conversion (for culture-positive patients) will 
be assessed in patients who are able to produce sputum 
(or provide other biological specimens) for 
microbiological evaluation according to the 
requirements of the National TB program

Palatability:  The palatability of the delamanid 
pediatric formulation (Groups 3 and 4 only) will be 
assessed using an age-appropriate visual hedonic scale 
and clinical assessment.
Endpoints:
The primary endpoints in this trial are:

Safety and tolerability: Changes in physical 
examination including visual testing and audiometry 
during screening, TEAEs, vital signs, ECGs, holter 
monitoring (if applicable), and clinical laboratory tests

Pharmacokinetics: 
Descriptive statistics of delamanid and metabolite 
plasma concentrations at each visit day per age and 
dose group. In addition, POPPK analysis for 
delamanid plasma concentrations 
The secondary endpoints in this trial are:

Pharmacokinetics/Pharmacodynamics: PK/PD analysis 
for changes in QTc as a function of delamanid and 
DM-6705 plasma concentrations

Efficacy: Culture conversion, normal chest 
radiography results, resolution of TB symptoms


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Amendment 5, 28 February 2019  
Statistical Methods:
No power calculation was performed for this trial because of 
the limited number of patients expected to be enrolled in the 
population of interest (ie, pediatrics). No formal statistical 
analysis is planned due to the small sample sizes; all statistical 
presentations will be descriptive. 
An interim analysis review of safety, tolerability, PK, and 
efficacy of delamanid will be conducted with complete 
follow-up data in children 6 to 17 years of age.
Trial Duration:
The trial duration per patient will be up to 760 days including 
the following: 30-day screening period, 182-day treatment 
period, 56-day post-treatment period, additional follow-up 
period through Day 365 (ie, 6 months after the last delamanid 
dose), and treatment outcome follow-up at Day 730 (Month 
24) + 2 months (ie, 1 year after the Day-365 follow-up visit).  


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Table of Contents
Protocol Synopsis...........................................................................................3
Table of Contents.........................................................................................12
List of In-text Tables ...................................................................................17
List of In-text Figures..................................................................................18
List of Appendices........................................................................................19
List of Abbreviations and Definitions of Terms .......................................20
1
Introduction ........................................................................................22
1.1
Nonclinical Trials..............................................................................................27
1.2
Clinical Trials....................................................................................................29
1.3
Pharmacokinetics...............................................................................................30
1.3.1
Healthy Subjects .............................................................................................30
1.3.2
Patients with Tuberculosis..............................................................................30
1.4
Known and Potential Risks and Benefits ..........................................................31
1.4.1
Delamanid.......................................................................................................31
1.4.2
Antituberculosis Medications for Treating MDR-TB ....................................35
2
Trial Rationale and Objectives..........................................................39
2.1
Trial Rationale...................................................................................................39
2.2
Dosing Rationale...............................................................................................40
2.3
Trial Objectives.................................................................................................40
3
Trial Design.........................................................................................41
3.1
Type/Design of Trial .........................................................................................41
3.2
Trial Treatments ................................................................................................45
3.2.1
Administration of Delamanid .........................................................................45
3.2.2
Administration of OBR...................................................................................46
3.3
Trial Population.................................................................................................46
3.3.1
Number of Subjects and Description of Population .......................................46
3.3.2
Subject Selection and Numbering ..................................................................46
3.4
Eligibility Criteria..............................................................................................46
3.4.1
Informed Consent ...........................................................................................46


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3.4.2
Inclusion Criteria ............................................................................................48
3.4.3
Exclusion Criteria...........................................................................................49
3.5
Outcome Variables............................................................................................50
3.5.1
Primary Outcome Variables ...........................................................................50
3.5.1.1
Safety Outcome Variables...........................................................................50
3.5.1.2
Pharmacokinetic Variables..........................................................................50
3.5.2
Secondary Variables .......................................................................................51
3.5.2.1
Pharmacokinetic/Pharmacodynamic Variables...........................................51
3.5.2.2
Efficacy Outcome Variables .......................................................................51
3.5.2.3
Palatability ..................................................................................................51
3.6
Measures to Minimize/Avoid Bias....................................................................51
3.6.1
Randomization................................................................................................51
3.7
Trial Procedures ................................................................................................51
3.7.1
Schedule of Assessments................................................................................57
3.7.1.1
Visit 1, Screening/Enrollment (Days −30 to −2) ........................................57
3.7.1.2
Visit 2, Baseline (Day −1)...........................................................................58
3.7.1.3
Visit 3 (Day 1).............................................................................................58
3.7.1.4
Visit 4, Day 14 2 Days (Week 2).............................................................59
3.7.1.5
Visit 5, Day 28 2 Days (Week 4).............................................................59
3.7.1.6
Visit 6, Day 422 Days (Week 6)..............................................................60
3.7.1.7
Visit 7, Day 562 Days (Week 8)..............................................................61
3.7.1.8
Visit 8, Day 70 2 Days (Week 10)...........................................................61
3.7.1.9
Visit 9, Day 84 2 Days (Week 12)...........................................................62
3.7.1.10
Visit 10, Day 98 2 Days (Week 14).........................................................63
3.7.1.11
Visit 11, Day 126 2 Days (Week 18).......................................................63
3.7.1.12
Visit 12, Day 154 2 Days (Week 22).......................................................64
3.7.1.13
Visit 13, Day 182 2 Days (Week 26).......................................................65
3.7.1.14
Visit 14, Day 189 2 Days (Week 27).......................................................65
3.7.1.15
Visit 15, Day 196 2 Days (Week 28).......................................................66
3.7.1.16
Visit 16, Day 203 2 Days (Week 29).......................................................66
3.7.1.17
Visit 17, Day 210 2 Days (Week 30).......................................................67


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Amendment 5, 28 February 2019  
3.7.1.18
Visit 18, Day 238 2 Days (Week 34).......................................................67
3.7.1.19
Visit 19, Day 365 5 Days (Week 52, 6 months post last delamanid 
dose)............................................................................................................68
3.7.1.20
Treatment Outcome Follow-up (Day 730 [Month 24] + 2 Months)...........68
3.7.1.21
Early Termination Visit...............................................................................69
3.7.1.22
Post Treatment and Follow-up....................................................................69
3.7.2
Efficacy Assessments .....................................................................................70
3.7.3
Safety Assessments.........................................................................................70
3.7.3.1
Clinical Laboratory Tests............................................................................70
3.7.3.2
Physical Examination and Vital Signs Assessments...................................71
3.7.3.3
Electrocardiogram Assessments..................................................................72
3.7.4
Pharmacokinetic Assessments........................................................................74
3.7.4.1
Blood Collection Times ..............................................................................74
3.7.4.2
Pharmacokinetic Assessment of Cerebral Spinal Fluid ..............................74
3.7.4.3
Sample Handling and Processing................................................................75
3.7.5
Pharmacodynamic Assessments.....................................................................75
3.7.6
Other Assessments..........................................................................................75
3.7.7
End of Trial.....................................................................................................75
3.7.8
Safety Monitoring Committee........................................................................75
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................75
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................75
3.8.2
Individual Site.................................................................................................76
3.9
Screen Failures ..................................................................................................76
3.10
Definition of Completed Patients......................................................................77
3.11
Definition of Lost to Follow-up ........................................................................77
3.12
Patient Compliance............................................................................................77
3.13
Protocol Deviations...........................................................................................77
4
Restrictions..........................................................................................78
4.1
Prohibited Medications......................................................................................78
5
Reporting of Adverse Events.............................................................78
5.1
Definitions.........................................................................................................78


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5.2
Collecting and Reporting Safety Information to the Sponsor...........................81
5.2.1
Period of Observation for Adverse Events and Immediately Reportable 
Events .............................................................................................................81
5.2.2
Adverse Events ...............................................................................................81
5.2.3
Immediately Reportable Events......................................................................81
5.3
Follow-up of Adverse Events and Immediately Reportable Events .................83
5.3.1
Safety Monitoring Committee........................................................................83
5.4
Pregnancy..........................................................................................................83
5.5
Overdose, Misuse, Abuse..................................................................................84
5.6
Safety Submissions to Regional and National Competent Authorities, 
IECs/IRBs, and Notifications to Investigators ..................................................84
6
Pharmacokinetic Analysis..................................................................85
6.1
Pharmacokinetic Methods.................................................................................85
6.2
Pharmacokinetic/Pharmacodynamic Methods ..................................................85
7
Statistical Analysis..............................................................................85
7.1
Sample Size.......................................................................................................85
7.2
Analysis of Demographic and Baseline Characteristics....................................85
7.3
Safety Analyses .................................................................................................85
7.3.1
Adverse Events ...............................................................................................85
7.3.2
Clinical Laboratory Data ................................................................................86
7.3.3
Physical Examination and Vital Signs Data ...................................................86
7.3.4
ECG Data........................................................................................................86
7.4
Efficacy Analyses..............................................................................................86
7.5
Palatability Analysis..........................................................................................86
7.6
Interim Analysis ................................................................................................87
8
Trial Drug Management ....................................................................87
8.1
Packaging and Labeling ....................................................................................87
8.1.1
Delamanid.......................................................................................................87
8.1.2
Optimized Background Treatment Regimen..................................................87
8.2
Storage...............................................................................................................88
8.3
Accountability ...................................................................................................88
8.4
Returns and Destruction....................................................................................89


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9
Records Management.........................................................................89
9.1
Source Documents.............................................................................................89
9.2
Data Collection..................................................................................................90
9.3
File Management at the Trial Site.....................................................................90
9.4
Records Retention at the Trial Site....................................................................90
10
Quality Control and Quality Assurance...........................................91
10.1
Monitoring.........................................................................................................91
10.2
Auditing.............................................................................................................91
11
Ethics and Responsibility...................................................................92
12
Confidentiality ....................................................................................93
13
Amendment Policy..............................................................................93
14
References............................................................................................95


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List of In-text Tables
Table 1-1
Age-specific Risks for Developing Tuberculosis after
Primary Infection ...........................................................................26
Table 1.4.2-1
Step-wise Approach in the Treatment of Multidrug-resistant 
Tuberculosis (Resistance to at Least Rifampicin and 
Isoniazid)
................................................................................36
Table 3.4.2-1
Inclusion Criteria ...........................................................................48
Table 3.4.3-1
Exclusion Criteria ..........................................................................49
Table 3.7-1
Schedule of Assessments...............................................................53
Table 3.7.3.1-1
Clinical Laboratory Tests...............................................................71
Table 4.1-1
List of Medications Prohibited During the Trial............................78


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................44


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List of Appendices
Appendix 1
Important Sponsor Contacts.........................................................104
Appendix 2
Institutions Concerned With the Trial..........................................105
Appendix 3
Handling and Shipment of Bioanalytical Samples ......................106
Appendix 4
Protocol Amendments..................................................................107


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ACTH
Adrenocorticotropic hormone
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT 
Alanine aminotransferase
ARV
Antiretroviral
AST 
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-24h
Area under the plasma concentration-time curve from time zero to 24 
hours
BID
Twice daily
BMI
Body mass index
CA
Competent authority
CD4 cell
Cluster of differentiation 4 (helper/inducer T-lymphocyte)
CI
Confidence interval
CFU
Colony-forming unit
Cmax
Peak (maximal) concentration of drug in plasma
CRO
Contract research organization
CSF
Cerebral spinal fluid
CYP
Cytochrome P450
DR-TB
Drug-resistant tuberculosis
DST
Drug susceptibility testing
DS-TB
Drug-sensitive tuberculosis
EBA
Early bactericidal activity
ECG
Electrocardiogram
eCRF
Electronic case report form
ET
Early termination
FDA
Food and Drug Administration
F/U
Follow up
GCP
Good Clinical Practices
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ID
Identification
IDM
Interval duration measurement
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional review board


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Abbreviation
Definition
IRE
Immediately reportable event
ISR
Immediate safety report
LMP
Last menstrual period
MDR
Multidrug resistant
MDR-TB
Multidrug-resistant tuberculosis 
MedDRA
Medical Dictionary for Regulatory Activities
MTB
Mycobacterium tuberculosis
n/a
Not applicable
OBR
Optimized background regimen
OEDC
Otsuka Europe Development and Commercialisation, Ltd
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
PD
Pharmacodynamic
P-gp
P-glycoprotein
PIP
Pediatric investigational plan
PK
Pharmacokinetics
POPPK
Population pharmacokinetics
PVRE
Pharmacovigilance Region Europe
QD
Once daily
QTc
Corrected QT interval
QTcB
QT interval corrected by Bazett’s formula
QTcF
QT interval corrected by Fridericia’s formula
RIF
Rifampicin
SAE
Serious adverse event
SCC
Sputum culture conversion
SD
Standard deviation
SMC
Safety monitoring committee
t1/2
Elimination half-life
TB
Tuberculosis
TSH
Thyroid stimulating hormone
TEAE
Treatment-emergent adverse event
ULN
Upper limit of the normal range
WHO
World Health Organization
XDR-TB
Extensively drug-resistant tuberculosis


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1
Introduction
The investigational compound delamanid (OPC 67683) is a novel 
nitro-dihydroimidazo-oxazole derivative being developed by Otsuka Pharmaceutical Co. 
Ltd., Japan (hereafter referred to as Otsuka) for the treatment of tuberculosis (TB).1
Tuberculosis, caused by infection with Mycobacterium tuberculosis (MTB), is one of the 
leading causes of death from infectious disease among adults worldwide.2  In 1993, the 
World Health Organization (WHO) declared TB a global emergency. The WHO and 
partners developed and launched the directly observed therapy short-course strategy as 
the global framework for the diagnosis, treatment, management, and control of the 
disease. Despite these efforts, the global burden of TB remains high.3
Currently, the global TB epidemic and efforts to control it are complicated by lethal 
synergy with the global epidemic of human immunodeficiency virus (HIV)/acquired 
immunodeficiency syndrome (AIDS), which has exploded over the past 2 decades, as 
well as the evolving crisis of drug-resistant TB.3,4
As part of a coordinated global response to the HIV-associated TB and the 
multidrug-resistant tuberculosis (MDR-TB) epidemics, as well as the emergence of 
extensively drug-resistant tuberculosis (XDR-TB), the WHO and the international 
community have called for the accelerated development of new anti-TB 
medications.5 As a result, Otsuka has undertaken the search for anti-TB medications 
with new structures and mechanisms of action, with activity against intracellular MTB, 
and with the ability to target latent TB infection with MDR-TB.6
Delamanid is being developed in conjunction with an optimized background 
regimen (OBR), in agreement with the WHO-recommended MDR-TB treatment 
paradigm.  The intended dosage in adult patients is delamanid 100 mg twice daily (BID; 
two 50-mg delamanid tablets) given under fed conditions (with a standard meal) for 
6 months.  It is anticipated that delamanid, used in combination with other registered 
therapies, will result in higher cure rates, a shorter treatment duration for MDR-TB 
patients, and fewer side-effects.
Delamanid has shown early bactericidal activity (EBA) in drug-sensitive tuberculosis 
(DS-TB) patients after 2 weeks of treatment with 100 to 400 mg once daily (QD) dosing.  
This bactericidal activity measured as a decrease in log colony-forming units (log CFU)
reached significance after 3 days of dosing and thereafter at a magnitude similar to the 
currently recommended 4-drug combination Rifater®.  The EBA effect was similar to that 


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reported for rifamycin, rifabutin, and the aminoglycosides streptomycin and amikacin.  
However, it was higher than that for pyrazinamide but lower than the highest effect 
reported for quinolones, isoniazid, ethambutol, linezolid, rifampicin, and rifapentine.7,8
A pediatric investigational plan (PIP) for the treatment of children with MDR-TB 
received a positive opinion from the Pediatric Committee in November 2011.  The PIP 
for delamanid in pediatric MDR-TB patients aims to determine whether delamanid 
plasma exposure in children of all ages with MDR-TB is similar to the efficacious plasma 
exposure in adults, and thereby determine the appropriate pediatric dose (using both the 
adult and pediatric formulations) and to document safety and tolerability.  The PIP 
essentially consists of 3 clinical trials in addition to the pediatric formulation 
development and juvenile toxicity assessment (EMEA-001113-PIP01-10-M02): a 
pharmacokinetic (PK) trial (Trial 242-12-232) in children of all ages with MDR-TB on 
therapy with OBR, followed by a 6-month safety and tolerability extension trial 
(Trial 242-12-233) in the same patient population, and a bioavailability/bioequivalence 
trial (Trial 242-12-245) in adults to investigate the comparative bioavailability of the 
pediatric formulation (5- and 25-mg immediate-dissolving tablets) with the delamanid 
50-mg tablet adult formulation.
Tuberculosis Incidence
In 2012, the estimated global incidence of TB was 8.6 million cases. Deaths among 
HIV-negative persons were 1.0 million and among HIV-infected persons were 
0.32 million. The majority of cases in 2012 were in Southeast Asia (29%), Africa (27%) 
and the Western Pacific Region (12%).  India (26%) and China (12%) were the 
individual countries with the highest proportion of cases.3
Although the overall global incidence of TB is decreasing, the number of incident cases 
in the last few years has remained relatively stable due to population increases. Further, 
the overall annual incidence of TB in high-income countries remains relatively low.
Multidrug-resistant and Extensively Drug-resistant Tuberculosis
In addition to the effects of the global HIV epidemic, the emergence of MDR-TB or TB 
caused by strains of MTB resistant to at least isoniazid and rifampicin has further 
complicated global efforts to control the TB epidemic. Approximately 450,000 people 
developed MDR-TB globally in 2012 and there were an estimated 170,000 deaths from 
MDR-TB.  There were 94,000 MDR-TB patients detected in 2012; 84,000 of those were 
confirmed to have resistance to rifampicin and isoniazid and a further 10,000 were found 
to have rifampicin (RIF) resistance by GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA).3


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The highest concentrations of MDR-TB are found in Eastern Europe and Central Asia 
where the percentage of new TB cases that are multidrug resistant (MDR) may reach 
20% and the percentage of those previously treated for TB may reach 50%.3
Patients with MDR-TB require longer treatment, usually 18 to 24 months, compared with 
6 to 8 months for patients with DS-TB.  Moreover, the so-called “second-line” drugs used 
to treat MDR-TB are less potent and more toxic than those used for DS-TB.9  At least 
4 medications from the various classes of second-line anti-TB drugs to which a given 
MDR-TB patient’s disease is susceptible or likely to be susceptible should be used in 
combination for MDR-TB treatment.9 Some data suggest that at least 5 different 
medications should be used to optimize the chance for a successful treatment 
outcome.10,11,12  Medications from the fluoroquinolone class of drugs and from the 
injectable classes either an aminoglycoside or a cyclic peptide as well as any 
remaining first-line medications to which a given patient’s disease is susceptible, are 
integral to an optimized treatment regimen for MDR-TB.9,10,11,13 Under the best of 
programmatic conditions, the cure rates achievable for MDR-TB, as demonstrated by 
studies of treatment outcomes for patient cohorts, are in the range of only 60% to 
70%.14,15  In contrast, cure rates for DS-TB in well-performing programs often exceed 
90%.16
TB and MDR-TB in Children
It is estimated that 3.6% of the TB cases worldwide are MDR (ie, resistant to isoniazid
and rifampicin).17  Childhood TB comprises approximately 10% to 15% of the global TB 
disease burden, with higher rates in developing countries.18  Based on estimates of total 
MDR-TB cases,17,18 this translates to a minimum global estimate of approximately 
40,000 pediatric cases of MDR-TB per year.19 If a child presenting with TB is a known 
contact of an adult with MDR pulmonary TB, the child is a probable MDR-TB case and 
should be managed accordingly.20
Childhood TB disease is very different from adult TB disease.  These differences include 
time from exposure to disease onset, epidemiologic differences in contagiousness, 
pathophysiology, bacillary load, and clinical and radiographic manifestations.  Most 
cases of childhood TB have a short period between exposure to a contagious individual 
and manifestation of symptoms.21  Differences in the pathophysiology and clinical 
presentation of TB in children make diagnosis more challenging in children than in 


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adults,21 and definitions of latent infection and active disease are not as clear.21 Children 
are also at a much higher risk of progression to active disease than adults.22  This risk is 
greatest for infants and children under 2 years of age.22,23,24 Overall, the risk of disease 
is highest in infants and individuals in their late teens; the lowest risk in children is 
between ages 5 and 10 years, the so-called “safe” school years.23,25
Infants have a particularly high rate of morbidity and mortality from TB.24  Children 
under the age of 5 years are frequently affected by peripheral lymphadenopathy and 65%
to 75% of these children have a thoracic and mediastinal location.26,27  In a setting with a 
high incidence of TB and ongoing transmission, the most common clinical presentation 
of TB in young children, ie, age 5 years, is likely to be pulmonary TB.27,28,29,30,31,32  
Young children with severe and complicated disease have a much higher mortality rate 
than older children and adults; some studies report a mortality rate exceeding 50% in 
children younger than 1 year who have not received anti-TB medication.33,34
Older children and adolescents (> 10 years) often present with adult- type cavitary 
disease with a high bacillary load.35 Pleural TB typically has been considered a disease 
of adulthood and is estimated to comprise approximately 4% of disease cases.36  
However, TB pleural effusions can complicate 12% to 38% of cases in children with 
untreated pulmonary TB.37,38,39,40,41 Pleural involvement is more common among 
adolescents, and the mean age at diagnosis is 13 years.39,40  Adult-type disease is a 
phenomenon that suddenly appears around puberty and is distinguished by cavitation that 
occurs predominantly in the lung apices.41
Overall, the lifetime risk of progression from infection to active disease is 5% to 20% for 
immunocompetent older children and 40% to 50% for children in the first 2 years of 
life.23 Adolescents have a slightly higher risk of disease progression than adults.33,34  
The age-specific risk of developing TB following MTB infection is shown in Table 1.1-1.


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Table 1.1-1
Age-specific Risks for Developing Tuberculosis after
Primary Infection
Age at Primary 
Infection
Disease Status
Risk (%) in 
Immunocompetent Children23
< 2 years
No Disease
50 - 70
Pulmonary Disease
10 - 30
Tuberculosis Meningitis or Miliary Disease
2 - 10
2 to 10 years
No Disease
95 - 98
Pulmonary Disease
2 - 5
Tuberculosis Meningitis or Miliary Disease
<0.5
> 10 years
No Disease
80 - 90
Pulmonary Disease
10 - 20
Tuberculosis Meningitis or Miliary Disease
< 0.5
The diagnosis of childhood TB is challenging.30,42  Microbiological confirmation is often 
not available due to the paucibacillary nature of disease and the difficulty of specimen 
collection (especially sputum) in younger children.  The diagnosis usually relies on 
nonspecific clinical and radiologic signs, as well as a history of exposure (ie, close 
contact with a TB case).43  Fever (possibly intermittent or low grade), weight loss or 
failure to thrive, and persistent cough for > 2 weeks are the most important clinical signs 
for pulmonary TB.26   
Children are diagnosed with either confirmed or presumed MDR-TB.  Confirmed disease 
occurs when an organism is isolated from the child and is shown either genotypically or 
phenotypically to be resistant to isoniazid and rifampicin.  Presumed disease occurs when 
TB is diagnosed in combination with either known contact with an MDR-TB case or after 
failure of appropriate first-line therapy when adherence has been verified.19  Incident 
cases of childhood TB reflect recent transmission, which implies that drug resistance 
patterns observed among pediatric TB cases reflect primary (transmitted) drug resistance 
within the community.44  
Monitoring and describing adverse effects of multidrug anti-TB therapy in children is 
challenging; young children often cannot articulate pain, nausea, vertigo, peripheral 
neuropathy, anxiety, or confusion.  Rashes are common frequently resulting from 
various etiologies and testing hearing and vision is more difficult than in adults.  In 
addition to life-threatening and unpleasant effects, TB may cause alterations in growth 
and neurocognitive development.  Children treated for MDR-TB are usually on multiple 
medications, and determining the drug responsible for an adverse effect can be difficult.19


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1.1
Nonclinical Trials 
Efficacy pharmacology studies have shown that delamanid is active against 
MTB. The minimum inhibitory concentration of delamanid required to inhibit the 
growth of 90% of organisms is 0.024 µg/mL; this is lower than in existing anti-TB drugs, 
such as rifampicin and isoniazid, indicating that delamanid is a highly potent 
drug. Results of microbiology and efficacy pharmacology studies have also 
demonstrated that delamanid has potent in vitro activity against drug-resistant MTB, 
including XDR-TB.6,45,46,47 Delamanid shows no cross-resistance with any of the 
currently used anti-TB drugs.46 At inoculum sizes in the range of 105-107 CFU/mL, 
delamanid was highly active against MTB and Mycobacterium bovis, and was more 
potent than drugs currently in clinical use. The activity of delamanid was decreased at 
large inoculum sizes such as 108 CFU/mL, which is similar to the activity of 
isoniazid.48 Delamanid demonstrated bactericidal activities against both growing 
bacteria in aerobic conditions and nongrowing bacteria in hypoxic conditions.49,50
The metabolites of delamanid have poor activity against MTB, suggesting that delamanid 
is responsible for the anti-TB activity of the compound.45,51  The mechanism of action of 
delamanid is thought to be due to an inhibitory activity against the synthesis of mycolic 
acid, a key component of the cell wall of MTB.52  The presumed mechanism of action 
explains why the compound possesses MTB-specific activity yet no activity against other 
gram-positive or gram-negative bacteria when tested in vitro.48 Delamanid also has 
potent activity against intracellular mycobacteria with a concentration of 0.199 to 
0.215 g/mL needed to inhibit 90% of bacterial growth.49,50,51  
Delamanid showed greater activity in an animal model of TB than the first-line anti-TB 
drugs rifampicin and isoniazid. Delamanid demonstrated therapeutic efficacy at a dose of 
0.625 mg/kg in an experimental mouse TB model, an efficacy considered to be 
equivalent to that of rifampicin.53 The effective plasma and lung concentrations of 
delamanid at a dose of 0.625 mg/kg were 0.100 µg/mL and 0.273 µg/g, respectively.54
Delamanid showed no antagonistic activity in vitro or in vivo when used in combination 
with drugs currently used to treat TB.55,56,57,58,59  Delamanid showed EBA comparable to 
the activity of isoniazid in the mouse EBA model, in which the EBA values of the 
reference drugs correlated well with those seen in clinical studies.60


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The general safety of delamanid has been evaluated in the following nonclinical safety 
studies. Single oral dose toxicity studies in rats and dogs, repeated oral dose toxicity 
studies in rats and dogs, effects on blood coagulation in rabbits, in vitro and in vivo 
genotoxicity studies, and reproductive and developmental toxicity studies in rats and 
rabbits. The nontoxic dose of the compound was estimated to be 300 mg/kg in female 
rats and 30 mg/kg in male rats in a 26-week repeated oral dose toxicity study.61 The 
nontoxic dose of delamanid was estimated to be 1 mg/kg for males and 3 mg/kg for 
females in a 39-week repeated oral dose toxicity study in dogs.62 In 2-week oral dose 
toxicity studies in dogs at doses of 25 mg/kg and higher, QT/corrected QT interval (QTc) 
prolongation was seen.63 In 13- and 39-week oral dose toxicity studies in dogs, QT/QTc 
prolongation was seen at doses ≥10 mg/kg and  ≥3 mg/kg, respectively.62,64 In 2-week 
repeated oral dose toxicity studies in male or female rabbits, decreases in body weight 
and food consumption, prolongation of prothrombin time and activated partial 
thromboplastin time, anemia, and hemorrhage were observed at both 30 mg/kg and 
100 mg/kg.65,66,67  
An embryo-fetal development study in rats showed no maternal general and reproductive 
toxicity at the maximal feasible dose of 300 mg/kg; there was fetal development toxicity 
at 300 mg/kg.68  A 13-day repeated oral dose toxicity study in rabbits showed toxic 
changes at 10 mg/kg with decreased food consumption at the 10 mg/kg 
dose.69 Additional evaluations of maternal, reproductive, and developmental toxicity in 
rabbits showed dams had nontoxic doses of 5 mg/kg for maternal general toxicity and 
10 mg/kg for reproductive toxicity. The nontoxic dose for embryo-fetal development 
was 5 mg/kg.70  A rat fertility/embryonic-development study showed no toxic effect on 
parent animals, fertility, or early embryonic development at the maximum feasible dose 
of 300 mg/kg. No genotoxicity of delamanid or its metabolites was 
observed.71,72,73,74,75,76,77,78,79,80,81,82,83,85,86,87,88
The absolute bioavailability of delamanid administered orally at 3 mg/kg in mice, rats, 
and dogs was 42.2%, 34.9%, and 61.3%, respectively, and a less than dose-dependent 
increase in area under the plasma time-concentration curve (AUC) was observed in all 
species.89,90,91,92,93  Delamanid distributed extensively in tissues with a lung/plasma ratio 
of ~2,94,95 and was primarily metabolized by albumin in plasma and to a lesser extent by 
cytochrome P450 (CYP) enzymes.96,97,98,99 Delamanid was not transported by 
P-glycoprotein (P-gp), did not affect P-gp transport, and showed neither inductory nor 


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inhibitory effects on human CYP activities.100,101  In rats and dogs, delamanid and its 
metabolites were essentially excreted in feces and poorly excreted in urine.94,102  In rats, 
approximately 35% of the administered dose was excreted in bile and partly underwent 
enterohepatic recycling.103
Additional information on delamanid nonclinical trials can be found in the 
Investigator’s Brochure (IB).1
1.2
Clinical Trials
Phase 1 clinical development in healthy subjects included 7 trials with delamanid 50-mg 
tablets and one mass-balance trial using 14C-delamanid 100-mg capsules.  These trials 
were conducted in the United Kingdom, United States, China, and Japan.  In addition to 
the usual single and repeated dose-ranging trials (including food effect), drug-drug 
interaction trials were conducted with the anti-TB drug combination Rifater + ethambutol 
and with the antiretroviral (ARV) drugs tenofovir, lopinavir/ritonavir as Kaletra®, and 
efavirenz.1
Two proof-of-concept trials were conducted with delamanid: Trial 242-03-101104, a 1-
week EBA trial (delamanid jet-milled tablet), followed by 2-week EBA Trial 242-04-101 
(delamanid 50-mg tablet).105  The decrease in log CFU was compared with that observed 
for the positive controls isoniazid and Rifater, respectively.
Clinical efficacy trials in MDR-TB patients included the 2-month randomized pivotal 
Trial 242-07-204 (Trial 204) and the 6-month extension Trial 242-07-208 (Trial 208) of 
delamanid 100 mg BID or delamanid 200 mg BID plus OBR therapy in the same patient 
population.  In addition, a 6-month dose escalation Trial 242-08-210 (Trial 210) was 
conducted in XDR-TB patients with MDR-TB at delamanid doses of 250 mg BID and 
300 mg BID.
Safety/tolerability, PK and PK/pharmacodynamic (PD) for efficacy (ie, EBA) and safety 
(ie, QTc prolongation), and efficacy of delamanid were investigated throughout this 
development program.  Refer to the IB for details of these findings in healthy subjects 
and in TB patients.1


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1.3
Pharmacokinetics
1.3.1
Healthy Subjects
In healthy subjects, the time of peak plasma concentration (tmax) of delamanid is 4 hours 
post dose, the apparent terminal elimination half-life (t1/2z) is approximately 30 hours, and 
steady-state is achieved within 7 to 10 days following dosing.  Delamanid has a 2- to 4-
fold higher bioavailability when taken with a standard or high-fat meal, respectively, 
compared with fasting conditions.  Systemic exposure to delamanid increased less than
proportionally with increasing dose, suggesting dose-limited dissolution and/or 
absorption.106  The plasma concentrations for the metabolites were considerably lower 
(3% to 10% of delamanid concentrations) after 7 days of administration but showed a 
long (150 to 600 hours) plasma elimination half-life (t1/2), suggesting further 
accumulation upon repeated dosing.  Delamanid is not excreted in urine, and delamanid 
metabolites are poorly excreted in urine.
When coadministered with other drugs, delamanid did not affect the plasma exposure of 
anti-TB agents such as Rifater (isoniazid, rifampicin, and pyrazinamide) and ethambutol, 
or ARV drugs such as tenofovir, Kaletra (lopinavir/ritonavir), or efavirenz.  Delamanid 
concentrations were decreased by 45% with Rifater and ethambutol.  Delamanid 
exposure was not markedly affected (< 25% change) by ARV drugs; a ~22% increase in 
delamanid exposure was noted with Kaletra.1
Additional information on delamanid in healthy subjects is provided in the IB.1
1.3.2
Patients with Tuberculosis
Available results indicate that the PK profile of delamanid in patients with TB is similar 
to the PK profile in healthy subjects.  In the 14-day EBA trial (Trial 242-06-101) in TB 
patients receiving delamanid 100, 200, 300, and 400 mg QD with food, delamanid 
concentrations increased less than dose-proportionately from 100 to 300 mg, were similar 
for the 300 and 400 mg doses, and accumulated 2-fold over time.  On Day 14 after the 
doses of delamanid 200 mg QD, delamanid mean maximal concentration of drug in 
plasma (Cmax) was 228 ng/mL and the area under the plasma concentration-time curve 
from time zero to 24 hours (AUC0-24h) was 3351 ng•h/mL.8
In MDR-TB patients in Trial 204 receiving delamanid 100 mg and 200 mg BID for 
2 months, delamanid exposure reached steady state after 2 weeks (38 hour t1/2), and 
metabolite exposure continued to increase.  On Day 56, after the 100-mg BID and 


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200-mg BID doses, mean delamanid Cmax was 414 (ng/mL and 611 ng/mL, respectively, 
and the AUC0-24h was 7925 ng•h/mL and 11,837 ng•h/mL, respectively.
Trial 208 demonstrated that, in general, steady-state exposure was reached by 8 weeks of 
dosing for DM-6705 and by 8 to 14 weeks of dosing for the other metabolites.  
PK/PD analysis of delamanid and DM-6705 plasma concentrations as a function of QTc 
changes were performed.  The results indicated that the predicted changes were similar to 
the observed increases in QTc.
Additional information may be found in the IB.1
1.4
Known and Potential Risks and Benefits
1.4.1
Delamanid
As of 31 Jan 2016, a total of 949 adult subjects (484 healthy adult subjects, 60 adult 
patients with uncomplicated DS-TB, 395 adult patients with MDR-TB, 10 adult patients 
with MDR-TB refractory to treatment) have been exposed to oral doses of delamanid in 
19 completed trials.
In addition, a total of 22 healthy adult subjects and 511 adult subjects with MDR-TB 
have been exposed to either delamanid or placebo (trial is still blinded) in ongoing trials 
(Trials 242-201-00001 and 242-09-213, respectively).
Fourteen children (ages 3 - 17 years) with MDR-TB have also been exposed to oral doses
of delamanid in 2 ongoing, open-label, pediatric trials (Trials 242-12-232 and 242-12-
233).
Delamanid is well tolerated by healthy adult subjects and adult patients with TB.1  One 
observational study (Trial 242-10-116) also was conducted that follows long-term 
outcome patients who were enrolled in Trial 204, Trial 208, or Trial 210.  No safety data 
was collected and no delamanid was administered in Trial 242-10-116.
In Trial 242-05-101, single oral doses of delamanid up to a maximum of 400 mg 
administered after a high-fat meal were well tolerated in healthy subjects; delamanid was 
also well tolerated with 10 days of repeated dosing after a standard meal in healthy 
subjects.106 There were no serious adverse events (SAEs) and no severe adverse events 
(AEs), and no subjects were withdrawn as a result of AEs.
In the 14-day EBA trial in patients with DS-TB (Trial 242-06-101), 5 treatment-emergent 
adverse events (TEAEs) considered serious were reported: 3 patients with 


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electrocardiogram (ECG) QT interval prolongation corrected by Bazett’s formula (QTcB) 
in the delamanid 100 mg, 200 mg, and 300 mg groups, respectively; and 2 patients with 
increased hepatic transaminases in the delamanid 300 mg and 400 mg groups, 
respectively. All 5 events were mild in severity.7 In this trial, QTc interval prolongation 
was defined as QTc > 450 msec for males or > 470 msec for females. One 
 patient
had a QTcB of 
 msec prior to receiving delamanid. One 
 patient had a QTcB >
470 msec at the follow-up visit after discontinuation of delamanid. Another 
 patient
had a QTcB > 450 msec during the treatment period. No patients experienced QTcB or 
QT interval corrected by Fridericia’s formula (QTcF) > 480 msec at any of the time 
points assessed. It is important to note that in patients with increased heart rate, QTcB 
may not be a reliable measure of QTc interval prolongation, as TB patients often have 
fever or respiratory compromise. Among the 3 reports of ECG QTc interval 
prolongation, only one episode (
, 200 mg group) that occurred during active 
treatment was considered by the investigator to be probably treatment related; the other 
2 events were judged unlikely to be related to treatment. All patients recovered 
fully. The mild and moderate AEs were evenly distributed between the treatment and 
placebo groups and revealed no trends. No patients discontinued delamanid due to AEs,
and there were no deaths.
The safety of delamanid and its effects on QT interval duration were evaluated in 
Trial 204, a randomized, double-blind trial evaluating delamanid 100 mg or 200 mg BID 
orally in combination with OBR versus placebo with OBR for 56 days.  TEAEs were 
reported for > 90% of patients in all treatment groups (including the placebo + OBR 
group).  Most TEAEs were mild or moderate in intensity.  In this trial, the incidences of 
most TEAEs were similar (difference < 5 percentage points) between the delamanid 
100 mg BID + OBR group and the placebo + OBR group.  Chest pain (9.9% vs 4.4%) 
and prolonged QT interval (9.9% vs 3.8%) were the only TEAEs reported at an incidence 
of 5 percentage points more in the delamanid 100 mg BID + OBR group than the 
placebo + OBR group.  QT prolongation (13.1% vs 3.8%) was the only TEAE reported at 
an incidence of 5 percentage points more in the delamanid 200 mg BID + OBR group 
than in the placebo + OBR group; the incidence of chest pain was similar between groups
(8.8% vs 4.4%).  In Trial 204, there appeared to be a dose response for the following 
TEAEs (> 5 percentage points lower in the delamanid 100 mg BID + OBR group 
compared with the delamanid 200 mg BID + OBR group): vomiting (29.8% vs 36.3%), 
dyspepsia (3.7% vs 8.8%), pyrexia (5.6% vs 11.3%), decreased appetite (14.9% vs 


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23.1%), hypokalemia (12.4% vs 19.4%), arthralgia (19.9% vs 26.9%), neck pain (0.6% 
vs 6.9%), insomnia (26.1% vs 32.5%), and depression (2.5% vs 8.1%).
Trial 208107 served as a treatment extension trial to provide safety and tolerability data 
for longer-term exposure to delamanid for up to 6 additional months beyond the exposure 
in Trial 204.  Although delamanid was administered for 6 months in this open-label trial 
(at least 4 months longer than in previous delamanid trials), no new safety concerns were 
identified when the data were compared with previous trials.  Additionally, QTcF data 
were not calculated from time-matched samples as in Trial 204 and, therefore, may have 
shown more variability because of normal expected diurnal variations during a given day.  
Overall, the mean QTcF interval stabilized after Week 6; differences from time point to 
time point were minor and not clinically relevant.  Only 6 (2.8%) patients had reported 
TEAEs related to prolonged QT.  A low percentage of patients (3.8%, 8/213) had a 
change in QTcF of > 60 msec.  These data do not suggest that further increases in QTcF 
duration occur with longer-term (6 months, 26 weeks) dosing of delamanid beyond the 2-
month (56 days) period of dosing in Trial 204, using the same dose levels.  
In Trial 208, no new clinically important TEAEs were reported relative to those in 
Trial 204.  The incidence of the following TEAEs were increased in Trial 208 relative to 
Trial 204 (> 5 percentage points higher in Trial 208 than in Trial 204 for the delamanid 
100 mg + OBR group):  hyperbilirubinemia (6.6% vs 0.6%), nasopharyngitis (8.8% vs 
2.5%), upper respiratory infection (8.0% vs 1.2%), increased blood cortisol (8.8% vs 
2.5%), and headache (30.7% vs 23.6%).
In Trial 242-07-209108 (14 days) evaluating coadministration of delamanid 100 mg BID 
with ARV treatment medications in healthy non-HIV infected adults, 2 SAEs were 
reported: one subject who received delamanid with efavirenz discontinued due to anxiety 
and the following day reported an SAE of acute delirium; another subject who was taking 
delamanid and the ARV medication Kaletra experienced an SAE of ischemic colitis. In 
addition to the discontinuation mentioned above, one subject who received delamanid 
with the ARV medication tenofovir discontinued due to vomiting. Additionally, one 
subject in the delamanid plus efavirenz group had a severe TEAE (hepatic enzyme 
elevation). Multiple oral doses of delamanid 200 mg were generally well tolerated alone 
and in combination with tenofovir and Kaletra. Overall, the most common side effects 
observed in the trial included nervous system (28/89 subjects, 31.5%), gastrointestinal 
(21/89 subjects, 23.6%), and psychiatric (14/89 subjects, 15.7%) side effects. Nervous 
system and psychiatric side effects occurred in 3 of 4 (75%) subjects who received 
delamanid with efavirenz; these effects occurred less frequently in subjects who received 


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delamanid alone (4/15 subjects [26.7%] had nervous system side effects and 1/15 
subjects [6.7%] had psychiatric side effects) or efavirenz alone (1/5 subjects [20.0%] had 
nervous system side effects and psychiatric side effects). The efavirenz and efavirenz
plus delamanid groups were placed on hold pending evaluation of the observed events, 
and then discontinued prior to Day 14; therefore, PK profiles were not obtained.
The primary objectives of Trial 210109 were to evaluate the safety, tolerability, and PK of 
orally administered delamanid BID given in sequentially escalated doses for up to 
196 days (28 weeks) at each dose to individual cohorts of MDR-TB patients refractory 
to treatment with OBR and to determine the potential dose-limiting factors and, 
potentially, the maximum tolerated dose in patients treated with delamanid.  Drug 
exposure did not increase with these higher doses, apparently due to lack of further 
absorption and limited increases in concentration.
In Trial 210, all patients reported at least one TEAE.  Most TEAEs were mild to 
moderate in severity.  The most frequently reported TEAEs (> 2 patients) were 
hyperglycemia (6/10 patients; 60%), tuberculosis (ie, progressive tuberculosis, 
5/10 patients; 50%), viral upper respiratory tract infection (4/10 patients; 40%), nausea 
(4/10 patients; 40%), vomiting (3/10 patients; 30%), hepatomegaly (3/10 patients; 30%), 
decreased appetite (3/10 patients; 30%), and cough (3/10 patients; 30%).
A total of 10 patients received at least one dose of the investigational medicinal product 
(IMP) in this trial and delamanid was analyzed for safety and efficacy.  Due to the 
resistance patterns in this heavily treated patient population, most patients were treated 
with an OBR composed of less potent anti-TB medications from categories 4 and 5.  
Seven of the 10 patients enrolled in the trial who had a ≥9-month history of previous 
treatment with second-line drugs for MDR-TB had XDR-TB at baseline, greatly limiting 
options for anti-TB drugs to use in combination with delamanid.  Five patients each were 
administered delamanid 250 mg or 300 mg BID (500 or 600 mg/day, respectively) plus
OBR.  Overall, 7/10 (70.0%) patients completed the trial.  Please see the IB for 
more details.
In Trial 242-08-211110, which evaluated 10 days of delamanid comparing the PK of 
300 mg QD vs 150 mg BID versus 100 mg 3 times daily among 36 healthy subjects, no 
SAEs occurred. Eight subjects discontinued the trial prematurely due to AEs, including 
3 events of hematochezia, 3 events of headache, 1 event of diarrhea, and 1 event of 
hematemesis. All of these AEs were mild or moderate in severity and all were 
considered causally related to the IMP except for an event of hematochezia.


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Trial 242-08-212111 was a randomized, multiple-dose trial conducted in healthy subjects
to investigate the PK and safety of delamanid when administered in combination with 
efavirenz.  No SAEs, including neuropsychiatric SAEs, were observed in subjects
receiving the combination of delamanid and efavirenz.  Coadministration of efavirenz did 
not appear to affect (< 25% change) delamanid exposure.  There were no serious 
neuropsychiatric TEAEs and no discontinuations due to neuropsychiatric TEAEs.
As of 31 Jan 2016 in Trial 242-09-213, the ongoing phase 3, randomized, double-blind, 
and placebo-controlled trial conducted in MDR-TB patients to determine the safety, PK, 
and efficacy of delamanid plus OBR versus placebo plus OBR, enrollment was complete 
and 511 patients had begun blinded treatment. A total of 238 serious TEAEs occurred. 
The most frequently reported serious TEAEs were hypokalaemia (12 [2.3%]), 
tuberculosis (14 [2.7%]), deafness bilateral (8 [1.6%]), acute kidney injury (8 [1.6%]), 
electrocardiogram QT prolonged (7 [1.4%]), haemoptysis (5 [1.0%]), and hepatotoxicity 
(5 [1.0%]). Nineteen deaths (19/511; [3.7%]) were reported for patients with MDR TB. 
Two patients died due to acute respiratory failure (one of these patients also had 
worsening of MDR-TB), 2 patients died due to haemoptysis, 2 patients died due to 
disseminated tuberculosis and sepsis, one due to cardiac arrest and pneumonia, and one 
patient each died of cardiopulmonary failure, myocardial ischemia, pulmonary edema, 
pulmonary embolism, respiratory failure, acute myocardial infarction, hypothermia, 
metastatic neoplasm of unknown primary site, squamous cell carcinoma of lung, renal 
impairment, lung adenocarcinoma metastatic, and completed suicide. All of these events 
were considered by the investigator as unrelated or unlikely related to IMP.1
In the ongoing trials in pediatric patients with MDR TB (Trials 242-12-232 and 242-12-
233), there was 1 serious TEAE of non-Hodgkin’s lymphoma reported as of the cutoff 
date of 31 Jan 2016. 1
Refer to the IB for additional information on the delamanid safety profile.1
1.4.2
Antituberculosis Medications for Treating MDR-TB
The design of treatment regimens for MDR-TB is highly complex. Often it is empiric in 
the initial stages of treatment until full information on drug susceptibility testing of the 
clinical isolate is available to tailor a patient’s regimen.  Up until that point, the patient’s 
previous treatment history for TB, information on drug resistance patterns of known 
MDR-TB patients with whom a given patient has been in close contact, and the patient’s  
HIV status are used to guide the choice of anti-TB drugs. Treatment is generally divided 
into an initial intensive phase, which is focused on achieving sputum culture conversion 


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(SCC) from positive growth of MTB to a negative culture as soon as 
possible. Thereafter, a much longer continuation phase of treatment ensues, focused on 
ensuring sterilization. For the intensive phase, at least 4 drugs that are known or 
suspected to have efficacy for a given patient’s MTB isolate are used; however, whenever 
possible, 5 drugs should be used to ensure a higher likelihood of a response to 
treatment. The drugs comprising a patient’s treatment regimen are selected in a stepwise 
manner, as recommended by the WHO Programmatic Guidelines for the Management of 
Drug-resistant Tuberculosis for 2011112 and outlined in Table 1.4.2-1. Whenever 
possible, the regimen includes one injectable agent (amikacin, kanamycin, or 
capreomycin), as these agents are among the most potent of the second-line drugs 
available for treating MDR-TB. The injectable agent is usually continued for 8 months,
however, at least 4 months beyond achieving sustained SCC defining the end of the 
intensive phase of treatment. Thereafter, the continuation phase of treatment the part 
more readily delivered in an ambulatory setting ensues, and a full treatment course can 
last for 24 months. 
Table 1.4.2-1
Step-wise Approach in the Treatment of Multidrug-resistant 
Tuberculosis (Resistance to at Least Rifampicin and 
Isoniazid)
Step 1
Group 1:
Available first-line oral agents 
as well as pyrazinamide
Group 1 drugs, the most potent and best tolerated, should 
be used if there is good laboratory evidence and clinical 
history to suggest that a drug from this group is 
effective. The WHO (2011) no longer recommends 
ethambutol as part of a routine standard treatment, although 
continues to recommend pyrazinamide use for all patients.
Step 2
Group 2:
At least one injectable agent:
kanamycin (or amikacin); 
capreomycin; streptomycin
All patients should receive a Group 2 injectable agent if 
susceptibility is documented or suspected. Kanamycin or 
amikacin is generally the first choice, given the high rates 
of streptomycin resistance in this population.
Step 3
Group 3: 
At least one fluoroquinolone:
moxifloxacin; levofloxacin; 
gatifloxacin; ofloxacin
A fluoroquinolone should be added based on DST and 
treatment history. In cases when resistance to ofloxacin is 
suspected, a higher-generation fluoroquinolone should be 
used. (Gatifloxacin should be used with caution and close 
monitoring, secondary to previous reports of a rare but 
severe side effect of dysglycemia.)
Step 4
Group 4: 
One or more second-line oral 
bacteriostatic agents: 
p-amino-salicylic acid; 
cycloserine (or terizadone), 
ethionamide (or protionamide)
Group 4 drugs are added until the patient is receiving at 
least four drugs likely to be effective. 
The best choice is based on treatment history, adverse 
effect profile, and cost. 
DST is not standardized for the drugs in this group. 


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Table 1.4.2-1
Step-wise Approach in the Treatment of Multidrug-resistant 
Tuberculosis (Resistance to at Least Rifampicin and 
Isoniazid)
Step 5
Group 5: 
Drugs of unclear role in DR-TB: 
clofazimine; linezolid; 
amoxicillin/clavulanate; 
thioacetazone imipenem/ 
cilastatin; high-dose H; 
clarithromycin
The efficacy of Group 5 drugs in multidrug regimens is 
unclear and should only be considered if there are not four 
drugs likely to be effective from Groups 1- 4. Consultation 
with an MDR-TB expert should be considered. If drugs are 
needed from this group, it is recommended to add at 
least two.
DST is not standardized for the drugs in this group.
DR: drug resistant; DST: drug susceptibility testing; WHO: World Health Organization.
Derived from WHO source.
Although long-term treatment with multiple anti-TB drugs based on drug susceptibility 
testing (DST) is likely to be effective for a given patient, the failure rate for MDR-TB 
remains high. In a meta-analysis of cohort and case-control studies performed over a 
3-decade period that included data on nearly 5000 MDR-TB patients treated in 
21 countries, successful outcome was reported for only 62% (range: 39% to 77%) of 
patients; unsuccessful outcome was reported for 38% (range: 23% to 61%) of 
patients, including death that specifically occurred among 11% of patients (range: 0% 
to 32%).15,113
Given the high proportion of patients with MDR-TB whose disease does not resolve with 
available treatment, and that many of them die, it is clear that new medications that have 
potent activity against MDR-TB are urgently needed to improve the outcome of this 
patient group and to reduce the risk of further global spread of MDR-TB.  With the 
advent of new medications for MDR-TB, new cotoxicities may be encountered.  For 
example, delamanid, as well as bedaquiline, moxifloxacin, and clofazimine, have been 
associated with QT prolongation and, in most instances, the combined QTcF 
prolongation of 2 or more of these drugs has not yet been characterized.114,115
Treatment of MDR-TB in Pediatric Patients
The principles for treating adults with drug-resistant TB have demonstrated over time that 
they generally apply to infants, children, and adolescents, and the regimens recommended 
by the WHO for childhood-type TB continue to be essentially the same as for adult-type 
TB.116  WHO guidelines for the treatment of drug-resistant TB in adults are based on 
evidence from meta-analyses of individual patient data.112  However, recommendations 
for children are based on expert opinion, drawing on data from case series and cohort 


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studies, often with small sample sizes.  Consequently, variation exists in programmatic 
choices of treatment regimens, with the choice of drugs informed by previous drug 
exposure and DST results, if available. Recent interest in pediatric TB resulted in a 
critical review of existing treatment recommendations and a number of new 
recommendations have been made regarding the appropriate dosing of first-line TB drugs 
in children.117
Children with MDR-TB are managed in much the same way as adults, although there are 
some differences.  Confirmation of MDR-TB may not be possible in children and child 
TB cases in recent close contact with an adult MDR-TB case or failing to respond to 
adherent first-line treatment should be empirically treated as MDR-TB cases.  Because of 
the paucibacillary nature of early primary disease (contained primary lung lesion or 
uncomplicated hilar/mediastinal lymph node enlargement), these children may need 
fewer drugs and shorter durations of treatment, although there are no randomized studies 
to confirm this.118,119  Children are best managed with empirical or individualized 
treatment regimens that utilize the same rationale.  Empirical treatment is designed on the 
basis of the previous treatment history and DST of the child (or likely source case); 
individualized treatment is based on the patient’s own current DST result and previous 
treatment history.120
Traditionally in TB therapy, pediatric dosing has been extrapolated from adult PK 
studies; however, children generally metabolize more rapidly than adults, which leads to 
lower drug concentrations by weight.121,122  Alternatively, neonates and very young 
infants who have immature liver and enzyme development seem to metabolize drugs less 
rapidly than older children.  Care must be taken when prescribing for this 
subpopulation.122 Most second-line drugs have been minimally studied in children with 
TB.  Additionally, few drugs are available in pediatric formulations and adult-sized 
preparations are frequently inappropriate for small children.  Tablets, for example, must 
frequently be broken and segments crushed before delivery.  However, this approach is 
associated with dosing errors that could lead to lowered effectiveness or toxic effects.19
Regular weight-based dose adjustment is also important, particularly in young and/or 
malnourished children during the intensive phase of treatment when weight gain may be 
pronounced and rapid.123


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2
Trial Rationale and Objectives
2.1
Trial Rationale
Delamanid has been extensively studied in healthy adults and in patients with both 
uncomplicated TB and with MDR-TB.  Delamanid has shown low toxicity and good 
tolerability in all populations studied.  For adults, marketing authorization has been
obtained in the European Union, Japan, and Korea for the use of delamanid with OBR 
during the 6-month intensive phase of OBR treatment.  However, until Trial 232, 
delamanid had not been studied in the pediatric population.  
Trial 232 was designed to define the pediatric dose in patients between 0-17 years of age 
that will result in a delamanid systemic exposure (AUC) equivalent to that observed in 
the pivotal adult trials where efficacy against MDR-TB has been demonstrated.  Trial 233
will investigate the safety, tolerability, PK, and efficacy of delamanid administered in a 
pediatric population also on concomitant OBR.  The goals of this extension trial are to
evaluate the long-term safety and tolerability of the age-specific delamanid doses used in 
Trial 232 and to determine, in pediatric MDR-TB patients, the dose that will result in 
delamanid plasma exposure similar to effective plasma exposure in adult MDR-TB
patients. The study will also assess the palatability of the pediatric formulation using an 
age-appropriate visual hedonic scale and clinical assessment.
Both Trial 232 and Trial 233 are age de-escalation trials in which pediatric patients will 
be enrolled in 4 age groups:  adolescents ages 12 to 17 years, inclusive (Group 1); 
children ages 6 to 11 years, inclusive (Group 2); children ages 3 to 5 years (Group 3); and 
infants ages birth to 2 years (Group 4)
Delamanid plasma concentrations in the pediatric population will be analyzed using a
population pharmacokinetics (POPPK) approach of the data collected in Trials 232 and 
233. 
In addition, a PK/PD analysis will be performed for changes in QTc as a function of 
delamanid and DM-6705 plasma concentrations of the data collected in Trials 232 and 
233.  
Patients in each age group will be sequentially enrolled into this 6-month treatment 
extension trial (Trial 233) to evaluate the safety, tolerability, PK, efficacy, and 
palatability of delamanid during the extended time period planned in this trial for 
treatment of MDR-TB.  To be eligible for Trial 233, all patients must rollover within 30 
days of completing Trial 232.


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This trial will be conducted in accordance with the 2010 “Guidelines for the Ethical 
Conduct of Studies to Evaluate Drugs in Pediatric Populations” of the American 
Academy of Pediatrics124 and the 2001 “Ethical Considerations for Clinical Trials 
performed in Children” from the European Union Directive.125
2.2
Dosing Rationale
Delamanid will be administered to pediatric MDR-TB patients on OBR therapy.  
Children will be given delamanid BID (except for the 5.5-8 kg group who will receive a 
QD dose) in agreement with the delamanid dosing regimen for adult MDR-TB patients, 
which is BID treatment for 6 months.  Delamanid will be administered with water and 
food as a morning and evening dose, approximately 10 hours apart.  Food composition 
will be equivalent to a standard meal and typical for the childrens’ ages and needs.
Children 6 to 17 years, inclusive, will receive the delamanid 50-mg tablet adult 
formulation.  Adolescents (12 to 17 years) will be given delamanid at the adult dose, 
100 mg BID, while children 6 to 11 years will be given one half of the adult dose, 50 mg 
BID.
Younger children (ages birth to 5 years, inclusive) will be given pediatric dispersible 
tablets admixed with water and administered orally as an extemporaneous suspension.  
Children ages 3 to 5 years, inclusive (Group 3) will be given pediatric delamanid 
formulation 25 mg BID.  
The delamanid dose for children ages birth to 2 years, inclusive (Group 4), will be 
determined based on body weight during baseline visit. Children with weight > 10 kg will 
be given delamanid pediatric formulation (DPF) , 10 mg BID, those with weight > 8 and 
≤ 10 kg will be given DPF 5 mg BID, while children with weight ≤8 kg will receive 
DPF 5 mg QD.  Delamanid dose will be adjusted as needed for Group 4 patients based on 
the weight measurement at specified study visits (Visits 5, 7, 9, 11 and 12).
Delamanid doses in younger children were confirmed using the PK, safety, and 
tolerability findings in the older age groups and based on the bioavailability of the 
pediatric formulation.
2.3
Trial Objectives
The primary objectives of this trial are:

To evaluate the long-term safety and tolerability of delamanid and its metabolites 
in combination with an OBR during a 6-month treatment period in pediatric 


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patients with MDR-TB for the age-specific delamanid doses determined in Trial 
232

To report delamanid and metabolite plasma concentrations at each visit day by 
age groups and to conduct a population pharmacokinetics (POPPK) analysis of 
delamanid when delamanid is administered in combination with an OBR during a 
6-month treatment period in pediatric patients with MDR-TB
The secondary objectives are:

To evaluate the PK/PD relationship of delamanid and its metabolite DM-6705 
plasma concentrations and change in QTc when delamanid is administered in 
combination with OBR during a 6-month treatment period in pediatric patients 
with MDR-TB

To evaluate the efficacy of delamanid when administered in combination with an 
OBR during a 6-month treatment period in pediatric patients with MDR-TB

To determine the palatability of the delamanid pediatric formulation
3
Trial Design
3.1
Type/Design of Trial
This is a phase 2, open-label, multiple-dose, age de-escalation trial to assess the
long-term safety, tolerability, PK, and efficacy of delamanid plus OBR over a 6-month 
period in pediatric patients with MDR-TB who have successfully completed Trial 232.  
This trial will be conducted at multiple phase 2 sites qualified to treat pediatric patients 
with MDR-TB.  The protocol will be approved by the appropriate national competent 
authorities (CAs) and the respective independent ethics committees (IECs) or institutional 
review boards (IRBs).  Compliance with any other regional or local notification or 
approval requirements will be met and maintained. 
All patients must have completed the pediatric PK Trial 232 prior to enrollment into 
Trial 233. Those patients who have completed Trial 232 and choose to enter Trial 233 
must rollover from Trial 232 within 30 days of completing that Trial. If any patients 
terminate Trial 232 early or choose not to enter Trial 233, patients will be recruited to 
first enter and complete Trial 232, and then to rollover into Trial 233.  Patients who 
terminate Trial 233 early will not be replaced.
Delamanid will be administered for 182 days.  The trial will be conducted sequentially in 
4 groups of pediatric patients:


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
Group 1 (ages 12 - 17 years, inclusive) will receive adult formulation delamanid 
100 mg BID + OBR (n = 6)

Group 2 (ages 6 - 11 years, inclusive) will receive adult formulation delamanid 50 
mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive pediatric formulation delamanid 
25 mg BID + OBR (n = 12)

Group 4 (ages birth - 2 years, inclusive) will receive the following delamanid 
pediatric formulation (DPF) dose based on body weight during baseline visit (n = 
12):

Patient > 10 kg will receive DPF 10 mg BID + OBR

Patient > 8 and ≤10 kg will receive DPF 5 mg BID + OBR

Patient ≤8 kg will receive DPF 5 mg QD + OBR

Delamanid dose will be adjusted as needed for Group 4 patients  based on the 
weight measurement  at specified study visits (Visits 5, 7, 9, 11 and 12).
The trial will comprise the following periods: 

Screening Period (Day −30 to −2): Study data will either be taken from 
screening or Day 10 of Trial 232 or will be performed during the post-Trial 232 
thirty (30)- day screening period for Trial 233, as described in the Schedule 
of Assessments

Baseline (Day −1):  Inclusion/exclusion criteria, physical examination, and safety 
assessments including laboratory tests, signs and symptoms of tuberculosis (TB), 
audiometry and visual assessments, vital signs, height, weight, head 
circumference (Group 4 only), percentiles for age, body mass index (BMI), and 
ECG as described in the Schedule of Assessments.  OBR administration as 
prescribed by investigator, and recording of concomitant medications  

Treatment Period (Days 1 to 182):  Morning and evening dosing of delamanid. 
PK sampling every 2 weeks through Week 14 at 0 hours predose, then as 
described in the Schedule of Assessments. Signs and symptoms of TB, physical 
examination, and other safety assessments including safety lab tests. Audiometry 
and visual assessments, and ECG at weeks and times shown in the Schedule of 
Assessments. Vital signs, head circumference (Group 4 only), height, weight, and 
BMI beginning at Week 2. OBR administration as prescribed by the investigator 
and collection of AEs, immediately reportable events (IREs), and concomitant 
medications

Post-treatment Period (Days 183 to 238): Physical examination, vital signs, 
ECGs, safety labs, blood draws for PK at visits and times described in the 
Schedule of Assessments.  Head circumference (Group 4 only), height, weight, 
signs and symptoms of TB, audiometry and visual assessments, thyroid function 
tests (for patients taking ethionamide or para-aminosalicylic acid), OBR 


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Amendment 5, 28 February 2019  
administration as prescribed by the investigator and collection of AEs/IREs, and 
concomitant medications

Follow-up Period (Days 239 to 365, 6 month Post Last Delamanid Dose
Visit): Physical examination, height and weight, BMI, percentiles for age, vital 
signs, head circumference (Group 4 only), height, weight, signs and symptoms of 
TB, chest radiograph, audiometry and visual assessments, safety labs, thyroid 
function tests (for patients taking ethionamide or para aminosalicylic acid), 
OBR administration as prescribed by the investigator and collection of AEs/IREs 
and concomitant medications

Treatment Outcome Follow-up (Day 730 [Month 24] + 2 months: All patients 
will either visit the clinic or be contacted by telephone for clinical assessment. 
Collection of treatment outcome information as routinely documented in the 
patient medical records or in a national TB program
See Figure 3.1-1 for a schematic of the overall trial design.


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Figure 3.1-1
Trial Design Schematic
TREATMENT PERIOD
Days 1 to 182
POST-TREATMENT 
PERIOD
Days 183 to 238
FOLLOW-UP 
PERIOD
Days 239 to 365
(6-month post last 
delamanid dose visit)
OBR only
Safety, PK, Efficacy
Evaluations
Population:
Pediatric patients with 
MDR-TB receiving OBR
Delamanid BID/QD + OBR
Safety, PK, Efficacy
Evaluations
OBR only
Safety, Efficacy
Evaluations
SCREENING/BASELINE
PERIOD
Days −30 to −1
Day 730
OBR only
Treatment Outcome


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3.2
Trial Treatments
Patients will be assigned by age group to receive one of the following treatments for 
182 days:  
1) Group 1 (12 to 17 years, inclusive): adult formulation delamanid 100 mg BID 
(administered as 2 x 50-mg tablets BID) + OBR
2) Group 2 (6 to 11 years, inclusive): adult formulation delamanid 50 mg BID 
(administered as 1 x 50-mg tablet BID) + OBR
3) Group 3 (3 to 5 years, inclusive): pediatric formulation delamanid 25 mg BID 
(administered as 1 x 25-mg tablet BID) + OBR
4) Group 4 (birth to 2 years, inclusive): pediatric formulation delamanid based on 
body weight  + OBR. Children with weight > 10 kg will be given delamanid 
pediatric formulation (DPF) 10 mg BID (administered as 2 x 5-mg dispersible 
tablet) + OBR; Children with weight > 8 and ≤10 kg will be given DPF 5 mg 
BID (administered as 1 x 5-mg dispersible tablet) + OBR, and children with 
weight ≤8 kg will be given DPF delamanid 5 mg QD (administered as 1 x 5-mg 
dispersible tablet) + OBR.   
Patient age group and dosing (Groups 1, 2 and 3) will be determined at the time of 
enrollment into Trial 232 and will not change during rollover into Trial 233.  Dosing for 
Group 4 will be determined during baseline visit and will be adjusted based on weight 
measurement during specific study visits (Visits 5, 7, 9, 11 and 12). 
3.2.1
Administration of Delamanid
All doses for Groups 1 and 2 will be given orally as the appropriate number of 50-mg 
adult formulation delamanid tablets (Section 3.2). Adult formulation delamanid tablets 
should be taken with water.  Children in Groups 3 and 4 will be given delamanid as an 
extemporaneous suspension using the delamanid pediatric dispersible tablet formulation.
According to the country-specific DOT plan, one dose per day for a minimum of 5 days 
per week will be given under direct observation.  It is recommended that all delamanid 
doses be administered under fed conditions in the morning and evening.  It is also 
recommended that delamanid be dosed within 30 minutes of the start of a meal, if 
possible.  Optimally, OBR medications should be given at least 1 hour prior to or 1 hour 
after dosing of delamanid.  The time of dosing with delamanid following the meal will be 


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documented when patients are in the hospital or clinic or for regularly scheduled 
assessments or for observation.
3.2.2
Administration of OBR
The specific medications comprising OBR for each patient will be selected by the lead 
investigator, who is a clinical expert on pediatric MDR-TB treatment and management.  
Selection and administration of the treatment medications will generally be based on 
WHO guidelines126 in conjunction with national TB program guidelines.  Moxifloxacin, 
a fluoroquinolone commonly used to treat MDR-TB, will not be used because of its 
known effect on QT prolongation.  Gatifloxacin, although not disallowed, will only be 
used with caution, secondary to the rare but serious side effect dysglycemia; close 
monitoring of blood glucose levels is recommended for those patients investigators 
choose to treat with gatifloxacin as per the WHO guidelines.  At any time during the trial, 
the lead investigator for a given site may change OBR for a given patient based on patient 
tolerability and subsequent DST results.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
At least 36 males and females ages birth to 17 years, inclusive, who have successfully 
completed Trial 232 and who are receiving OBR for confirmed or presumptive MDR-TB 
will be enrolled in 4 sequential age groups.  These patients (and age groups) will be the 
same groups who successfully completed Trial 232:  Group 1 (ages 12 to 17 years) will 
contain a minimum of 6 patients and must include at least 2 but no more than 5 females.  
Group 2 (ages 6 to 11 years, inclusive) will contain a minimum of 6 patients.  Group 3 
(ages 3 to 5 years, inclusive) and Group 4 (ages birth to 2 years, inclusive) each will 
contain a minimum of 12 patients. Groups 2, 3, and 4 will include both genders.
3.3.2
Subject Selection and Numbering
All patients must have completed Trial 232 prior to enrollment in Trial 233.  Subjects 
who enter Trial 233 will retain the same unique identification number assigned to them in 
Trial 232.  Patients who terminate Trial 233 early will not be replaced.  
3.4
Eligibility Criteria
3.4.1
Informed Consent
Written informed consent and/or assent will be obtained from all patients (or their 
parents, guardian, or legal representative), as applicable for local laws, before any 


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trial-related procedures (including any pretreatment procedures) are performed.  
Investigators may discuss the availability of the trial and the possibility for entry with a 
potential patient and his/her parent, guardian, or legal representative without first 
obtaining consent/assent.  However, assent of the adolescent and informed consent of the 
parent, guardian, or legal representative, as applicable for local laws, must be obtained 
and documented prior to the initiation of any procedures that are performed solely for the 
purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of or in preparation for the research, it is 
considered to be part of the research.  When a screening informed consent form 
(ICF)/assent form is used for general health assessment prior to identifying or consenting 
candidates for this specific trial, the screening ICF/assent form will also become part of 
this study’s file and the patient’s chart.  Parent/guardian/legal representative informed 
consent and patient assent will be obtained in conformance with “Ethical Considerations 
for Clinical Trials Performed in Children,” Guidelines for Implementing Directive 
2001/20 /EC, 6 October 2006.124
The investigator(s) have both ethical and legal responsibility to ensure that each patient 
being considered for inclusion in the trial and his/her parent(s), guardian(s), or legal 
representative(s) are given a full explanation of the protocol.  This shall be documented 
on a written ICF, which shall be approved by the same IRB/IEC responsible for approval 
of this protocol.  Each ICF shall include the elements required by the United States Food 
and Drug Administration (FDA) regulations in 21 Code of Federal Regulations Part 50
and International Conference on Harmonisation (ICH) Good Clinical Practices (GCP),
and must adhere to the ethical principles that have their origin in the Declaration of 
Helsinki, as well as local regulatory requirements. The investigator agrees to obtain 
approval from the sponsor of any written ICF used in the trial, preferably prior to 
submission to the IRB/IEC with the exception of a screening ICF.  However, the 
screening ICF must have been approved by the IRB/IEC.
Once appropriate essential information has been provided to the parent, guardian, or legal 
representative and/or the patient and fully explained in layman’s language by the 
investigator (or a qualified designee) and it is felt the parent/guardian/legal representative
understands the implications of participating in the trial, the IRB/IEC-approved written 
assent and ICF shall be signed and dated by the patient and his/her parent/guardian/legal 
representative and the person obtaining consent (investigator or designee), and by any 
other parties required by the IRB/IEC.  The parent/guardian/legal representative and/or 
patient shall be given a copy of the signed ICF/assent form; the original shall be kept on 


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file by the investigator.  All of the above-mentioned activities must be completed prior to 
the patient participating in the trial.
Patients for whom an ICF/assent form is signed but who are not started on treatment are 
permitted to be rescreened under the conditions specified in Section 3.9. In the event the 
patient is rescreened for trial participation, a new ICF/assent form must be signed.
If any patient should turn 18 years of age (or the age of adulthood as specified by local 
laws or regulations) within 4 weeks prior to entry into Trial 233 or during Trial 233 
participation, an ICF must be signed by the patient.  The patient shall be given a copy of 
the signed ICF/assent, and the original shall be kept on file by the investigator.  A patient
who turns age 18 (or the age of adulthood as specified by local laws or regulations)
during the study must sign an appropriate ICF/assent form for himself/herself at that time.
In addition to the English version of the ICF/assent form, the document may also be 
translated into local languages for use in this study.  Translation with back-translation for 
confirmation will be used to ensure accuracy.
In accordance with applicable regulations and guidance for subject data protection, 
patients who have completed the Post-treatment Follow-up Period (Visit 19) prior to 
regulatory authority and EC approval of this protocol will be asked to sign an ICF/assent 
form authorizing the release of TB-related clinical information from the treatment 
centers. The parent/guardian/legal representative and/or patient shall be given a copy of 
the signed ICF/assent form; the original shall be kept on file by the investigator.      
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria listed in Table 3.4.2-1 prior to 
enrollment:
Table 3.4.2-1
Inclusion Criteria
1.
Patient must have successfully completed Trial 232 and have and met all inclusion criteria for 
that trial
2.
Male or female
3.
Age birth to 17 years, inclusive
4.
Confirmed diagnosis of MDR-TB,a,b ie, culture positive for MTB with isoniazid and rifampicin 
resistance on DST, or a positive rapid test demonstrating resistance to rifampicin alone or to 
rifampicin and isoniazid
OR
Presumptive diagnosis of pulmonary or extrapulmonary MDR-TBb such that the treating physician 
has decided to treat the patient for MDR-TBa who has one of the following:
-Clinical specimen (eg, cerebrospinal fluid, pleural fluid, ascitic fluid, lymph node aspirate, or 
other tissue) suggestive of tuberculosis disease


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Table 3.4.2-1
Inclusion Criteria
-Persistent cough lasting > 2 weeks
-Fever, weight loss, and failure to thrive
-Findings on recent chest radiograph (prior to Visit 1) consistent with TB
AND
-Household contact with a person with known MDR-TB or with a person who died while 
appropriately taking drugs for sensitive TB
OR
-On first-line TB treatment but with no clinical improvement
5.
Negative urine pregnancy test for female patients who have reached menarche
6.
Study-specific written informed consent/assent obtained from a parent/guardian or legally 
acceptable representative, as applicable for local laws prior to the initiation of any protocol-
required procedures.  In addition, for patients in Groups 1 and 2 or as required by local law, the 
patient must provide informed assent at screening and must be able to fully understand that he or 
she can withdraw from the study at any time.   
a Patients should be on OBR for at least 2 weeks prior to baseline assessments.
b Includes pre−XDR TB.
3.4.3
Exclusion Criteria
Subjects will be excluded from the trial if they meet any of the exclusion criteria listed in 
Table 3.4.3-1 prior to enrollment in Trial 233.
Table 3.4.3-1
Exclusion Criteria
1.
Patients who have not completed Trial 232
2.
Children with laboratory evidence of hepatitis B or C
3.
Children with body weight < 5.5 kg.
4. 
For patients with HIV co-infection, CD4 cell count ≤ 1000/mm3 for children 1-5 years old, and ≤ 
1500/mm3 for children less than 1 year old 
5.
History of allergy to metronidazole and any disease or condition in which the use of metronidazole 
is required
6.
Use of amiodarone within 12 months prior to the first dose of IMP or use of other predefined 
antiarrhythmic medications within 30 days prior to the first dose of IMP
7.
Serious concomitant conditions (cardiovascular disorders; severe respiratory disease; severe 
diarrheal disease; or renal, hepatic, or neurological impairment)
8.
Abnormalities in screening ECG (including atrioventricular block, bundle branch block or hemi-
block. QRS prolongation > 120 msec or QTcF interval > 450 msec in both males and females)
9.
Preexisting cardiac conditions including but not limited to structural cardiac disease including 
suspected TB involvement of the heart on clinical or radiographic grounds
10.
A concomitant condition such as renal impairment characterized by serum creatinine levels 
>1.5 mg/dL, hepatic impairment (ALT or AST > 3 x ULN), or hyperbilirubinemia characterized by
total bilirubin > 2 x ULN
11.
Concurrent diagnosis of severe malnutrition or kwashiorkor
12.
Positive urine drug screen (Groups 1 and 2 only)
13.
Use of rifampicin and/or moxifloxacin within 1 week prior to the first dose of IMP and/or any prior 
concurrent use of bedaquiline
14.
Lansky Play Performance Score < 50 (not applicable for children < 1 year old) or Karnofsky Score 
< 50


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Table 3.4.3-1
Exclusion Criteria
15.
Administered an IMP within 1 month prior to Visit 1 other than delamanid given as IMP in 
Trial 232
16.
Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described 
in the informed consent form (Groups 1 and 2 only)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; QTcF = QT interval corrected using
Fridericia’s method; ULN = upper limit of normal.
Patients ages 6 to 17 years excluded for a positive drug/alcohol screen are not eligible to 
be rescreened for participation in the trial.  However, a positive urine drug screen could 
be the result of authorized medications prescribed by a physician for a nonabuse-related 
indication and the investigator will need to ascertain relevant information to make this 
distinction before proceeding further with screening and enrollment.  Patients excluded 
for any other reason may be rescreened at any time if the exclusion characteristic has 
changed. In the event that the subject is rescreened, a new ICF/assent form must be 
signed and a new screening number assigned.
3.5
Outcome Variables
3.5.1
Primary Outcome Variables
3.5.1.1
Safety Outcome Variables
Safety and tolerability of delamanid will be assessed by the following variables:

Reported TEAEs

Physical examination including visual testing and audiometry 

Vital signs

ECGs

Holter monitoring (if applicable)

Clinical laboratory assessments (hematology, serum chemistry, urinalysis, and 
other laboratory tests [see Table 3.7.3.1-1])
3.5.1.2
Pharmacokinetic Variables
PK parameters from the population pharmacokinetic analysis, using data from this trial 
and from the -232 trial, will be reported.  


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3.5.2
Secondary Variables
3.5.2.1
Pharmacokinetic/Pharmacodynamic Variables
PK/PD analysis to determine the relationship between delamanid and DM-6705 plasma 
concentrations and changes in QTc interval will be performed.
3.5.2.2
Efficacy Outcome Variables
The efficacy of delamanid in treating pediatric MDR-TB patients will be assessed by 
chest radiography (patients with pulmonary disease), body weight/height, and resolution 
of TB symptoms (based on investigator evaluation).
In addition, SCC (for culture-positive patients) will be assessed in patients who are able 
to produce sputum (or provide other biological specimens) for microbiological evaluation 
according to the requirements of the National TB Program.  Microbiological assessment 
of sputum or other biological specimens (eg, cerebrospinal fluid, pleural fluid, ascitic 
fluid, joint fluid, lymph node aspirates) are not required as part of this protocol; however, 
they may be collected by the investigator as part of routine management of the subject.  
In patients who are able to produce sputum (or provide other specimens) for 
microbiological evaluation according to the requirements of the National TB Program, all 
available results for smear microscopy, culture, identification, and drug susceptibility will 
be collected from the patient chart as an unscheduled visit.
3.5.2.3
Palatability
The palatability of the pediatric formulation will be assessed using an-age appropriate 
visual hedonic scale and clinical assessment (Groups 3 and 4 only).
3.6
Measures to Minimize/Avoid Bias
This is an open-label, noncontrolled PK and safety trial of delamanid in pediatric patients
with MDR-TB and who are also receiving OBR.
3.6.1
Randomization
Randomization of patients is not planned.
3.7
Trial Procedures
Delamanid will be administered with a standard meal for the duration of the trial.  OBR 
will be administered as prescribed, under the DOTS guidelines of the WHO.  
Each patient will participate in the trial for up to 760 days.  The trial will comprise the 
screening period (29 days); baseline (Day −1); treatment period (182 days of delamanid 


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plus OBR administration); post-treatment period (56 days with visits at Days 189, 196, 
203, 210, and 238 [Day 238 corresponds to 2 months post last delamanid dose]); and a
follow-up period with a visit at 6 months after the last delamanid dose (Day 365) and an 
additional 365-day treatment outcome follow-up period from the last follow-up visit.  
Trial assessment time points are summarized in Table 3.7-1. 


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Table 3.7-1
Schedule of Assessments
Trial Period
SCR
BSL
Treatment Period
Post-treatment Period
F/U
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
ET
14
15
16
17
18
19
20
Day
and
Visit Window
−30 
to −2
−1
1
14
28
42
56
70
84
98
126
154
182
n/a
189
196
203
210
238
365
730
n/a
2 days
5 
days
+ 2Ms
Week
2
4
6
8
10
12
14
18
22
26
n/a
27
28
29
30
34
52
Informed 
consent/assenta
Xa
Inclusion/
exclusion criteria
Xb
X
Diagnosis of 
MDR-TB
X b,f
Demographic data
Xb
Medical history
X
Complete PE
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body mass index
and percentiles for 
age
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
Date of birth and
gender
X
Vital signsg
Xg,h
Xg,h
Xg
Xg,h
Xg
Xg,h
Xg
Xg,h
Xg
Xg,h
Xg,h
Xg,h
Xg,h
Xg, h
Xg
Xg
Xg
Xg,h
Xg,h
Xg,h
12-Lead ECG
Xc
X
Xj
Xi
Xj
Xi
Xi
Xj
Xj
Xi
X
Signs and 
symptoms of TB
Xb
X
X
X
X
X
X
X
X
X
X
Chest radiograph
(only for patients 
with pulmonary 
TB)
Xb
X
X
Audiometry 
assessment
Xb
X
X
X
X
X
X
X
X
X
X
Visual assessment
Xb
X
X
X
X
X
X
X
X
X
X
Urinalysis
Xb
X
X
X
X
X
X
X
X
X
X


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Table 3.7-1
Schedule of Assessments
Trial Period
SCR
BSL
Treatment Period
Post-treatment Period
F/U
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
ET
14
15
16
17
18
19
20
Day
and
Visit Window
−30 
to −2
−1
1
14
28
42
56
70
84
98
126
154
182
n/a
189
196
203
210
238
365
730
n/a
2 days
5 
days
+ 2Ms
Week
2
4
6
8
10
12
14
18
22
26
n/a
27
28
29
30
34
52
Urine pregnancy 
test (only female 
patients who have 
reached menarche)
Xd,k
Xk
Xk
Urine drug screen
(Groups 1 and 2 
only)
Xd
Hematologyl
Xb
X
X
X
X
X
X
X
X
X
X
Serum chemistry
Xb
X
X
X
X
X
X
X
X
X
X
HIV test
Xb,v
CD4 cell count
Xb,w
HBsAg test
Xb
Anti-HCV test
Xb
ACTH test
Xb
X
Adrenal function 
(cortisol)
Xb
X
Thyroid functionm
Xb,m
Xm
Xm
Xm
Xm
C-reactive protein
(Groups 1 and 2 
only)
Xb
X
PK blood draw
Xn
Xp
Xn
Xp
Xn
Xn
Xe
Xp
Xp
Xp
Xo
Xp
Delamanid dosing
X
X
Xt
X
Xt
X
Xt
X
Xt
Xt
X
Palatability 
assessment 
(Groups 3 and 4 
only)
X
X
X
X
Xq
OBR 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 3.7-1
Schedule of Assessments
Trial Period
SCR
BSL
Treatment Period
Post-treatment Period
F/U
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
ET
14
15
16
17
18
19
20
Day
and
Visit Window
−30 
to −2
−1
1
14
28
42
56
70
84
98
126
154
182
n/a
189
196
203
210
238
365
730
n/a
2 days
5 
days
+ 2Ms
Week
2
4
6
8
10
12
14
18
22
26
n/a
27
28
29
30
34
52
Record AEs 
and IREs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record prior anti-
TB medications
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Menarche/LMP 
assessment
(Groups 1 and 2 
only)
Xd
X
X
X
X
X
X
X
X
X
X
Follow-up contact 
for ET
Xr
Collection of 
treatment outcome 
data
X
Holter Monitoringu
X
X
X
X
X
X
X
X
X
X
ACTH = adenocorticotropic hormone; aPTT = activated partial thromboplastin time; BP = blood pressure; bpm = beats per minute; BSL = baseline; d = days; CD4 
= cluster of differentiation 4; ET = early termination; F/U = follow up; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HR = heart rate; IRE = 
immediately reportable event; LMP = last menstrual period; n/a = not applicable; OBR = optimized background regimen; PE = physical examination; PT = 
prothrombin time; RR = respiratory rate; SCR = screening; TB = tuberculosis.
aConsenting/Assenting for Trial 233 can occur prior to Day −30.
bInformation to be obtained from screening visit of Trial 232.
cInformation to be obtained from Day 10 of Trial 232.
dFor Groups 1 and 2 only, information to be obtained during Screening for this Trial 233, between Days −30 to −1.
eFor the early termination visit, the PK blood sample will be labeled with the study day, date, and time of the PK blood draw.
fConfirmed or presumptive diagnosis of MDR-TB (based on inclusion criteria no. 4, Table 3.4.2-1).
gVital signs include systolic and diastolic BP (mm Hg), HR (bpm), RR (bpm), and body temperature (C) after the patient has been in a supine or semi-recumbent 
position for ≥3 minutes (as possible for Groups 3 and 4), height (cm), and weight (kg).  Note: height and weight do not need to be measured on Day 1.
hHead circumference should also be measured for children in Group 4 (ages birth - 2 years, inclusive).
iThree consecutive 12-lead ECGs must be performed predose after the subject has been in a supine or semi-recumbent position and at rest for 10 minutes (as 
possible for Groups 3 and 4).


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jECG paired with PK blood sampling: Three consecutive 12-lead ECGs must be performed predose after the subject has been in a supine or semi-recumbent position 
and at rest for 10 minutes (as possible for Groups 3 and 4), followed by PK blood draw, and then patients will receive their dose of delamanid.
kUrine pregnancy test will be performed for all females who have reached menarche .
lCoagulation tests (activated partial thromboplastin time and prothrombin time) performed with safety laboratory assessments.
mThyroid tests (T4 and thyroid stimulating hormone) performed for patients taking ethionamide or p-aminosalicylic acid.
nPK blood draw paired with 12-lead ECG at predose (0 hours during treatment).
oPK blood draw paired with 12-lead ECG at theoretical predose.
pPK blood draw to be obtained at any time point.
qOnly in Groups 3 and 4 and only if within 25 - 30 minutes postdose and prior to Day 182.
rFollow-up contact for patients who terminate early from Trial 233 should occur 28 to 32 days after the early termination visit to assess for AEs and IREs.  All 
patients will continue treatment with OBR as prescribed by the investigator according to WHO guidelines.
sDay 730 (Month 24) + 2 months.
t For Group 4 only, delamanid dose will be adjusted based on the subject’s weight measurement during study visit
uTwenty-four-hour Holter monitor tracing if QTcF>490 msec.
v Not required if patientt had a documented HIV test and result within 1 year prior to the screening visit AND there is no known exposure to HIV. 
w Screening CD4 cell count test will only be performed for patients with positive HIV test results unless the patient has documented CD4 cell count test and results 
within 3 months prior to screening visit.


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3.7.1
Schedule of Assessments
All patients participating in the trial must be evaluated according to the assessment 
schedule of the trial outlined in Table 3.7-1.
3.7.1.1
Visit 1, Screening/Enrollment (Days −30 to −2)
For patients who elect to be rolled over from Trial 232 into Trial 233, the following 
procedures will either be collected from screening data for Trial 232 or from Day 10 data 
of Trial 232, or will be assessed/performed within 30 days prior to Trial 233.
The following information will be taken from the screening data of Trial 232 and used as 
screening data for this Trial 233:

Inclusion/exclusion criteria 

Diagnosis of MDR-TB, confirmed or suspected  

Demographic data 

Complete physical examination

Signs and symptoms of TB

Audiometry and visual assessments 

Chest radiograph for confirmation of radiological picture compatible with TB 

Laboratory assessments including serum chemistry, hematology and coagulation, 
urinalysis, HIV, CD4 cell count (if HIV test is positive), hepatitis B surface 
antigen (HBsAg), antibody to hepatitis C virus (anti-HCV), adrenocorticotropic 
hormone (ACTH), adrenal function (cortisol), C-reactive protein (Groups 1 and 2 
only), and thyroid function tests (T4 and thyroid stimulating hormone [TSH])
The following information will be taken from Day 10 data of Trial 232 and used as 
screening data for this Trial 233:

12-lead ECG
The following information will be obtained during the screening period of this Trial 233 
between Days −30 and −2:

Informed consent/assent (may be completed prior to Day −30)

Medical history

Vital signs assessments (blood pressure, heart rate, respiratory rate, and body 
temperature) after the subject has been in a supine or semi-recumbent position for 
≥3 minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages birth - 2 years, 
inclusive)  

BMI and percentiles for age

Date of birth and gender

Urine pregnancy test for all female subjects who have reached menarche


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
For Groups 1 and 2 only, urine drug screen (as per Table 3.7-1)

Record prior concomitant medications including prior concomitant anti-TB 
medications.  (Note: Patients will have been on OBR in Trial 232 for at least 2
weeks prior to baseline assessments)

Groups 1 and 2 only, record date of menarche and/or date of last menstrual period 
(LMP)
3.7.1.2
Visit 2, Baseline (Day −1)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s electronic case report form (eCRF) for Baseline (Day −1):

Review of inclusion/exclusion criteria

Complete physical examination.  Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (blood pressure, heart rate, respiratory rate, and body 
temperature) after the subject has been in a supine or semi-recumbent position for 
≥3 minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages birth - 2 years, 
inclusive)

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Three consecutive 12-lead ECGs after the patient has been in a supine or 
semi-recumbent position and at rest for 10 minutes (as possible for Groups 3 
and 4)  

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis

OBR administration, as prescribed by investigator

Record concomitant medications including concomitant anti-TB medications
3.7.1.3
Visit 3 (Day 1)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 1:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4).  Note: height and weight do not need to be measured at this visit


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
Three consecutive 12-lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4) prior to 
blood draw for PK.  Sequence should be ECG assessment, then blood draw for 
PK, then administration of delamanid 

Blood draw for PK at predose (0 hours) (see Section 3.7.4)

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator). For Group 4, 
delamanid dosing will be determined based on weight measurement during 
baseline visit.  

Groups 3 and 4 only, palatability assessment of the delamanid pediatric 
formulation within 25 - 30 minutes postdose (see trial operations manual for 
details)

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec following 
the first dosing of delamanid pediatric formulation. 
3.7.1.4
Visit 4, Day 14 2 Days (Week 2)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 14:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Blood draw for PK at any time point (see Section 3.7.4)

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications.

Groups 1 and 2 only, record date of menarche and/or date of LMP
3.7.1.5
Visit 5, Day 28 2 Days (Week 4)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 28:


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
Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed.

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis 

Three consecutive 12-lead ECGs Three consecutive 12-lead ECGs after the 
subject has been in a supine or semi-recumbent position for ≥ 10 minutes (as
possible for Groups 3 and 4).  Sequence should be ECG assessment then 
administration of delamanid 

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  For Group 4 only,
delamanid dosing will be adjusted as needed based on weight measurement 
during this visit.  Study personnel must determine whether or not delamanid 
dosing will be adjusted prior to IWRS drug dispensation. 

Groups 3 and 4 only, palatability assessment of the delamanid pediatric 
formulation within 25 - 30 minutes postdose (see trial operations manual for 
details)

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.6
Visit 6, Day 422 Days (Week 6)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 42:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  

Record AEs and IREs


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
Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP
3.7.1.7
Visit 7, Day 562 Days (Week 8)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 56:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis 

Three consecutive 12-lead ECGs.  Sequence should be ECG assessment then PK 
blood draw followed by administration of delamanid

Blood draw for PK at predose (0 hours) (see Section 3.7.4)

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  For Group 4 only, 
delamanid dosing will be adjusted as needed based on weight measurement 
during this visit.  Study personnel must determine whether or not delamanid 
dosing will be adjusted prior to IWRS drug dispensation.  

Groups 3 and 4 only, palatability assessment of the delamanid pediatric 
formulation within 25 - 30 minutes postdose (see trial operations manual for 
details)

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.8
Visit 8, Day 70 2 Days (Week 10)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 70:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed


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
Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP
3.7.1.9
Visit 9, Day 84 2 Days (Week 12)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 84:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis

Blood draw for thyroid function tests (T4 and TSH) for patients taking 
ethionamide or PAS

Three consecutive 12-lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4).  Sequence 
should be ECG assessment then administration of delamanid

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  For Group 4 
delamanid dosing will be adjusted as needed based on weight measurement 
during this visit.  Study personnel must determine whether or not delamanid 
dosing will be adjusted prior to IWRS drug dispensation.

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 


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3.7.1.10
Visit 10, Day 98 2 Days (Week 14)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 98:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Blood draw for PK at any time point (see Section 3.7.4)

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP
3.7.1.11
Visit 11, Day 126 2 Days (Week 18)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 126:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis

Three consecutive 12-lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4).  Sequence 
should be ECG assessment then administration of delamanid

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  For Group 4 only, 
delamanid dosing will be adjusted as needed based on weight measurement 


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during this visit.  Study personnel must determine whether or not delamanid 
dosing will be adjusted prior to IWRS drug dispensation. 

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.12
Visit 12, Day 154 2 Days (Week 22)
The following procedures will be conducted and/or recorded in the patient’s eCRF for 
Day 154:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 ( ages birth - 2 years, inclusive)

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis

Three consecutive 12-Lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4) and prior to 
blood draw for PK. Sequence should be ECG assessment, then blood draw for 
PK, then administration of delamanid.

Blood draw for PK at predose (0 hours) (see Section 3.7.4)

Delamanid dispensed (plus OBR administration either one hour before or one 
hour after delamanid dosing, as prescribed by investigator).  For Group 4 only,
delamanid dosing will be adjusted as needed based on weight measurement 
during this visit.  Study personnel must determine whether or not delamanid 
dosing will be adjusted prior to IWRS drug dispensation. 

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 


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3.7.1.13
Visit 13, Day 182 2 Days (Week 26)
Note:  Day 182 is the last day of delamanid dosing. For all treatment groups the 
following procedures will be conducted and/or recorded in the patient’s eCRF for Day 
182:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Signs and symptoms of TB

Chest radiograph

Audiometry and visual assessments 

Urine pregnancy test for all female subjects who have reached menarche

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, C-reactive protein (Groups 1 and 2 
only) testing and urinalysis

Three consecutive 12-lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4).  Sequence 
should be ECG assessment then PK blood draw followed by administration of 
delamanid

Blood draw for PK at predose (0 hours) (see Section 3.7.4)

Delamanid dosing (plus OBR administration either one hour before or one hour 
after delamanid dosing, as prescribed by investigator). NOTE:  This is the last 
day of delamanid dosing

Groups 3 and 4 only, palatability assessment of the delamanid pediatric 
formulation within 25 - 30 minutes postdose (see trial operations manual for 
details)

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.14
Visit 14, Day 189 2 Days (Week 27)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 189:


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
Complete physical examination.  Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight

BMI and percentiles for age

Blood draw for ACTH and adrenal function (cortisol)

Blood draw for thyroid function tests (T4 and TSH) for patients taking 
ethionamide or PAS

Blood draw for PK at any time point (see Section 3.7.4)

OBR administration, as prescribed by investigator

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications
3.7.1.15
Visit 15, Day 196 2 Days (Week 28)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 196:

Complete physical examination.  Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight

BMI and percentiles for age

Blood draw for PK at any time point (see Section 3.7.4)

OBR administration, as prescribed by investigator

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications
3.7.1.16
Visit 16, Day 203 2 Days (Week 29)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 203:

Complete physical examination.  Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight

BMI and percentiles for age


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
Blood draw for PK at any time point (see Section 3.7.4)

OBR administration, as prescribed by investigator

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications
3.7.1.17
Visit 17, Day 210 2 Days (Week 30)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 210:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Clinical laboratory assessments (as per Table 3.7-1): serum chemistry, 
hematology, coagulation, and urinalysis

Three consecutive 12-lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4).  Sequence 
should be ECG assessment then PK blood draw at the theoretical predose

Blood draw for PK at theoretical predose (0 hours) (see Section 3.7.4)

OBR administration, as prescribed by investigator

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.18
Visit 18, Day 238 2 Days (Week 34)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 238:

Complete physical examination. Please refer to the trial Operations Manual for
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 


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Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

Blood draw for PK at any time point (see Section 3.7.4)

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments   

Thyroid function tests for those patients taking ethionamide or PAS

OBR administration, as prescribed by investigator

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP
3.7.1.19
Visit 19, Day 365 5 Days (Week 52, 6 months post last 
delamanid dose)
For all treatment groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 365:

Complete physical examination. Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Signs and symptoms of TB

Audiometry and visual assessments 

Thyroid function tests for those patients taking ethionamide or PAS

Chest radiograph

Clinical laboratory assessments (as per Table 3.7-1): serum chemistry, 
hematology, coagulation, and urinalysis

OBR administration, as prescribed by investigator

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.20
Treatment Outcome Follow-up (Day 730 [Month 24] + 2 Months)
All patients who complete the study will come into the clinic or be contacted by 
telephone on Day 730 (Month 24) + 2 months for clinical assessment.  Treatment 


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outcome and microbiology information will be collected as routinely documented in the 
patient medical records or in a National TB Program. 
3.7.1.21
Early Termination Visit
For all patients who terminate early from the trial, the following procedures will be 
conducted and/or recorded in the eCRF:

Complete physical examination.  Please refer to the trial Operations Manual for 
details on the assessments to be performed

Vital signs assessments (BP, HR, RR, and body temperature) after the subject has 
been in a supine or semi-recumbent position for ≥ 3 minutes (as possible for 
Groups 3 and 4); height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)

BMI and percentiles for age

Blood draw for PK (see Section 3.7.4)

Blood draw for clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and urinalysis

Three consecutive 12-Lead ECGs after the subject has been in a supine or semi-
recumbent position for ≥ 10 minutes (as possible for Groups 3 and 4)

Urine pregnancy test for all female subjects who have reached menarche

Groups 3 and 4 only and only if prior to Day 182 and within 25 - 30 minutes 
postdose, palatability assessment of the delamanid pediatric formulation (see trial 
operations manual for details)

OBR administration, as prescribed by investigator 

Record AEs and IREs

Record concomitant medications including concomitant anti-TB medications

Groups 1 and 2 only, record date of menarche and/or date of LMP

Patients who terminate early from Trial 233 prior to their last scheduled visit will 
have a follow-up contact (phone call or visit) 28 to 32 days after the Early 
Termination Visit to assess for AEs and IREs.  All patients will continue 
treatment with OBR as prescribed by the investigator according to WHO 
guidelines

Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
3.7.1.22
Post Treatment and Follow-up
The last dose of delamanid will be given on Day 182.  Patients will continue on OBR, as 
prescribed by the investigator, and have post-delamanid treatment visits on Days 189, 
196, 203, 210, 238 (2-month post last dose), and 365 (6-month post last dose), and a 
treatment outcome follow-up on Day 730 (Month 24) + 2 months.


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3.7.2
Efficacy Assessments
This is a safety, tolerability, PK, and efficacy trial of delamanid administered for
6 months to patients with MDR-TB who are also receiving OBR for their disease.  
There is no placebo or control group, and the sample size is small, comprising only 
patients who have completed Trial 232.  All efficacy evaluations will be performed by 
the investigator at his/her discretion and will be analyzed and presented in a 
descriptive manner.
Efficacy assessments will include:

assessment of clinical signs and symptoms of TB

chest radiograph

abnormality/extent of abnormality
In addition, although microbiological assessment of sputum or other biological specimens 
(eg, cerebral spinal fluid [CSF], pleural fluid, ascitic fluid, joint fluid, lymph node 
aspirates, etc.) are not required as part of this protocol, they may be collected by the 
investigator as part of routine management of the subject.  In patients who are able to 
produce sputum (or provide other specimens) for microbiological evaluation according to 
the requirements of the National TB Program, all available results for smear microscopy, 
culture, identification, and drug susceptibility will be collected from the patient chart as 
an unscheduled visit.
3.7.3
Safety Assessments
3.7.3.1
Clinical Laboratory Tests
The tests listed in Table 3.7.3.1-1 will be performed at the times listed in Table 3.7-1 and
will be processed in accordance with directions from the analytical laboratory.


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Table 3.7.3.1-1
Clinical Laboratory Tests
Hematology:
White blood cell count with differential
Red blood cell count
Hematocrit 
Hemoglobin
Mean corpuscular volume
Mean corpuscular hemoglobin concentration
Prothrombin time
Activated partial thromboplastin time
Platelets
International normalized ratio
Urinalysis
Color
pH
Specific gravity
Protein
Bilirubin
Urobilinogen
Blood
Glucose
Ketones
Leukocytes
Nitrites
Microscopic examination when urinalysis is 
abnormal:  casts, crystals, red blood cells, white 
blood cells, bacteria
Drug Screen (Groups 1 and 2 only)
Alcohol
Amphetamine/methamphetamine
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine 
Cotinine
Methadone 
Opiates 
Tetrahydrocannabinol
Serum Chemistry:
Blood urea nitrogen
Creatinine
Aspartate transaminase
Alanine transaminase
Gamma glutamyl transferase
Lactic dehydrogenase
Alkaline phosphatase
Total bilirubin
Triglycerides (Groups 1 and 2 only)
Cholesterol (Groups 1 and 2 only)
Calcium
Glucose
Magnesium
Sodium
Potassium
Chloride
Total protein
Uric acid
Inorganic phosphorous
Albumin
Globulin
Albumin/globulin ratio
Other Laboratory Tests
Morning cortisol
Thyroid function tests (serum thyroid stimulating 
hormone and free T4)
Urine pregnancy test (for female patients who have 
reached menarche)
Adrenocorticotrophic hormone
HIV (screening onlya)
CD4 cell count (screening onlyb)
Hepatitis B surface antigen (screening HBsAg only)
Antibody to hepatitis C virus (screening only)
C-reactive protein (Groups 1 and 2 only)
a Not required if patient had a documented HIV test and result within 1 year prior to the screening visit 
AND there is no known exposure to HIV. 
b Screening CD4 cell count test will only be performed for patients with positive HIV test results unless 
the patient has documented CD4 cell count test and results within 3 months prior to screening visit.
3.7.3.2
Physical Examination and Vital Signs Assessments
A complete medical history will be taken at the screening visit, and physical 
examinations and vital signs measurements will be performed according to the schedule 
provided in Table 3.7-1.


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A complete physical examination will include examination of the head, eyes, ears, nose,
throat, thorax, abdomen, skin and mucosae, lymph nodes, extremities, and urogenital (for 
Groups 3 and 4, required only at screening and subsequently at the discretion of the 
investigator) systems. The physical examination will also include a neurological 
examination and a psychiatric assessment (Groups 1 and 2 only) as described in the trial 
operations manual.  The principal investigator or appointed medical doctor designee is 
primarily responsible for performing the physical examination. Whenever possible, the 
same individual should perform all physical examinations for each patient. If the 
appointed medical doctor designee is to perform the physical examination, he or she must 
be permitted by local regulations and his or her name must be included on FDA Form 
1572. Any clinically significant condition present at the post-treatment examination that 
was not present at the baseline examination should be documented as an AE and followed 
to satisfactory conclusion.
Vital signs assessments include head circumference for patients in Group 4 (ages birth - 2 
years, inclusive), blood pressure, heart rate, respiration rate, and body temperature. Vital 
signs are to be recorded after the patient has remained in a supine or semi-recumbent
position and at rest for 3 minutes (as possible for Groups 3 and 4). When vital signs
and safety ECGs are scheduled for the same nominal time, vital signs assessments should 
be obtained prior to the ECG.
Body weight and height, BMI, and age percentiles will also be recorded. 
3.7.3.3
Electrocardiogram Assessments
Electrocardiograms for on-site evaluation of safety will be recorded at the nominal times 
according to the schedule outlined in Table 3.7-1. Twelve-lead ECGs will be recorded 
with the subject in a supine or semi-recumbent position and at rest for ≥10 minutes (as 
possible for Groups 3 and 4).  ECGs should be taken before PK blood draws when 
assessments are scheduled on the same day (Visit).  Three tracings will be obtained at 
each time point (approximately 3 to 5 minutes between each tracing) with the ECG leads 
left in place.  Heart rate, PR interval, QRS interval, QT interval, QTcF, and QTcB will be 
recorded. The principal investigator or designated medical doctor will review, sign, and 
date each ECG reading. Whenever possible, the same reviewer should evaluate, sign, 
and date the ECGs. The reviewer must be listed on FDA Form 1572. Original ECG 
tracings will be added to the patient’s medical record with the reviewer’s interpretation 
recorded.  In addition to the initial clinical interpretation for ongoing safety evaluation by 
the investigator, all ECGs will be analyzed by a specialized central laboratory.  Specific
guidance for investigators for determining AEs related to ECG results is available in the 
trial operations manual.


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Digitally acquired ECGs will be received by the central laboratory for processing.  
Graphic tools will be used to perform manual measurements, including the RR, PR, QRS, 
and QT interval durations.  Parameters will also be measured electronically.
The onset of the QRS complex and the end of the T wave will be identified to define the 
QT interval.  The RR duration will similarly be determined by selecting the peak of 
2 consecutive R waves (starting with the previous R from the first PQRST complex).  
In addition to the parameters directly drawn on the ECG image, a number of independent 
parameters will automatically be derived and stored in memory (eg, QTcB, QTcF).
Technicians will be responsible for performing the interval duration measurements 
(IDMs) using specialized technology linked into the central laboratory’s data 
management system.  The IDMs will be transferred to the data management system 
following a quality control process and will automatically be populated in a worksheet 
for a cardiologist to review in conjunction with the ECG.
ECG analyses will be provided by the central laboratory according to the specific 
requirements of Otsuka.  Measurements of the following intervals will be made for each 
ECG tracing:

3 RR mean RR will be reported

3 PR mean PR interval will be reported

3 QRS mean QRS width will be reported

3 QT mean QT interval will be reported
Highly trained physician electrocardiographers will be available to interpret all standard 
12-lead ECGs generated from this trial.  Cardiologist ECG assessments will include 
standard comments on normal/abnormal, rhythm, arrhythmia, conduction, morphology, 
myocardial infarction, ST segment, T wave, and U wave observations.  Each ECG report 
will include the following:

Patient information
-
Select Summary Information

Interpretation
-
Normal
-
Abnormal
-
Unable to evaluate

Interval duration measurements
-
Rhythm


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-
Arrhythmia
-
Conduction
-
Morphology
-
Myocardial infarction
-
ST segment

T wave observations

U wave observations

Physician’s comments
Following completion of all internal quality procedures, the dataset will be transferred in 
electronic format to Otsuka or Otsuka’s designee for the generation of tables and listings 
for inclusion in the trial report.
3.7.4
Pharmacokinetic Assessments
Approximately 3 mL of blood will be collected per PK sample in the 12- to 17-year-old 
children (Group 1); 2 mL per PK sample in the 3- to 11-year-old children (Groups 2 and 
3) and 0.6 mL per PK sample for children ages 2 years and younger (Group 4). 
Delamanid data from this trial are to be combined with PK data from Trial 232 for the 
POPPK analysis.
3.7.4.1
Blood Collection Times
Blood collection for PK will occur on Days 1 to 2 and 10 to 11.  Blood draws will occur 
at predose (0 hours during treatment) paired with the 12-lead ECGs on Days 1, 56, 154, 
and 182.  A PK blood sample will be obtained on Day 210 paired with the 12-lead ECG 
at the theoretical predose.  Additional PK blood samples will be drawn on Days 14, 98, 
189, 196, 203, and 238.  A PK blood draw will be collected at ET.  When blood 
collection for PK is paired with ECGs, the ECG will be performed first, followed by the 
PK blood draw, and then dosing with delamanid.    
3.7.4.2
Pharmacokinetic Assessment of Cerebral Spinal Fluid
In patients in whom a lumbar puncture is clinically indicated during the routine 
management of a child enrolled in the trial, CSF concentrations of delamanid will be 
measured.  The timing of the lumbar puncture will be recorded in relation to the timing of 
the dose of delamanid and any proximate blood collections.  See the trial manual of 
operations for specific information about handling, processing, and storage of CSF 
samples. 


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3.7.4.3
Sample Handling and Processing
Specific information about blood sample collection processing, storage, and shipping is 
provided in Appendix 3.
3.7.5
Pharmacodynamic Assessments
ECGs and PK measurements for determination of delamanid and DM-6705 plasma 
concentrations will be collected (see Section 3.7).  These assessments should be time-
matched if possible.
3.7.6
Other Assessments
The palatability of the delamanid pediatric formulation will be assessed (Groups 3 and 4 
only) within 25 - 30 minutes after the morning dose on Days 1, 28, 56, 182, and ET if 
prior to Day 182 using an age-appropriate visual hedonic scale and clinical assessment.
See the trial operations manual for details.
3.7.7
End of Trial
The end-of-trial date is defined as the last date of contact or the date of the final contact 
attempt from the post-treatment follow-up eCRF for the last subject completing or 
withdrawing from the trial.
3.7.8
Safety Monitoring Committee
A safety monitoring committee (SMC) composed of external consultants with expertise 
in pediatric TB and pediatric cardiology will review safety and laboratory test results 
during the conduct of the trial.  The SMC will comprise not less than 2 members who are 
not involved with enrolling patients into the trial.  The SMC will convene and operate 
based on the availability of patient safety information.  The SMC will seek additional 
independent expertise, if needed.
The primary responsibility of the SMC will be to monitor safety and to determine 
whether or not the safety concerns merit stopping the trial.  
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
If a subject discontinues from the trial, the reason given must be fully evaluated and 
recorded appropriately in source documentation and in the eCRF. If the subject is being 
withdrawn because of an AE, that AE must be indicated as the reason for 
withdrawal. All assessments scheduled to be completed at the final trial visit will be 
performed at early termination.  If delamanid is stopped due to an AE and/or investigator 


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decision, subjects should continue with visits/assessments for the rest of the trial with the 
exception of taking delamanid.  This will allow analysis of comparable assessments 
between those who stopped and those who completed delamanid dosing.
All subjects have the right to withdraw from the trial at any point during treatment 
without prejudice. The investigator can discontinue a subject at any time, if medically 
necessary. In addition, subjects who meet any of the following criteria must be 
withdrawn from the trial:
1) Occurrence of any AE, intercurrent illness, or laboratory abnormality that, in the 
opinion of the investigator, warrants the subject’s permanent withdrawal from the 
trial
2) Occurrence of QTcF > 500 msec or occurrence of proarrhythmic events
3) Treatment with a prohibited concomitant medication other than the use 
of appropriate medications for the treatment of AEs under direction of 
the investigator
4) Patient noncompliance, defined as refusal or inability to adhere to the 
trial schedule.  Please refer to the trial Operations Manual for further information 
on the definition of noncompliance
5) At the request of the patient or patient’s parent/guardian, investigator, Otsuka 
Pharmaceutical Development & Commercialization, Inc., or regulatory authority
6) Subject is lost to follow-up
The sponsor should be notified promptly when a patient is withdrawn or if the trial is 
stopped. Patients in this trial who terminate early will not be replaced. 
If the sponsor terminates or suspends the trial for safety or unanticipated other reasons, 
prompt notification will be given to investigators, IRBs/IECs, and regulatory authorities 
in accordance with regulatory requirements.
3.8.2
Individual Site
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site.  A particular site may be terminated from the trial 
at the discretion of the investigator, sponsor, or IRB/IEC, eg, for nonenrollment of 
subjects or noncompliance with the protocol.
3.9
Screen Failures
A screen failure patient is one from whom informed consent is obtained and is 
documented in writing (ie, patient and parent/designee sign an ICF/assent) but who is not 
started on treatment, whether through randomization or open assignment. Patients 
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rescreened; however, patients excluded for any other reasons may be rescreened at any 
time, if the exclusion characteristic has changed. In the event a patient is rescreened, a 
new ICF/assent must be signed and a new screening number assigned.
3.10
Definition of Completed Patients
The treatment period is defined as the time period during which patients are evaluated for 
primary and/or secondary objectives of the trial regardless of whether or not the patients
actually consumed all doses of trial medication. Patients who are evaluated at the last 
scheduled visit of the trial, the follow-up visit (Visit 19, Day 365), will be defined as trial
completers.
3.11
Definition of Lost to Follow-up
Patients who cannot be contacted on or before the scheduled M24 follow-up visit and 
who do not have a known reason for discontinuation (eg, withdrew consent or AE) will 
be classified as “lost to follow-up” as the reason for discontinuation. The site will make 
3 attempts to contact the patient or parent/guardian/legal representative by telephone and
in the event the site is unable to reach the patient or parent/guardian/legal representative
by telephone, the site will attempt to contact the patient or parent/guardian/legal 
representative via certified mail or an alternative similar method, as appropriate. 
3.12
Patient Compliance
The time and dose of each IMP administered will be recorded on the source documents 
and on the eCRF. Information regarding any missed or inappropriately administered 
doses will also be documented on the source document and on the eCRF. Compliance 
will be ensured by a hand and mouth check during the oral dosing administration.
3.13
Protocol Deviations
This trial is intended to be conducted as described in this protocol. In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake, the 
investigator or designee must contact the sponsor at the earliest possible time by 
telephone. This will allow an early joint decision regarding the subject’s continuation in 
the trial. This decision will be documented by the investigator and the sponsor and 
reviewed by the monitor. 


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4
Restrictions
4.1
Prohibited Medications
Table 4.1-1
List of Medications Prohibited During the Trial
Antiarrhythmic Medications with Potential for QT Interval Prolongation
1.
Quinidine
2.
Procainamide
3.
Disopyramide
4.
Encainide
5.
Flecainide
6.
Sotalol
7.
Amiodarone
8.
Digitalis
Other Medications With Potential For QT Interval Prolongation
1.
Moxifloxacin
Other Medications
1.
Rifampicin
2.
Bedaquiline
5
Reporting of Adverse Events
The investigator is to use the following definitions when entering details on AEs or 
immediately reportable events (IREs) in the CRF or on the immediate safety report (ISR) 
Form.
5.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial patient and that
does not necessarily have a causal relationship with the treatment.  An AE can therefore 
be any unfavorable and unintended sign (including eg, an abnormal laboratory 
assessment result), symptom or disease temporally associated with participation in the 
clinical trial, whether or not it is considered causally related to the medicinal product or 
procedures of the clinical trial.  An SAE includes any event that results in any of the 
following outcomes:

Death

Life-threatening, ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death

Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions

Requires in-patient hospitalization or prolongs hospitalization.  The following 
hospitalizations, including hospitalizations for social purposes, are not considered 
SAEs for the clinical trial:


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
A visit to the emergency room or other hospital department < 24 hours that 
does not result in admission (unless considered “important medical event” or 
life-threatening event)

Hospitalizations as outlined in the protocol that are part of the clinical 
trial conduct

Routine health assessment requiring admission for baseline/trending of 
health status

Medical/surgical admission (hospitalization) for a purpose other than 
remedying ill health state and such hospitalizations that were planned prior to 
entry into the trial, ie, prior to signing the ICF/assent.  Appropriate 
documentation is required in these cases

Hospital admission(s) encountered for another life circumstance that carries 
no bearing on health status and requires no medical/surgical intervention (eg, 
lack of housing, economic inadequacy, care-giver respite, family 
circumstances, administrative reasons), ie, for social reasons

A hospitalization due to an unmanageable distance between the patient’s 
domicile and the investigational site

Congenital anomaly/birth defect

Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above, eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse
Nonserious adverse events are all AEs that do not meet the criteria of a "serious" AE.
Immediately Reportable Event:  

Any SAE

Any AE that necessitates discontinuation of delamanid

Any increase of aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥3 times the upper limit of normal (ULN), with an increase in total 
bilirubin ≥2 times the ULN

QTcF interval prolongation > 500 msec or occurrence of proarrhythmic events

Pregnancies are also defined as IREs; although a normal pregnancy is not an 
adverse event, it will mandate delamanid discontinuation and must be reported on 
an IRE form to Otsuka Europe Development and Commercialisation Ltd (OEDC)
Pharmacovigilance Region Europe (PVRE) (See also Section 5.4).  This includes 
pregnancies occurring in the female partner of a male patient.  Pregnancy will 
only be documented on the AE CRF if there is an abnormality or complication

All events involving overdose, misuse, and abuse.  This includes accidental 
overdose by investigator or patient.  It also includes all such events, whether the 
course is symptomless, or whether an AE or SAE results.  These events may 


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involve delamanid or any other medicinal products or illicit drugs (see also 
Section 5.5)
Clinical Laboratory Changes:  It is the investigator’s responsibility to review the results 
of all laboratory tests as they become available.  This review will be documented by the 
investigator’s dated signature on the laboratory report.  For each abnormal laboratory test 
result, the investigator needs to ascertain if this is a clinically significant abnormal change 
from baseline for that individual patient.  (This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed.  The 
investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests).  If this laboratory value is determined by the investigator 
to be a clinically significant abnormal change from baseline for that patient, it is 
considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity
3 = Severe:
Inability to work or perform normal daily activity
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP
(delamanid) or conduct of trial procedure:
Related:
The AE and the administration of delamanid are related in time 
and a direct association can be demonstrated
Possibly related: The AE and the administration of delamanid are reasonably related 
in time and the AE can be equally well explained by causes other 
than delamanid administration.  The result of dechallenge is 
lacking or unclear
Unlikely related: A temporal relationship to the administration of delamanid cannot 
be ruled out, but the AE can be more likely explained by reasons 
other than the delamanid administration
Not related:
The AE is clearly explained by another cause not related to the 
delamanid administration. 


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5.2
Collecting and Reporting Safety Information to the Sponsor
5.2.1
Period of Observation for Adverse Events and Immediately 
Reportable Events
All AEs and IREs will be collected and documented from the time of first dosing in
Trial 233 until the end of the Post-treatment Follow-up Period for the individual patient.  
(Exceptions are pregnancy and SAEs considered possibly causally related to delamanid 
or trial procedures; see Section 5.4 and Section 5.3, respectively).  If there are any
ongoing AEs at the end of the post-treatment follow-up period, a 1-month follow-up visit 
should be scheduled.
A clinically significant worsening in the health of the patient compared with the patient’s 
health status documented at baseline constitutes an AE.  Abnormal assessment results 
from screening or baseline examinations are not AEs.
5.2.2
Adverse Events
The investigator must assess patients for the occurrence of AEs at each trial visit, whether 
scheduled or unscheduled, during the period of observation for safety.  In order to avoid 
bias in inquiring about AEs, patients should be asked the following nonleading question:  
“How have you been feeling since the last visit?”
The investigator must also promptly review all results of assessments performed as part 
of the clinical trial (eg, laboratory assessment results, ECGs, vital signs monitoring, 
physical examinations, and urinalysis) and assess them for clinically relevant changes 
(worsenings) compared with baseline, which constitute AEs.
All AEs occurring during the period of observation must be entered into the source 
documents and also on the AE page of the patient’s eCRF.  The investigator is also 
responsible for providing or arranging appropriate supportive care for the patient.
An AE that has been entered into the eCRF and undergoes a clinically significant 
worsening in severity, or that changes and fulfills a criterion of seriousness, must be 
entered as a new AE.  See instructions for completing AE pages in the eCRF Completion
Guidelines. 
5.2.3
Immediately Reportable Events
In addition to the documentation of all SAEs as defined in Section 5.1, some events must 
be reported to the sponsor immediately, according to the procedures outlined below.
IREs for this clinical trial are:

SAEs, as defined above


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
Note:  Hospitalization in order to conduct this clinical trial does not constitute an 
SAE and should not be reported as an IRE, nor entered in the eCRF as an SAE.  
Section 5.1 provides additional information about which hospitalizations are not 
considered SAEs

AEs (serious or nonserious) that result in premature discontinuation of IMP

Any increase of AST or ALT ≥3 times ULN with an increase in total bilirubin 
≥2 times ULN

QTcF interval prolongation > 500 msec or occurrence of proarrhythmic events

Pregnancies in trial patients or their partners (see also Section 5.4)

All events involving overdose, misuse, and abuse.  This includes accidental overdose 
by investigator or patient.  It also includes all such events, whether the course is 
symptomless or whether an AE or SAE results.  These events may involve delamanid 
or any other medicinal product or illicit drugs (see also Section 5.5)
All SAEs must be reported to the medical monitor via telephone when they occur (see 
Appendix 1). 
As soon as the investigator becomes aware of an IRE in a patient (this includes SAEs and 
is in addition to reporting the SAE to the medical monitor by telephone), he/she must fill 
out the ISR form as completely as possible and send it, within 24 hours, as a 
password-protected attachment to an e-mail, or as a fax to:
E-mail:  
Fax:  
The investigator should sign the ISR form personally.
If the ISR cannot be sent successfully electronically or on time (eg, due to technical 
difficulties) using the contact information above, the report should be made by fax or, if 
not possible, via phone to the contact person above.
Receipt of the ISR by the sponsor will be confirmed as soon as possible, usually within 
24 hours.  If further information is required, the sponsor will contact the investigator 
(usually via the clinical research associate responsible for the site).  The investigator is 
responsible for promptly providing any additional information that is requested.
It can be arranged for the ISRs to be sent to the sponsor via the local contract research 
organization (CRO) or Otsuka affiliate, but the timelines described above must still be 
fulfilled.


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5.3
Follow-up of Adverse Events and Immediately Reportable Events
All AEs must be followed up until they have resolved (returned to normal or baseline 
status), stabilized, or been explained.  
Adverse events that have not resolved at the end of the period of observation, or that
become known at the last visit of the period of observation, must be followed up beyond 
this visit until satisfactorily resolved, as described above.  These AEs must be treated, 
reported, and documented as described in Section 5.2.  Any exceptions must be agreed 
upon with the safety contact of the sponsor.
In general, events with onset after the period of observation is over are not AEs and do 
not need to be collected, reported, and documented.  (Exceptions:  see below.)
Follow-up information on IREs should be reported to the safety contact of the sponsor as 
soon as possible.
Note:  SAEs that are possibly causally related to delamanid or the trial procedures remain 
reportable after the period of observation is over.  There is no time limit for this 
reportability.
Note:  The period of observation and the follow-up for pregnancy are different.  See
Section 5.4.
5.3.1
Safety Monitoring Committee
The SMC will actively review AEs throughout the trial.  See Section 3.7.8 for full details 
on the constituents, operational processes, and responsibilities of the SMC for this trial.
5.4
Pregnancy
Females of childbearing potential and males who are sexually active must avoid 
pregnancy or fathering a child for 8 weeks after the last dose of delamanid and abstain 
from sex during the clinical trial.  Pregnancy testing will be performed during the 
screening period prior to study enrollment and at the end of the trial according to the 
schedule of assessments for all female patients who have reached menarche.
If the patient or investigator suspects the patient may be pregnant prior to delamanid 
administration, delamanid must be withheld until the results of urine pregnancy tests are 
available.  A confirmed pregnancy before first administration of delamanid must result in 
immediate exclusion or withdrawal from the trial.  If pregnancy is suspected while the 
patient is taking delamanid during the trial, delamanid must be withheld immediately. If
pregnancy is confirmed, the delamanid will be permanently discontinued but the patient 
will not be automatically withdrawn from the trial.


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The investigator must immediately notify the sponsor of any pregnancy during delamanid 
exposure, including and for 8 weeks after the last dose of delamanid, and record the event 
on the IRE form and forward it to the sponsor.  The sponsor will forward the pregnancy 
surveillance form(s) for monitoring the outcome of the pregnancy.  
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the patient unless contraindicated by pregnancy (eg, radiograph studies).  Other 
appropriate pregnancy follow-up procedures should be considered if indicated.  
Pregnancy in a female patient or in the female partner of a male patient is an IRE and 
must be reported immediately as such using the ISR form.  It is not an AE, and should not 
be entered as such in the eCRF.  
Upon receipt of an ISR concerning pregnancy, the safety contact of the sponsor will 
inform the investigator of the further information required.  The investigator must report 
to the sponsor, on appropriate pregnancy surveillance form(s), follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome.  Infants 
will be followed for a minimum of 6 months.  Any congenital anomaly or birth defect 
constitutes an SAE and must be entered as follow-up information on the ISR form and on 
the AE eCRF.
5.5
Overdose, Misuse, Abuse
Overdose, misuse, or abuse of delamanid or any other medication or illicit drug constitute 
IREs, and must be reported and recorded as such. 
If such an event fulfills the definition of an AE or an SAE, it must be documented as such 
on the AE eCRF as well.
5.6
Safety Submissions to Regional and National Competent 
Authorities, IECs/IRBs, and Notifications to Investigators
The safety contact of the sponsor is responsible for conducting or organizing the 
submission of safety reports according to international guidelines (eg, ICH), regional and 
national regulatory requirements, and the applicable standard operating procedures.  This 
includes expedited submissions of individual case safety reports and aggregate periodic 
safety reports, as required for the European Medicines Agency, FDA, other CAs, national 
and local IECs/IRBs, and investigators. 
The investigator is responsible for any direct submissions from the investigator to the CA 
or IEC/IRB, as locally required.  
Further details are provided in the safety reporting plan for this trial. 


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6
Pharmacokinetic Analysis
6.1
Pharmacokinetic Methods
Delamanid and metabolite plasma concentrations will be reported with descriptive 
statistics at each visit day per age group. In addition, delamanid plasma concentrations 
will be analyzed using a POPPK approach.
6.2
Pharmacokinetic/Pharmacodynamic Methods
Delamanid and DM-6705 plasma concentrations will be examined in conjunction with 
QTcF data to explore if there is a PK/PD correlation. 
7
Statistical Analysis
7.1
Sample Size
No formal sample size calculation was performed because this is a trial in a pediatric 
population.  The primary objectives of this trial are to construct long-term profiles of 
safety and tolerability, PK, and efficacy of the 6-month use of delamanid for the 
treatment of pediatric patients with MDR-TB.
7.2
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics of the trial population will be summarized for 
each age group using descriptive statistics (mean, standard deviation [SD], median, 
minimum, and maximum for continuous variables [eg, age], and the number and 
percentage of patients for discrete variables [eg, race and gender]).  Individual 
demographic data will be presented in the data listings.
7.3
Safety Analyses
Safety analysis will be conducted based on the safety population, which is defined as all 
patients who take at least 1 dose of IMP. Safety variables to be analyzed include clinical 
laboratory tests, vital signs, ECGs, and TEAEs.
7.3.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary.  Treatment-emergent AEs, defined as all AEs that occur after the 
administration of IMP, will be summarized for each age group by system organ class and 
preferred term, maximum severity, and potential relationship to IMP, as well as TEAEs 
with an outcome of death, serious TEAEs, and discontinuations due to TEAEs.  A 


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complete listing of TEAEs for each patient will be provided, including severity, 
relationship to trial drug, onset, duration, and outcome.
7.3.2
Clinical Laboratory Data
The quantitative change in clinical chemistry, hematology, coagulation, and urinalysis 
assessment results will be calculated relative to baseline.  Baseline is defined as the last 
measurement before the first administration of delamanid.  Summary statistics for 
quantitative laboratory assessment results will be presented by treatment (age) group and 
visit for the change from baseline (Day −1) will be provided.  Shift tables will be 
produced for assessing changes from baseline in clinical laboratory measurements.
All laboratory data, including unscheduled assessments, will be presented in data listings.  
The incidence rate of abnormal laboratory assessment results and clinically significant 
laboratory abnormalities will be summarized as appropriate.  
7.3.3
Physical Examination and Vital Signs Data
By-subject listings will be provided for physical examinations.  Summary statistics 
for changes from baseline (predose Day 1) in vital signs will be provided for 
each treatment (age) group.  All vital signs data will be presented in a data listing 
by patient.
7.3.4
ECG Data
Summary statistics for changes from baseline (average of screening and baseline predose 
ECGs) in ECG intervals (PR, QRS, QT, QTcF, and QTcB) will be provided for each 
treatment (age) group.  Categorical changes in ECG results will also be summarized.  
Electrocardiogram data from all subjects will be presented in data listings.
7.4
Efficacy Analyses
Because of the small sample sizes per group, large-sample-based statistical methods 
cannot be used. Exact methods, if available, will be pursued. All statistical presentations 
will be descriptive.  
7.5
Palatability Analysis
The palatability of the delamanid pediatric formulation will be assessed (Groups 3 and 4 
only) using an age-appropriate visual hedonic scale and clinical assessment. The data 
will be summarized by descriptive statistics (mean, SD, min, max).


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7.6
Interim Analysis
An interim analysis of safety, tolerability, PK, and efficacy of delamanid in children 6 to 
17 years of age is planned in the 1st quarter of 2019.
8
Trial Drug Management
8.1
Packaging and Labeling
Investigational medicinal product will be provided to the investigator(s) by the sponsor 
(or designated agent). The IMP will be packaged in blister cards. Each blister card used 
in the dosing period will be labeled to clearly disclose the compound ID, protocol 
number, sponsor's name and address, instructions for use, route of administration, and 
appropriate precautionary statements (see Section 8.1.1).
8.1.1
Delamanid
Each blister card of delamanid used during the 182-day dosing period will be labeled to 
clearly disclose the following information:

Trial/protocol number

Compound ID

Patient ID number and/or initials (to be filled in by the investigator/designee when 
delamanid is assigned and/or dispensed to the patient)

Name/number of the trial site and the name of the principal investigator of the 
trial site (to be filled in by the investigator/designee when delamanid is assigned 
and/or dispensed to the patient)

Name and address of the sponsor of the trial

Storage instructions

Expiration/retest date

Batch number

The statement “Clinical Trial Material - for investigational use only,” or 
similar statement

Instructions on how to use the IMP
8.1.2
Optimized Background Treatment Regimen
Medications for the OBR for MDR-TB treatment for each trial patient will be procured 
through the standard mechanisms available for a given site ordinarily used for 
procurement of OBR medications for treating MDR-TB patients.  The second-line 


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medications generally used in developing OBR for MDR-TB patient treatment are as 
follows:

Amikacin

Capreomycin

Cycloserine

Ethambutol

Ethionamide

Prothionamide

Gatifloxacin

Levofloxacin

Kanamycin

Ofloxacin

P-aminosalicylic acid

Pyrazinamide

Streptomycin
Medications with an unclear role in the treatment of MDR-TB and not recommended for 
routine use for MDR-TB treatment, though sometimes used for highly drug-resistant 
MDR-TB patients, are described in the WHO treatment guidelines for MDR-TB.2
8.2
Storage
Trial drugs will be stored in a securely locked cabinet or enclosure. Access should be 
strictly limited to the investigators and their designees. Neither the investigators nor any 
designees may provide IMP to any subject not participating in this protocol.
The IMP will be stored according to the conditions specified in the IMP blister card label. 
The clinical site staff will maintain a temperature log in the drug storage area, recording 
the temperature at least once each working day.
The OBR medications should be stored, dispensed, and administered per the package 
inserts and the trial site standard operating procedures.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.  The IMP sent to the trial centers will be verified 
by the investigators or designees regarding the amount sent, date received, and that 
supplies were undamaged and not adulterated on arrival.  This will be documented by 


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signing and dating the appropriate accountability documents.  The investigator or 
designee will record the subject’s number and initials and the date dispensed on the drug 
accountability form.
The investigators must keep an accurate running accountability of IMP that will include 
the batch number and shipment tracking number, as well as the date and patient number 
of the container dispensed to each patient.  All used and unused/unopened IMP containers 
must be inventoried and accounted for and kept at the site until return of the containers 
and any unused IMP is authorized by Otsuka.  An overall accountability of IMP will be 
performed and verified throughout the trial and at the site closeout by Otsuka or the 
designated CRO monitor.
Accountability of OBR medications will be performed per the trial site’s standard 
operating procedures.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to Otsuka (or a designated contractor) unless authorized by Otsuka (in writing).
All IMP returned to Otsuka must be accompanied by the appropriate documentation and 
be clearly identified by protocol number and trial site number on the outermost shipping 
container. Returned supplies should be in the original containers. The assigned trial 
monitor will facilitate the return of unused and/or partially used IMP.
If IMP is authorized to be destroyed at the trial site by Otsuka (in writing), it is the 
investigator’s responsibility to ensure that arrangements have been made for the disposal.  
Written authorization should be issued by Otsuka, procedures for proper disposal should 
be established according to applicable regulations, guidelines, and procedures, and 
appropriate records of the disposal should be documented and forwarded to Otsuka.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include, but are not limited to, progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons. Investigator(s)/institution(s) will 
permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s) by 
providing direct access to source data/documents by authorized persons, as defined in 
the ICF.


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9.2
Data Collection
For each day of the trial during the subject’s hospitalization, a clinician participating in 
the trial will record progress notes to document all significant observations.  At a 
minimum, these notes will contain:

Documentation of the informed consent/assent process, including any revised 
consents/assents

The date of the visit and the corresponding visit or day in the trial schedule

General subject status remarks including any significant medical findings.  The 
severity, frequency, and duration of any AEs and the investigator's assessment of 
relationship to IMP must also be recorded

Any changes in concomitant medications or dosages

A general reference to the procedures completed

The signature (or initials) and date of all clinicians who made an entry in the 
progress notes
In addition, any contact with the patient via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. Any changes to information in the trial progress notes, other source 
documents, and eCRFs will be initialed and dated on the day the change is made by a site 
trial staff member authorized to make the change.  Changes will be made by striking a 
single line through erroneous data and clearly entering the correct data (eg, wrong data 
right data).  If the reason for the change is not apparent, a brief explanation for the change 
will be written in the source document adjacent to the change by the clinician.
Information from the trial progress notes and other source documents will be promptly 
and LEGIBLY transcribed to eCRFs for transmission to the sponsor.  Changes will be 
made using the same process described above.
9.3
File Management at the Trial Site
The investigator will ensure that the trial center file is maintained in accordance with 
Section 8 of the ICH GCP guideline and as required by applicable local regulations. The 
investigator/institution will take measures to prevent accidental or premature destruction 
of these documents.
9.4
Records Retention at the Trial Site
FDA regulations require all investigators participating in clinical drug trials to maintain 
detailed clinical data for one of the following periods:


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
A period of ≥3 years following the date on which a new drug application is 
approved by the FDA.

A period of 3 years after the sponsor notifies the investigator that no further 
application is to be filed with the FDA

Longer, region-specific storage requirements, if applicable
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records.  The investigator shall take responsibility for maintaining adequate 
and accurate electronic or hard-copy source documents of all observations and data 
generated during this trial, including any data clarification forms received from the 
sponsor.  Such documentation is subject to inspection by the sponsor and relevant 
regulatory agencies.  If the investigator withdraws from the trial (eg, due to relocation or 
retirement), all trial-related records should be transferred to a mutually agreed upon 
designee within a sponsor-specified timeframe.  Notice of such transfer will be given to 
the sponsor in writing.  
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in a detailed 
and orderly manner in accordance with established research principles, the ICH GCP 
guidelines, FDA regulations, and applicable regulatory requirements and local laws.  As 
part of a concerted effort to fulfill these obligations (maintain current personal knowledge 
of the progress of the trial), the sponsor's monitors will visit the site during the trial, as 
well as communicate frequently via telephone and written communication(s).  
10.2
Auditing
The sponsor's quality management unit (or representative) may conduct trial site audits.  
Audits will include, but are not be limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of eCRFs with source 
documents.  The investigator agrees to participate with audits.
Regulatory authorities worldwide may inspect the investigative site during or after the 
trial.  The investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.


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11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, the ICH GCP guidelines, 
and all other applicable local laws and regulatory requirements.  The patient’s informed 
consent will be obtained according to the ethical principles stated in the Declaration of 
Helsinki (Tokyo 2004), the applicable guidelines for GCP, and any local regulations.  
Details of the trial and regular progress reports will be submitted to the appropriate 
IRB/IEC and CAs as required.
An IRB/IEC should safeguard the dignity, rights, safety, and well-being of all trial 
participants.  Special attention should be given to trials that may include vulnerable 
participants, such as children.
At a minimum, the IRB/IEC should be supplied with the following documents:  trial 
protocol(s)/amendment(s), written ICFs and ICF/assent form updates that the 
investigators propose for use in the trial, patient recruitment procedures (for example, 
advertisements), written information to be provided to participants, IB, additional 
available safety information, information about payments and compensation available to 
participants, the investigator’s current curriculum vitae and/or other documentation 
evidencing qualifications, and any other documents that the IRB/IEC may need to fulfill 
its responsibilities.
The IRB/IEC should review a proposed clinical trial within a reasonable time and 
document its views in writing, clearly identifying the trial, the documents reviewed, and 
the dates for the following:

Approval

Modifications required prior to its approval

Disapproval

Termination/suspension of any prior approval
The IRB/IEC should consider the qualifications of the investigators for the proposed trial 
as documented in their curricula vitae and/or by any other relevant documentation the 
IEC requests.
The IRB/IEC should conduct a continuing review of each ongoing trial at intervals 
appropriate to the degree of risk to human participants, but at least once per year.
Where the protocol indicates that prior consent of the trial patient or the patient’s legally 
acceptable representative is not possible, the IRB/IEC should determine the appropriate 
means of meeting ethical requirements.


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Financial aspects, patient insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
Otsuka will also obtain CA approval, as applicable, in accordance with applicable 
regulations and laws.
12
Confidentiality
All information generated in this trial will be considered highly confidential and will not 
be disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  However, authorized regulatory officials and sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All 
IMPs, subject bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by the sponsor.
Patients will be identified only by initials and unique subject numbers in eCRFs.  Their 
full names may, however, be made known to a regulatory agency or other authorized 
officials, if necessary.  The investigators will maintain a current confidential patient 
identification code list of names of all patients allocated to patient ID numbers in this 
trial.  This information will be held in the strictest confidence and will only be used for 
emergency purposes, if needed.
The eCRFs will be designed by Otsuka.  eCRFs are used to transmit the information 
collected in the conduct of this trial to Otsuka and CAs, as appropriate.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval by the IRB/IEC.  Any permanent change to the 
protocol, whether it be an overall change or a change for specific trial site(s), must be 
handled as a protocol amendment.  Any amendment will be written by the sponsor.  
Each amendment will be submitted to the IRB/IEC.  Except for nonsubstantial 
(ie, administrative) amendments, investigators will wait for IRB/IEC approval of the 
amended protocol before implementing the change(s).  Administrative amendments are 
defined as having no effect on the safety or physical or mental integrity of the research 
patients, the conduct or management of the trial, the scientific value of the trial, or the 
quality or safety of IMP(s) used in the trial.  However, a protocol change intended to 
eliminate an apparent immediate hazard to patients should be implemented immediately, 
followed by IRB/IEC notification within 5 working days.  The sponsor will submit 
protocol amendments to the FDA or other regulatory agencies.


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When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification.  In such 
cases, after approval of the new ICF by the IRB/IEC, repeat informed consent will be 
obtained from patients in a timely manner before expecting continued participation in 
the trial.


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14
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retrospective study of 12 cases. Pediatr Inf Dis. 2006;25:930-932.
40 Marais BJ, Childhood tuberculosis: epidemiology and natural history. Indian J 
Pediatr. 2011;78:321-327.
41 Tuberculosis in childhood and pregnancy. In: Friedman LN (ed). Tuberculosis: 
current concepts and treatment, 2nd edition 2006. CRC, Boca Raton, FL., pp 191-
229.
42 Zar HJ, Connell TG, Nicol M. Diagnosis of pulmonary tuberculosis in children: new 
advances. Expert Rev Anti-Infect Ther. 2010;8:277-288.
43 Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards 
for tuberculosis care. Lancet Infect Dis. 2006;6:710-725.
44 Schaaf HS, Marais BJ, Hesseling AC, et al. Childhood drug-resistant tuberculosis in 
the Western Cape Province of South Africa. Acta Paediatr. 2008;12:225-227.
45
  In vitro activities of DM-6704, DM-6705, and DM-6706 against 
Mycobacterium tuberculosis standard strains.  Otsuka Study No. 020953, Otsuka 
Report No. 016705, 2004.
46
  In vitro activities of OPC-67683 and reference compounds against 
clinically isolated Mycobacterium tuberculosis.  Otsuka Study No. 019196, Otsuka 
Report No. 015366, 2003.
47
 Susceptibility testing of OPC-67683 against clinically isolated 
Mycobacterium tuberculosis in South Africa. Otsuka Study No. 024892, Otsuka 
Report No. 019641, 2007.
48
 Influence of inoculum size on antimycobacterial activity of OPC-67683. 
Otsuka Study No. 021570, Otsuka Report No. 017392, 2005.
49
 Bactericidal activity of OPC-67683 against dormant Mycobacterium 
bovis BCG. Otsuka Study No. 26116, Otsuka Report No. 020482, 2008.
50
 Bactericidal effects of OPC-67683 and reference compounds against 
Mycobacterium bovis BCG Tokyo under aerobic conditions. Otsuka Study No. 
27266, Otsuka Report No. 022008, 2008.


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51
 Antimycobacterial activity of OPC-67683 metabolites. Otsuka Study 
No. 025144, Otsuka Report No. 019629, 2007.
52
  Inhibitory activity of OPC-67683 against mycolic acid synthesis in 
Mycobacterium bovis BCG.  Otsuka Study No. 021327, Otsuka Report No. 017300, 
2005.
53
 Therapeutic efficacy of OPC-57998, OPC-67683, and reference 
compounds by oral administration in the experimental mouse model of chronic 
tuberculosis. Otsuka Study N0. 019072, Ostuka Report No. 015667, 2003.
54
 Plasma and lung level of OPC-67683 after oral administration in mice. 
Otsuka Study No. 020691, Otsuka report No. 016022, 2004.
55
  Evaluation of the anti-mycobacterial activity of OPC-67683 in 
combination with rifampicin against clinically isolated Mycobacterium tuberculosis.  
Otsuka Study No. 020206, Otsuka Report No. 016012, 2004.
56
  Evaluation of the anti-mycobacterial activity of OPC-67683 in 
combination with isoniazid against clinically isolated Mycobacterium tuberculosis.  
Otsuka Study No. 020207, Otsuka Report No. 016013, 2005.
57
  Evaluation of the anti-mycobacterial activity of OPC-67683 in 
combination with ethambutol against clinically isolated Mycobacterium tuberculosis. 
Otsuka Study No. 020208, Otsuka Report No. 016014, 2005.
58
  Evaluation of the anti-mycobacterial activity of OPC-67683 in 
combination with streptomycin against clinically isolated Mycobacterium 
tuberculosis.  Otsuka Study No. 020209, Otsuka Report No. 016015, 2005.
59
  Combination therapy of OPC-67683 with reference drug on 
experimental chronic tuberculosis model in mice by intratracheal infection.  Otsuka 
Study No. 019828, Otsuka Report No. 017089, 2005.
60
  Early bactericidal activity (EBA) of OPC-67683 by oral 
administration in the experimental mouse model of chronic tuberculosis induced by 
intratracheal infection.  Otsuka Study No. 022557, Otsuka Report No. 017561, 2005.
61
 Twenty-six week repeated oral dose toxicity study of OPC-67683 (SD 
powder) in rats. Otsuka Study No. 023338, Otsuka Report No. 018760, 2006.
62
  Thirty-nine-week repeated oral dose toxicity study of OPC-67683 (SD 
powder) in beagle dogs. Otsuka Study No. 023229, Otsuka Report No.019347, 2006.
63
  Supplementary two-week repeated oral toxicity study of OPC-67683 in 
dogs.  Otsuka Study No. 020393, Otsuka Report No. 016070, 2004.
64
  Thirteen-week repeated oral dose toxicity study with 4-week recovery 
test of OPC-242 in beagle dogs.  Otsuka Study No. 020618, Otsuka Report No. 
016772, Bozo Research Center Study No. B-5245, 2004.
65
 Two-week repeated oral dose toxicity study of OCP-67683 in female rabbits 
and 2-week recovery study. Otsuka Study No. 020710, Otsuka Report No. 016211, 
2004.


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66
 Two-week repeated oral dose toxicity study of OCP-67683 in male rabbits 
and 2-week recovery study. Otsuka Study No. 020719, Otsuka Report No. 016417, 
2004.
67
 Two-week repeated oral dose toxicokinetics study of OPC-67683 (SD 
powder) in female rabbits. Otsuka Study No. 023899, Otsuka Report No. 018762, 
2006.
68
  Embryo-fetal development study of OPC-67683 administered orally to rats.  
Otsuka Study No. 021070, Otsuka Report No. 016633, 2004.
69
 Thirteen-day oral toxicity study of OPC-67683 in female rabbits. 
Otsuka Study No. 020453, Otsuka Report No. 015968, 2003.
70
  Embryo-fetal development study of OPC-67683 administered orally to 
rabbits.  Otsuka Study No. 021245, Otsuka Report No. 016695, 2004.
71
  DM-6704, a metabolite of OPC-67683:  Salmonella/microsome reverse 
mutation assay by plate incorporation method.  Otsuka Study No. 020396, Otsuka 
Report No. 016030, 2004.
72
  DM-6705, a metabolite of OPC-67683: Salmonella/microsome reverse 
mutation assay by plate incorporation method.  Otsuka Study No. 020617, Otsuka 
Report No. 016113, 2004.
73
  DM-6706, a metabolite of OPC-67683: Salmonella/microsome reverse 
mutation assay by plate incorporation method.  Otsuka Study No. 020845, Otsuka 
Report No. 016177, 2004.
74
  OPC-67683:  Salmonella/microsome reverse mutation assay by plate 
incorporation method.  Otsuka Study No. 020066, Otsuka Report No. 015823, 2003.
75
 DM-6704:  Two consecutive daily oral toxicokinetics study for 
micronucleus test in rats.  Otsuka Study No. 028202, Otsuka Report No. 022412, 
2008.
76
  DM-6704:  Micronucleus test in rat bone marrow erythrocytes after oral 
administration for 2 consecutive days.  Otsuka Study No. 027673, Otsuka Report No. 
022409, 2008.
77
  DM-6706:  Micronucleus test in rat bone marrow erythrocytes after oral 
administration for 2 consecutive days.  Otsuka Study No. 027674, Otsuka Report No. 
022410, 2008.
78
  DM-6705:  Micronucleus test in rat bone marrow erythrocytes after oral 
administration for 2 consecutive days.  Otsuka Study No. 027862, Otsuka Report No. 
022411, 2008.
79
 DM-6706:  Two consecutive daily oral toxicokinetics study for 
micronucleus test in rats.  Otsuka Study No. 028203, Otsuka Report No. 022413, 
2008.
80
 DM-6705:  Two consecutive daily oral toxicokinetics study for
micronucleus test in rats.  Otsuka Study No. 028205, Otsuka Report No. 022414, 
2008.


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81
  (S)-DM-6718:  Micronucleus test in rat bone marrow erythrocytes after 
oral administration for 2 consecutive days.  Otsuka Study No. 029507, Otsuka Report
No. 023642, 2009.
82
  (S)-DM-6718:  Two consecutive daily oral toxicokinetics study for 
micronucleus test in rats.  Otsuka Study No. 029760, Otsuka Report No. 023685, 
2009.
83
  25% OPC-67683 spray-dried formulation:  preliminary micronucleus 
test in bone marrow erythrocytes of Sprague-Dawley rats after 2 consecutive daily 
peroral administration.  Otsuka Study No. 020082, Otsuka Report No. 015844, 2003.
84
  25% OPC-67683 spray-dried formulation: micronucleus test in bone 
marrow erythrocytes of Sprague-Dawley rats after 2 consecutive daily peroral 
administration.  Otsuka Study No. 020397, Otsuka Report No. 015942, 2003.
85
  OPC-67683:  forward mutation test at the thymidine kinase locus of 
L5178Y mouse lymphoma cells using 96-well-plate fluctuation method.  Otsuka 
Study No. 020055, Otsuka Report No. 015794, 2003.
86
  OPC-67683:  reverse mutation test in Salmonella typhimurium YG1041 
and YG1042/male rat liver microsome by plate incorporation method.  Otsuka Study 
No. 020292, Otsuka Report No. 015795, 2003.
87
  OPC-67683:  in vitro toxicokinetic test for forward mutation test of 
L5178Y mouse lymphoma cells using male rat liver S9.  Otsuka Study No. 021524, 
Otsuka Report No. 016389, 2004.
88
  (S)-DM-6718:  Reverse mutation test in Salmonella typhimurium with 
male rat liver S9 by plate incorporation method.  Otsuka Study No. 029481, Otsuka 
Report No. 023483, 2009.
89
 Pharmacokinetic study of jet-milled OPC-67683 in rats: Plasma and lung 
concentrations of OPC-67683 and its metabolites (DM-6701, DM-6702, and DM-
6703) after single oral or intravenous dose. Otsuka Study No. 020302, Otsuka Report 
No. 015985, 2003.
90
 Plasma concentrations of OPC-67683 and its metabolites (DM-6701, DM-
6702, and DM-6703) after single oral dose of jet-milled OPC-67683 at 1000 mg/kg in 
male rats. Otsuka Study No. 020338, Otsuka Report No. 015986, 2003.
91
 Pharmacokinetic study of jet-milled and spray-dried OPC-67683 in dogs: 
Plasma concentrations of OPC-67683 and its metabolites (DM-6701, DM-6702, and 
DM-6703) after single oral or intravenous dose. Otsuka Study No. 019666, Otsuka 
Report No. 015988, 2004.
92
 Plasma concentrations of OPC-67683 and its metabolites (DM-6701, DM-
6702, and DM-6703) after single oral dose of jet-milled OPC-67683 at 1000 mg/kg in 
dogs. Otsuka Study No. 020299, Otsuka Report No. 015989, 2003.
93
 Pharmacokinetic study of jet-milled OPC-67683 in male mice: Plasma and 
lung concentrations of OPC-67683 and its metabolites (DM-6701, DM-6702, and 
DM-6703) after single oral or intravenous dose. Otsuka Study No. 020303, Otsuka 
Report No. 015987, 2004.


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94
 Distribution and excretion of radioactivity after single oral administration of 
14C-OPC-67683 to male and female rats. Otsuka Study No. 020612, Otsuka Report 
No. 016335, 2004.
95
 Whole body autoradiographic study in rats following single oral dose of 
14C-OPC-67683 at 3 mg/kg. Otsuka Study No. 021105, Otsuka Report No. 016543, 
2004.
96
 In vitro metabolism of 14C-OPC-67683 in human, rat, mouse, dog, 
rabbit, and monkey liver microsomes and 9000g supernatant fractions (S9s). Otsuka 
Study No. 020474, Otsuka Report No. 016431, 2004.
97
 In vitro metabolism of 14C-OPC-67683 in human, rat, mouse, dog, 
rabbit, and monkey plasma. Otsuka Study No. 019948, Otsuka Report No. 016510, 
2004.
98
 In vitro metabolic mechanism of OPC-67683 to its metabolite (DM-
6705) in dogs and rabbits. Otsuka Study No. 023634, Otsuka Report No. 019052, 
2006.
99
 In vitro metabolic mechanism of OPC-67683 to its metabolite (DM-
6705) in mouse, rat and human plasma. Otsuka Study No. 026028, Otsuka Report No. 
022213, 2008.
100
 Effect of OPC-67683 on cytochrome P450 mediated reactions in 
human liver microsomes. Otsuka Study No. 019806, Otsuka Report No. 015757, 
2003.
101
  In vitro evaluation of OPC-242 as an inducer of cytochrome P450 
expression in cultured human hepatocytes.  Otsuka Study No. 027958, Otsuka Report 
No. 022782, 2009.
102
 Absorption and excretion of radioactivity following a single oral dose of 
14C-OPC-242 in dogs at 10 mg/kg. Otsuka Study No. 020399, Otsuka Report No. 
015990, Mitsubishi Chemical Safety Institute Study No. B031035, 2003.
103
 Biliary and urinary excretions and enterohepatic circulation of 
radioactivity following a single oral administration of 14C-OPC-67683 at 3 mg/kg to 
rats. Otsuka Study No. 021446, Otsuka Report No. 016787, 2004.
104 Otsuka Frankfurt Research Institute GmbH. A phase 1 study to evaluate the safety, 
tolerability, pharmacokinetics and food effect of single oral doses of OPC-67683 in 
healthy male and female subjects. Otsuka Clinical Study Report for Protocol 242-03-
101, issued 16 Dec 2004.
105 Otsuka Frankfurt Research Institute GmbH. A phase 1 study to evaluate the safety, 
tolerability, pharmacokinetics of multiple oral doses of OPC-67683 in healthy male 
and female subjects. Otsuka Clinical Study Report for Protocol 242-04-101, issued 05 
Dec 2005.
106 Otsuka Frankfurt Research Institute GmbH. A phase 1 study to evaluate the safety, 
tolerability, pharmacokinetics of single oral doses of spray-dried OPC-67683 in 
healthy male and female subjects. Otsuka Clinical Study Report for Protocol 242-05-
101, issued 30 Oct 2006.


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107 Otsuka Pharmaceutical Development and Commercialization, Inc.  A phase 2, multi-
center, uncontrolled, open-label trial to evaluate safety, tolerability, and efficacy of 
orally administered OPC-67683 as 100 mg BID with optional titration to 200 mg BID 
for up to six months exposure in patients with pulmonary multi-drug resistant 
tuberculosis.  Otsuka Clinical Study Report for Protocol 242-07-208, issued 14 Oct 
2011.
108 Otsuka Pharmaceutical Development and Commercialization, Inc. Pilot, open-label, 
randomized, parallel-arm, multiple-dose evaluation of the pharmacokinetic and safety 
interactions following oral 200 mg OPC-67683 given alone and with or without 
efavirenz, tenofovir and ritonavir/lopinavir in healthy subjects. Otsuka Protocol 242-
07-209, issued 06 Feb 2008, amended 10 Mar 2008, amended 03 Nov 2008, amended 
26 Jun 2009.
109
 A phase 2, multi-center, non-controlled, open-label dose escalation trial to 
assess the safety, tolerability, pharmacokinetics, and efficacy of orally administered 
OPC-67683 two times daily to patients with pulmonary multidrug-resistant 
tuberculosis refractory to conventional treatment. Otsuka Clinical Study Report for 
Protocol 242-08-210, issued 17 May 2012.
110 Otsuka Pharmaceutical Development and Commercialization, Inc.  Open-label, 
randomized, parallel-arm evaluation of the pharmacokinetics and safety of OPC-
67683 following different multiple oral dose regimens of OPC-67683, for a total daily 
dose of 300 mg, in healthy subjects.  Otsuka Clinical Study Report for Protocol 242-
08-211, issued 16 Jul 2009.
111 Otsuka Pharmaceutical Development and Commercialization, Inc.  Phase 1, open-
label, randomized, multiple-dose evaluation of the pharmacokinetic and safety 
interactions of oral 200-mg OPC-67683 tablets and oral 600-mg efavirenz tablets in 
healthy subjects.  Otsuka Clinical Study Report for Protocol 242-09-212, issued 12 
July 2011.
112 World Health Organization (WHO).  Guidelines for the programmatic management 
of drug-resistant tuberculosis. WHO/HTM/TB/2011.6. Geneva: WHO, 2011.
113 World Health Organization (WHO). Tuberculosis global report, 2006.  
WHO/HTM/TB/2006.343. Geneva: WHO, 2006.
114 Sirturo Package Insert, Janssen, December 2012.
115 Trial 242-09-213 Medical Monitoring Plan.
116 Perez-Velez CM. Pediatric tuberculosis: new guidelines and recommendations. Curr 
Opin Pediatr. 2012;24:319-328.
117 World Health Organization. Rapid Advice. Treatment of tuberculosis in children. 
2010. WHO, Geneva, Switzerland. WHO/HTM/TB/2010.13. Available on-line at: 
http://whqlibdoc.who.int/publications/2010/9789241500449_eng.pdf
118 Schaaf HS, Gie RP, Kennedy M, Beyers N, Heswseling PB, Donald PR. Evaluation 
of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 
30-month follow-up. Pediatrics. 2002;109:765-771.


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119 Schaaf HS, Shean K, Donald PR. Culture-confirmed multidrug-resistant tuberculosis 
in children: diagnostic delay, clinical features, response to treatment and outcome. 
Arch Dis Child. 2003;88:1106-1111.
120 Schaaf HS, Marais BJ. Management of multidrug-resistant tuberculosis in children: 
survival guide for pediatricians. Pediatr Resp Rev. 2011;12:31-38.
121 Loebstein R, Koren G. Clinical pharmacology and therapeutic drug monitoring in 
neonates and children. Pediatr Rev. 1998;19:423-428.
122 Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin 
Pharmacokinet. 1984;9:511-544.
123 Marais BJ, Schaaf HS, Donald PR. Management of tuberculosis in children and new 
treatment options. Infectious Disorders-Drug Targets. 2011;11:144-156
124 Ethical considerations for clinical trials performed in children. Recommendations of 
the Ad hoc group for the development of implementing guidelines for Directive 
2001/20/EC relating to good clinical practice in the conduct of clinical trials on 
medicinal products for human use. 2006.
125 Shaddy RE, Denne SC. The Committee on Drugs and Committee on Pediatric 
Research. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric 
populations. Pediatrics. 2010;125:850-60.
126 WHO Global TB Report, 2011. World Health Organization, Geneva. 
WHO/HTM/TB/2011.16;2011


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Appendix 1
Important Sponsor Contacts
Report Immediately Reportable Events to:
Otsuka Europe Development and Commercialisation, Ltd (OEDC)
Pharmacovigilance Region Europe (PVRE)
Fax:  
E-mail:  
For Medical Emergencies in the Philippines or South Africa:
, 
2440 Research Blvd
Rockville, MD  20850
Phone:  
Fax:  
E-mail:  
Additional Personnel:
, 
2440 Research Blvd
Rockville, MD  20850
Phone: 
Fax:  
E-mail:  


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Appendix 2 Institutions Concerned With the Trial
Otsuka (Philippines) Pharmaceutical Inc. (OPPI)
3F King's Court II Building 
2126 Chino Roces Avenue
Makati City, Philippines
Covance Central Lab Services
8211 SciCor Drive 
Indianapolis, IN 46214 
eResearch Technology
1818 Market Street, Suite 1000
Philadelphia, PA 19103-3638
IVRS/IWRS
S-Clinica
6, chaussée de Boondael
B-1050 Brussels
Belgium
Quintiles East Asia Pte Ltd
79 Science Park Drive #06-08
CINTECH IV, Science Park One
Singapore 118264


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Appendix 3
Handling and Shipment of Bioanalytical Samples
All tubes must be labeled using the central lab’s bar code labels provided with the sample 
collection kits.  The central lab’s requisition form must be completely filled out in regard
to the PK sample information.  On the sample tube, the subject ID/screening number and 
subject initials must be handwritten on the label.  On the requisition form, it is important 
to note the date and exact time of the blood collection.
Plasma Samples for Delamanid
Blood (0.6 - 3 mL) will be collected into green-top Vacutainertubes containing sodium 
heparin/lithium heparin anticoagulant.  The tubes must be gently inverted 3 to 4 times 
and then centrifuged at 2500 rpm for at least 10 minutes at 4°C.  The separated plasma 
from each tube should then be divided equally between the 2 barcode-labeled 
polypropylene tubes (Groups 1-3).  For Group 4, the separated plasma should be 
transferred to a single barcode-labeled polypropylene tube.  The PK sample must be 
stored at −65°C or below.
One PK tube (primary sample) will be shipped on dry ice to the central lab (Groups 1-4).    
Following confirmation that the first tube arrived safely, the second tubes (backup 
samples) can also be shipped to the central lab (Groups 1-3).  There will be no backup 
samples for Group 4.
Shipment of Plasma
Each frozen specimen must be sealed in a vial and labeled with a waterproof pen.  The 
label containing the subject ID number and date of collection must correspond to the 
requisition form, and must be firmly attached to the tube.  The requisition form must 
contain the name, address, and telephone number of the contact person from the trial site.  
Samples must be neatly packed in the specimen collection bag and restrained in a 
Styrofoamcontainer (place the Styrofoam container within the shipping box).  Boxes 
should be completely filled with dry ice to avoid air spaces that allow more rapid 
evaporation of the dry ice.  Follow all instructions included in the sample collection kit 
provided by the central lab.


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Appendix 4
Protocol Amendments
Amendment Number: 1
Issue Date:
11 Mar 2013
PURPOSE: The purpose of this amendment is to delete information in the introduction 
that is specific to childhood tuberculosis in the Philippines, to modify the exclusion 
criteria, to change the start of the AE observation period, to make modifications and 
additions/deletions to the schedule of assessments and the associated text, to change the 
number of doses to be given under direct observation, to add INR to the list of 
coagulation tests, and to modify the definition of IRE.
BACKGROUND:  In the previous protocol, it was anticipated that this trial would be 
conducted at a single center in the Philippines; however, since the protocol for Trial 232 
(parent trial to Trial 233) has been amended to include multiple phase 1 sites not 
specifically in the Philippines, it is necessary to amend this protocol accordingly.  
Additional changes are to add or delete assessments, modify eligibility criteria, and to 
provide more detail or clarifications on how and when to perform certain procedures.
MODIFICATIONS TO PROTOCOL:
Bold and underlined text:
Changed Text
Bold and strike through text:
Deleted Text
Bold and italicized text:
Added Text
Global Changes:

Corrected minor typographical, grammatical, and formatting errors.

Removed the subsection in the Introduction (Section 1) specific to childhood 
tuberculosis in the Philippines.

Modified the exclusion criteria.

Change the start of the AE observation period from informed consent/assent to the 
time of first dose in Trial 233.


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
Added medical history to the assessment schedule and the related text and delete 
it as being obtained from Trial 232.

Added collection of date of birth and gender to the assessment schedule and the 
related text for screening.

Added  BMI to the assessment schedule and the related text at all visits at which 
height and weight are collected.

Added Menarche/LMP Assessment to the assessment schedule and the related 
text for Visits 1 (screening), 4, 6, 8, 10, 11, 12, 13, 17, 18, and Early Termination.

Added assessment of C-reactive protein at Visit 13

Changed the number of doses to be given under direct observation.

Clarified that sputum culture conversion is a secondary efficacy outcome variable 
in Section 3.5 and renumbered the subsections under Sections 3.5.1 and 3.5.2 
accordingly.

Added INR as a coagulation test.

Updated the criterion related to hepatic enzymes in the definition of IRE.


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Sectional Revisions:
Location
Old Text
Updated Text
Title Page
Added text.
Amendment 1 Issue Date
11 March 2013
Synopsis
(Trial 
Design)
Baseline (Day 0): Inclusion/exclusion criteria, physical 
examination and safety assessments including lab tests, signs and 
symptoms of tuberculosis (TB), sputum culture (results will be 
obtained from the National TB Program or the patient’s care 
provider), audiometry and visual assessments, vital signs, and ECG 
as described in the Schedule of Assessments. OBR administration as 
prescribed by investigator, and recording of adverse events 
(AEs)/immediately reportable events (IREs), and concomitant 
medications.
Baseline (Day 0): Inclusion/exclusion criteria, physical examination 
and safety assessments including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and ECG as 
described in the Schedule of Assessments. OBR administration as 
prescribed by investigator, and recording of adverse events 
(AEs)/immediately reportable events (IREs), and concomitant 
medications. 
Synopsis
(Trial 
Design)
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by 
investigator.  Sparse blood draws for PK as described in the 
Schedule of Assessments. Signs and symptoms of TB, physical 
examination and other safety assessments including safety lab tests. 
Audiometry and visual assessments, sputum culture (results will be 
obtained from the National TB Program or the patient’s care 
provider), and ECG at weeks and times shown in the Schedule of 
Assessments. Height and weight beginning Week 2 and assessed 
monthly, and collection of AEs/IREs, and concomitant medications.
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by investigator.  
Sparse blood draws for PK as described in the Schedule of Assessments. 
Signs and symptoms of TB, physical examination and other safety 
assessments including safety lab tests. Audiometry and visual 
assessments, and ECG at weeks and times shown in the Schedule of 
Assessments. Height, weight, and BMI beginning at Week 2 and 
assessed monthly, and collection of AEs/IREs, and concomitant 
medications.
Synopsis
(Trial 
Design)
Follow-up Period (Days 239 to 365, 6 month Post Last Delamaid 
Dose Visit): Physical examination, height and weight, percentiles for 
age, vital signs, and symptoms of TB, sputum culture (results will be 
obtained from the National TB program or the patient’s care 
provider), chest radiograph, audiometry and visual assessments, 
safety labs, thyroid function tests (for patients taking ethionamide or 
PAS), OBR administration, and collection of AEs/IREs and 
concomitant medications.
Follow-up Period (Days 239 to 365, 6 month Post Last Delamaid 
Dose Visit): Physical examination, height and weight, BMI, percentiles 
for age, vital signs, and symptoms of TB, chest radiograph, audiometry 
and visual assessments, safety labs, thyroid function tests (for patients 
taking ethionamide or PAS), OBR administration, and collection of 
AEs/IREs and concomitant medications.
Synopsis
(Inclusion/
Exclusion 
Criteria)
Key Exclusion Criteria:
•Patients who have not completed Trial 232
•Children with a positive test for human immunodeficiency virus 
(HIV) or who have been previously identified as having HIV or with 
laboratory evidence of hepatitis B or C
•History of allergy to metronidazole and any disease or condition in 
which metronidazole is required
•Prior use of predefined medications: amiodarone at any time over 
Key Exclusion Criteria:
•Patients who have not completed Trial 232
•Children with a positive test for human immunodeficiency virus (HIV) 
or who have been previously identified as having HIV or with 
laboratory evidence of hepatitis B or C
•History of allergy to metronidazole and any disease or condition in 
which metronidazole is required
•Use of amiodarone within 12 months prior to the first dose of 


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Location
Old Text
Updated Text
the past 12 months or use of other predefined antiarrhythmic 
medications over the last 30 days
•Current use of rifampicin and/or moxifloxacin
•Serious concomitant conditions (cardiovascular disorders, severe 
respiratory disease, severe diarrheal disease, renal, hepatic, or 
neurological impairment)
•Preexisting cardiac conditions including but not limited to structural 
cardiac disease including suspected TB involvement of the heart on 
clinical or radiographic grounds
•A concomitant condition such as renal impairment characterized by 
serum creatinine levels >1.5 mg/dL or hepatic impairment (ALT or 
AST >3 x ULN)
•Abnormalities in screening ECG (including atrioventricular [AV] 
block, bundle branch block [BBB] or hemi-block, QRS prolongation 
>120 msec, or QTcF >420 msec in both males and females)
•Positive urine drug screen
•Concurrent diagnosis of severe malnutrition or kwashiorkor
•Lansky Play Performance Score < 50 or Karnofsky Score < 50
investigational medicinal product (IMP) or use of other predefined 
antiarrhythmic medications within the 30 days prior to the first dose of 
IMP
•Use of rifampicin and/or moxifloxacin within 1 week prior to the first 
dose of IMP
•Serious concomitant conditions (cardiovascular disorders, severe 
respiratory disease, severe diarrheal disease, renal, hepatic, or 
neurological impairment)
•Preexisting cardiac conditions including but not limited to structural 
cardiac disease including suspected TB involvement of the heart on 
clinical or radiographic grounds
•A concomitant condition such as renal impairment characterized by 
serum creatinine levels >1.5 mg/dL, hepatic impairment (ALT or AST 
>3 x ULN), or hyperbilirubinemia characterized by total bilirubin > 2x 
ULN
•Abnormalities in screening ECG (including atrioventricular [AV] 
block, bundle branch block [BBB] or hemi-block, QRS prolongation 
>120 msec, or QTcF >450 msec in both males and females)
•Positive urine drug screen
•Concurrent diagnosis of severe malnutrition or kwashiorkor
•Lansky Play Performance Score < 50 or Karnofsky Score < 50
Synopsis
(Outcome 
Variables)
Efficacy: assessed by determining the percentage of culture positive 
patients achieving sputum culture conversion (SCC); results of chest 
radiography (for patients with pulmonary disease); change in body 
weight and height measurements; and evaluation of TB symptoms.
Efficacy: assessed by results of chest radiography (for patients with 
pulmonary disease); change in body weight and height measurements; 
and evaluation of TB symptoms. In addition, sputum culture conversion 
(for culture-positive patients) will be assessed in patients who are able 
to produce sputum (or other specimen) for microbiological evaluation 
according to the requirements of the National TB Program.
List of 
Abbrev-
iations
Added text.
INR
International normalized ratio
LMP
Last menstrual period
Section 1
Deleted Text
Childhood tuberculosis in the Philippines
Among the 22 countries with the highest TB burden, the Philippines 
ranks fifth in prevalence (502 cases/100,000 population), eighth in 
incidence (275/100,000) and tenth in mortality (33/100,000).129  
Children with TB are usually infected by adults or adolescents in the 
immediate household with positive sputum acid-fast bacilli (AFB) 


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smear and/or culture for MTB.
There were over 163,000 new cases of TB reported in 2010 in the 
Philippines; of these, 965 occurred in patients <15 years of age.129 Of 
the total new TB cases, 4% (95% CI, 2.9 - 5.5%) were MDR-TB for a 
total of 6500 cases (95% CI, 4700-8900).129  
In a study of the contacts of 62 reference TB patients in a Philippine 
clinic (44 patients or 71%, with MDR-TB), there were 166 child 
contacts.114  Of these, 153 completed the screening procedures.  In 68 
(52%) of 130 child contacts interviewed, the reference case was a 
parent, in 12 (9%) it was a sibling, in 11 (9%) it was a grandparent, and 
in 36 (28%) it was another family member.  A live-in household helper 
or a baby sitter was the reference case for the remaining three (2%) 
children.  Fifty-eight (38%) contacts had symptoms attributable to TB at 
the time of the study.  Lymphadenopathy was noted in 44 (30%) of 148 
children examined.  Cough of more than 2 weeks duration was 
experienced by 15 (10%) and weight loss by 26 (17%) of 153 contacts.  
Of the 153 contacts, five (3.3%) individuals had TB disease, and one 
(0.65%) had bacillary TB.  Excluding 23 who had no tuberculin skin 
test (TST), 90 (69.2%) of 130 examined had LTBI, and 40 (30.8%) 
were exposed but not infected.  The majority of the reference cases 
included in the study had MDR-TB.  No difference was found in 
the transmission of MDR-TB compared with non-MDR-TB,6 as has 
previously been reported.130,131
Section 3.1
Baseline (Day 0): Inclusion/exclusion criteria, physical 
examination and safety assessments including lab tests, signs and 
symptoms of tuberculosis (TB), sputum culture (results will be 
obtained from the National TB Program or the patient’s care 
provider), audiometry and visual assessments, vital signs, and ECG 
as described in the Schedule of Assessments. OBR administration as 
Baseline (Day 0): Inclusion/exclusion criteria, physical examination 
and safety assessments including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and ECG as 
described in the Schedule of Assessments. OBR administration as 
prescribed by investigator, and recording of adverse events 


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prescribed by investigator, and recording of adverse events 
(AEs)/immediately reportable events (IREs), and concomitant 
medications.
(AEs)/immediately reportable events (IREs), and concomitant 
medications. 
Section 3.1
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by 
investigator.  Sparse blood draws for PK as described in the 
Schedule of Assessments. Signs and symptoms of TB, physical 
examination and other safety assessments including safety lab tests. 
Audiometry and visual assessments, sputum culture (results will be 
obtained from the National TB Program or the patient’s care 
provider), and ECG at weeks and times shown in the Schedule of 
Assessments. Height and weight beginning Week 2 and assessed 
monthly, and collection of AEs/IREs, and concomitant medications.
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by investigator.  
Sparse blood draws for PK as described in the Schedule of Assessments. 
Signs and symptoms of TB, physical examination and other safety 
assessments including safety lab tests. Audiometry and visual 
assessments, and ECG at weeks and times shown in the Schedule of 
Assessments. Height, weight, and BMI beginning at Week 2 and 
assessed monthly, and collection of AEs/IREs, and concomitant 
medications.
Section 3.1
Follow-up Period (Days 239 to 365, 6 month Post Last Delamaid 
Dose Visit): Physical examination, height and weight, percentiles for 
age, vital signs, and symptoms of TB, sputum culture (results will be 
obtained from the National TB program or the patient’s care 
provider), chest radiograph, audiometry and visual assessments, 
safety labs, thyroid function tests (for patients taking ethionamide or 
PAS), OBR administration, and collection of AEs/IREs and 
concomitant medications.
Follow-up Period (Days 239 to 365, 6 month Post Last Delamaid 
Dose Visit): Physical examination, height and weight, BMI, percentiles 
for age, vital signs, and symptoms of TB, chest radiograph, audiometry 
and visual assessments, safety labs, thyroid function tests (for patients 
taking ethionamide or PAS), OBR administration, and collection of 
AEs/IREs and concomitant medications.
Section 
3.2.1
All doses will be given under direction observation per standard 
practice for the investigational site.
According to the country-specific DOT plan, one dose per day for a 
minimum of 5 days per week will be given under direct observation.
Table 
3.4.3-1
Key Exclusion Criteria:
1. Patients who have not completed Trial 232
2. Children with a positive test for human immunodeficiency virus 
(HIV) or who have been previously identified as having HIV or with 
laboratory evidence of hepatitis B or C
3. History of allergy to metronidazole and any disease or condition 
in which metronidazole is required
4. Prior use of predefined medications: amiodarone at any time over 
the past 12 months or use of other predefined antiarrhythmic 
medications over the last 30 days
5. Current use of rifampicin and/or moxifloxacin
6. Serious concomitant conditions (cardiovascular disorders, severe 
respiratory disease, severe diarrheal disease, renal, hepatic, or 
neurological impairment)
7. Preexisting cardiac conditions including but not limited to 
Key Exclusion Criteria:
1. Patients who have not completed Trial 232
2. Children with a positive test for human immunodeficiency virus 
(HIV) or who have been previously identified as having HIV or with 
laboratory evidence of hepatitis B or C
3. History of allergy to metronidazole and any disease or condition in 
which metronidazole is required
4. Use of amiodarone within 12 months prior to the first dose of 
investigational medicinal product (IMP) or use of other predefined 
antiarrhythmic medications within the 30 days prior to the first dose of 
investigational medicinal product
5. Use of rifampicin and/or moxifloxacin within 1 week prior to the first 
dose of IMP
6. Serious concomitant conditions (cardiovascular disorders, severe 
respiratory disease, severe diarrheal disease, renal, hepatic, or 


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structural cardiac disease including suspected TB involvement of the 
heart on clinical or radiographic grounds
8. A concomitant condition such as renal impairment characterized 
by serum creatinine levels >1.5 mg/dL or hepatic impairment (ALT 
or AST >3 x ULN)
9. Abnormalities in screening ECG (including atrioventricular [AV] 
block, bundle branch block [BBB] or hemi-block, QRS prolongation 
>120 msec, or QTcF >420 msec in both males and females)
10. Positive urine drug screen
11. Concurrent diagnosis of severe malnutrition or kwashiorkor
12. Lansky Play Performance Score < 50 or Karnofsky Score < 50
neurological impairment)
7. Preexisting cardiac conditions including but not limited to structural 
cardiac disease including suspected TB involvement of the heart on 
clinical or radiographic grounds
8. A concomitant condition such as renal impairment characterized by 
serum creatinine levels >1.5 mg/dL, hepatic impairment (ALT or AST 
>3 x ULN), or hyperbilirubinemia characterized by total bilirubin > 2x 
ULN
9. Abnormalities in screening ECG (including atrioventricular [AV] 
block, bundle branch block [BBB] or hemi-block, QRS prolongation 
>120 msec, or QTcF >450 msec in both males and females)
10. Positive urine drug screen
11. Concurrent diagnosis of severe malnutrition or kwashiorkor
12. Lansky Play Performance Score < 50 or Karnofsky Score < 50
Table 
3.4.3-1
ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
AV = atrioverntricular; BBB = bundle branch block; ECG = 
electrocardiogram; HIV = human immunodeficiency virus; ULN = 
upper limit of normal.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AV 
= atrioverntricular; BBB = bundle branch block; ECG = 
electrocardiogram; HIV = human immunodeficiency virus; IMP = 
investigational medicinal product; ULN = upper limit of normal.
Section 
3.5.1.2
3.5.1.2
Efficacy Outcome Variables 
The efficacy of delamanid in treating pediatric MDR-TB patients 
will be assessed by culture conversion (for culture-positive patients), 
chest radiography (patients with pulmonary disease), body 
weight/height, and resolution of TB symptoms (based on 
investigator evaluation).
3.5.2.2
Efficacy Outcome Variables 
The efficacy of delamanid in treating pediatric MDR-TB patients will 
be assessed by chest radiography (patients with pulmonary disease), 
body weight/height, and resolution of TB symptoms (based on 
investigator evaluation).
In addition, sputum culture conversion (for culture-positive patients) 
will be assessed in patients who are able to produce sputum (or other 
specimen) for microbiological evaluation according to the requirements 
of the National TB Program.  Sputum collection is not required as part 
of this protocol; however, it may be collected by the investigator as part 
of routine management of the subject.  In patients who are able to 
produce sputum (or other specimen) for microbiological evaluation 
according to the requirements of the National TB Program, all available 
results for smear microscopy, culture, identification, and drug 
susceptibility will be collected from the patient chart as an unscheduled 
visit.
Table 3.7-1
Added row 
Visit window for visits during Days 2 - 238 is 2 days.
Visit window for visit on Day 356 is 5 days.
Table 3.7-1
For Medical History at Visit 1:
Xa
For Medical History at Visit 1:
Xc


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Table 3.7-1
Height (cm)
Weight (kg)
Height (cm)
Weight (kg)
Body mass index
Table 3.7-1
Added row.
Date of birth and Gender collected at Visit 1 
Xc
Table 3.7-1
Added row.
Menarche/LMP Assessment (Visits 1 [Xc], 4, 6, 8, 10, 11, 12, 13, ET, 
17, 18)
Table 3.7-1
Chest radiograph
Serum chemistry
Hematology 
Urinalysis
Thyroid function
C-reactive protein
added assessment at Visit 13
deleted assessments at Visits 4, 6, 8, 10
deleted assessments at Visits 4, 6, 8 10
deleted assessments at Visits 4, 6, 8, 10
added assessment at Visit 9
added assessment at Visit 13
Table 3.7-1
Added text to list of abbreviations.
LMP = last menstrual period
Section 
3.7.1.1
The following information will be taken from screening data of Trial 
232 and used as screening data for this Trial 233:

Inclusion/exclusion criteria 

Diagnosis of MDR-TB, confirmed or suspected  

Demographic data

Medical history and signs and symptoms of TB

Signs and symptoms of TB

Audiometry and visual assessments  

Chest radiograph for confirmation of radiological picture 
compatible with TB.  Final official interpretation must be 
available prior to enrollment

Laboratory assessments including HIV, hepatitis B surface 
antigen (HBsAg), anti-hepatitis C virus (HCV) antibody, 
adrenocorticotropic hormone (ACTH), adrenal function 
(cortisol), thyroid function tests (T4 and thyroid stimulating 
hormone [TSH]), and C reactive protein testing
The following information will be taken from screening data of Trial 
232 and used as screening data for this Trial 233:

Inclusion/exclusion criteria 

Diagnosis of MDR-TB, confirmed or suspected  

Demographic data

Medical history and signs and symptoms of TB

Signs and symptoms of TB

Audiometry and visual assessments  

Chest radiograph for confirmation of radiological picture 
compatible with TB.  Final official interpretation must be 
available prior to enrollment

Laboratory assessments including HIV, hepatitis B surface 
antigen (HBsAg), anti-hepatitis C virus (HCV) antibody, 
adrenocorticotropic hormone (ACTH), adrenal function 
(cortisol), thyroid function tests (T4 and thyroid stimulating 
hormone [TSH]), and C reactive protein testing
Section 
3.7.1.1
The following information will be obtained during the screening 
period of this Trial 233 between Days −30 and −1:

Informed consent/assent (may be completed prior to Day 
−30)

Sputum culture results will be obtained from patient 
records and documentation used from the National TB 
program or the patient’s care provider

Vital signs assessments (blood pressure [BP], HR, 
The following information will be obtained during the screening period 
of this Trial 233 between Days −30 and −1:

Informed consent/assent (may be completed prior to Day −30)

Medical history

Vital signs assessments (blood pressure [BP], HR, respiratory 
rate [RR], and body temperature) after the subject has been 
supine for ≥ 3 minutes 

Height, weight, and BMI


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respiratory rate [RR], and body temperature) after the 
subject has been supine for ≥ 3 minutes 

Height and weight

Percentiles for age

Urine pregnancy test for all female subjects who have 
reached menarche

Urine drug screen (as per Table 3.7-1)

Record AEs and immediately reportable events (IREs)

Record prior concomitant medications including prior 
concomitant anti-TB medications.  (Note: Patients will have 
been on OBR in Trial 232 for at least two weeks prior to 
baseline assessments)

Date of birth and gender

Percentiles for age

Urine pregnancy test for all female subjects who have reached 
menarche

Urine drug screen (as per Table 3.7-1)

Record AEs and immediately reportable events (IREs)

Record prior concomitant medications including prior 
concomitant anti-TB medications.  (Note: Patients will have 
been on OBR in Trial 232 for at least two weeks prior to 
baseline assessments)

Record start date of menstrual period and/or date of last 
menstrual period (LMP)
Section 
3.7.1.2

Height and weight

Height, weight, and BMI
Section 
3.7.1.4

Height and weight

Height, weight, and BMI
Section 
3.7.1.4
Added bullet.
Deleted bullet.

Record start date of menstrual period and/or date of LMP

Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
Section 
3.7.1.6

Height and weight

Height, weight, and BMI
Section
3.7.1.6
Added bullet.
Deleted bullet.

Record start date of menstrual period and/or date of LMP

Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
Section 
3.7.1.8

Height and weight

Height, weight, and BMI
Section 
3.7.1.8
Added bullet.
Deleted bullet.

Record start date of menstrual period and/or date of LMP

Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
Section 
3.7.1.9

Added bullet.

Blood draw for thyroid function tests (T4 and thyroid 
stimulating hormone [TSH]) for patients taking ethionamide or 
PAS.
Section 

Height and weight

Height, weight, and BMI


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3.7.1.10
Section 
3.7.1.10
Added bullet.
Deleted bullet.

Record start date of menstrual period and/or date of LMP

Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
Section 
3.7.1.11

Height and weight

Height, weight, and BMI
Section 
3.7.1.11
Added bullet.

Record start date of menstrual period and/or date of LMP
Section 
3.7.1.12

Height and weight

Height, weight, and BMI
Section 
3.7.1.12
Added bullet.

Record start date of menstrual period and/or date of LMP
Section 
3.7.1.13

Height and weight

Height, weight, and BMI
Section 
3.7.1.13
Added bullet.
Added bullet

Record start date of menstrual period and/or date of LMP

Chest radiograph
Section 
3.7.1.13
•Blood draw for clinical laboratory assessments (as per Table 3.7-1): 
serum chemistry, hematology, coagulation, and full urinalysis

Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, C reactive 
protein testing and full urinalysis
Section 
3.7.1.17

Height and weight

Height, weight, and BMI
Section 
3.7.1.17
Added bullet.

Record start date of menstrual period and/or date of LMP
Section 
3.7.1.18

Height and weight

Height, weight, and BMI
Section 
3.7.1.18
Added bullet.

Record start date of menstrual period and/or date of LMP
Section 
3.7.1.19

Height and weight

Height, weight, and BMI
Section 
3.7.1.20

Height and weight

Height, weight, and BMI
Section 
3.7.1.20
Added bullet.

Record start date of menstrual period and/or date of LMP
Sections 
3.7.1.4 -
Added visit window
2 days


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3.7.1.18, 
3.7.1.20
Sections 
3.7.1.1, 
3.7.1.2, 
3.7.1.5, 
3.7.1.7, 
3.7.1.9, 
3.7.1.11-
3.7.1.13, 
3.7.1.17-
3.7.1.19
Deleted bullet

Sputum culture results from NTBP
Section 
3.7.1.20
Added visit window
5 days
Section 
3.7.2
Efficacy assessments will include:
sputum cultures 

Patients will be assessed as having achieving SCC 
from positive growth of MTB to negative growth.  
SCC is defined as a sputum specimen from a patient 
negative for growth of MTB, followed by at least one 
confirmatory negative sputum culture at least 27 days 
after the first negative sputum test and not followed by 
any sputum cultures positive for growth.  

assessment of clinical signs and symptoms of TB

list provided in eCRF

chest radiograph

abnormality/extent of abnormality
Efficacy assessments will include:

assessment of clinical signs and symptoms of TB

chest radiograph

abnormality/extent of abnormality
In addition, although sputum collection is not required as part of this 
protocol, sputum may be collected by the investigator as part of routine 
management of the subject.  In patients who are able to produce sputum 
(or other specimen) for microbiological evaluation according to the 
requirements of the National TB Program, all available results for smear 
microscopy, culture, identification, and drug susceptibility will be 
collected from the patient chart as an unscheduled visit.
Table 
3.7.3.1-1
Renumbered table.  Added test under Coagulation Tests
International normalized ratio (INR)
Section 
3.8.1
4) Patient noncompliance, defined as refusal or inability to adhere to 
the trial schedule.
4) Patient noncompliance, defined as refusal or inability to adhere to the 
trial schedule.  Please refer to the trial Operations Manual for further 
information on the definition of non-compliance.
Section 5.1

Any increase of aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) 3 times the upper limit 
of normal (ULN), an increase in total bilirubin 2 times 
the ULN

Any increase of aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) 3 times the upper limit of normal 
(ULN) with an increase in total bilirubin 2 times the ULN


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Section 
5.2.1
All AEs and IREs will be collected and documented from the time 
the ICF/assent is signed in Trial 233 until the end of the Post-
treatment Follow-up Period for the individual patient.
All AEs and IREs will be collected and documented from the time of 
first dosing in Trial 233 until the end of the Post-treatment Follow-up 
Period for the individual patient.
Appendix 1
For Medical Emergencies:
2440 Research Blvd
Rockville, MD  20850
Phone:  
Global phone:  
Fax:  
E-mail:  
Otsuka (Philippines) Pharmaceutical Inc.
3F King's Court II Building 
2126 Chino Roces Avenue
Makati City, Philippines
Phone:  
Fax:  
E-mail:  
For Medical Emergencies in the Philippines or South Africa:
2440 Research Blvd
Rockville, MD  20850
Phone:  
Fax:  
E-mail:  
For Medical Emergencies in the Philippines:
Otsuka (Philippines) Pharmaceutical Inc.
3F King's Court II Building 
2126 Chino Roces Avenue
Makati City, Philippines
Phone:  
Fax:  
E-mail:  
Appendix 2
Added text.
IVRS/IWRS
S-Clinica
6, chaussée de Boondael
B-1050 Brussels
Belgium
Quintiles East Asia Ptd Ltd
79 Science Park Drive #06-08
CINTECH IV, Science Park One
Singapore 118264
ADDITIONAL RISK TO THE SUBJECT:
This amendment will not affect the safety of patients, the scope of the investigation, or the scientific quality of the trial.


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Amendment 5, 28 February 2019
Amendment Number: 2
Issue Date:
14 October 2014
PURPOSE: The purpose of this amendment is to add to and slightly modify the 
inclusion/exclusion criteria, to update the list of prohibited medications, to add a PK 
blood draw at the early termination visit on the table of assessments and in the 
corresponding text, to add collection of treatment outcome information, to update the 
footnotes to the table of assessments, to make minor corrections and editorial changes to 
the text and references, and to update sponsor representative information. It also updates 
the contraceptive language which reflects the stage of clinical development and available 
animal safety data.
BACKGROUND:  In the previous protocol, eligibility criteria related to prior exposure 
to an investigational medicinal product and pregnancy were not included, and the 
presumptive diagnosis of MDR-TB was incomplete.   
MODIFICATIONS TO PROTOCOL:
Bold and underlined text:
Changed Text
Bold and strike through text:
Deleted Text
Bold and italicized text:
Added Text
Global Changes:

Corrected minor typographical, grammatical, and formatting errors.

Made minor corrections to the introduction, including references.

Updated and corrected table of contents, section numbering, and cross
referencing.

In the inclusion criteria, revised the definition of presumptive diagnosis of MDR-
TB.

Modified the exclusion criteria to exclude children who were administered an 
investigational medicinal product within 1 month prior to Visit 1 and Patients who 
are pregnant, breastfeeding, or planning to conceive or father a child within the 
timeframe described in the informed consent form.


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Sectional Revisions:
Location
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Updated Text
Title Page
2440 Research Boulevard
Rockville, MD  20850, 
United States
Phone:  
Fax:  
E-mail:  
2440 Research Boulevard
Rockville, MD  20850, 
United States
Phone:  
Fax:  
E-mail:  
Title Page
Immediately Reportable:
Events 
                                           PharmacoVigilance Region Europe 
(PVRE)
Otsuka Frankfurt Research Institute 
GmbH
Hochhaus am Park, Grüneburgweg 102
60323 Frankfurt am Main
Germany
                                           Fax:  
Phone:  
 (24h/7d PVRE 
Blackberry)
Immediately Reportable
                                           
                                           Otsuka Frankfurt Research Institute 
              GmbH
                                           Hochhaus am Park
                                           Grüneburgweg 102
Otsuka Europe Development and  
                                           Commercialisation, Ltd (OEDC) 
                                           Pharmacovigilance Region Europe (PVRE)
                             Zweigniederlassung Frankfurt am Main 
              Europa-Allee 52
                                           60327 Frankfurt am Main
              Germany
Fax:  
Phone: 
 (24h/7d PVRE 
Blackberry)
Title Page
Added text.
Amendment 2 Issue Date
14 October 2014
Synopsis 
(Trial 
Design)
Baseline (Day 0): Inclusion/exclusion criteria, physical examination 
and safety assessments including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and 
ECG as described in the Schedule of Assessments. OBR 
administration as prescribed by investigator, and recording of 
adverse events (AEs)/immediately reportable events (IREs), and 
concomitant medications. 
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by 
Baseline (Day 0): Inclusion/exclusion criteria, physical examination and 
safety assessments including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and ECG as 
described in the Schedule of Assessments. OBR administration as 
prescribed by investigator, and recording of adverse events 
(AEs)/immediately reportable events (IREs), and concomitant 
medications. 
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by investigator.  


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investigator.  Sparse blood draws for PK as described in the 
Schedule of Assessments. Signs and symptoms of TB, physical 
examination and other safety assessments including safety lab tests. 
Audiometry and visual assessments, and ECG at weeks and times 
shown in the Schedule of Assessments. Height, weight, and BMI 
beginning at Week 2 and assessed monthly, and collection of 
AEs/IREs, and concomitant medications.
Post-Treatment Period (Days 183 to 238): Physical examination, 
vital signs, ECGs, safety labs, sparse blood draws for PK at visits 
and times described in the Schedule of Assessments. OBR dosing 
and collection of AEs/IREs, and concomitant medications. 
Follow-up Period (Days 239 to 365) Six Month Post Last Delamanid 
Dose: Physical examination, height and weight, BMI, percentiles for 
age, vital signs, and symptoms of TB, chest radiograph, audiometry 
and visual assessments, safety labs, thyroid function tests (for 
patients taking ethionamide or PAS), OBR administration, and 
collection of AEs/IREs and concomitant medications.  
Sparse blood draws for PK as described in the Schedule of Assessments. 
Signs and symptoms of TB, physical examination and other safety 
assessments including safety lab tests. Audiometry and visual 
assessments, and ECG at weeks and times shown in the Schedule of 
Assessments. Height, weight, and BMI beginning at Week 2 and 
assessed monthly, and collection of adverse events (AEs) and 
immediately reportable events (/IREs), and concomitant medications.
Post-Treatment Period (Days 183 to 238): Physical examination, vital 
signs, ECGs, safety labs, sparse blood draws for PK at visits and times 
described in the Schedule of Assessments. OBR dosing and collection 
of AEs/IREs, and concomitant medications. 
Follow-up Period (Days 239 to 365) Six Month Post Last Delamanid 
Dose: Physical examination, height and weight, BMI, percentiles for 
age, vital signs, signs and symptoms of TB, chest radiograph, 
audiometry and visual assessments, safety labs, thyroid function tests 
(for patients taking ethionamide or PAS), OBR administration, and 
collection of AEs/IREs and concomitant medications.
Treatment Outcome Follow-up (Day 730 (M24) or until treatment for 
MDR-TB is completed or discontinued, whichever comes first):  
Collection of treatment outcome information as routinely documented 
in the patient medical records or in a National TB Program.
Synopsis
Twelve to sixteen pediatric patients will be enrolled to obtain a 
minimum of twelve male and female patients, at least six each in 
Group 1 (ages 12 to 17 years) and in Group 2 (ages 6 to 11 years) 
who have MDR-TB and are also receiving an OBR. Group 1 (ages 
12 to 17 years) must contain at least two but no more than five 
females.
At least twelve male and female pediatric patients who have 
successfully completed Trial 232 will be enrolled in two sequential 
age groups, at least six each in Group 1 (ages 12 to 17 years) and in 
Group 2 (ages 6 to 11 years) who have confirmed or presumptive MDR-
TB and are also receiving an OBR. Group 1 (ages 12 to 17 years) must 
contain at least two but no more than five females.
Synopsis
(Inclusion
Criteria)

Presumptive diagnosis of MDR TB such that the treating 
physician has decided to treat the patient for MDR-TB who has 
one of the following:
-
Persistent cough lasting > 2 weeks
-
Fever, weight loss, and failure to thrive
-
Findings on recent chest radiograph (within 4 weeks 
prior to Visit 1) consistent with TB
-
Sputum smear positive for acid-fast bacilli (AFB)
-
AND 
-
Household contact of a person with known MDR TB or 
a person who died while appropriately taking drugs for 
sensitive TB/OR
•
Presumptive diagnosis of MDR-TB such that the treating physician 
has decided to treat the patient for MDR-TB who has one of 
the following:
-
Sputum smear positive for acid-fast bacilli (AFB)
-
Clinical specimen (eg, cerebral spinal fluid [CSF], 
pleural fluid, ascitic fluid, lymph node aspirate, or 
other tissue) suggestive of tuberculosis disease
-
Persistent cough lasting > 2 weeks
-
Fever, weight loss, and failure to thrive
-
Findings on recent chest radiograph consistent with 
TB
AND


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-
On first-line TB treatment but with no clinical 
improvement
-
Trial-specific written informed consent/assent obtained 
from a parent(s) or guardian or legally acceptable 
representative, as applicable for local laws prior to the 
initiation of any protocol required procedures. In 
addition, the subject must provide informed assent at 
screening and must be able to understand that he or she 
can withdraw from the trial at any time.  All informed 
consent/assent procedures must be in accordance with 
the trial center’s institutional review board/ethics 
committee (IRB/EC) and local regulatory requirements
-
Household contact of a person with known MDR TB 
or a person who died while appropriately taking drugs 
for sensitive TB 
OR
-
On first-line TB treatment but with no clinical 
improvement
-
Negative urine pregnancy test for female patients who 
have reached menarche
-
Trial-specific written informed consent/assent obtained 
from a parent(s) or guardian or legally acceptable 
representative, as applicable for local laws prior to the 
initiation of any protocol required procedures. In addition, the 
subject must provide informed assent at screening and must be 
able to understand that he or she can withdraw from the trial at 
any time.  All informed consent/assent procedures must be in 
accordance with the trial center’s institutional review 
board/ethics committee (IRB/EC) and local regulatory 
requirements
Synopsis
(Exclusion 
Criteria)

Added text

Administered an IMP within 1 month prior to Visit 1.

Pregnant, breast-feeding, or planning to conceive or father a 
child within the timeframe described in the informed consent 
form.
Synopsis
(Criteria 
for 
Evaluation)

Efficacy: assessed by results of chest radiography (for 
patients with pulmonary disease); change in body weight 
and height measurements; and evaluation of TB symptoms.  
In addition, sputum culture conversion (for culture-positive 
patients) will be assessed in patients who are able to 
produce sputum (or other specimen) for microbiological 
evaluation according to the requirements of the National TB 
Program.

Efficacy: assessed by results of chest radiography (for patients 
with pulmonary disease); change in body weight and height 
measurements; and evaluation of TB symptoms.  In addition, 
sputum culture conversion (for culture-positive patients) will 
be assessed in patients who are able to produce sputum (or 
provide other biological specimens) for microbiological 
evaluation according to the requirements of the National TB 
Program.
Synopsis 
(Trial 
Duration)
The trial duration per patient (Screening, Baseline, Treatment, Post 
Treatment, and Follow-up Periods) will be 395 days including the 
following: 30-day Screening period, 182-day Treatment period, 56-
day Post-treatment period, and a 127-day follow-up period 
(incorporating a 6 month post last delamanid dose follow-up visit).
The trial duration per patient (Screening, Baseline, Treatment, Post 
Treatment, and Follow-up Periods) will be 760 days including the 
following: 30-day Screening period, 182-day Treatment period, 56-day 
Post-treatment period, and a 492-day follow-up period (127-day from 
the last Post-treatment period, incorporating a 6 month post last 
delamanid dose follow-up visit and additional 365-day treatment 
outcome follow up period from the last follow up visit or until 
treatment for MDR-TB is completed or discontinued, whichever 
comes first).


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List of 
Abbrevia-
tions
Added text
OEDC  Otsuka Europe Development and Commercialisation, Ltd 
PAS  p-aminosalicylic acid
Section 1 -
1.4.2
Made minor corrections to text and references.
Section 
1.4.1
As of 31 January 2012, there had been 887 subjects and patients 
exposed to delamanid in clinical trials.3
A total of 887 subjects and patients have been exposed to delamanid 
in 17 completed clinical trials.3
Section 2.2
Adolescents (ages 12 to 17 years) will be given delamanid at the 
adult dose, which will be delamanid 100 mg BID; children (ages 6 to 
11 years) will be given half the adult dose, which will be delamanid 
50 mg BID. Delamanid will be given as delamanid 50 mg tablets, 
not crushed
Adolescents (ages 12 to 17 years) will be given delamanid at the adult 
dose, which will be delamanid 100 mg BID; children (ages 6 to 11 
years) will be given half the adult dose, which will be delamanid 50 mg 
BID. Delamanid will be given as delamanid 50 mg tablets, not crushed.
Section 3.1
A total of twelve male and female patients will be enrolled to obtain 
a minimum of 12 completed patients, at least 6 in each age group.  
Patients will be assigned to one of two treatment groups based on 
age:
At least 12 male and female patients will be enrolled to obtain a 
minimum of 12 completed patients, at least 6 in each age group.  
Patients will be assigned to one of two treatment groups based on age:
Section 3.1
Baseline (Day 0): Inclusion/exclusion criteria, physical examination 
and safety assessments including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and 
ECG as described in the Schedule of Assessments. OBR 
administration as prescribed by investigator, and recording of 
adverse events (AEs)/immediately reportable events (IREs), and 
concomitant medications. 
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by 
investigator.  Sparse blood draws for PK as described in the 
Schedule of Assessments. Signs and symptoms of TB, physical 
examination and other safety assessments including safety lab tests. 
Audiometry and visual assessments, and ECG at weeks and times 
shown in the Schedule of Assessments. Height, weight, and BMI 
beginning at Week 2 and assessed monthly, and collection of 
AEs/IREs, and concomitant medications.
Post-Treatment Period (Days 183 to 238): Physical examination, 
vital signs, ECGs, safety labs, sparse blood draws for PK at visits 
and times described in the Schedule of Assessments. OBR dosing 
and collection of AEs/IREs, and concomitant medications. 
Follow-up Period (Days 239 to 365, 6 month Post Last Delamanid 
Baseline (Day 0): Inclusion/exclusion criteria, physical examination and 
safety assessments including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and ECG as 
described in the Schedule of Assessments. OBR administration as 
prescribed by investigator, and recording of adverse events 
(AEs)/immediately reportable events (IREs), and concomitant 
medications. 
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal. OBR administration as prescribed by investigator.  
Sparse blood draws for PK as described in the Schedule of Assessments. 
Signs and symptoms of TB, physical examination and other safety 
assessments including safety lab tests. Audiometry and visual 
assessments, and ECG at weeks and times shown in the Schedule of 
Assessments. Height, weight, and BMI beginning at Week 2 and 
assessed monthly, and collection of adverse events (AEs) and 
immediately reportable events (/IREs), and concomitant medications.
Post-Treatment Period (Days 183 to 238): Physical examination, vital 
signs, ECGs, safety labs, sparse blood draws for PK at visits and times 
described in the Schedule of Assessments. OBR dosing and collection 
of AEs/IREs, and concomitant medications. 
Follow-up Period (Days 239 to 365, 6 month Post Last Delamanid 


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Dose): Physical examination, height and weight, BMI, percentiles 
for age, vital signs, and symptoms of TB, chest radiograph, 
audiometry and visual assessments, safety labs, thyroid function tests 
(for patients taking ethionamide or PAS), OBR administration, and 
collection of AEs/IREs and concomitant medications. 
Dose): Physical examination, height and weight, BMI, percentiles for 
age, vital signs, signs and symptoms of TB, chest radiograph, 
audiometry and visual assessments, safety labs, thyroid function tests 
(for patients taking ethionamide or PAS), OBR administration, and 
collection of AEs/IREs and concomitant medications.  
Treatment Outcome Follow-up (Day 730 (M24) or until treatment for 
MDR-TB is completed or discontinued, whichever comes first):
Collection of treatment outcome information as routinely documented 
in the patient medical records or in a National TB Program.
Figure 3.1-
1
Added Text
Day 730 
Group 1 and 2 OBR only
Treatment Outcome
Section 
3.3.1
A total of 12 male and female patients from 6 to 17 years of age 
inclusive, who have successfully completed Trial 232, who are 
receiving OBR for confirmed or presumptive MDR-TB will be 
enrolled in two sequential age groups.  
At least 12 male and female patients from 6 to 17 years of age,
inclusive, who have successfully completed Trial 232, who are 
receiving OBR for confirmed or presumptive MDR-TB will be enrolled 
in two sequential age groups.  
Section 
3.4.1
Added Text
In accordance with applicable regulations and guidance for subject 
data protection, patients who have completed the Post-treatment 
Follow-up Period (V19) prior to regulatory authority and EC approval 
of this protocol will be asked to sign a patient informed consent form 
(ICF) authorizing the release of MDR-TB treatment outcome from the 
treatment centers. The parent/ guardian/legal representative and/or 
patient shall be given a copy of the signed ICF/Assent Form; the 
original shall be kept on file by the investigator.
Section 
3.4.2
Presumptive diagnosis of MDR TB such that the treating physician 
has decided to treat the patient for MDR-TB who has one of the 
following:
-Sputum smear positive for AFB
-Persistent cough lasting > 2 weeks
-Fever, weight loss, and failure to thrive
-Findings on recent chest radiograph (within 4 weeks prior to Visit 
1) consistent with TB
AND
-Household contact of a person with known MDR-TB or of a person 
who died while appropriately taking drugs for sensitive TB, OR
-On first-line TB treatment but with no clinical improvement
Presumptive diagnosis of MDR-TB such that the treating physician has 
decided to treat the patient for MDR-TB who has one of the following:
-Sputum smear positive for AFB
-Clinical specimen (eg, CSF, pleural fluid, ascitic fluid, lymph node 
aspirate, or other tissue) suggestive of tuberculosis disease
-Persistent cough lasting > 2 weeks
-Fever, weight loss, and failure to thrive
-Findings on recent chest radiograph (within 4 weeks prior to Visit 1) 
consistent with TB
AND
-Household contact with a person with known MDR-TB or with a 
person who died while appropriately taking drugs for sensitive TB
OR
-On first-line TB treatment but with no clinical improvement
Section 
Added text
13. Administered an IMP within 1 month prior to Visit 1


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3.4.3
14. Pregnant, breast-feeding, or planning to conceive or father a child 
within the timeframe described in the informed consent form
Section 
3.5.2.2
In addition, sputum culture conversion (for culture-positive patients) 
will be assessed in patients who are able to produce sputum (or other 
specimen) for microbiological evaluation according to the 
requirements of the National TB Program.  Sputum collection is not 
required as part of this protocol; however, they may be collected by 
the investigator as part of routine management of the subject.  In 
patients who are able to produce sputum (or other specimen) for 
microbiological evaluation according to the requirements of the 
National TB Program, all available results for smear microscopy, 
culture, identification, and drug susceptibility will be collected from 
the patient chart as an unscheduled visit.
In addition, sputum culture conversion (for culture-positive patients) 
will be assessed in patients who are able to produce sputum (or provide 
other biological specimens) for microbiological evaluation according 
to the requirements of the National TB Program.  Microbiological 
assessment of sputum or other biological specimens (e.g. CSF, pleural 
fluid, ascitic fluid, joint fluid, lymph node aspirates, etc.) are not 
required as part of this protocol; however, they may be collected by the 
investigator as part of routine management of the subject.  In patients 
who are able to produce sputum (or provide other specimens) for 
microbiological evaluation according to the requirements of the 
National TB Program, all available results for smear microscopy, 
culture, identification, and drug susceptibility will be collected from the 
patient chart as an unscheduled visit.
Section 3.7 
Each patient will participate in the trial for up to 395 days.  The trial 
will be comprised of the Screening Period (30 days); Baseline (Day 
0); Treatment Period (182 days of delamanid plus OBR 
administration); Post-treatment Period (56 days with visits at Days 
189, 196, 203, 210, and 238 [Day 238 corresponds to 2-months post 
last delamanid dose]); and a Follow-up Period with a visit at 6 
months post last delamanid dose (Day 365).  Trial assessment time 
points are summarized in Table 3.7-1.
Each patient will participate in the trial for up to 760 days.  The trial 
will be comprised of the Screening Period (30 days); Baseline (Day 0); 
Treatment Period (182 days of delamanid plus OBR administration); 
Post-treatment Period (56 days with visits at Days 189, 196, 203, 210, 
and 238 [Day 238 corresponds to 2-months post last delamanid dose]); 
and a Follow-up Period with a visit at 6 months post last delamanid 
dose (Day 365) and additional 365-day treatment outcome follow up 
period from the last follow up visit or until treatment for MDR-TB is 
completed or discontinued, whichever comes first). Trial assessment 
time points are summarized in Table 3.7-1.
Table 3.7-1
Added text
Added X mark for the Early Termination Visit PK blood draws
Added column labeled as Visit 20, Day 730 in the Follow up Period
Added row “Collection of treatment outcome data”
Added X mark for the Day 730 Collection of treatment outcome data
Table 3.7-1
Deleted text
Deleted X mark for Record AEs and IEs at Visits 1 and 2.
Table 3.7-1
a Information to be obtained from Screening visit of Trial 232.
b Information to be obtained from Day 10 of Trial 232.
c Information to be obtained during Screening for this Trial 233, 
between Days -30 to -1.   
d Follow-up 6 months  post last dose of delamanid. 
f Consenting/Assenting for Trial 233 can occur prior to Day -30.
g Confirmed or presumptive diagnosis of MDR-TB (based on 
inclusion criteria #3, Table 3.4.2-1) 
h Vital signs include systolic and diastolic BP (mm Hg), HR 
a Information to be obtained from Screening visit of Trial 232.
b Information to be obtained from Day 10 of Trial 232.
c Information to be obtained during Screening for this Trial 233, 
between Days -30 to -1.  
dFollow-up 6 months post last dose of delamanid. 
d For the early termination visit, the PK blood sample will be 
labeled with the date, study day, and time of the PK blood draw.
e Consenting/Assenting for Trial 233 can occur prior to Day -30.


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(bpm), RR (bpm), and body temperature (C) after the patient 
has been supine for ≥3 minutes.
i Three consecutive 12-Lead ECGs must be performed predose.
j ECG paired with PK blood sampling: Three consecutive 12-
Lead ECGs must be performed predose, followed by PK blood 
draw, and  then patients will receive their dose of delamanid.
k Urine pregnancy test will be performed for all females who have 
reached menarche.  Urine pregnancy testing will be performed 
at screening, and Day 182 or the early termination visit.
l Coagulation tests (aPTT and PT) performed with safety labs.
m Thyroid tests performed for patients taking ethionamide or 
PAS.
n PK blood draw (3 mL) paired with 12-lead ECG at predose (0 
hours during treatment).
o PK blood draw (3 mL) paired with 12-lead ECG at theoretical 
predose. 
p PK blood draw (3 mL) to be obtained at any time point. 
qFollow-up contact for patients who early terminate from Trial 
233 should occur 28 to 32 days after the early termination visit.
f Confirmed or presumptive diagnosis of MDR-TB (based on 
inclusion criteria #3, Table 3.4.2-1) 
g Vital signs include systolic and diastolic BP (mm Hg), HR (bpm), 
RR (bpm), and body temperature (C) after the patient has been 
supine for ≥3 minutes.
h Three consecutive 12-Lead ECGs must be performed predose.
i ECG paired with PK blood sampling: Three consecutive 12-Lead 
ECGs must be performed predose, followed by PK blood draw, 
and  then patients will receive their dose of delamanid.
j Urine pregnancy test will be performed for all females who have 
reached menarche.  Urine pregnancy testing will be performed at 
screening, and Day 182 or the early termination visit.
k Coagulation tests (aPTT and PT) performed with safety labs.
l Thyroid tests (T4 and thyroid stimulating hormone) performed for 
patients taking ethionamide or p-aminosalicylic acid.
m PK blood draw (3 mL) paired with 12-lead ECG at predose (0 
hours during treatment).
n PK blood draw (3 mL) paired with 12-lead ECG at theoretical
predose. 
o PK blood draw (3 mL) to be obtained at any time point. 
pFollow-up contact for patients who early terminate from Trial 233 
should occur 28 to 32 days after the early termination visit to 
assess for AEs and IREs.  All patients will continue treatment 
with OBR as prescribed by the investigator according to WHO 
guidelines.
q Day 730 (M24) or until treatment for MDR-TB is completed or 
discontinued, whichever comes first


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Section 
3.7.1.1
The following information will be obtained during the screening 
period of this Trial 233 between Days -30 and -1:
• Informed consent/assent (may be completed prior to Day -30)
• Medical history
• Vital signs assessments (blood pressure [BP], HR, respiratory rate 
[RR], and body temperature) after the subject has been supine for ≥ 
3 minutes 
• Height,weight, and BMI
• Date of birth and gender
• Percentiles for age
• Urine pregnancy test for all female subjects who have reached 
menarche
• Urine drug screen (as per Table 3.7-1)
• Record AEs and immediately reportable events (IREs)
• Record prior concomitant medications including prior concomitant 
anti-TB medications.  (Note: Patients will have been on OBR in 
Trial 232 for at least two weeks prior to baseline assessments)
• Record start date of menstrual period and/or date of last menstrual 
period (LMP)
The following information will be obtained during the screening period 
of this Trial 233 between Days -30 and -1:
• Informed consent/assent (may be completed prior to Day -30)
• Medical history
• Vital signs assessments (blood pressure [BP], HR, respiratory rate 
[RR], and body temperature) after the subject has been supine for ≥ 3 
minutes 
• Height,weight, and BMI
• Date of birth and gender
• Percentiles for age
• Urine pregnancy test for all female subjects who have reached 
menarche
• Urine drug screen (as per Table 3.7-1)
• Record AEs and immediately reportable events (IREs)
• Record prior concomitant medications including prior concomitant 
anti-TB medications.  (Note: Patients will have been on OBR in Trial 
232 for at least two weeks prior to baseline assessments)
• Record start date of menstrual period and/or date of last menstrual 
period (LMP)
Section 
3.7.1.2
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Baseline (Day 0):
• Review of inclusion/exclusion criteria
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Height,weight, and BMI
• Percentiles for age
• Vital signs assessments (BP, HR, RR, and body temperature) after 
the subject has been supine for ≥3 minutes 
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Three consecutive 12-lead ECGs.   
• Blood draw for clinical laboratory assessments (as per Table 3.7-
1): serum chemistry, hematology, coagulation, and full urinalysis 
• OBR administration, as prescribed by investigator
• Record AEs and IREs
• Record concomitant medications including concomitant anti TB 
medications.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Baseline (Day 0):
• Review of inclusion/exclusion criteria
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed.
• Height,weight, and BMI
• Percentiles for age
• Vital signs assessments (BP, HR, RR, and body temperature) after the 
subject has been supine for ≥3 minutes 
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Three consecutive 12-lead ECGs.   
• Blood draw for clinical laboratory assessments (as per Table 3.7-1): 
serum chemistry, hematology, coagulation, and full urinalysis 
• OBR administration, as prescribed by investigator
• Record AEs and IREs
• Record concomitant medications including concomitant anti TB 
medications.


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Section 
3.7.1.13

Delamanid dispensed (plusOBR administration either one 
hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be 
administered twice daily (morning and evening).  NOTE:  
This is the last day of delamanid dosing.

Delamanid dispensed, if needed (plus OBR administration 
either one hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be administered 
twice daily (morning and evening).  NOTE:  This is the last 
day of delamanid dosing.
Section 
3.7.1.19
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 546:
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 365:
Section 
3.7.1.20
Added Text
Treatment Outcome Follow-up (Day 730 (M24) or until treatment for 
MDR-TB is completed or discontinued, whichever comes first)
Treatment outcome information will be collected as routinely 
documented in the patient medical records or in a National TB 
Program.
Section 
3.7.1.21
Added text
• Blood draw (3 mL) for PK
Section 
3.7.1.22
Added text
The last dose of delamanid will be given on Day 182.  Patients will 
continue on OBR, as prescribed by the investigator, and have post-
delamanid treatment visits on Days 189, 196, 203, 210, 238 (2-month 
post last dose), Day 365 (6-month post last dose), treatment outcome 
follow-up on (Day 730 (M24) or until treatment for MDR-TB is 
completed or discontinued, whichever comes first).
Section 
3.7.2
In addition, although sputum collection is not required as part of this 
protocol, it may be collected by the investigator as part of routine 
management of the subject.  In patients who are able to produce 
sputum (or other specimen) for microbiological evaluation according 
to the requirements of the National TB Program, all available results 
for smear microscopy, culture, identification, and drug susceptibility 
will be collected from the patient chart as an unscheduled visit.
In addition, although microbiologic assessment of sputum or other 
biologic specimens (e.g. CSF, pleural fluid, ascitic fluid, joint fluid, 
lymph node aspirates, etc.) are not required as part of this protocol, 
they may be collected by the investigator as part of routine management 
of the subject.  In patients who are able to produce sputum (or provide
other specimens) for microbiological evaluation according to the 
requirements of the National TB Program, all available results for smear 
microscopy, culture, identification, and drug susceptibility will be 
collected from the patient chart as an unscheduled visit.
Section 
3.7.3.1
Added text
The tests listed in Table 3.7.3.1-1 will be collected at the times 
presented in Table 3.7-1, and processed in accordance with directions 
from the analytical laboratory.


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Section 
3.7.3.3
Electrocardiograms for on-site evaluation of safety will be recorded 
at the nominal times according to the schedule outlined in Table 3.7-
1. Twelve-lead ECGs will be recorded with the subject supine and 
at rest for ≥10 minutes.  ECGs should be taken before PK blood 
draws when assessments are scheduled on the same day (Visit).  
Three tracings will be obtained at each time point (approximately 5
to 10 minutes between each tracing) with the ECG leads left in 
place.  Heart rate, PR interval, QRS interval, QT intervals and QTc 
(including both QTcB and QTcF), will be recorded. The principal 
investigator or appointed MD designee will review, sign, and date 
each ECG reading. Whenever possible, the same reviewer should 
evaluate, sign, and date the ECGs. The reviewer must be listed on 
the FDA Form 1572. Original ECG tracings will be added to the 
patient’s medical record with the reviewer’s interpretation recorded.  
In addition to the initial clinical interpretation for ongoing safety 
evaluation by the investigator, all ECGs will be analyzed by a 
specialized central laboratory.  Specific guidance for investigators 
for determining AEs related to ECG results is available in the trial 
operations manual.
Electrocardiograms for on-site evaluation of safety will be recorded at 
the nominal times according to the schedule outlined in Table 3.7-
1. Twelve-lead ECGs will be recorded with the subject supine and at 
rest for ≥10 minutes.  ECGs should be taken before PK blood draws 
when assessments are scheduled on the same day (Visit).  Three tracings 
will be obtained at each time point (approximately 3 to 5 minutes 
between each tracing) with the ECG leads left in place.  Heart rate, 
PR interval, QRS interval, QT intervals and QTc (including both QTcB 
and QTcF), will be recorded. The principal investigator or appointed 
MD designee will review, sign, and date each ECG reading. Whenever 
possible, the same reviewer should evaluate, sign, and date the 
ECGs. The reviewer must be listed on the FDA Form 1572. Original 
ECG tracings will be added to the patient’s medical record with the 
reviewer’s interpretation recorded.  In addition to the initial clinical 
interpretation for ongoing safety evaluation by the investigator, all 
ECGs will be analyzed by a specialized central laboratory.  Specific 
guidance for investigators for determining AEs related to ECG results is 
available in the trial operations manual.
Section 
3.7.5.1.1
deleted section
3.7.5.1.1Laboratory Tests
The tests listed in Section 3.7.3.1 will be collected at the times 
presented in the schedule of assessments, Table 3.7-1, and processed in 
accordance with directions from the analytical laboratory.
Section 
3.7.5.1.2
3.7.5.1.2  End of Trial
3.7.6  End of Trial
Section 
3.7.5.2
Section 3.7.5.2  Safety Monitoring Committee
3.7.7  Safety Monitoring Committee
Section 
3.8.1
If a subject discontinues from the trial, the reason given must be 
fully evaluated and recorded appropriately in source documentation 
and in the eCRF.  If the subject is being withdrawn because of an 
AE, that AE must be indicated as the reason for withdrawal.  All 
assessments scheduled to be completed at the final trial visit will be 
performed at early termination.  
If a subject discontinues from the trial, the reason given must be fully 
evaluated and recorded appropriately in source documentation and in 
the eCRF.  If the subject is being withdrawn because of an AE, that AE 
must be indicated as the reason for withdrawal.  All assessments 
scheduled to be completed at the final trial visit will be performed at 
early termination.  If delamanid is stopped due to an AE and/or 
Investigator decision, subjects should continue with visits/assessments 
for the rest of the trial with the exception of taking delamanid.  This 
will allow analysis of comparable assessments between those who 
stopped and those who completed delamanid dosing.
Section 
3.10
Patients who are evaluated at the last scheduled visit during the 
treatment period (complete Day 182 assessments) will be defined as 
Patients who are evaluated at the last scheduled visit of the trial, the 
follow-up visit (Visit 19, Day 365), will be defined as trial completers.


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trial completers.
Table 4.1-1
Table 4.1-1
List of Medications Prohibited During the Trial
1.
Quinidine
2.
Procainamide
3.
Disopyramide
4.
Encainide
5.
Flecainide
6.
Sotalol
7.
Amiodarone
8.
Rifampicin
9.
Moxifloxacin
Table 4.1-1
List of Medications Prohibited During the Trial
Anti-Arrhythmic medications with potential for QT interval 
prolongation
1.Quinidine
2.Procainamide
3.Disopyramide
4.Encainide
5.Flecainide
6.Sotalol
7.Amiodarone
8. Digitalis
Other Medications With Potential For QT Interval Prolongation
1.Moxifloxacin
Other Medications
1.Antiretroviral Medications
2.Rifampicin
Section 5.4 
Females of childbearing potential (FOCBP) and males who are 
sexually active must avoid pregnancy or fathering a child for 22 
weeks for a female patient and 30 weeks for a male patient after the 
last dose of delamanid and abstain from sex during the clinical trial.  
Pregnancy testing will be performed during the screening period 
prior to trial enrollment and at the end of the trial according to the 
Schedule of Assessments for FOCBP who have reached menarche.
If the patient or investigator suspects the patient may be pregnant 
prior to delamanid administration, delamanid must be withheld until 
the results of urine pregnancy tests are available.  A confirmed 
pregnancy before first administration of delamanid must result in 
immediate exclusion or withdrawal from the trial.  If pregnancy is 
suspected while the patient is taking delamanid during the trial, 
delamanid must be withheld immediately and if pregnancy is 
confirmed, the delamanid will be permanently discontinued and the 
Females of childbearing potential (FOCBP) and males who are sexually 
active must avoid pregnancy or fathering a child for 8 weeks for a 
female patient and 30 weeks for a male patient after the last dose of 
delamanid and abstain from sex during the clinical trial.  Pregnancy 
testing will be performed during the screening period prior to trial 
enrollment and at the end of the treatment period according to the 
Schedule of Assessments for FOCBP who have reached menarche.
If the patient or investigator suspects the patient may be pregnant prior 
to delamanid administration, delamanid must be withheld until the 
results of urine pregnancy tests are available.  A confirmed pregnancy 
before first administration of delamanid must result in immediate 
exclusion or withdrawal from the trial.  If pregnancy is suspected while 
the patient is taking delamanid during the trial, delamanid must be 
withheld immediately and if pregnancy is confirmed, the delamanid will 
be permanently discontinued and the patient must be withdrawn 


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patient must be withdrawn from the trial.
The investigator must immediately notify the sponsor of any 
pregnancy associated with delamanid exposure, including and for 22 
weeks for a female patient and 30 weeks for a male patient after the 
last dose of delamanid and record the event on the IRE form and 
forward it to the sponsor.  The sponsor will forward Pregnancy 
Surveillance Form(s) for monitoring the outcome of the pregnancy.
from the trial.
The investigator must immediately notify the sponsor of any pregnancy 
associated with delamanid exposure, during the course of the trial and 
for 8 weeks after the last dose of delamanid and record the event on the 
IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the 
pregnancy.
Appendix 1
PharmacoVigilence Region Europe (PVRE)
Otsuka Frankfurt Research Institute GMbH
Hochhaus am Park, Grüneburgweg 102
60323 Frankfurt am Main Germany
Phone: 
 (24h/7d PVRE Blackberry)
Fax:  
Otsuka Frankfurt Research Institute GMbH
Hochhaus am Park, Grüneburgweg 102
Otsuka Europe Development and Commercialisation, Ltd (OEDC)
Pharmacovigilance Region Europe (PVRE)
Zweigniederlassung Frankfurt am Main
Europa-Allee 52
60327 Frankfurt am Main
Germany
Fax:  
Phone: 
 (24h/7d PVRE Blackberry)
E-mail:  
Appendix 1
For Medical Emergencies in the Philippines or South Africa:
2440 Research Blvd
Rockville, MD  20850
Phone:  
Fax:  
E-mail:  
For Medical Emergencies in the Philippines or South Africa:
2440 Research Blvd
Rockville, MD  20850
Phone:  
Fax:  
E-mail:  
Appendix 3
Appendix 3
Handling and Shipment of Bioanalytical Samples
Handling of Specimens
All tubes must be labeled using the central lab’s bar code labels 
provided with the sample collection kits.  The central lab’s 
requisition form must be completely filled out in regards to the PK 
sample information.  On the sample tube, the subject ID/screening 
number and subject initials must be handwritten on the label.  On the 
Appendix 3
Handling and Shipment of Bioanalytical Samples
Handling of Specimens
All tubes must be labeled using the central lab’s bar code labels 
provided with the sample collection kits.  The central lab’s requisition 
form must be completely filled out in regards to the PK sample 
information.  On the sample tube, the subject ID/screening number and 
subject initials must be handwritten on the label.  On the requisition 


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requisition form, it is important to note the date and exact time of the 
blood collection.
form, it is important to note the date and exact time of the blood 
collection.
Appendix 3
Appendix 3
Handling and Shipment of Bioanalytical Samples
Plasma Samples for Delamanid
Blood (1.5-3 mL) will be collected into green-top Vacutainer tubes 
containing sodium heparin anticoagulant.  The tubes must be gently 
inverted 3 to 4 times and then centrifuged at 2500 rpm for at least 10 
minutes at 4°C.  The separated plasma from each tube should then be 
divided equally between the 2 bar-code labeled polypropylene tubes.  
The PK sample must be stored at -70°C or below.
Appendix 3
Handling and Shipment of Bioanalytical Samples
Plasma Samples for Delamanid
Blood (1.5-3 mL) will be collected into green-top Vacutainer tubes 
containing sodium heparin anticoagulant.  The tubes must be gently 
inverted 3 to 4 times and then centrifuged at 2500 rpm for at least 10 
minutes at 4°C.  The separated plasma from each tube should then be 
divided equally between the 2 bar-code labeled polypropylene tubes.  
The PK sample must be stored at -65°C or below.
Appendix 4
Appendix 3
Protocol Amendment
Appendix 4
Protocol Amendments
ADDITIONAL RISK TO THE SUBJECT:
This amendment will not affect the safety of patients, the scope of the investigation, or the scientific quality of the trial.


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Amendment Number: 3
Issue Date:
29 June 2015
PURPOSE: The purpose of this amendment is to add information for Groups 3 and 4 to 
the protocol including dosage for group 3, to remove certain laboratory assessments to 
decrease the required blood volume for younger age groups as mandated by the 
applicable EC in South Africa, to simplify the text associated with the schedule of 
assessments, to clarify that the safety monitoring committee is composed of only external 
consultants, to make minor editorial changes to the text, make minor content and editorial 
changes to the Introduction and references. 
BACKGROUND:  In the previous protocol, information was only included for Groups 1
and 2 and now information for Groups 3 and 4 has been added.  In addition, the text 
associated with the schedule of assessments was unnecessarily lengthy.  Due to the 
maximum blood volumes allowed to be drawn within a specified time period for pediatric 
patients of certain weights (as mandated by the University of Stellenbosch Ethics 
Committee), certain laboratory and PK assessments have been removed from the protocol 
to comply with these guidelines.  Various minor editorial changes to the text have been 
made to increase clarity and consistency with the 242-12-232 protocol.
MODIFICATIONS TO PROTOCOL:
Bold and underlined text:
Changed Text
Bold and strike through text:
Deleted Text
Bold and italicized text:
Added Text
Global Changes:

Corrected minor typographical, grammatical, and formatting errors.

Made minor content and editorial changes, including references, to the 
Introduction.

Added an objective to assess the palatability of the delamanid pediatric 
formulation.

Updated and corrected table of contents, section numbering, and cross references.

Added an objective to assess the palatability of the delamanid pediatric 
formulation.

Clarified that the minimum number of patients to be enrolled is 36.


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
Clarified that patients should be in a supine or semi-recumbent position prior to 
vital signs and ECGs.

Updated the schedule of assessments.

Added dosing and assessment information for Groups 3 and 4.


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Sectional Revisions:
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Title Page
Immediately Reportable:
Events 
                                           PharmacoVigilance Region Europe 
(PVRE)
Otsuka Frankfurt Research Institute 
GmbH
Hochhaus am Park, Grüneburgweg 102
60323 Frankfurt am Main
Germany
                                           Fax:  
Phone:  
 (24h/7d 
PVRE 
Blackberry)
Immediately Reportable
Otsuka Europe Development and
Events
  Commercialisation, Ltd (OEDC) 
Pharmacovigilance Region Europe (PVRE)
Grüneburgweg 102
60323 Frankfurt am Main
Germany
Fax:  
Phone: 
 (24h/7d PVRE 
Blackberry)
Title Page
Added text.
Amendment 3 Issue Date
29 June 2015

Pharmacokinetics: To report delamanid and metabolite 
plasma concentrations at each visit by age groups and to 
conduct population pharmacokinetics (POPPK) of 
delamanid when delamanid is administered in 
combination with an OBR during a 6 month treatment 
period in pediatric patients with MDR TB. 

To report delamanid and metabolite plasma concentrations at 
each visit day by age groups and to conduct a population 
pharmacokinetics (POPPK) analysis of delamanid when 
delamanid is administered in combination with an OBR 
during a 6-month treatment period in pediatric patients with 
MDR TB
Synopsis 
(Objectives)

To conduct  the pharmacokinetic (PK)/ 
pharmacodynamics (PD) relationship analysis of the 
metabolite DM-6705 plasma concentrations and QTc 
prolongation when delamanid is administered in 
combination with OBR during a 6 month treatment 
period in pediatric patients with MDR-TB

To conduct the pharmacokinetic (PK)/pharmacodynamic (PD) 
relationship analysis of delamanid and its metabolite DM-
6705 plasma concentrations and change in corrected QT 
interval (QTc) when delamanid is administered in 
combination with OBR during a 6 month treatment 
period in pediatric patients with MDR-TB

To determine the palatability of the delamanid pediatric 
formulation 
Synopsis 
(Trial Design)
The current Trial 242-12-233 (Trial 233) will initially be 
conducted sequentially in two groups of pediatric patients by age 
group: Group 1 (ages 12 to 17 years) and Group 2 (ages 6 to 11 
years).
Younger age groups (Group 3, [3 to 5 years] and Group 4, [0 to 2 
years]) will be enrolled when the pediatric formulation becomes 
available. Details describing Groups 3 and 4 will be included in an 
amendment to this protocol.
The current Trial 242-12-233 (Trial 233) will be conducted 
sequentially in 4 groups of pediatric patients with MDR-TB. 
  
•
Group 1 (ages 12 - 17 years, inclusive) will receive adult 
formulation delamanid 100 mg BID + OBR (n = 6)
•
Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)
•
Group 3 (ages 3 - 5 years, inclusive) will receive pediatric 
formulation delamanid 25 mg BID + OBR (n = 12)
•
Group 4 (ages birth - 2 years, inclusive) will receive pediatric 


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Group 1 includes pediatric patients with MDR-TB age 12 to 17 
years receiving OBR.  Group 2 includes pediatric patients with 
MDR-TB age 6 to 11 years receiving OBR.  Patients will be 
assigned to one of two treatment groups based on age:
Group 1 will receive delamanid 100 mg (2 x 50 mg tablets) (twice 
daily) BID orally (PO) plus OBR for 6 months (180 days).
Group 2 will receive delamanid 50 mg (1 x 50 mg tablet) BID PO 
plus OBR for 6 months (180 days).
formulation delamanid (dose to be determined) BID + OBR (n = 
12)
Synopsis
(Trial Design)
Screening Period (Day -30 to -1): Study data will either be taken 
from screening or Day 10 of Trial 232 
or will be 
performed during the 30-day period immediately after completion 
of Trial 232 as described in the Schedule of Assessments. 
Baseline (Day 0): Inclusion/exclusion criteria, physical 
examination and safety assessments including lab tests, signs and 
symptoms of tuberculosis (TB), audiometry and visual 
assessments, vital signs, height, weight, percentiles for age, body 
mass index (BMI), and ECG as described in the Schedule of 
Assessments. OBR administration as prescribed by investigator, 
and recording of concomitant medications.
Treatment Outcome Follow-up (Day 730 (M24) or until treatment 
for MDR-TB is completed or discontinued, whichever comes 
first): Collection of treatment outcome information as routinely 
documented in the patient medical records or in a National TB 
Program.
Screening Period (Day −30 to −2):  Study data will either be taken 
from screening or Day 10 of Trial 232 or will be performed during the 
30-day period immediately after completion of Trial 232 as described 
in the Schedule of Assessments. 
Baseline (Day −1):  Inclusion/exclusion criteria, physical examination, 
and safety assessments, including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index (BMI), and 
electrocardiogram (ECG) as described in the Schedule of Assessments.  
OBR administration as prescribed by investigator, and recording of 
concomitant medications.
Treatment Outcome Follow-up (Day 730 [Month 24] + 2 months:  
Collection of treatment outcome information as routinely documented 
in the patient medical records or in a national TB program.
Synopsis
(Patient 
Population)
At least twelve male and female pediatric patients who have 
successfully completed Trial 232 will be enrolled in two 
sequential age groups, at least six each in Group 1 (ages 12 to 
17 years) and in Group 2 (ages 6 to 11 years) who have 
confirmed or presumptive MDR-TB and are also receiving an 
OBR. Group 1 (ages 12 to 17 years) must contain at least two 
but no more than five females.
At least 36 male and female MDR-TB patients ages birth to 17 
years, inclusive, who meet all of the inclusion criteria and none 
of the exclusion criteria and who are also receiving OBR will 
be assigned to one of 4 treatment groups based on age.  For 
Groups 1 and 2, a minimum of 6 patients will be included in 
each age group, and Group 1 (12 to 17 years, inclusive) must 
include at least 2 but no more than 5 females.  For Groups 3 
and 4, a minimum of 12 patients will be included in each age 
group.
Synopsis
(Inclusion
Key Inclusion Criteria:

Patients enrolled in this Trial 233 must have successfully 
Key Inclusion Criteria:

Successfully completed Trial 232 


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Criteria)
completed the previous Trial 232. 

Male and female children

Negative urine pregnancy test for female patients who 
have reached menarche

Age 6 to 17 years 
In two sequential cohorts of 12 to 17 years (Group 1) and 
6 to 11 years (Group 2)

Confirmed diagnosis of MDR-TB
OR

Presumptive diagnosis of MDR-TB such that the treating 
physician has decided to treat the patient for MDR-TB 
who has one of the following:
-
Sputum smear positive for acid-fast bacilli (AFB)
-
Clinical specimen (eg, cerebral spinal fluid, pleural
fluid, ascitic fluid, lymph node aspirate, or other 
tissue) suggestive of turberculosis disease
-
Persistent cough lasting > 2 weeks
-
Fever, weight loss, and failure to thrive
-
Findings on recent chest radiograph consistent 
with TB
AND
-
Household contact of a person with known MDR-TB 
or a person who died while appropriately taking 
drugs for sensitive TB 
OR
-
On first-line TB treatment but with no clinical 
improvement

Negative urine pregnancy test for female patients who 
have reached menarche

Trial-specific written informed consent/assent obtained 
from a parent(s) or guardian or legally acceptable 
representative, as applicable for local laws prior to the 
initiation of any protocol required procedures. In 
addition, the subject must provide informed assent at 
screening and must be able to understand that he or she 
can withdraw from the trial at any time.  All informed 

Male or female

Age birth to 17 years, inclusive 

Confirmed diagnosis of MDR-TB, ie, culture positive for 
Mycobacterium tuberculosis (MTB) with isoniazid and 
rifampicin resistance on drug-susceptibility testing, or a 
positive rapid test demonstrating resistance to rifampicin 
alone or to rifampicin and isoniazid
OR

Presumptive diagnosis of pulmonary or extrapulmonary
MDR-TB such that the treating physician has decided to treat 
for MDR-TB the patient who has one of the following:

Clinical specimen (eg, cerebral spinal fluid, pleural fluid, 
ascitic fluid, lymph node aspirate, or other tissue specimen) 
suggestive of tuberculosis (TB) disease

Persistent cough lasting > 2 weeks

Fever, weight loss, and failure to thrive

Findings on recent chest radiograph or other imaging studies 
(prior to Visit 1) consistent with TB
AND
-
Household contact of a person with known MDR TB or a 
person who died while appropriately taking drugs for 
drug-sensitive TB
OR
-
On first-line TB treatment but with no clinical 
improvement

Negative urine pregnancy test for female patients who have 
reached menarche

Study-specific written informed consent/assent obtained from 
a parent(s) or guardian or legally acceptable representative, as 
applicable for local laws prior to the initiation of any 
protocol-required procedures.  In addition, for patients in 
Groups 1 and 2 and as required by local laws, the patient 
must provide informed assent at screening and must be able to 
fully understand that he or she can withdraw from the study at 


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consent/assent procedures must be in accordance with the 
trial center’s institutional review board/ethics committee 
(IRB/EC) and local regulatory requirements
any time.   
Synopsis
(Exclusion 
Criteria)

Patients who have not completed Trial 232

Children with a positive test for human 
immunodeficiency virus (HIV) or who have been 
previously identified as having HIV or with laboratory 
evidence of hepatitis B or C

History of allergy to metronidazole and any disease or 
condition in which metronidazole is required

Use of amiodarone within 12 months of the first dose of 
investigational medicinal product (IMP) or use of other 
predefined antiarrhythmic medications within 30 days 
prior to the first dose of IMP

Use of rifampicin and/or moxifloxacin within 1 week 
prior to the first dose of IMP

Serious concomitant conditions (cardiovascular disorders, 
severe respiratory disease, severe diarrheal disease, renal, 
hepatic, or neurological impairment)

Preexisting cardiac conditions including but not limited 
to structural cardiac disease including suspected TB 
involvement of the heart on clinical or radiographic 
grounds

A concomitant condition such as renal impairment 
characterized by serum creatinine levels >1.5 mg/dL, 
hepatic impairment (ALT or AST >3 x ULN), or 
hyperbilirubinemia characterized by total bilirubin > 2x 
ULN

Abnormalities in screening ECG (including 
atrioventricular [AV] block, bundle branch block [BBB] 
or hemi-block, QRS prolongation >120 msec, or QTcF 
>450 msec in both males and females)

Positive urine drug screen

Concurrent diagnosis of severe malnutrition or 
kwashiorkor

Lansky Play Performance Score < 50 or Karnofsky Score 
< 50

Patients who have not completed Trial 232

Children with a positive test result for human 
immunodeficiency virus (HIV) or who have been previously
identified as having HIV or with laboratory evidence of active
hepatitis B or C

History of allergy to metronidazole and any disease or 
condition in which metronidazole is required

Use of amiodarone within 12 months prior to the first dose of 
investigational medicinal product (IMP) or use of other 
predefined antiarrhythmic medications within 30 days prior to 
the first dose of IMP

Serious concomitant conditions (cardiovascular disorders, 
severe respiratory disease, severe diarrheal disease, renal, 
hepatic, or neurological impairment)

Preexisting cardiac conditions including but not limited to 
structural cardiac disease including suspected TB involvement 
of the heart on clinical or radiographic grounds

Abnormalities in screening electrocardiogram (ECG) 
(including atrioventricular block, bundle branch block or 
hemi-block, QRS prolongation > 120 msec, or QT interval 
corrected using Fridericia’s method (QTcF) > 450 msec in 
both males and females)

A concomitant condition such as renal impairment 
characterized by serum creatinine levels > 1.5 mg/dL, hepatic 
impairment (alanine aminotransferase or aspartate 
aminotransferase > 3 times the upper limit of normal [ULN]), 
or hyperbilirubinemia characterized by total bilirubin > 2x 
ULN

Concurrent diagnosis of severe malnutrition or kwashiorkor

Positive urine drug screen (Groups 1 and 2 only)

Use of rifampicin and/or moxifloxacin within 1 week prior to 
the first dose of IMP and/or any prior or concurrent use 
bedaquiline

Lansky Play Performance Score < 50 or Karnofsky Score < 


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
Administered an IMP within 1 month prior to Visit 1 
other than delamanid given as IMP in Trial 232

Pregnant, breast-feeding, or planning to conceive or 
father a child within the study timeframe described in the 
informed consent form
50

Administered an IMP within 1 month prior to Visit 1 other 
than delamanid given as IMP in Trial 232

Pregnant, breast-feeding, or planning to conceive or father a 
child within the timeframe described in the informed consent 
form (Groups 1 and 2 only)
Investigational 
Medicinal 
Product, Dose, 
Dosage 
regimen, 
Formulation, 
Mode of 
Administration
:
Delamanid 50 mg oral tablets provided in blister cards and 
administered orally. 

Dose for Group 1 (ages 12 to 17 years) will be delamanid 
100 mg BID PO with meals for 180 days.  

Dose for Group 2 (ages 6 to 11 years) will be delamanid 50 
mg BID PO with meals for 180 days.
OBR is generally comprised of 4 classes or more of first-line 
(other than isoniazid [INH] and rifampicin) and second-line anti-
TB medications to which the patient’s strain of Mycobacterium 
tuberculosis (MTB) has confirmed or likely susceptibility based 
on previous treatment history and epidemiologic and clinical 
factors.
3) Fluoroquinolone class: preferred order of selection:   
levofloxacin, gatifloxacin > ofloxacin (Gatifloxacin to be used 
with caution, secondary to rare but severe side effect of 
dysglycemia; moxifloxacin causes QT interval prolongation and 
therefore will not be used in this trial; and ciprofloxacin is not 
recommended for use in this trial because of poor efficacy).  
Delamanid 50-mg adult formulation tablets administered orally 
for 6 months to Groups 1 and 2:

Group 1 (ages 12 to 17 years, inclusive) -
100 mg (2 x 50-mg tablet) BID

Group 2 (ages 6 to 11 years, inclusive) -
50 mg (1 x 50-mg tablet) BID 
Delamanid pediatric dispersible tablets admixed with water and 
administered orally as an extemporaneous suspension to Groups 3 
and 4 for 6 months:

Group 3 (ages 3 to 5 years, inclusive) -
25 mg (1 x 25-mg tablet) BID

Group 4 (ages birth to 2 years, inclusive) -
dose to be determined
OBR generally comprises 4 or more classes of first-line (other than 
isoniazid and rifampicin) and second-line anti-TB medications to 
which the patient’s strain of MTB has suspected or documented 
susceptibility based on previous treatment history and 
epidemiologic and clinical factors.  
3) Fluoroquinolone class; preferred order of selection:  
moxifloxacin, levofloxacin, gatifloxacin > ofloxacin (gatifloxacin to 
be used with caution secondary to rare but severe side effect of 
dysglycemia; ciprofloxacin not recommended for use).  
Moxifloxacin causes QT interval prolongation and should not be 
used in this trial


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Synopsis 
(Criteria for 
Evaluation)
The secondary criteria for assessment in this trial are:
• Pharmacokinetics/Phamacodynamics: Time-matched ECG and 
blood samples for PK/PD analysis for changes in QTc interval 
as a function of DM-6705 plasma concentrations 
• Efficacy: assessed by results of chest radiography (for patients 
with pulmonary disease); change in body weight and height 
measurements; and evaluation of TB symptoms.  In addition, 
sputum culture conversion (for culture-positive patients) will be 
assessed in patients who are able to produce sputum (or provide 
other biological specimens) for microbiological evaluation 
according to the requirements of the National TB Program.
The secondary criteria for evaluation in this trial are:
•
Pharmacokinetics/Pharmacodynamics:  ECG and blood samples 
for PK/PD analysis for changes in QTc as a function of delamanid
and DM-6705 plasma concentrations 
•
Efficacy:  evaluated on the basis of results of chest radiography 
(for patients with pulmonary disease); change in body weight and 
height measurements; and evaluation of TB symptoms.  In 
addition, sputum culture conversion (for culture-positive patients) 
will be assessed in patients who are able to produce sputum (or 
provide other biological specimens) for microbiological evaluation 
according to the requirements of the national TB program
•
Palatability:  The palatability of the delamanid pediatric 
formulation (Groups 3 and 4 only) will be assessed using an age-
appropriate visual hedonic scale and clinical assessment
Synopsis 
(Endpoints)
The secondary endpoints in this trial are:
•
Pharmacokinetics/Pharmacodynamics: PK/PD analysis for 
changes in QTc as a function of DM-6705 plasma 
concentrations.
The secondary endpoints in this trial are:
•
Pharmacokinetics/Pharmacodynamics: PK/PD analysis for 
changes in QTc as a function of delamanid and DM-6705 plasma 
concentrations.
Synopsis 
(Statistical 
Methods)
No power calculation was performed for this trial because of the 
limited number of patients expected to be enrolled in the 
population of interest (i.e. pediatrics). No formal statistical 
analysis is planned due to the small sample sizes; all statistical 
presentations will be descriptive. The number of patients enrolled 
should be at least 6 per age and dose group.
No power calculation was performed for this trial because of the 
limited number of patients expected to be enrolled in the population of 
interest (ie, pediatrics).  No formal statistical analysis is planned due to 
the small sample sizes; all statistical presentations will be descriptive.  
Synopsis
Trial Duration
The trial duration per patient (Screening, Baseline, Treatment, 
Post Treatment, and Follow-up Periods) will be 760 days 
including the following: 30-day Screening period, 182-day 
Treatment period, 56-day Post-treatment period, and a 492-day 
follow-up period (127-day from the last Post-treatment period, 
incorporating a 6 month post last delamanid dose follow-up visit 
and additional 365-day treatment outcome follow up period from 
the last follow up visit or until treatment for MDR-TB is 
completed or discontinued, whichever comes first).  
The trial duration per patient will be up to 760 days including the 
following: 30-day screening period, 182-day treatment period, 56-
day post-treatment period, additional follow-up period through 
Day 365 (ie, 6 months after the last delamanid dose), and 
treatment outcome follow-up at Day 730 (Month 24) + 2 months (ie, 
1 year after the Day-365 follow-up visit).  
Section 1 
through 1.4.2
Minor editorial and content updates, including references.


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Section 1
Tuberculosis Incidence
In 2011, the estimated global incidence was 8.8 million cases.  
Deaths among HIV negative persons were 1.1 million and 
among HIV infected persons were 0.35 million.  It was 
estimated that Asia (55%) and Africa (30%) accounted for 
most cases of TB.  This contrasts to the number of cases that 
were estimated to have occurred in the Eastern Mediterranean 
Region (7%); the European Region (4%); and in the Americas 
(3%).  During that year, the 5 countries with the highest 
burden included: India (1.6 to 2.4 million), China (1.1 to 1.5 
million), South Africa (0.40 to 0.59 million), Nigeria (0.37 to 
0.55 million), and Indonesia (0.35 to 0.52 million).9  India 
and China alone accounted for 35% of estimated cases. 
Although the overall global incidence of TB is falling, the 
number of incident cases in the last few years has remained 
relatively stable due to population increases.  Further, the 
overall annual incidence of TB in high income countries 
remains relatively low.
Tuberculosis Incidence
In 2012, the estimated global incidence of TB was 8.6 million 
cases.  Deaths among HIV negative persons were 1.0 million 
and among HIV infected persons were 0.32 million.  The 
majority of cases in 2012 were in Southeast Asia (29%), Africa 
(27%) and the Western Pacific Region (12%). India (26%) 
and China (12%) were the individual countries with the 
highest proportion of 
cases.{+WHO_TB_Global_Report_2013}


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Section 1
Multidrug-resistant and Extensively Drug-resistant 
Tuberculosis
In addition to the effects of the global HIV epidemic, the 
emergence of MDR-TB or TB caused by strains of MTB 
resistant to at least INH and rifampicin, has further 
complicated global efforts to control the TB epidemic.  
Approximately 500,000 cases of MDR-TB occur in the world 
annually, representing nearly 5% of the world’s annual TB 
burden.10  The estimated prevalence of MDR-TB is 1.5 
million cases and the annual incidence is 500,000 cases (60% 
new cases, 40% retreatment).  The 4 countries with the largest 
number of cases of MDR-TB in 2008 were China (100,000), 
India (99,000), the Russian Federation (38,000), and South 
Africa (13,000).9  In some countries, such as Latvia and Peru, 
where comprehensive TB control measures have been 
established, including the WHO-recommended DOTS 
strategy and program activities to address the diagnosis and 
treatment of MDR-TB, the prevalence of MDR-TB has 
decreased.11  However, the prevalence of MDR-TB continues 
to increase in many regions where these measures have not 
been implemented and in regions where the prevalence of 
HIV is high.
Patients with MDR-TB require longer treatment, usually 18 to 
24 months, compared with 6 to 8 months for patients with 
drug-susceptible tuberculosis (DS-TB).  Moreover, and the 
so-called “second-line” drugs used to treat MDR-TB are less 
potent and more toxic than those for DS-TB.12  At least 4 
medications from the various classes of second-line anti-TB 
drugs to which a given MDR-TB patient’s disease is 
susceptible or likely to be susceptible should be used in 
combination for MDR TB treatment.12  Some data suggest 
that at least 5 different medications should be used to 
optimize the chance for a successful treatment 
Multidrug-resistant and Extensively Drug-resistant Tuberculosis
In addition to the effects of the global HIV epidemic, the 
emergence of MDR-TB or TB caused by strains of MTB 
resistant to at least isoniazid and rifampicin has further 
complicated global efforts to control the TB epidemic.  
Approximately 450,000 people developed MDR-TB globally in 
2012 and there were an estimated 170,000 deaths from MDR-
TB.  There were 94,000 MDR-TB patients detected in 2012; 
84,000 of those were confirmed to have resistance to 
rifampicin and isoniazid and a further 10,000 were found to 
have rifampicin (RIF) resistance by GeneXpert MTB/RIF 
(Cepheid, Sunnyvale, CA).{+WHO_TB_Global_Report_2013}  
The highest concentrations of MDR-TB are found in Eastern 
Europe and Central Asia where the percentage of new TB 
cases that are multidrug resistant (MDR) may reach 20% and 
the percentage of those previously treated for TB may reach 
50%.{+WHO_TB_Global_Report_2013}


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outcome.13,14,15  Medications from the fluoroquinolone class of 
drugs and from the injectable classes – either an aminoglycoside or 
a cyclic peptide - as well as any remaining first-line medications to 
which a given patient’s disease is susceptible are integral to an 
optimized treatment regimen for MDR TB.12,13,14,16  Under the 
best of programmatic conditions, the cure rates achievable for 
MDR-TB, as demonstrated by studies of treatment outcomes for 
patient cohorts, are in the range of only 60% to 70%.17,18  In 
contrast, cure rates for drug susceptible TB in well- performing 
programs often exceed 90%.19
Section 1.3.2
In MDR-TB patients receiving delamanid 100 mg and 200 mg 
BID for 2 months, delamanid exposure reached steady-state 
after 2 weeks (38 hour t1/2), and metabolite exposure 
continued to increase.  On Day 56, after the 200-mg BID and 
200 mg BID doses, delamanid Cmax was 414 (39.9%) ng/mL 
and 611 (35.6%) ng/mL, respectively, and AUC0-24h was 
7925 (37.5%) ng•h/mL and 11,837 (33.6%) ng•h/mL, 
respectively.
In MDR-TB patients in Trial 204 receiving delamanid 100 mg and 
200 mg BID for 2 months, delamanid exposure reached steady 
state after 2 weeks (38 hour t1/2), and metabolite exposure 
continued to increase.  On Day 56, after the 100-mg BID and 200 
mg BID doses, delamanid Cmax was 414 (39.9%) ng/mL and 611 
(35.6%) ng/mL, respectively, and AUC0-24h was 7925 (37.5%) 
ng•h/mL and 11,837 (33.6%) ng•h/mL, respectively.
Section 1.3.2
Trial 242-07-208 demonstrated that in general, steady-state 
exposure was reached by 8 weeks of dosing for DM-6705 and 
by 8 to 14 weeks of dosing for the other metabolites.  
PK/PD analysis for QTc prolongation indicated that DM-
6705, in agreement with human ether-à-go-go-(hERG) 
inhibition potential and exposure, contributed to the QTc 
prolonging effect.  This analysis, conducted in all Phase 2 
trials, allowed the estimation of the maximal QTc effect at 
DM-6705 Cmax.  The most accurate PK/PD analysis (Trial 
204) predicted a maximal QTc effect of 13.7 msec (14.9 msec 
upper bound) and 19.4 msec (20.9 msec upper bound) after 
doses of delamanid 100 mg BID and 200 mg BID plus OBR, 
respectively.111
From the EBA and clinical efficacy trials, it appears that the 
minimal exposure (AUC0 24h) of delamanid for efficacy is 
approximately 2500 ng•h/mL; the effect appears to be 
maximal at delamanid 100 mg BID exposure.  Additional 
information may be found in the IB.1
Trial 208 demonstrated that, in general, steady-state exposure was 
reached by 8 weeks of dosing for DM-6705 and by 8 to 14 weeks 
of dosing for the other metabolites.  
PK/PD analysis of delamanid and DM-6705 plasma 
concentrations as a function of QTc changes were performed.  The 
results indicated that the predicted changes were similar to the 
observed increases in QTc.
Additional information may be found in the IB.{+IB_ed_10}
Section 1.4.1
As of 31 January 2012, 887 subjects and patients had been 
exposed to delamanid in clinical trials.3  Of these 887, 422 
were healthy subjects, 60 were patients with uncomplicated 
As of 26 Mar 2014, 887 adult subjects have been exposed to 
oral doses of delamanid in 17 completed trials in Japan, 
China, South Africa, Peru, Korea, Philippines, Egypt, the 


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DS TB, 395 were patients with MDR-TB, and 10 were 
patients with MDR-TB refractory to conventional therapy.  In 
total, 18 clinical trials involving delamanid have been carried 
out worldwide: 4 in multiple countries; 4 in the United States 
(US); 4 in the United Kingdom; 2 in Japan; 2 in China; and 2 
in South Africa.  One of the trials is currently ongoing in 
multiple countries.  Also, one observational study (Trial 242-
10-116) which follows patients for long-term outcomes who 
were enrolled in Trial 242 07-204 (also referred to as Trial 
204)103, Trial 242-07-208 (also referred to as Trial 208)104, 
or Trial 242-08-210105 was completed.  No safety data were 
collected and no delamanid was administered in Trial 242-10-
116.
In Trial 242-05-101, single oral doses of delamanid up to a 
maximum of 400 mg administered after a high-fat meal were 
well tolerated in healthy subjects.100  Similarly, 10 days of 
repeated dosing with delamanid after a standard meal was also 
well tolerated in healthy subjects.100 102  There were no 
serious or severe adverse events (AEs), and no subjects were 
withdrawn as a result of AEs.  Of AEs reported in 3 or more 
subjects, only headache (12%) and abdominal pain (7%) 
occurred more frequently with delamanid than with placebo 
(there were no occurrences of either event with placebo).  
Headache (delamanid, 42%; placebo, 25%) and dizziness 
(delamanid, 14%; placebo, 0%) were among the most 
common AEs reported by subjects who received multiple 
doses of delamanid up to 400 mg daily for 10 days.  There 
were no clinically significant changes in QTc interval 
duration.  
European Union, and the United States.  Of these 887 adult 
subjects, 422 were healthy subjects, 60 were patients with 
uncomplicated DS-TB, 395 were patients with MDR-TB, and 
10 were patients with MDR-TB refractory to treatment.  Of 
these 887 adult subjects, 791 subjects (338 healthy subjects, 48 
patients with uncomplicated DS-TB, 395 patients with MDR-
TB, and 10 patients with MDR-TB refractory to treatment) 
have been exposed to oral doses of delamanid tablets (ie, the 
modified spray-dried tablet formulation).  Delamanid is well 
tolerated by healthy adult subjects and adult patients with 
TB.{+IB_ed_10}  One observational study (Trial 242-10-116) 
also was conducted that follows long-term outcome patients 
who were enrolled in Trial 204, Trial 208, or Trial 210.  No 
safety data was collected and no delamanid was administered 
in Trial 242-10-116.  
In Trial 242-05-101, single oral doses of delamanid up to a 
maximum of 400 mg administered after a high-fat meal were 
well tolerated in healthy subjects; delamanid was also well 
tolerated with 10 days of repeated dosing after a standard 
meal in healthy subjects.{+CSR_242_05_101}  There were no 
serious adverse events (SAEs) and no severe adverse events 
(AEs), and no subjects were withdrawn as a result of AEs.  
Section 1.4.1
Results were similar for delamanid 200 mg BID + OBR 
compared with placebo + OBR for the incidence of QT 
interval prolongation (13.1% vs 3.8%), but the incidence of 
chest pain was not 5 percentage points greater than placebo + 
OBR (8.8% vs 4.4%).  
QT prolongation (13.1% vs 3.8%) was the only TEAE 
reported at an incidence of > 5 percentage points more in the 
delamanid 200 mg BID + OBR group than in the placebo + 
OBR group; the incidence of chest pain was similar between 
groups (8.8% vs 4.4%).  
Section 1.4.1
Drug exposure did not increase with these higher doses, 
apparently due to absorption and limited increases in 
concentration.
Drug exposure did not increase with these higher doses, 
apparently due to lack of further absorption and limited increases 
in concentration.


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Section 1.4.1
As of 31 Jan 2012, in the phase 3 Trial 242-09-213, a 
randomized, double-blind, and placebo-controlled conducted 
in patients to determine the safety, PK, and efficacy of 
delamanid plus OBR versus placebo in patients with MDR-
TB, there were no serious TEAEs, no TEAEs leading to 
discontinuation, and no deaths.  This trial was conducted in 
patients with MDR-TB who had previously been treated in 
other delamanid trials.
As of 31 Jan 2014 in Trial 242-09-213, the ongoing phase 3, 
randomized, double-blind, and placebo-controlled trial 
conducted in MDR-TB patients to determine the safety, PK, and 
efficacy of delamanid plus OBR versus placebo plus OBR, 
enrollment was complete and 511 patients had begun blinded 
treatment.  Three deaths had been reported, 65 patients had 
reported SAEs, and 8 patients had discontinued IMP due to 
TEAEs.{+IB_ed_10} 
Section 1.4.2
The design of treatment regimens for MDR-TB is highly 
complex.  Often it is empiric in the initial stages of treatment 
until full information on drug susceptibility testing is 
available on the MTB isolate to tailor a patient’s regimen, the 
patient’s previous treatment history for TB, information on 
drug resistance patterns of known MDR-TB patients with 
whom a given patient has been in close contact, and available 
information on HIV status.  Treatment is generally divided 
into an initial intensive phase, which is focused on achieving 
sputum culture conversion (SCC) from positive growth of 
MTB to a negative culture as soon as possible.  
Thereafter, the continuation phase of treatment − the part 
more readily delivered in an ambulatory setting – ensues, and 
a full treatment course can last for 20 to 24 months; 
occasionally some patients are successfully treated for less 
than 18 months.
The design of treatment regimens for MDR-TB is highly 
complex.  Often it is empiric in the initial stages of treatment 
until full information on drug susceptibility testing of the 
clinical isolate is available to tailor a patient’s regimen.  Up 
until that point, the patient’s previous treatment history for 
TB, information on drug resistance patterns of known MDR-
TB patients with whom a given patient has been in close 
contact, and the patient’s  HIV status are used to guide the 
choice of anti-TB drugs.  Treatment is generally divided into 
an initial intensive phase, which is focused on achieving 
sputum culture conversion (SCC) from positive growth of 
MTB to a negative culture as soon as possible.  
Thereafter, the continuation phase of treatment − the part 
more readily delivered in an ambulatory setting –ensues, and a 
full treatment course can last for 24 months.
Section 1.4.2
Given the high proportion of patients with MDR-TB whose 
disease does not resolve with available treatment, and that 
many of them die, it is clear that new medications that have 
potent activity against MDR-TB are urgently needed to 
improve the outcome of this patient group and to reduce the 
risk of further global spread of MDR-TB.
Given the high proportion of patients with MDR-TB whose 
disease does not resolve with available treatment, and that many of 
them die, it is clear that new medications that have potent activity 
against MDR-TB are urgently needed to improve the outcome of 
this patient group and to reduce the risk of further global spread of 
MDR-TB.  With the advent of new medications for MDR-TB, 
new cotoxicities may be encountered.  For example, delamanid, 
as well as bedaquiline, moxifloxacin, and clofazimine, have been 
associated with QT prolongation and, in most instances, the 
combined QTcF prolongation of 2 or more of these drugs has 
not yet been 
characterized.{+Sirturo_pkg_insert}{+Trial_213_MMP}
Section 2.1
Delamanid has been extensively studied in healthy adults and 
in patients with both uncomplicated TB and with MDR-TB.  
Delamanid has been extensively studied in healthy adults and in 
patients with both uncomplicated TB and with MDR-TB.  


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Delamanid has shown low toxicity and good tolerability in all 
populations studied.  For adults, marketing authorization in 
the European Union (EU) is being sought for the use of 
delamanid with OBR during the 6 month intensive phase of 
OBR treatment.  However, until Trial 232, delamanid had not 
been studied in the pediatric population.  
Delamanid has shown low toxicity and good tolerability in all 
populations studied.  For adults, marketing authorization has 
been obtained in the European Union, Japan, and Korea for 
the use of delamanid with OBR during the 6 month intensive 
phase of OBR treatment.  However, until Trial 232, delamanid 
had not been studied in the pediatric population.  
Section 2.1
Both Trial 232 and this Trial 233 are age de-escalation trials 
designed to study the safety, tolerability, and PK of delamanid 
in four pediatric age groups:
Group 1:  Adolescents 12 to 17 years (100 mg BID)
Group 2:  Children 6 to 11 years (50 mg BID)
Group 3:  Children 3 to 5 years (25 mg BID and 50 mg BID)
Group 4:  Newborns and infants 0 to 2 years (5 mg BID and 
25 mg BID)
The present protocol for Trial 233 outlines the trial 
specification in children and adolescents ages 6 to 17 years.  
Younger age groups (Group 3, [3 to 5 years] and Group 4, [0 
to 2 years]) will be enrolled when the pediatric formulation 
becomes available.  Details describing Groups 3 and 4 will be 
included in an amendment to this protocol.
Delamanid plasma concentrations in the pediatric population 
will be described by POPPK analysis of the data collected in 
trials 232 and 233. 
In addition, a PK/PD analysis will be performed for changes 
in QTc as a function of DM-6705 plasma concentrations 
throughout Trials 232 and 233.  
The safety and PK data from each dose group in Trial 232 
will be analyzed before initiation of enrollment in the next 
younger group.  The patients in each group will then be 
sequentially enrolled into this Trial 233 six-month treatment 
extension trial to receive the dose determined from Trial 232 
and to evaluate the safety, tolerability, PK, and efficacy of 
delamanid during the extended time period planned in this 
trial for treatment of MDR-TB.  To be eligible for Trial 233, 
all patients must rollover from Trial 232 within 30 days of 
completing that trial.
Both Trial 232 and Trial 233 are age de-escalation trials in 
which pediatric patients will be enrolled in 4 age groups:  
adolescents ages 12 to 17 years, inclusive (Group 1); children 
ages 6 to 11 years, inclusive (Group 2); children ages 3 to 5 
years (Group 3); and infants ages birth to 2 years (Group 4)
Delamanid plasma concentrations in the pediatric population will 
be analyzed using a population pharmacokinetics (POPPK) 
approach of the data collected in Trials 232 and 233. 
In addition, a PK/PD analysis will be performed for changes in 
QTc as a function of delamanid and DM-6705 plasma 
concentrations of the data collected in Trials 232 and 233.  
Patients in each age group will be sequentially enrolled into 
this 6-month treatment extension trial (Trial 233) to evaluate 
the safety, tolerability, PK, and efficacy of delamanid during 
the extended time period planned in this trial for treatment of 
MDR-TB.  To be eligible for Trial 233, all patients must 
rollover within 30 days of completing Trial 232.


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Section 2.2
Adolescents (ages 12 to 17 years) will be given delamanid at 
the adult dose, which will be delamanid 100 mg BID; children 
(ages 6 to 11 years) will be given half the adult dose, which 
will be delamanid 50 mg BID.  Delamanid will be given as 
delamanid 50 mg tablets.
Dosing in children younger than those in this trial will be 
defined based upon safety and PK findings in Trial 232.
Children 6 to 17 years, inclusive, will receive the delamanid 
50-mg tablet adult formulation.  Adolescents (12 to 17 years) 
will be given delamanid at the adult dose, 100 mg BID, while 
children 6 to 11 years will be given one half of the adult dose, 
50 mg BID.
Younger children (ages birth to 5 years, inclusive) will be 
given pediatric dispersible tablets admixed with water and 
administered orally as an extemporaneous suspension.  The 
delamanid dose for children ages 3 to 5 years, inclusive (Group 
3) will be 25 mg BID.  The delamanid dose for children ages 
birth to 2 years, inclusive (Group 4) will be confirmed using 
the PK, safety, and tolerability findings in the older age groups 
and based on the bioavailability of the pediatric formulation.
Section 2.3
The primary objectives of this trial are:
• Safety and tolerability: To evaluate the long-term safety and 
tolerability of delamanid and its metabolites in combination 
with an OBR during a 6-month treatment period in pediatric 
patients with MDR-TB for the age-specific delamanid doses 
determined in Trial 232.
• Pharmacokinetics: To report delamanid and metabolite 
plasma concentrations at each visit day by age groups and 
to conduct POPPK of delamanid when delamanid is 
administered in combination with an OBR during a 6-month 
treatment period in pediatric patients with MDR TB.
The secondary objectives are: 
• To evaluate the PK/PD relationship of the metabolite DM-
6705 plasma concentrations and QTc prolongation when 
delamanid is administered in combination with OBR during 
a 6 month treatment period in pediatric patients with MDR-
TB
• Efficacy: To evaluate the efficacy of delamanid when 
administered in combination with an OBR during a 6 month 
treatment period in pediatric patients with MDR-TB
The primary objectives of this trial are:
• To evaluate the long-term safety and tolerability of delamanid 
and its metabolites in combination with an OBR during a 6-
month treatment period in pediatric patients with MDR-TB for 
the age-specific delamanid doses determined in Trial 232
• To report delamanid and metabolite plasma concentrations at 
each visit day by age groups and to conduct a population 
pharmacokinetics (POPPK) analysis of delamanid when 
delamanid is administered in combination with an OBR during a 
6-month treatment period in pediatric patients with MDR TB
The secondary objectives are: 
• To evaluate the PK/PD relationship of delamanid and its 
metabolite DM-6705 plasma concentrations and change in QTc  
when delamanid is administered in combination with OBR 
during a 6 month treatment period in pediatric patients with 
MDR-TB
• To evaluate the efficacy of delamanid when administered in 
combination with an OBR during a 6 month treatment period in 
pediatric patients with MDR-TB
• To determine the palatability of the delamanid pediatric 
formulation
Section 3.1
At least 12 male and female patients will be enrolled to obtain 
a minimum of 12 completed patients, at least 6 in each age 
group.  Patients will be assigned to one of two treatment 
Delamanid will be administered twice daily for 182 days.  The 
trial will be conducted sequentially in 4 groups of pediatric
patients:


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groups based on age:
Group 1 (patients with MDR-TB age 12 to 17 years) 
Delamanid 100 mg BID for 6 months plus OBR  
Group 2 (patients with MDR-TB age 6 to 11 years) 
Delamanid 50 mg BID for 6 months plus OBR

Group 1 (ages 12 - 17 years, inclusive) will receive adult 
formulation delamanid 100 mg BID + OBR (n = 6)

Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive 
pediatric formulation delamanid 25 mg BID + OBR (n 
= 12)

Group 4 (ages birth - 2 years, inclusive) will receive 
pediatric formulation delamanid BID  + OBR (n = 12) 
(dose will be determined after data from at least 6 
subjects from Group 3 in Trial 232 is available)
Screening Period (Day -30 to -1): Study data will either be taken 
from screening or Day 10 of Trial 232 or will be performed 
during the post-Trial 232 thirty (30) - day screening period for 
Trial 233, as described in the Schedule of Assessments. 
Baseline (Day 0):  Inclusion/exclusion criteria, physical 
examination and safety assessments including lab tests, signs 
and symptoms of tuberculosis (TB), audiometry and visual 
assessments, vital signs, height, weight, percentiles for age, 
body mass index (BMI), and ECG as described in the 
Schedule of Assessments.  OBR administration as prescribed 
by investigator, and recording of concomitant medications.  
Treatment Outcome Follow-up (Day 730 (M24) or until 
treatment for MDR-TB is completed or discontinued, 
whichever comes first): Collection of treatment outcome 
information as routinely documented in the patient medical 
records or in a National TB Program.
Screening Period (Day −30 to −2):  Study data will either be taken 
from screening or Day 10 of Trial 232 or will be performed during 
the post-Trial 232 thirty (30)- day screening period for Trial 233, 
as described in the Schedule of Assessments 
Baseline (Day −1):  Inclusion/exclusion criteria, physical examination, 
and safety assessments including laboratory tests, signs and 
symptoms of tuberculosis (TB), audiometry and visual 
assessments, vital signs, height, weight, percentiles for age, body 
mass index (BMI), and ECG as described in the Schedule of 
Assessments.  OBR administration as prescribed by investigator, 
and recording of concomitant medications  
Treatment Outcome Follow-up (Day 730 [Month 24] + 2 months:  
Collection of treatment outcome information as routinely 
documented in the patient medical records or in a national TB 
program
Figure 3.1-1
Updated to include Groups 3 and 4


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Section 3.2
Patients will be assigned by age group to receive one of the 
following treatments for 182 days.  
1.
Group 1 (ages 12 to 17 years):  delamanid 100 mg (2 x 50 
mg tablets) BID PO plus OBR 
2.
Group 2 (ages 6 to 11 years):  delamanid 50 mg (1 x 50 
mg tablet) BID PO plus OBR 
It should be noted that patient age group and dosing will be 
determined at the time of enrollment into Trial 232 and will not 
change during rollover into Trial 233.
Patients will be assigned by age group to receive one of the following 
treatments for 182 days:  
7)
Group 1 (12 to 17 years, inclusive):  adult formulation 
delamanid 100 mg BID (administered as 2 x 50-mg tablets 
BID) + OBR
8)
Group 2 (6 to 11 years, inclusive):  adult formulation 
delamanid 50 mg BID (administered as 1 x 50-mg tablet 
BID) + OBR
9)
Group 3 (3 to 5 years, inclusive):  pediatric formulation 
delamanid 25 mg BID (administered as 1 x 25-mg tablet 
BID) + OBR
10) Group 4 (birth to 2 years, inclusive):  pediatric formulation 
delamanid  + OBR (dose will be determined after data from 
at least 6 subjects from Group 3 in Trial 232 are available)
Patient age group and dosing will be determined at the time of 
enrollment into Trial 232 and will not change during rollover into 
Trial 233.
Section 3.2.1
All delamanid doses will be given PO as the appropriate number 
of 50 mg tablets depending on the age group, as described in 
Section 3.2. 
All Group 1 patients who complete screening will receive 100 mg 
delamanid (2 x 50 mg tablets) BID for 6 months.  All Group 2 
patients who complete screening will receive 50 mg delamanid (1 
x 50 mg tablet) BID for 6 months.  
According to the country-specific DOT plan, one dose per day for 
a minimum of 5 days per week will be given under direct 
observation.  It is recommended that all delamanid doses be 
administered under fed conditions in the morning and evening.  It 
All doses for Groups 1 and 2 will be given orally as the appropriate 
number of 50-mg adult formulation delamanid tablets (Section
3.2).  Adult formulation delamanid tablets should be taken with 
water.  Children in Groups 3 and 4 will be given delamanid as an 
extemporaneous suspension using the delamanid pediatric 
dispersible tablet formulation.
According to the country-specific DOT plan, one dose per day for a 
minimum of 5 days per week will be given under direct observation.  It 
is recommended that all delamanid doses be administered under fed 
conditions in the morning and evening.  It is also recommended that 
delamanid be dosed within 30 minutes of the start of a meal, if 
possible.  Optimally, OBR medications should be given at least 1 hour 


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is also recommended that delamanid be dosed within 30 minutes 
of the start of a meal, if possible.  Each dose is to be taken with 
water. Optimally, OBR medications should be given at least 1 
hour prior to or 1 hour after dosing of delamanid.  The time of 
dosing with delamanid following the meal will be documented 
when patients are in the hospital or clinic or for regularly 
scheduled assessments or for observation.
prior to or 1 hour after dosing of delamanid.  The time of dosing with 
delamanid following the meal will be documented when patients are in 
the hospital or clinic or for regularly scheduled assessments or for 
observation.
Section 3.3.1
At least 12 male and female patients from 6 to 17 years of age, 
inclusive, who have successfully completed Trial 232, who are 
receiving OBR for confirmed or presumptive MDR-TB will be 
enrolled in two sequential age groups.  These patients (and age 
groups) will be the same groups who successfully completed Trial 
232:  Group 1 (ages 12 to 17 years) will contain a minimum of six 
patients and must include at least two but no more than five 
females.  Group 2 (ages 6 to 11 years) will also contain a 
minimum of six patients and will include both genders.
At least 36 males and females ages birth to 17 years, inclusive, who 
have successfully completed Trial 232 and who are receiving OBR 
for confirmed or presumptive MDR-TB will be enrolled in 4 
sequential age groups.  These patients (and age groups) will be the 
same groups who successfully completed Trial 232:  Group 1 (ages 
12 to 17 years) will contain a minimum of 6 patients and must 
include at least 2 but no more than 5 females.  Group 2 (ages 6 to 
11 years, inclusive) will contain a minimum of 6 patients.  Group 3 
(ages 3 to 5 years, inclusive) and Group 4 (ages birth to 2 years, 
inclusive) each will contain a minimum of 12 patients. Groups 2, 3, 
and 4 will include both genders.
Section 3.4.1
When a screening informed consent form (ICF) is used for general 
health assessment prior to identifying or consenting candidates for 
this specific trial, the screening ICF/assent will also become part 
of this study’s file and the patient’s chart.  
If any patient should turn 18 years of age (or the age of adulthood, 
as specified by local laws or regulations) within 4 weeks prior to 
entry into Trial 233 or during Trial 233 participation, an ICF must 
be signed by the patient.  The patient shall be given a copy of the 
signed ICF and the original shall be kept on file by the 
investigator.  In addition to the English version of the ICF, the 
document may also be translated into local languages for use in 
When a screening informed consent form (ICF)/assent form is used for 
general health assessment prior to identifying or consenting candidates 
for this specific trial, the screening ICF/assent form will also become 
part of this study’s file and the patient’s chart.  
If any patient should turn 18 years of age (or the age of adulthood as 
specified by local laws or regulations) within 4 weeks prior to entry 
into Trial 233 or during Trial 233 participation, an ICF must be signed 
by the patient.  The patient shall be given a copy of the signed 
ICF/assent, and the original shall be kept on file by the investigator.  A 
patient who turns age 18 (or the age of adulthood as specified by 
local laws or regulations) during the study must sign an appropriate 


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this trial.  Translation with back-translation for confirmation will 
be utilized to ensure accuracy.
ICF/assent form for himself/herself at that time. In addition to the 
English version of the ICF/assent form, the document may also be 
translated into local languages for use in this study.  Translation with 
back-translation for confirmation will be used to ensure accuracy.
Table 3.4.2-1
1. Patient must have successfully completed Trial 232 and have 
and met all inclusion criteria for that trial
2. Male and female children
3. Age 6 to 17 years  
4. In two sequential cohorts of 12 to 17 years (Group 1) and 6 to 
11 years (Group 2)
5. Confirmed diagnosis of MDR-TB 
OR
Presumptive diagnosis of MDR-TB such that the treating 
physician has decided to treat the patient for MDR-TB who has 
one of the following:
-
Sputum smear positive for AFB
-
Clinical specimen (eg, CSF, pleural fluid, ascitic fluid, lymph 
node aspirate, or other tissue) suggestive of tuberculosis disease
-
Persistent cough lasting > 2 weeks
-
Fever, weight loss, and failure to thrive
-
Findings on recent chest radiograph consistent with TB
AND
-
Household contact with a person with known MDR-TB or with 
a person who died while appropriately taking drugs for sensitive 
TB
OR
-
On first-line TB treatment but with no clinical improvement
6. Negative urine pregnancy test for female patients who have 
reached menarche
7. Trial-specific written informed consent/assent obtained from a 
parent(s) or guardian or legally acceptable representative, as 
applicable for local laws prior to the initiation of any protocol 
required procedures. In addition, the subject must provide 
informed assent at screening and must be able to understand that 
he or she can withdraw from the trial at any time.  All informed 
consent/assent procedures must be in accordance with the trial 
IRB/EC and local regulatory requirements
1. Patient must have successfully completed Trial 232 and have and 
met all inclusion criteria for that trial
2. Male or female
3. Age birth to 17 years, inclusive
4. Confirmed diagnosis of MDR-TB,a,b ie, culture positive for MTB 
with isoniazid and rifampicin resistance on DST, or a positive 
rapid test demonstrating resistance to rifampicin alone or to 
rifampicin and isoniazid
OR
Presumptive diagnosis of pulmonary or extrapulmonary MDR-TBb 
such that the treating physician has decided to treat the patient for 
MDR-TBa who has one of the following:
-Clinical specimen (eg, cerebrospinal fluid, pleural fluid, ascitic fluid, 
lymph node aspirate, or other tissue) suggestive of tuberculosis disease
-Persistent cough lasting > 2 weeks
-Fever, weight loss, and failure to thrive
-Findings on recent chest radiograph (prior to Visit 1) consistent with 
TB
AND
-Household contact with a person with known MDR-TB or with a 
person who died while appropriately taking drugs for sensitive TB
OR
-On first-line TB treatment but with no clinical improvement
5. Negative urine pregnancy test for female patients who have reached 
menarche
6. Study-specific written informed consent/assent obtained from a 
parent/guardian or legally acceptable representative, as applicable for 
local laws prior to the initiation of any protocol-required procedures.  
In addition, for patients in Groups 1 and 2 or as required by local 


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AFB = acid-fast bacilli; CSF = cerebral spinal fluid; EC = Ethics 
Committee; IRB = Institutional Review Board; MDR TB = Multi-
drug resistant tuberculosis; TB = tuberculosis.
law, the patient must provide informed assent at screening and 
must be able to fully understand that he or she can withdraw from 
the study at any time.   
a Patients should be on OBR for at least 2 weeks prior to baseline 
assessments.
b Includes pre−XDR TB.
Table 3.4.3-1
10.
Positive urine drug screen
11.
Use of rifampicin or moxifloxacin within 1 week prior to 
the first dose of IMP
14.
Pregnant, breast-feeding, or planning to conceive or 
father a child within the study timeframe described in the 
informed consent form
10.
Positive urine drug screen (Groups 1 and 2 only)
11.
Use of rifampicin and/or moxifloxacin within 1 
week prior to the first dose of IMP
14.
Pregnant, breast-feeding, or planning to conceive or 
father a child within the timeframe described in the informed 
consent form (Groups 1 and 2 only)
Section 3.5.1.2
Delamanid and metabolite plasma concentrations will be measured 
during the treatment period at predose (0 hours) on Days 1, 56, 
154, and 182; and during the post-treatment period on Day 210 at 
the theoretical predose time when delamanid would have been 
administered. Delamanid and metabolite plasma concentrations 
will be measured at any time point on Days 14, 98, 189, 196, 203, 
and 238.  In addition, population PK (POPPK) analysis for 
delamanid plasma concentrations will be performed.
PK parameters from the population pharmacokinetic analysis, using 
data from this trial and from the -232 trial, will be reported.  
Section 3.5.2.1
PK/PD analysis to determine the relationship between DM-6705 
plasma concentrations and changes in QTc interval will be 
performed using the paired PK/PD assessments.
PK/PD analysis to determine the relationship between delamanid and
DM-6705 plasma concentrations and changes in QTc interval will be 
performed.
Section 3.5.2.3
New Section
3.5.2.3
Palatability
The palatability of the pediatric formulation will be assessed using 
an-age appropriate visual hedonic scale and clinical assessment.
Section 3.7
Each patient will participate in the trial for up to 760 days.  The 
trial will be comprised of the Screening Period (30 days); Baseline 
(Day 0); Treatment Period (182 days of delamanid plus OBR 
administration); Post-treatment Period (56 days with visits at Days 
189, 196, 203, 210, and 238 [Day 238 corresponds to 2-months 
post last delamanid dose]); and a Follow-up Period with a visit at 
6 months post last delamanid dose (Day 365) and additional 365-
day treatment outcome follow up period from the last follow up 
visit or until treatment for MDR-TB is completed or discontinued, 
whichever comes first).  Trial assessment time points are 
summarized in Table 3.7-1
Each patient will participate in the trial for up to 760 days.  The trial 
will comprise the screening period (29 days); baseline (Day −1); 
treatment period (182 days of delamanid plus OBR administration); 
post-treatment period (56 days with visits at Days 189, 196, 203, 210, 
and 238 [Day 238 corresponds to 2 months post last delamanid dose]); 
and a follow-up period with a visit at 6 months after the last delamanid 
dose (Day 365) and an additional 365-day treatment outcome follow-
up period from the last follow-up visit.  Trial assessment time points 
are summarized in Table 3.7-1.
Table 3.7-1
Modified to correspond with changes to Section 3.7.1 Schedule of 


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Assessments
Table 3.7-1 
footnotes
Updated to correspond with changes to the table and to clarify table 
content.
Section
3.7.1.1
3.7.1.1
Visit 1, Screening/Enrollment (Days -30 to -1)
For patients who elect to be rolled-over from Trial 232 into Trial 
233, the following procedures will either be collected from 
screening data for Trial 232, from Day 10 data of Trial 232, or will 
be assessed/performed within 30 days prior to Trial 233: 
The following information will be taken from screening data of 
Trial 232 and used as screening data for this Trial 233:
• Inclusion/exclusion criteria 
• Diagnosis of MDR-TB, confirmed or suspected  
• Demographic data 
• Signs and symptoms of TB
• Audiometry and visual assessments  
• Chest radiograph for confirmation of radiological picture 
compatible with TB.  Final official interpretation must be 
available prior to enrollment
• Laboratory assessments including HIV, hepatitis B surface 
antigen (HBsAG), anti hepatitis C virus (HCV) antibody, 
adrenocorticotropic hormone (ACTH), adrenal function (cortisol), 
thyroid function tests (T4 and thyroid stimulating hormone 
[TSH]), and C reactive protein testing
The following information will be taken from Day 10 data of Trial 
232 and used as screening data for this Trial 233:
• Complete physical examination
• 12-lead ECG
• Safety lab assessments including urinalysis, hematology and 
coagulation, and serum chemistry
The following information will be obtained during the screening 
period of this Trial 233 between Days -30 and -1:
• Informed consent/assent (may be completed prior to Day -30)
• Medical history
• Vital sign assessments (blood pressure [BP], HR, respiratory rate 
[RR], and body temperature) after the subject has been supine for 
≥ 3 minutes 
• Height,weight, and BMI
3.7.1.1
Visit 1, Screening/Enrollment (Days −30 to −2)
For patients who elect to be rolled over from Trial 232 into Trial 233, 
the following procedures will either be collected from screening data 
for Trial 232 or from Day 10 data of Trial 232, or will be 
assessed/performed within 30 days prior to Trial 233. 
The following information will be taken from the screening data of 
Trial 232 and used as screening data for this Trial 233:
• Inclusion/exclusion criteria 
• Diagnosis of MDR-TB, confirmed or suspected  
• Demographic data 
• Complete physical examination
• Signs and symptoms of TB
• Audiometry and visual assessments  
• Chest radiograph for confirmation of radiological picture compatible 
with TB 
• Laboratory assessments including serum chemistry, hematology 
and coagulation, urinalysis, HIV, hepatitis B surface antigen 
(HBsAg), antibody to hepatitis C virus (anti-HCV), 
adrenocorticotropic hormone (ACTH), adrenal function (cortisol), 
C-reactive protein (Groups 1 and 2 only), and thyroid function 
tests (T4 and thyroid stimulating hormone [TSH])
The following information will be taken from Day 10 data of Trial 232 
and used as screening data for this Trial 233: 
• 12-lead ECG
The following information will be obtained during the screening period 
of this Trial 233 between Days −30 and −2:
• Informed consent/assent (may be completed prior to Day −30)
• Medical history
• Vital signs assessments (blood pressure, heart rate, respiratory rate, 
and body temperature) after the subject has been in a supine or semi-
recumbent position for ≥ 3 minutes (as possible for Groups 3 and 4); 
height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)   


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• Date of birth and gender
• Percentiles for age
• Urine pregnancy test for all female subjects who have reached 
menarche
• Urine drug screen (as per Table 3.7-1)
• Record prior concomitant medications including prior 
concomitant anti-TB medications.  (Note: Patients will have been 
on OBR in Trial 232 for at least two weeks prior to baseline 
assessments)
• Record start date of menstrual period and/or date of last 
menstrual period (LMP)
• BMI and percentiles for age
• Date of birth and gender
• Urine pregnancy test for all female subjects who have reached 
menarche
• For Groups 1 and 2 only, urine drug screen (as per Table 3.7-1)
• Record prior concomitant medications including prior concomitant 
anti-TB medications.  (Note: Patients will have been on OBR in Trial 
232 for at least 2 weeks prior to baseline assessments)
• Groups 1 and 2 only, record date of menarche and/or date of last 
menstrual period
Section 3.7.1.2
3.7.1.2
Visit 2, Baseline, (Day 0)
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Baseline (Day 
0):
• Review of inclusion/exclusion criteria
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Height,weight, and BMI
• Percentiles for age
• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Three consecutive 12-lead ECGs.   
• Blood draw for clinical laboratory assessments (as per Table 3.7-
1): serum chemistry, hematology, coagulation, and full urinalysis 
• OBR administration, as prescribed by investigator
• Record concomitant medications including concomitant anti TB 
medications.
3.7.1.2
Visit 2, Baseline (Day −1)
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s electronic case report form (eCRF) for 
Baseline (Day −1):
• Review of inclusion/exclusion criteria
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital signs assessments (blood pressure, heart rate, respiratory 
rate, and body temperature) after the subject has been in a supine
or semi-recumbent position for ≥ 3 minutes (as possible for Groups 3 
and 4); height and weight; and measurement of head circumference 
for children in Group 4 (ages birth - 2 years, inclusive)
• BMI and percentiles for age
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Three consecutive 12-lead ECGs after the patient has been in a 
supine or semi recumbent position and at rest for ≥ 10 minutes (as 
possible for Groups 3 and 4)   
• Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, and urinalysis 
• OBR administration, as prescribed by investigator
• Record concomitant medications including concomitant anti TB 
medications
Section 3.7.1.3
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 1:
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Vital sign assessments (BP, HR, RR, and body temperature) 
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 1:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital signs assessments (BP, HR, RR, and body temperature) 


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after the subject has been supine for ≥3 minutes 
• Three consecutive 12-lead ECGs prior to blood draw for PK.  
Sequence should be ECG assessment, then blood draw for PK, 
then administration of delamanid 
• Blood draw (3 mL) for PK at predose (0 hours).
• Delamanid dispensed, if needed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice daily 
(morning and evening).
• Record AEs and IREs
• Record concomitant medications including concomitant anti TB 
medications.
after the subject has been in a supine or semi-recumbent position 
for ≥ 3 minutes (as possible for Groups 3 and 4).  Note: height and 
weight do not need to be measured at this visit
• Three consecutive 12-lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible for 
Groups 3 and 4) prior to blood draw for PK.  Sequence should be ECG 
assessment, then blood draw for PK, then administration of delamanid 
• Blood draw for PK at predose (0 hours) (see Section 3.7.4)
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
• Groups 3 and 4 only, palatability assessment of the delamanid 
pediatric formulation within 25 - 30 minutes postdose (see trial 
operations manual for details)
• Record AEs and IREs
• Record concomitant medications including concomitant anti TB 
medications
Section 3.7.1.4
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 14:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
•
Vital sign assessments (BP, HR, RR, and body 
temperature) after the subject has been supine for ≥3 minutes
•
Height,weight, and BMI
•
Blood draw (3 mL) for PK at any time point.
•
Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice daily 
(morning and evening).
•
Record AEs and IREs
•
Record concomitant medications including concomitant 
anti-TB medications.
•
Record start date of menstrual period and/or date of LMP
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 14:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body 
temperature) after the subject has been in a supine or semi-
recumbent position for ≥ 3 minutes (as possible for Groups 3 and 4); 
height and weight; and measurement of head circumference for 
children in Group 4 (ages birth - 2 years, inclusive)
•
BMI and percentiles for age
•
Blood draw for PK at any time point (see Section 3.7.4)
•
Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
•
Groups 1 and 2 only, record date of menarche and/or date of 
LMP
Section 3.7.1.5
For all treatment groups the following procedures will be 
For all treatment groups the following procedures will be conducted 


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conducted and/or recorded in the patient’s eCRF for Day 28:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
•
Vital sign assessments (BP, HR, RR, and body 
temperature) after the subject has been supine for ≥3 minutes 
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Blood draw for clinical laboratory assessments (as per 
Table 3.7-1): serum chemistry, hematology, coagulation, and full
urinalysis 
•
Three consecutive 12-lead ECGs.  Sequence should be 
ECG assessment then administration of delamanid. 
•
Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice daily 
(morning and evening).
•
Record AEs and IREs
•
Record concomitant medications including concomitant 
anti-TB medications.
and/or recorded in the patient’s eCRF for Day 28:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been in a supine or semi-recumbent position for ≥ 
3 minutes (as possible for Groups 3 and 4); height and weight
•
BMI and percentiles for age
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Blood draw for clinical laboratory assessments (as per Table 
3.7-1):  serum chemistry, hematology, coagulation, and urinalysis 
•
Three consecutive 12-lead ECGs after the subject has been 
in a supine or semi-recumbent position for ≥ 10 minutes (as possible 
for Groups 3 and 4).  Sequence should be ECG assessment then 
administration of delamanid 
•
Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
•
Groups 3 and 4 only, palatability assessment of the 
delamanid pediatric formulation within 25 - 30 minutes postdose (see 
trial operations manual for details)
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications
Section 3.7.1.6
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 42:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
•
Vital sign assessments (BP, HR, RR, and body 
temperature) after the subject has been supine for ≥3 minutes 
•
Height,weight, and BMI
•
Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice daily 
(morning and evening).
•
Record AEs and IREs
•
Record concomitant medications including concomitant 
anti-TB medications.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 42:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages 
birth - 2 years, inclusive) 
• BMI and percentiles for age
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)


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•
Record start date of menstrual period and/or date of LMP
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
• Groups 1 and 2 only, record date of menarche and/or date of LMP
Section 3.7.1.7
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 56:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
•
Vital sign assessments (BP, HR, RR, and body 
temperature) after the subject has been supine for ≥3 minutes 
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Blood draw for clinical laboratory assessments (as per 
Table 3.7-1): serum chemistry, hematology, coagulation, and full
urinalysis 
•
Three consecutive 12-lead ECGs.  Sequence should be 
ECG assessment then PK blood draw followed by administration 
of delamanid.
•
Blood draw (3 mL) for PK at predose (0 hours).
•
Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice daily 
(morning and evening).
•
Record AEs and IREs
•
Record concomitant medications including concomitant 
anti-TB medications.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 56:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight
• BMI and percentiles for age
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, and urinalysis 
• Three consecutive 12-lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible for 
Groups 3 and 4).  Sequence should be ECG assessment then PK blood 
draw followed by administration of delamanid
• Blood draw for PK at predose (0 hours) (see Section 3.7.4)
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
• Groups 3 and 4 only, palatability assessment of the delamanid 
pediatric formulation within 25 - 30 minutes postdose (see trial 
operations manual for details)
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
Section 3.7.1.8
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 70:
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Height, weight, and BMI
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 70:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been in a supine or semi-recumbent position for ≥ 
3 minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages 


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• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by
investigator).  Delamanid will be administered twice daily 
(morning and evening).
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications.
• Record start date of menstrual period and/or date of LMP
birth - 2 years, inclusive)
•
BMI and percentiles for age
•
Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications
•
Groups 1 and 2 only, record date of menarche and/or date 
of LMP
Section 3.7.1.9
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 84:
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
• Blood draw for thyroid function tests (T4 and thyroid 
stimulating hormone [TSH]) for patients taking ethionamide or 
PAS.
• Three consecutive 12-Lead ECGs.  Sequence should be ECG 
assessment then administration of delamanid.
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 84:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight
• BMI and percentiles for age
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, and urinalysis
• Blood draw for thyroid function tests (T4 and TSH) for patients 
taking ethionamide or PAS
• Three consecutive 12-lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible for 
Groups 3 and 4).  Sequence should be ECG assessment then 
administration of delamanid
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
Section 
3.7.1.10
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 98:
• Complete physical examination.  Please refer to the trial 
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 98:
• Complete physical examination.  Please refer to the trial Operations 


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Operations Manual for details on the assessments to be performed.
• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Height, weight, and BMI
• Blood draw (3 mL) for PK at any time point
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications.
• Record start date of menstrual period and/or date of LMP
Manual for details on the assessments to be performed
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages 
birth - 2 years, inclusive)
• BMI and percentiles for age
• Blood draw for PK at any time point (see Section 3.7.4) 
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
• Groups 1 and 2 only, record date of menarche and/or date of 
LMP
Section 
3.7.1.11
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 126:
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Height, weight, and BMI
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
• Three consecutive 12-Lead ECGs.  Sequence should be ECG 
assessment then administration of delamanid.
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications.
• Record start date of menstrual period and/or date of LMP
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 126:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages 
birth - 2 years, inclusive)
• BMI and percentiles for age
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, and urinalysis
• Three consecutive 12-lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible for 
Groups 3 and 4).  Sequence should be ECG assessment then 
administration of delamanid
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)


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• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
• Groups 1 and 2 only, record date of menarche and/or date of 
LMP
Section 
3.7.1.12
The following procedures will be conducted and/or recorded in the 
patient’s eCRF for Day 154:
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Height, weight, and BMI
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
• Three consecutive 12-Lead ECGs prior to blood draw for PK.  
Sequence should be ECG assessment, then blood draw for PK, 
then administration of delamanid. 
• Blood draw (3 mL) for PK at predose (0 hours).
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications.
• Record start date of menstrual period and/or date of LMP
The following procedures will be conducted and/or recorded in the 
patient’s eCRF for Day 154:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 ( ages 
birth - 2 years, inclusive)
• BMI and percentiles for age
• Signs and symptoms of TB
• Audiometry and visual assessments 
• Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, and urinalysis
• Three consecutive 12-Lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible for 
Groups 3 and 4) and prior to blood draw for PK.  Sequence should be 
ECG assessment, then blood draw for PK, then administration of 
delamanid. 
• Blood draw for PK at predose (0 hours) (see Section 3.7.4)
• Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening)
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
• Groups 1 and 2 only, record date of menarche and/or date of 
LMP
Section
3.7.1.13
Note:  Day 182 is the last day of delamanid dosing.  For all 
treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 182:
• Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be performed.
Note:  Day 182 is the last day of delamanid dosing.  For all treatment 
groups the following procedures will be conducted and/or recorded in 
the patient’s eCRF for Day 182:
• Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed


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• Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
• Height, weight, and BMI
• Percentiles for age
• Signs and symptoms of TB
• Chest radiograph
• Audiometry and visual assessments 
• Urine pregnancy test for all female subjects who have reached 
menarche
• Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, C reactive 
protein testing and full urinalysis
• Blood draw for adrenocorticotropic hormone (ACTH), and 
adrenal function (cortisol)
• Blood draw for thyroid function tests (T4 and thyroid 
stimulating hormone [TSH]) for patients taking ethionamide or 
PAS.
• Three consecutive 12-lead ECGs.  Sequence should be ECG 
assessment then PK blood draw followed by administration of 
delamanid.
• Blood draw (3 mL) for PK at predose (0 hours).
• Delamanid dispensed, if needed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice daily 
(morning and evening).  NOTE:  This is the last day of delamanid 
dosing.
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications.
• Record start date of menstrual period and/or date of LMP
• Vital sign assessments (BP, HR, RR, and body temperature) after the 
subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 (ages 
birth - 2 years, inclusive)
• BMI and percentiles for age
• Signs and symptoms of TB
• Chest radiograph
• Audiometry and visual assessments 
• Urine pregnancy test for all female subjects who have reached 
menarche
• Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, C-reactive protein (Groups 
1 and 2 only) testing and urinalysis
• Blood draw for ACTH and adrenal function (cortisol)
• Blood draw for thyroid function tests (T4 and TSH) for patients 
taking ethionamide or PAS
• Three consecutive 12-lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible for 
Groups 3 and 4).  Sequence should be ECG assessment then PK blood 
draw followed by administration of delamanid
• Blood draw for PK at predose (0 hours) (see Section 3.7.4)
• Delamanid dispensed, if needed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily (morning 
and evening).  NOTE:  This is the last day of delamanid dosing
• Groups 3 and 4 only, palatability assessment of the delamanid 
pediatric formulation within 25 - 30 minutes postdose (see trial 
operations manual for details)
• Record AEs and IREs
• Record concomitant medications including concomitant anti-TB 
medications
• Groups 1 and 2 only, record date of menarche and/or date of 
LMP
Section
3.7.1.14
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 189:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 189:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 


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•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Blood draw (3 mL) for PK at any time point
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
the subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight
•
BMI and percentiles for age
•
Blood draw for PK at any time point (see Section 3.7.4)
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 
medications
Section
3.7.1.15
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 196:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Blood draw (3 mL) for PK at any time point
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 196:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 
the subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight
•
BMI and percentiles for age
•
Blood draw for PK at any time point (see Section 3.7.4)
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 
medications


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3.7.1.16
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 203:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Blood draw (3 mL) for PK at any time point
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 203:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 
the subject has been in a supine or semi-recumbent position for ≥ 3
minutes (as possible for Groups 3 and 4); height and weight
•
BMI and percentiles for age
•
Blood draw for PK at any time point (see Section 3.7.4)
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 
medications
3.7.1.17
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 210:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Height, weight, and BMI
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and full urinalysis
•
Three consecutive 12-lead ECGs.  Sequence should be ECG 
assessment then PK blood draw at the theoretical predose.
•
Blood draw (3 mL) for PK at theoretical predose (0 hours).
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
•
Record start date of menstrual period and/or date of LMP
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 210:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 
the subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 
(ages birth - 2 years, inclusive)
•
BMI and percentiles for age
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Clinical laboratory assessments (as per Table 3.7-1):  serum 
chemistry, hematology, coagulation, and urinalysis
•
Three consecutive 12-lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible 
for Groups 3 and 4). Sequence should be ECG assessment then PK 
blood draw at the theoretical predose
•
Blood draw for PK at theoretical predose (0 hours) (see Section 
3.7.4)
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 
medications
•
Groups 1 and 2 only, record date of menarche and/or date of 
LMP


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3.7.1.18
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 238:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Blood draw (3 mL) for PK at any time point.
•
Height, weight, and BMI
•
Percentiles for age
•
Signs and symptoms of TB
•
Audiometry and visual assessments   
•
Thyroid function tests for those patients taking ethionamide or 
PAS
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
•
Record start date of menstrual period and/or date of LMP
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 238:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 
the subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 
(ages birth - 2 years, inclusive)
•
Blood draw for PK at any time point (see Section 3.7.4)
•
BMI and percentiles for age
•
Signs and symptoms of TB
•
Audiometry and visual assessments   
•
Thyroid function tests for those patients taking ethionamide or PAS
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 
medications
•
Groups 1 and 2 only, record date of menarche and/or date of 
LMP
3.7.1.19
For all treatment groups the following procedures will be 
conducted and/or recorded in the patient’s eCRF for Day 365:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Height, weight, and BMI
•
Percentiles for age
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Thyroid function tests for those patients taking ethionamide or 
PAS
•
Chest radiograph
•
Clinical laboratory assessments (as per Table 3.7-1): serum 
chemistry, hematology, coagulation, and full urinalysis
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
For all treatment groups the following procedures will be conducted 
and/or recorded in the patient’s eCRF for Day 365:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 
the subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 
(ages birth - 2 years, inclusive)
•
BMI and percentiles for age
•
Signs and symptoms of TB
•
Audiometry and visual assessments 
•
Thyroid function tests for those patients taking ethionamide or PAS
•
Chest radiograph
•
Clinical laboratory assessments (as per Table 3.7-1):  serum 
chemistry, hematology, coagulation, and urinalysis
•
OBR administration, as prescribed by investigator
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 


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TB medications.
medications
Section 
3.7.1.20
3.7.1.20 Treatment Outcome Follow-up (Day 730 (M24) or 
until treatment for MDR-TB is completed or discontinued, 
whichever comes first)
Treatment outcome information will be collected as routinely 
documented in the patient medical records or in a National TB 
Program.
3.7.1.20 Treatment Outcome Follow-up (Day 730 [Month 24] + 2 
Months)
All patients who complete the study will come into the clinic or be 
contacted by telephone on Day 730 (Month 24) + 2 months for 
clinical assessment.  Treatment outcome and microbiology
information will be collected as routinely documented in the patient 
medical records or in a National TB Program.


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Section 
3.7.1.21
For all patients who early terminate from the trial, the following 
procedures will be conducted and/or recorded in the eCRF:
•
Complete physical examination.  Please refer to the trial 
Operations Manual for details on the assessments to be 
performed.
•
Vital sign assessments (BP, HR, RR, and body temperature) 
after the subject has been supine for ≥3 minutes 
•
Height, weight, and BMI
•
Percentiles for age
•
Blood draw (3 mL) for PK
•
Blood draw for clinical laboratory assessments (as per Table 
3.7-1): serum chemistry, hematology, coagulation, and full 
urinalysis
•
Three consecutive 12-Lead ECGs.
•
Urine pregnancy test for all female subjects who have reached 
menarche
•
OBR administration, as prescribed by investigator.  
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-
TB medications.
•
Record start date of menstrual period and/or date of LMP
•
Patients who terminate early from Trial 233 prior to their last 
scheduled visit will have a follow-up contact (phone call or 
visit) 28 to 32 days after the Early Termination Visit to assess 
for AEs and IREs.  All patients will continue treatment with 
OBR as prescribed by the investigator according to WHO 
guidelines.
For all patients who terminate early from the trial, the following 
procedures will be conducted and/or recorded in the eCRF:
•
Complete physical examination.  Please refer to the trial Operations 
Manual for details on the assessments to be performed
•
Vital sign assessments (BP, HR, RR, and body temperature) after 
the subject has been in a supine or semi-recumbent position for ≥ 3 
minutes (as possible for Groups 3 and 4); height and weight; and 
measurement of head circumference for children in Group 4 
(ages birth - 2 years, inclusive)
•
BMI and percentiles for age
•
Blood draw for PK (see Section 3.7.4)
•
Blood draw for clinical laboratory assessments (as per Table 3.7-1):  
serum chemistry, hematology, coagulation, and urinalysis
•
Three consecutive 12-Lead ECGs after the subject has been in a 
supine or semi-recumbent position for ≥ 10 minutes (as possible 
for Groups 3 and 4)  
•
Urine pregnancy test for all female subjects who have reached 
menarche
•
Groups 3 and 4 only and only if prior to Day 182 and within 25 -
30 minutes postdose, palatability assessment of the delamanid 
pediatric formulation (see trial operations manual for details)
•
OBR administration, as prescribed by investigator 
•
Record AEs and IREs
•
Record concomitant medications including concomitant anti-TB 
medications
•
Groups 1 and 2 only, record date of menarche and/or date of 
LMP
•
Patients who terminate early from Trial 233 prior to their last 
scheduled visit will have a follow-up contact (phone call or visit) 28 
to 32 days after the Early Termination Visit to assess for AEs and 
IREs.  All patients will continue treatment with OBR as prescribed 
by the investigator according to WHO guidelines
Section 
3.7.1.22
The last dose of delamanid will be given on Day 182.  Patients 
will continue on OBR, as prescribed by the investigator, and have 
post-delamanid treatment visits on Days 189, 196, 203, 210, 238 
(2-month post last dose), Day 365 (6-month post last dose), 
treatment outcome follow-up on (Day 730 (M24) or until 
treatment for MDR-TB is completed or discontinued, whichever 
comes first).
The last dose of delamanid will be given on Day 182.  Patients will 
continue on OBR, as prescribed by the investigator, and have post-
delamanid treatment visits on Days 189, 196, 203, 210, 238 (2-month 
post last dose), and 365 (6-month post last dose), and a treatment 
outcome follow-up on Day 730 (Month 24) + 2 months.


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Table 3.7.4.1-1
Updated table to indicate which tests are group/cohort specific
Triglycerides (Groups 1 and 2 only)
Cholesterol (Groups 1 and 2 only)
Urine pregnancy test (for female patients who have reached menarche)
C-reactive protein (Groups 1 and 2 only)
Drug screen (Groups 1 and 2 only)
Section 3.7.2.2
Complete physical examinations of the head, eyes, ears, nose and 
throat (HEENT), thorax, abdomen, skin and mucosae, lymph 
nodes, extremities, BMI and neurological, including body weight 
and height will be performed and vital signs obtained at the times 
indicated in Table 3.7-1.  The principal investigator or appointed 
medical doctor (MD) designee is primarily responsible for 
performing the physical examination.  Whenever possible, the 
same individual should perform all physical examinations for each 
subject.  If the appointed MD designee is to perform the physical 
examination, he or she must be permitted by local regulations and 
his/her name must be included on the FDA Form 1572.  Any 
clinically significant condition present at the post treatment 
examination that was not present at the baseline examination 
should be documented as an AE and followed to satisfactory 
conclusion.
Vital sign assessments include BP, HR, respiration rate, and body 
temperature.  Vital signs are to be recorded after the subject has 
remained in a supine position and at rest for ≥3 minutes.  When 
vital signs and safety ECGs are scheduled for the same nominal 
time, vital sign assessments should be obtained prior to the ECG.
A complete medical history will be taken at the screening visit, and 
physical examinations and vital signs measurements will be 
performed according to the schedule provided in Table 3.7-1.
A complete physical examination will include examination of the 
head, eyes, ears, nose, throat, thorax, abdomen, skin and mucosae, 
lymph nodes, extremities, and urogenital (for Groups 3 and 4, 
required only at screening and subsequently at the discretion of the 
investigator) systems.  The physical examination will also include a 
neurological examination and a psychiatric assessment (Groups 1 
and 2 only) as described in the trial operations manual.  The 
principal investigator or appointed medical doctor designee is 
primarily responsible for performing the physical examination.  
Whenever possible, the same individual should perform all physical 
examinations for each patient.  If the appointed medical doctor 
designee is to perform the physical examination, he or she must be 
permitted by local regulations and his or her name must be included on 
FDA Form 1572.  Any clinically significant condition present at the 
post-treatment examination that was not present at the baseline 
examination should be documented as an AE and followed to 
satisfactory conclusion.
Vital signs assessments include head circumference for patients in 
Group 4 (ages birth - 2 years, inclusive), blood pressure, heart rate, 
respiration rate, and body temperature.  Vital signs are to be recorded 
after the patient has remained in a supine or semi-recumbent position 
and at rest for ≥ 3 minutes (as possible for Groups 3 and 4).  When 
vital signs and safety ECGs are scheduled for the same nominal time, 
vital signs assessments should be obtained prior to the ECG.
Body weight and height, BMI, and age percentiles will also be 
recorded.
Section 3.7.3.3
Twelve-lead ECGs will be recorded with the subject supine and at 
rest for ≥10 minutes.  
Twelve-lead ECGs will be recorded with the subject in a supine or 
semi-recumbent position and at rest for ≥ 10 minutes (as possible for 
Groups 3 and 4).


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Section 3.7.4
Minimal blood volume will be collected at optimal sparse PK 
sampling times.  
Approximately 3 mL of blood will be collected per PK sample in 
the 12 to 17 year old group and 1.5 mL to 3 mL per PK sample in 
the 6 to 11 year old group.  Delamanid data from this trial are to 
be combined with PK data from Trial 232 for the POPPK analysis.
Approximately 3 mL of blood will be collected per PK sample in the 
12- to 17-year-old group (Group 1) and 2 mL per PK sample for 
children ages 11 years and younger (Groups 2, 3, and 4).  Delamanid 
data from this trial are to be combined with PK data from Trial 232 for 
the POPPK analysis.
Section 3.7.4.1
Blood will be collected for PK as per the Schedule of Assessments 
in Table 3.7-1.  When blood collection for PK is paired with 
ECGs, the ECG will be performed first, followed by the PK blood 
draw, and then, dosing with delamanid.  Optimized PK sampling 
times and volumes will vary according to age/weight group as the 
trial progresses to younger age groups according to standards put 
forth in the PIP, applicable norms and standards in the local 
region, and modified according to findings in the older age groups 
during the trial, as appropriate.
Blood collection for PK will occur on Days 1 to 2 and 10 to 11.  
Blood draws will occur at predose (0 hours during treatment) paired 
with the 12-lead ECGs on Days 1, 56, 154, and 182.  A PK blood 
sample will be obtained on Day 210 paired with the 12-lead ECG at 
the theoretical predose.  Additional PK blood samples will be drawn 
on Days 14, 98, 189, 196, 203, and 238.  A PK blood draw will be 
collected at ET.  When blood collection for PK is paired with ECGs, 
the ECG will be performed first, followed by the PK blood draw, and 
then dosing with delamanid.    
Section 3.7.5
Time-matched ECGs and PK measurements for determination of 
delamanid and DM 6705 plasma concentrations will be analyzed
(see Section 3.7) to determine the relationship of DM-6705 levels 
to any changes in QTc interval.
ECGs and PK measurements for determination of delamanid and DM 
6705 plasma concentrations will be collected (see Section 3.7).  These 
assessments should be time-matched if possible.
Section 3.7.6
3.7.6  End of Trial
The End of Trial Date is defined as the last Date of Contact or the 
Date of Final Contact Attempt from the Post-treatment Follow-up 
eCRF page for the last subject completing or withdrawing from 
the trial.
3.7.6
Other Assessments
The palatability of the delamanid pediatric formulation will be 
assessed (Groups 3 and 4 only) within 25 - 30 minutes after the 
morning dose on Days 1, 28, 56, 182, and ET if prior to Day 182
using an age-appropriate visual hedonic scale and clinical 
assesssment.  See the trial operations manual for details.
Section 3.7.7
3.7.7
Safety Monitoring Committee
To provide trial oversight for the monitoring of patient safety, an 
independent Safety Monitoring Committee (SMC) will be 
established.  Patient care will be in accordance with the pediatric 
guidelines for TB in the local region.
3.7.7
End of Trial
The end-of-trial date is defined as the last date of contact or the date of 
the final contact attempt from the post-treatment follow-up eCRF for 
the last subject completing or withdrawing from the trial.
Section 3.7.8
3.7.7
Safety Monitoring Committee
To provide trial oversight for the monitoring of patient safety, an 
independent Safety Monitoring Committee (SMC) will be 
established.  Patient care will be in accordance with the pediatric 
guidelines for TB in the local region.
3.7.8
Safety Monitoring CommitteeA safety monitoring committee 
(SMC) composed of external consultants with expertise in pediatric TB 
and pediatric cardiology will review safety and laboratory test results 
during the conduct of the trial.  The SMC will comprise not less than 2 
members who are not involved with enrolling patients into the trial.  
The SMC will convene and operate based on the availability of patient 
safety information.  The SMC will seek additional independent 


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expertise, if needed.
The primary responsibility of the SMC will be to monitor safety and to 
determine whether or not the safety concerns merit stopping the trial.  
Section 3.8.2
New section
3.8.2
Individual Site
The investigator will notify the sponsor promptly if the trial is 
terminated by the investigator or the IRB/IEC at the site.  A particular 
site may be terminated from the trial at the discretion of the 
investigator, sponsor, or IRB/IEC, eg, for nonenrollment of subjects or 
noncompliance with the protocol.
Section 3.11
Patients who cannot be contacted on or before the scheduled 
discharge visit and who do not have a known reason for 
discontinuation (eg, withdrew consent or AE, etc.) will be 
classified as “lost to follow-up” as the reason for discontinuation.  
The site will make 3 attempts to contact the patient/parent or 
guardian by telephone; in the event the site is unable to reach the 
patient or parent/guardian by telephone, the site will attempt to 
contact the patient/parent or guardian via certified mail or an 
alternative similar method, where appropriate.
Patients who cannot be contacted on or before the scheduled M24
follow-up visit and who do not have a known reason for 
discontinuation (eg, withdrew consent or AE) will be classified as “lost 
to follow-up” as the reason for discontinuation.  The site will make 3 
attempts to contact the patient or parent/guardian/ legal representative
by telephone and in the event the site is unable to reach the patient or 
parent/guardian/ legal representative by telephone, the site will 
attempt to contact the patient or parent/guardian/legal representative
via certified mail or an alternative similar method, as appropriate.
Table 4.1-1
added bedaquiline as an other medication
Section 5.1
•Pregnancies are also defined as IREs.  Although normal 
pregnancy is not an AE, it will mandate delamanid discontinuation 
and must be reported on an IRE form to Otsuka Frankfurt 
Research Institute - Pharmacovigilance Region Europe (OFRI 
PVRE; See also Section 5.4).  Pregnancy will only be documented 
on the AE-eCRF if there is an abnormality or complication.
•Pregnancies are also defined as IREs; although a normal pregnancy is 
not an adverse event, it will mandate delamanid discontinuation and 
must be reported on an IRE form to Otsuka Europe Development and 
Commercialisation Ltd (OEDC) Pharmacovigilance Region Europe 
(PVRE) (See also Section 5.4).  This includes pregnancies occurring 
in the female partner of a male patient.  Pregnancy will only be 
documented on the AE CRF if there is an abnormality or complication
Section 5.1
If this laboratory value is determined by the investigator to be an 
abnormal change from baseline for that subject, it is considered an 
AE.
If this laboratory value is determined by the investigator to be a 
clinically significant abnormal change from baseline for that patient, it 
is considered an AE.
Section 5.4
Pregnancy testing will be performed during the screening period 
prior to trial enrollment and at the end of the treatment period
according to the Schedule of Assessments for FOCBP who have 
reached menarche.
If pregnancy is suspected while the patient is taking delamanid 
during the trial, delamanid must be withheld immediately and if 
pregnancy is confirmed, the delamanid will be permanently 
discontinued.
Pregnancy testing will be performed during the screening period prior 
to study enrollment and at the end of the trial according to the 
schedule of assessments for all female patients who have reached 
menarche.
If pregnancy is suspected while the patient is taking delamanid 
during the trial, delamanid must be withheld immediately.  If 
pregnancy is confirmed, the delamanid will be permanently 
discontinued but the patient will not be automatically withdrawn 
from the trial.


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Section 6.1
Delamanid and metabolite plasma concentrations will be reported 
with descriptive statistics at each visit day per age and dose group. 
In addition, delamanid plasma concentrations will be included in a 
delamanid population PK (POPPK) model.
Delamanid and metabolite plasma concentrations will be reported with 
descriptive statistics at each visit day per age group.  In addition, 
delamanid plasma concentrations will be analyzed using a POPPK 
approach.
Section 6.2
PK/PD relationship analysis will be conducted for DM-6705 
plasma concentrations and QTcF prolongation.
Pharmacokinetic/pharmacodynamic relationship analysis will be 
conducted for delamanid and DM-6705 plasma concentrations and 
QTcF prolongation.
Sections 7.4 
and 7.5
7.4
Pharmacokinetics
Descriptive statistics of delamanid and metabolite plasma 
concentrations will include N, mean, SD, minimum, median, 
maximum, and % coefficient of variation and will be provided in 
the clinical study report (CSR).  The POPPK analysis, when 
completed, will be provided together with the data analysis plan 
(DAP) in a separate report.
7.5
Pharmacokinetic/Pharmacodynamic Relationships
A PK/PD relationship analysis of DM-6705 plasma concentrations 
and QTcF prolongation will be conducted using regression 
analysis. Changes in QTc from baseline will be estimated using 
the ECG baseline assessment on Day-1 (at theoretical pre-dose 
time) in Trial 232. The maximal change in QTcF prolongation 
(with one-sided upper 95% CI] will be reported at the observed 
mean maximal DM-6705 plasma concentrations.
7.4
Efficacy Analyses
Because of the small sample sizes per group, large-sample-based 
statistical methods cannot be used.  Exact methods, if available, will be 
pursued.  All statistical presentations will be descriptive.  
7.5
Palatability Analysis
The palatability of the delamanid pediatric formulation will be 
assessed (Groups 3 and 4 only) using an age-appropriate visual 
hedonic scale and clinical assessment.  The data will be summarized 
by descriptive statistics (mean, SD, min, max).
Section 8.1
Trial drugs will be provided to the investigator(s) by the sponsor 
(or designated agent).  Delamanid will be supplied as 50 mg 
tablets packaged in blister packs.  Each blister packs used in the 
dosing period will be labeled to clearly disclose the compound 
identification (ID), protocol number, the sponsor's name and 
address, instructions for use, route of administration, and 
appropriate precautionary statements (see Section 8.1.1).
Investigational medicinal product will be provided to the 
investigator(s) by the sponsor (or designated agent).  The IMP will be 
packaged in blister cards.  Each blister card used in the dosing period 
will be labeled to clearly disclose the compound ID, protocol number, 
sponsor's name and address, instructions for use, route of 
administration, and appropriate precautionary statements (see Section 
8.1.1).
Section 8.1.1
Delamanid will be supplied as 50-mg tablets packaged in blister 
packs.  Each blister pack of delamanid 50-mg used during the 182-
day dosing period will be labeled to clearly disclose the following 
information:
•
Trial/protocol number
•
Compound ID
•
Patient ID number or initials (to be filled in by the 
investigator designee of the trial site(to be filled in by the 
investigator when delamanid is assigned and/or dispensed to the 
patient)
Each blister card of delamanid used during the 182-day dosing period 
will be labeled to clearly disclose the following information:
• Trial/protocol number
• Compound ID
• Patient ID number and/or initials (to be filled in by the 
investigator/designee when delamanid is assigned and/or dispensed to 
the patient)


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Section 11
At a minimum, the IRB/IEC should be supplied with the following 
documents:  trial protocol(s)/amendment(s), written ICFs and 
consent form updates that the investigators propose for use in the 
trial, patient recruitment procedures (for example, advertisements), 
written information to be provided to participants, IB, additional 
available safety information, information about payments and 
compensation available to participants, the investigator’s current 
curriculum vitae and/or other documentation evidencing 
qualifications, and any other documents the IRB/IEC may need to 
fulfill its responsibilities.
At a minimum, the IRB/IEC should be supplied with the following 
documents:  trial protocol(s)/amendment(s), written ICFs and 
IFC/assent form updates that the investigators propose for use in the 
trial, patient recruitment procedures (for example, advertisements), 
written information to be provided to participants, IB, additional 
available safety information, information about payments and 
compensation available to participants, the investigator’s current 
curriculum vitae and/or other documentation evidencing qualifications, 
and any other documents that the IRB/IEC may need to fulfill its 
responsibilities.
Section 14
Updated reference list to match updated citations.
Appendix 1
Report Immediately Reportable Events (serious adverse events, 
liver enzyme elevation cases, pregnancies, and adverse events 
requiring discontinuation of trial drug) to:
Otsuka Europe Development and Commercialisation, Ltd (OEDC) 
Pharmacovigilance Region Europe (PVRE)
Zweigniederlassung Frankfurt am Main 
Europa-Allee 52
60327 Frankfurt am Main
Germany
Fax:  
Phone: 
 (24h/7d PVRE Blackberry)
E-mail:  
Report Immediately Reportable Events to:
Otsuka Europe Development and Commercialisation, Ltd (OEDC) 
Pharmacovigilance Region Europe (PVRE)
Fax:  
Phone:  
 (24h/7d PVRE Blackberry)
E-mail:  
Appendix 3
Blood (1.5-3 mL) will be collected into green-top Vacutainer 
tubes containing sodium heparin anticoagulant.  
Blood (2 - 3 mL) will be collected into green-top Vacutainer® tubes 
containing sodium heparin anticoagulant.  
Appendix 4
Added Amendment 3
ADDITIONAL RISK TO THE SUBJECT:
This amendment will not affect the safety of patients, the scope of the investigation, or the scientific quality of the trial.


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Amendment Number: 4
Issue Date:
04 October 2016
PURPOSE:  The purpose of this amendment is to add information for Group 4 including weight 
based computation of dosage, dose adjustment if needed based on weight change during specific 
visits, to modify the schedule of laboratory assessments in order to meet the required blood 
volume for younger age groups as mandated by the applicable regulatory authorities, to add and 
to modify the exclusion criteria, to add holter monitoring in the safety assessments, to reduce the 
blood volume requirement for PK samples, to add the occurrence of proarryhthmic events in the 
stopping rule and immediately reportable events,  to make minor editorial changes to the text, to 
make minor content and editorial changes to the Introduction and references, and to update 
sponsor representative information.
BACKGROUND:  In the previous version of the protocol, delamanid pediatric formulation 
dosing for Group 4 was not yet included, and HIV patients were excluded from the trial.  Also, 
due to the maximum blood volumes allowed to be drawn within a specified time period for 
pediatric patients of certain weights, the schedule of blood extractions for safety assessments 
during screening period need to be modified to comply with regulatory guidelines.
MODIFICATIONS TO PROTOCOL:
Bold and underlined text:
Changed Text
Bold and strike through text:
Deleted Text
Bold and italicized text:
Added Text
Global Changes:

Corrected minor typographical, grammatical, and formatting errors.

Made minor content and editorial changes and corrections to the Introduction.

Modified the exclusion criteria.

Added the weight based computation of delamanid pediatric formulation for Group 4.

Added holter monitoring in the safety assessments

Reduce the blood volume requirement for PK sample collection

Updated the schedule of assessments.

Added the occurrence of proarryhthmic events in the stopping rule and immediately 
reportable events.


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Title Page
Otsuka Europe Development and
Commercialisation Ltd (OEDC)
Pharmacovigilance Region Europe (PVRE)
Grüneburgweg 102
60323 Frankfurt am Main
Germany
Fax:  
Phone:   
 (24h/7d PVRE
Blackberry)
Otsuka Europe Development and
Commercialisation Ltd (OEDC)
Pharmacovigilance Region Europe (PVRE)
Grüneburgweg 102
60323 Frankfurt am Main
Germany
Fax:  
E-mail:  
Phone:   
 (24h/7d PVRE
Blackberry)
Title Page
Added text
Amendment 4 Issue Date                         04 October 2016
Synopsis (Trial 
Design)
This is a phase 2, open-label, multiple-dose, multicenter trial to 
assess the safety, tolerability, PK, and efficacy of delamanid in 
pediatric patients with MDR-TB over a 6-month treatment 
period.  This long-term trial, an extension of Trial 242-12-232 
(Trial 232), will be conducted in patients who have completed 
Trial 232.  The current Trial 242-12-233 (Trial 233) will be 
conducted sequentially in 4 groups of pediatric patients with 
MDR-TB. 
  

Group 1 (ages 12 - 17 years, inclusive) will receive adult 
formulation delamanid 100 mg BID + OBR (n = 6)

Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive 
pediatric formulation delamanid 25 mg BID + OBR (n = 
12)

Group 4 (ages birth - 2 years, inclusive) will receive 
pediatric formulation delamanid (dose to be determined) 
BID + OBR (n = 12)
This is a phase 2, open-label, multiple-dose, multicenter trial to assess 
the safety, tolerability, PK, and efficacy of delamanid in pediatric 
patients with MDR-TB over a 6-month treatment period.  This long-
term trial, an extension of Trial 242-12-232 (Trial 232), will be 
conducted in patients who have completed Trial 232.  The current Trial 
242-12-233 (Trial 233) will be conducted sequentially in 4 groups of 
pediatric patients with MDR-TB.
  

Group 1 (ages 12 - 17 years, inclusive) will receive adult 
formulation delamanid 100 mg BID + OBR (n = 6)

Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive pediatric 
formulation delamanid 25 mg BID + OBR (n = 12)

Group 4 (ages birth - 2 years, inclusive) will receive the 
following delamanid pediatric formulation (DPF) dose 
based on patient’s body weight during baseline visit (n = 
12):

Patient > 10 kg will receive DPF 10 mg BID + OBR

Patient > 8 and < 10 kg will receive DPF 5 mg BID + 
OBR


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
Patient < 8 kg will receive DPF 5 mg QD + OBR

Delamanid dose will be adjusted as needed for Group 4 
patients based on the weight measurement at specified 
study visits (Visits 5, 7, 9, 11 and 12).
Synopsis (Trial 
Design 
(continued))
The trial will comprise the following periods:
Screening Period (Day −30 to −2):  Study data will either be 
taken from screening or Day 10 of Trial 232 or will be 
performed during the 30-day period immediately after 
completion of Trial 232 as described in the Schedule 
of Assessments. 
Baseline (Day −1):  Inclusion/exclusion criteria, physical 
examination, and safety assessments, including lab tests, signs 
and symptoms of tuberculosis (TB), audiometry and visual 
assessments, vital signs, height, weight, percentiles for age, body 
mass index (BMI), and electrocardiogram (ECG) as described in 
the Schedule of Assessments.  OBR administration as prescribed 
by investigator, and recording of concomitant medications. 
Treatment Period (Days 1 to 182):  Morning and evening 
dosing of delamanid with meal.  OBR administration as 
prescribed by investigator.  Sparse blood draws for PK as 
described in the Schedule of Assessments. Signs and symptoms 
of TB, physical examination, and other safety assessments, 
including safety lab tests. Audiometry and visual assessments, 
and ECG at weeks and times shown in the Schedule of 
Assessments.  Height, weight, and BMI beginning at Week 2 and 
assessed monthly, and collection of adverse events (AEs) and 
immediately reportable events (IREs), and concomitant 
medications.
Post-treatment Period (Days 183 to 238):   
Physical examination, vital signs, ECGs, safety labs, and sparse 
blood draws for PK at visits and times described in the Schedule 
of Assessments. OBR dosing and collection of AEs/IREs, and 
concomitant medications. 
Follow-up Period (Days 239 to 365) Six Month Post Last 
Delamanid Dose: Physical examination, height and weight, 
BMI, percentiles for age, vital signs, signs and symptoms of TB, 
The trial will comprise the following periods: 
Screening Period (Day −30 to −2):  Study data will either be taken 
from screening or Day 10 of Trial 232 or will be performed during the 
30-day period immediately after completion of Trial 232 as described 
in the Schedule of Assessments. 
Baseline (Day −1):  Inclusion/exclusion criteria, physical examination, 
and safety assessments, including lab tests, signs and symptoms of 
tuberculosis (TB), audiometry and visual assessments, vital signs, 
height, weight, head circumference (Group 4 only), percentiles for 
age, body mass index (BMI), and electrocardiogram (ECG) as 
described in the Schedule of Assessments.  OBR administration as 
prescribed by investigator, and recording of concomitant medications. 
Treatment Period (Days 1 to 182):  Morning and evening dosing of 
delamanid with meal.  OBR administration as prescribed by 
investigator.  Sparse blood draws for PK as described in the Schedule 
of Assessments. Signs and symptoms of TB, physical examination, and 
other safety assessments, including safety lab tests. Audiometry and 
visual assessments, and ECG at weeks and times shown in the 
Schedule of Assessments.  Vital signs, head circumference (Group 4 
only), height, weight, and BMI beginning at Week 2, and collection 
of adverse events (AEs) and immediately reportable events (IREs), and 
concomitant medications.
Post-treatment Period (Days 183 to 238):  Physical examination, 
vital signs, ECGs, safety labs, and sparse blood draws for PK at visits 
and times described in the Schedule of Assessments. Head 
circumference (Group 4 only), height, weight, signs and symptoms of 
TB, audiometry and visual assessments, thyroid function tests (for 
patients taking ethionamide or para-aminosalicylic acid), 
OBR administration, and collection of AEs/IREs and concomitant 
medications.  
Follow-up Period (Days 239 to 365) Six Month Post Last 
Delamanid Dose: Physical examination, height and weight, BMI, 


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chest radiograph, audiometry and visual assessments, safety labs, 
thyroid function tests (for patients taking ethionamide or para-
aminosalicylic acid, OBR administration, and collection of 
AEs/IREs and concomitant medications.  
Treatment Outcome Follow-up (Day 730 [Month 24] + 2
months):  Collection of treatment outcome information as 
routinely documented in the patient medical records or in a 
national TB program.
percentiles for age, vital signs, head circumference (Group 4 only),
height, weight, signs and symptoms of TB, chest radiograph, 
audiometry and visual assessments, safety labs, thyroid function tests 
(for patients taking ethionamide or para-aminosalicylic acid), 
OBR administration, and collection of AEs/IREs and concomitant 
medications.  
Treatment Outcome Follow-up (Day 730 [Month 24] + 2 months):  
All patients will either visit the clinic or be contacted by telephone for 
clinical assessment.  Collection of treatment outcome information as 
routinely documented in the patient medical records or in a national TB 
program.
Synopsis 
(InclusionExclu
sion Criteria)
Key Exclusion Criteria:

Patients who have not completed Trial 232

Children with a positive test result for human 
immunodeficiency virus (HIV) or who have been 
previously identified as having HIV or with laboratory 
evidence of active hepatitis B or C

History of allergy to metronidazole and any disease or 
condition in which metronidazole is required

Use of amiodarone within 12 months prior to the first 
dose of investigational medicinal product (IMP) or use of 
other predefined antiarrhythmic medications within 30 
days prior to the first dose of IMP

Serious concomitant conditions (cardiovascular 
disorders, severe respiratory disease, severe diarrheal 
disease, renal, hepatic, or neurological impairment)

Preexisting cardiac conditions including but not limited 
to structural cardiac disease including suspected TB 
involvement of the heart on clinical or radiographic 
grounds

Abnormalities in screening electrocardiogram (ECG) 
(including atrioventricular block, bundle branch block or 
hemi-block, QRS prolongation > 120 msec, or QT 
interval corrected using Fridericia’s method (QTcF) 
> 450 msec in both males and females)

A concomitant condition such as renal impairment 
Key Exclusion Criteria:

Patients who have not completed Trial 232

Children with laboratory evidence of active hepatitis B or 
C

Children with body weight < 5.5 kg.

For patients with HIV co-infection, CD4 cell count ≤ 
1000/mm3 for children 1-5 years old, and ≤ 1500/mm3 for 
children less than 1 year old

History of allergy to metronidazole and any disease or 
condition in which metronidazole is required

Use of amiodarone within 12 months prior to the first dose of 
investigational medicinal product (IMP) or use of other 
predefined antiarrhythmic medications within 30 days prior to 
the first dose of IMP

Serious concomitant conditions (cardiovascular disorders, 
severe respiratory disease, severe diarrheal disease, renal, 
hepatic, or neurological impairment)

Preexisting cardiac conditions including but not limited to 
structural cardiac disease including suspected TB involvement 
of the heart on clinical or radiographic grounds

Abnormalities in screening electrocardiogram (ECG) 
(including atrioventricular block, bundle branch block or hemi-
block, QRS prolongation > 120 msec, or QT interval corrected 
using Fridericia’s method (QTcF) > 450 msec in both males 


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characterized by serum creatinine levels > 1.5 mg/dL, 
hepatic impairment (alanine aminotransferase or 
aspartate aminotransferase > 3 times the upper limit of 
normal [ULN]), or hyperbilirubinemia characterized by 
total bilirubin > 2x ULN

Concurrent diagnosis of severe malnutrition or 
kwashiorkor

Positive urine drug screen (Groups 1 and 2 only)

Use of rifampicin and/or moxifloxacin within 1 week 
prior to the first dose of IMP and/or any prior or 
concurrent use bedaquiline

Lansky Play Performance Score < 50 or Karnofsky 
Score < 50

Administered an IMP within 1 month prior to Visit 1 
other than delamanid given as IMP in Trial 232
Pregnant, breast-feeding, or planning to conceive or father a child 
within the timeframe described in the informed consent form 
(Groups 1 and 2 only)
and females)

A concomitant condition such as renal impairment 
characterized by serum creatinine levels > 1.5 mg/dL, hepatic 
impairment (alanine aminotransferase or aspartate 
aminotransferase > 3 times the upper limit of normal [ULN]), 
or hyperbilirubinemia characterized by total bilirubin > 2x 
ULN

Concurrent diagnosis of severe malnutrition or kwashiorkor

Positive urine drug screen (Groups 1 and 2 only)

Use of rifampicin and/or moxifloxacin within 1 week prior to 
the first dose of IMP and/or any prior or concurrent use of
bedaquiline

Lansky Play Performance Score < 50 (not applicable for 
children < 1 year old) or Karnofsky Score < 50

Administered an IMP within 1 month prior to Visit 1 other 
than delamanid given as IMP in Trial 232

Pregnant, breast-feeding, or planning to conceive or father a 
child within the timeframe described in the informed consent 
form (Groups 1 and 2 only)
Synopsis 
(Investigational 
Medicinal 
Product, Dose, 
Formulation, 
Mode of 
Administration:
Delamanid pediatric dispersible tablets admixed with water and 
administered orally as an extemporaneous suspension to Groups 
3 and 4 for 6 months:

Group 3 (ages 3 to 5 years, inclusive) -
25 mg (1 x 25-mg tablet) BID

Group 4 (ages birth to 2 years, inclusive) -
dose to be determined
Delamanid pediatric dispersible tablets admixed with water and 
administered orally as an extemporaneous suspension to Groups 3 and 
4 for 6 months:

Group 3 (ages 3 to 5 years, inclusive) -
25 mg (1 x 25-mg tablet) BID

Group 4 (ages birth to 2 years, inclusive) -
will receive the following dose depending on patient’s 
weight:

Patient > 10 kg will receive pediatric formulation 
delamanid 10 mg BID + OBR

Patient > 8 and ≤ 10 kg will receive pediatric 
formulation delamanid 5 mg BID + OBR

Patient ≤ 8 kg will receive pediatric formulation 
delamanid 5 mg QD + OBR


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Synopsis 
(Criteria for 
Evaluation)
The primary criteria for evaluation in this trial are:

Safety and Tolerability:  assessed by physical 
examination, vital signs, treatment-emergent adverse 
events (TEAEs), ECGs, and clinical laboratory tests

Pharmacokinetics:  Delamanid and metabolite plasma 
concentrations at each visit day per age and dose group
The primary criteria for evaluation in this trial are:

Safety and Tolerability:  assessed by physical examination, 
vital signs, treatment-emergent adverse events (TEAEs), 
ECGs, Holter monitoring (if applicable), and clinical 
laboratory tests

Pharmacokinetics:  Delamanid and metabolite plasma 
concentrations at each visit day per age and dose group
Synopsis 
(Endpoints)
The primary endpoints in this trial are:

Safety and tolerability:  Changes in physical 
examination including visual testing and audiometry 
during screening, TEAEs, vital signs, ECGs, and clinical 
laboratory tests
The primary endpoints in this trial are:

Safety and tolerability:  Changes in physical examination 
including visual testing and audiometry during screening, 
TEAEs, vital signs, ECGs, holter monitoring (if applicable),
and clinical laboratory tests
List of 
Abbreviations 
and Definitions 
of Terms
Added text
Abbreviation        Defintion
CD4 cell               Cluster of differentiation 4 (helper/inducer T-
                             lymphocyte)
Section 1
Justification for Exclusion of HIV Co-infected Patients
Tuberculosis and HIV/AIDS constitute the main burden of 
infectious disease in resource-limited countries.45  Tuberculosis 
remains the most common opportunistic infection and is the most 
common cause of death in HIV-infected patients.46  In 
HIV-affected communities, the highest TB incidence rates now 
occur among men and women in their reproductive years (ages 
20 to 45 years) who are likely to be parents of young and 
vulnerable children.30  However, HIV coinfected children will be 
excluded from this trial because the diagnosis, management, and 
treatment of TB in the presence of HIV coinfection are 
complicated by the following factors28:

The tuberculin skin test is much less sensitive in HIV-
infected children than in those without HIV.

Smear microscopy is less sensitive in HIV-infected 
individuals who are more likely to have smear-negative 
Justification for Exclusion of HIV Co-infected Patients
Tuberculosis and HIV/AIDS constitute the main burden of 
infectious disease in resource-limited countries.45  Tuberculosis 
remains the most common opportunistic infection and is the most 
common cause of death in HIV-infected patients.46  In 
HIV-affected communities, the highest TB incidence rates now 
occur among men and women in their reproductive years (ages 20 
to 45 years) who are likely to be parents of young and vulnerable 
children.30  However, HIV coinfected children will be excluded 
from this trial because the diagnosis, management, and treatment 
of TB in the presence of HIV coinfection are complicated by the 
following factors28:

The tuberculin skin test is much less sensitive in HIV-infected 
children than in those without HIV.

Smear microscopy is less sensitive in HIV-infected individuals 
who are more likely to have smear-negative disease.


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disease.

Chronic pulmonary symptoms may be related to HIV-related 
conditions, such as gastroesophageal reflux disease, 
bronchiectasis, and other opportunistic infections that reduce 
the specificity of symptom-based diagnostic approaches. 

Weight loss or failure to thrive are typical characteristics of 
both TB and HIV infections.

Rapid TB progression is more likely to occur in HIV-
infected children, reducing the sensitivity of diagnostic and 
treatment approaches that focus on persistent, nonremitting 
symptoms.6  

Interpretation of chest radiographs is complicated by HIV-
associated comorbidities, such as bacterial pneumonia, 
lymphocytic interstitial pneumonitis, bronchiectasis, 
pulmonary Kaposi sarcoma, and the atypical presentation of 
TB.35  

Treatment of both HIV and TB are complicated by 
overlapping side effects, the immune reconstitution 
inflammatory syndrome, drug-drug interactions, and high 
pill burden, all with the potential to complicate adherence.

Chronic pulmonary symptoms may be related to HIV-related 
conditions, such as gastroesophageal reflux disease, 
bronchiectasis, and other opportunistic infections that reduce 
the specificity of symptom-based diagnostic approaches. 

Weight loss or failure to thrive are typical characteristics of 
both TB and HIV infections.

Rapid TB progression is more likely to occur in HIV-infected 
children, reducing the sensitivity of diagnostic and treatment 
approaches that focus on persistent, nonremitting symptoms.6  

Interpretation of chest radiographs is complicated by HIV-
associated comorbidities, such as bacterial pneumonia, 
lymphocytic interstitial pneumonitis, bronchiectasis, 
pulmonary Kaposi sarcoma, and the atypical presentation of 
TB.35  

Treatment of both HIV and TB are complicated by 
overlapping side effects, the immune reconstitution 
inflammatory syndrome, drug-drug interactions, and high pill 
burden, all with the potential to complicate adherence.
Section 1.3.1 
through 1.3.2
Minor editorial and content updates.
Section 1.4.1
As of 26 Mar 2014, 887 adult subjects have been exposed to oral 
doses of delamanid in 17 completed trials in Japan, China, South 
Africa, Peru, Korea, Philippines, Egypt, the European Union, and 
the United States.  Of these 887 adult subjects, 422 were healthy 
subjects, 60 were patients with uncomplicated DS-TB, 395 were 
patients with MDR-TB, and 10 were patients with MDR-TB 
refractory to treatment.  Of these 887 adult subjects, 791 subjects 
(338 healthy subjects, 48 patients with uncomplicated DS-TB, 
395 patients with MDR-TB, and 10 patients with MDR-TB 
refractory to treatment) have been exposed to oral doses of 
delamanid tablets (ie, the modified spray-dried tablet 
formulation).  
As of 31 Jan 2016, a total of 949 adult subjects (484 healthy adult 
subjects, 60 adult patients with uncomplicated DS-TB, 395 adult 
patients with MDR-TB, 10 adult patients with MDR-TB refractory 
to treatment) have been exposed to oral doses of delamanid in 19 
completed trials.
In addition, a total of 22 healthy adult subjects and 511 adult 
subjects with MDR-TB have been exposed to either delamanid or 
placebo (trial is still blinded) in ongoing trials (Trials 242-201-
00001 and 242-09-213, respectively).
Fourteen children (ages 3 - 17 years) with MDR-TB have also been 
exposed to oral doses of delamanid in 2 ongoing, open-label, 


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pediatric trials (Trials 242-12-232 and 242-12-233).
Section 1.4.1
As of 31 Jan 2014 in Trial 242-09-213, the ongoing phase 3, 
randomized, double-blind, and placebo-controlled trial conducted 
in MDR-TB patients to determine the safety, PK, and efficacy of 
delamanid plus OBR versus placebo plus OBR, enrollment was 
complete and 511 patients had begun blinded treatment.  Three 
deaths had been reported, 65 patients had reported SAEs, and 8 
patients had discontinued IMP due to TEAEs.1
Refer to the IB for additional information on the delamanid 
safety profile.1
As of 31 Jan 2016 in Trial 242-09-213, the ongoing phase 3, 
randomized, double-blind, and placebo-controlled trial conducted in 
MDR-TB patients to determine the safety, PK, and efficacy of 
delamanid plus OBR versus placebo plus OBR, enrollment was 
complete and 511 patients had begun blinded treatment. Three deaths 
had been reported, 65 patients had reported SAEs, and 8 patients 
had discontinued IMP due to TEAEs.1 A total of 238 serious 
TEAEs occurred. The most frequently reported serious TEAEs were 
hypokalaemia (12 [2.3%]), tuberculosis (14 [2.7%]), deafness 
bilateral (8 [1.6%]), acute kidney injury (8 [1.6%]), 
electrocardiogram QT prolonged (7 [1.4%]), haemoptysis (5 [1.0%]), 
and hepatotoxicity (5 [1.0%]). Nineteen deaths (19/511; [3.7%]) were 
reported for patients with MDR-TB. Two patients died due to acute 
respiratory failure (one of these patients also had worsening of MDR 
TB), 2 patients died due to haemoptysis, 2 patients died due to 
disseminated tuberculosis and sepsis, one due to cardiac arrest and 
pneumonia, and one patient each died of cardiopulmonary failure, 
myocardial ischemia, pulmonary edema, pulmonary embolism, 
respiratory failure, acute myocardial infarction, hypothermia, 
metastatic neoplasm of unknown primary site, squamous cell 
carcinoma of lung, renal impairment, lung adenocarcinoma 
metastatic, and completed suicide. All of these events were considered 
by the investigator as unrelated or unlikely related to IMP.1
In the ongoing trials in pediatric patients with MDR TB (Trials 242-
12-232 and 242-12-233), there was 1 serious TEAE of non-Hodgkin’s 
lymphoma reported as of the cutoff date of 31 Jan 2016.1
Section 2.1
Trial 232 was designed to define the pediatric dose that will 
result in a delamanid systemic exposure (AUC) equivalent to that 
observed in the pivotal adult trials where efficacy against MDR-
TB has been demonstrated.  
Trial 232 was designed to define the pediatric dose in patients between 
0-17 years of age that will result in a delamanid systemic exposure 
(AUC) equivalent to that observed in the pivotal adult trials where 
efficacy against MDR-TB has been demonstrated.  
Section 2.1
Patients in each age group will be sequentially enrolled into this 
6-month treatment extension trial (Trial 233) to evaluate the 
Patients in each age group will be sequentially enrolled into this 6-
month treatment extension trial (Trial 233) to evaluate the safety, 


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safety, tolerability, PK, and efficacy of delamanid during the 
extended time period planned in this trial for treatment of MDR-
TB.  To be eligible for Trial 233, all patients must rollover within 
30 days of completing Trial 232.
tolerability, PK, efficacy, and palatability of delamanid during the 
extended time period planned in this trial for treatment of MDR-TB.  
To be eligible for Trial 233, all patients must rollover within 30 days of 
completing Trial 232.
Section 2.2
Delamanid will be administered to pediatric MDR-TB patients on 
OBR therapy.  Children will be given delamanid BID in 
agreement with the delamanid dosing regimen for adult MDR-TB 
patients, which is BID treatment for 6 months.  
Delamanid will be administered to pediatric MDR-TB patients on OBR 
therapy.  Children will be given delamanid BID (except for the 5.5-8
kg group who will receive a QD dose) in agreement with the 
delamanid dosing regimen for adult MDR-TB patients, which is BID 
treatment for 6 months.  
Section 2.2
Younger children (ages birth to 5 years, inclusive) will be given 
25-mg pediatric dispersible tablets admixed with water and 
administered orally as an extemporaneous suspension.  The 
delamanid dose for children ages 3 to 5 years, inclusive (Group 
3) will be 25 mg BID.  The delamanid dose for children ages 
birth to 2 years, inclusive (Group 4), will be confirmed using the 
PK, safety, and tolerability findings in the older age groups and 
based on the bioavailability of the pediatric formulation.
Younger children (ages birth to 5 years, inclusive) will be given 
pediatric dispersible tablets admixed with water and administered 
orally as an extemporaneous suspension.  Children ages 3 to 5 years, 
inclusive (Group 3) will be given pediatric delamanid formulation 25 
mg BID.  
The delamanid dose for children ages birth to 2 years, inclusive 
(Group 4), will be determined based on body weight during baseline 
visit. Children with weight > 10 kg will be given delamanid pediatric 
formulation (DPF) , 10 mg BID, those with weight > 8 and ≤  10 kg 
will be given DPF 5 mg BID, while children with weight ≤  8 kg will 
receive DPF 5 mg QD.  Delamanid dose will be adjusted as needed 
for Group 4 patients  based on the weight measurement   at specified 
study visits (Visits 5, 7, 9, 11 and 12).
Delamanid doses in younger children were confirmed using the PK, 
safety, and tolerability findings in the older age groups and based on 
the bioavailability of the pediatric formulation.
Section 3.1
Delamanid will be administered twice daily for 182 days.  The 
trial will be conducted sequentially in 4 groups of pediatric 
patients:

Group 1 (ages 12 - 17 years, inclusive) will receive adult 
Delamanid will be administered for 182 days.  The trial will be 
conducted sequentially in 4 groups of pediatric patients:

Group 1 (ages 12 - 17 years, inclusive) will receive adult 
formulation delamanid 100 mg BID + OBR (n = 6)


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formulation delamanid 100 mg BID + OBR (n = 6)

Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive 
pediatric formulation delamanid 25 mg BID + OBR (n = 
12)

Group 4 (ages birth - 2 years, inclusive) will receive 
pediatric formulation delamanid BID  + OBR (n = 12) 
(dose will be determined after data from at least 6 
subjects from Group 3 in Trial 232 is available)
The trial will comprise the following periods: 

Screening Period (Day −30 to −2):  Study data will 
either be taken from screening or Day 10 of Trial 232 or 
will be performed during the post-Trial 232 thirty (30)-
day screening period for Trial 233, as described in the 
Schedule of Assessments 

Baseline (Day −1):  Inclusion/exclusion criteria, 
physical examination, and safety assessments including 
laboratory tests, signs and symptoms of tuberculosis 
(TB), audiometry and visual assessments, vital signs, 
height, weight, percentiles for age, body mass index 
(BMI), and ECG as described in the Schedule of 
Assessments.  OBR administration as prescribed by 
investigator, and recording of concomitant medications  

Treatment Period (Days 1 to 182):  Morning and 
evening dosing of delamanid.  PK sampling every 
2 weeks through Week 14 at 0 hours predose, then as 
described in the Schedule of Assessments. Signs and 
symptoms of TB, physical examination, and other safety 
assessments including safety lab tests. Audiometry and 
visual assessments, and ECG at weeks and times shown 
in the Schedule of Assessments. Height, weight, and 
BMI beginning at Week 2 and assessed monthly.  OBR 
administration as prescribed by the investigator and 
collection of AEs, immediately reportable events 
(IREs), and concomitant medications

Group 2 (ages 6 - 11 years, inclusive) will receive adult 
formulation delamanid 50 mg BID + OBR (n = 6)

Group 3 (ages 3 - 5 years, inclusive) will receive pediatric 
formulation delamanid 25 mg BID + OBR (n = 12)

Group 4 (ages birth - 2 years, inclusive) will receive the 
following delamanid pediatric formulation (DPF) dose based 
on body weight during baseline visit.(n = 12):

Patient > 10 kg will receive DPF 10 mg BID + OBR

Patient > 8 and ≤ 10 kg will receive DPF 5 mg BID + 
OBR 

Patient ≤ 8 kg will receive DPF5 mg QD + OBR
Delamanid dose will be adjusted as needed for Group 4 patients  
based on the weight measurement  at specified study visits (Visits 5, 7, 
9, 11 and 12).
The trial will comprise the following periods: 

Screening Period (Day −30 to −2):  Study data will either be 
taken from screening or Day 10 of Trial 232 or will be 
performed during the post-Trial 232 thirty (30)- day screening 
period for Trial 233, as described in the Schedule 
of Assessments 

Baseline (Day −1):  Inclusion/exclusion criteria, physical 
examination, and safety assessments including laboratory 
tests, signs and symptoms of tuberculosis (TB), audiometry 
and visual assessments, vital signs, height, weight, head 
circumference (Group 4 only), percentiles for age, body mass 
index (BMI), and ECG as described in the Schedule of 
Assessments.  OBR administration as prescribed by 
investigator, and recording of concomitant medications  

Treatment Period (Days 1 to 182):  Morning and evening 
dosing of delamanid.  PK sampling every 2 weeks through 
Week 14 at 0 hours predose, then as described in the Schedule 
of Assessments. Signs and symptoms of TB, physical 
examination, and other safety assessments including safety lab 
tests. Audiometry and visual assessments, and ECG at weeks 
and times shown in the Schedule of Assessments. Vital signs, 
head circumference (Group 4 only), height, weight, and 


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
Post-treatment Period (Days 183 to 238):  
Physical examination, vital signs, ECGs, safety labs, 
blood draws for PK at visits and times described in the 
Schedule of Assessments.  OBR administration as 
prescribed by the investigator and collection of 
AEs/IREs, and concomitant medications

Follow-up Period (Days 239 to 365, 6 month Post Last 
Delamanid Dose Visit): Physical examination, height 
and weight, BMI, percentiles for age, vital signs, signs 
and symptoms of TB, chest radiograph, audiometry and 
visual assessments, safety labs, thyroid function tests 
(for patients taking ethionamide or para aminosalicylic 
acid), OBR administration as prescribed by the 
investigator and collection of AEs/IREs and 
concomitant medications

Treatment Outcome Follow-up (Day 730 [Month 24] 
+ 2 months:  Collection of treatment outcome 
information as routinely documented in the patient 
medical records or in a national TB program
BMI beginning at Week 2.  OBR administration as 
prescribed by the investigator and collection of AEs, 
immediately reportable events (IREs), and concomitant 
medications

Post-treatment Period (Days 183 to 238):
Physical examination, vital signs, ECGs, safety labs, blood 
draws for PK at visits and times described in the Schedule of 
Assessments.  Head circumference (Group 4 only), height, 
weight, signs and symptoms of TB, audiometry and visual 
assessments, thyroid function tests (for patients taking 
ethionamide or para-aminosalicylic acid), OBR 
administration as prescribed by the investigator and collection 
of AEs/IREs, and concomitant medications

Follow-up Period (Days 239 to 365, 6 month Post Last 
Delamanid Dose Visit): Physical examination, height and 
weight, BMI, percentiles for age, vital signs, head 
circumference (Group 4 only), height, weight, signs and 
symptoms of TB, chest radiograph, audiometry and visual 
assessments, safety labs, thyroid function tests (for patients 
taking ethionamide or para aminosalicylic acid), 
OBR administration as prescribed by the investigator and 
collection of AEs/IREs and concomitant medications

Treatment Outcome Follow-up (Day 730 [Month 24] + 2 
months:  All patients will either visit the clinic or be 
contacted by telephone for clinical assessment. Collection of 
treatment outcome information as routinely documented in the 
patient medical records or in a national TB program
Figure 3.1-1
Delamanid BID + OBR 
Safety, PK, Efficacy
Evaluations
Delamanid BID/QD + OBR 
Safety, PK, Efficacy
Evaluations
Section 3.2
Patients will be assigned by age group to receive one of the 
following treatments for 182 days:  
1)
Group 1 (12 to 17 years, inclusive):  adult formulation 
delamanid 100 mg BID (administered as 2 x 50-mg 
tablets BID) + OBR
Patients will be assigned by age group to receive one of the following 
treatments for 182 days:  
1)
Group 1 (12 to 17 years, inclusive):  adult formulation 
delamanid 100 mg BID (administered as 2 x 50-mg tablets 
BID) + OBR


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2)
Group 2 (6 to 11 years, inclusive):  adult formulation 
delamanid 50 mg BID (administered as 1 x 50-mg tablet 
BID) + OBR
3)
Group 3 (3 to 5 years, inclusive):  pediatric formulation 
delamanid 25 mg BID (administered as 1 x 25-mg tablet 
BID) + OBR
4)
Group 4 (birth to 2 years, inclusive):  pediatric 
formulation delamanid  + OBR (dose will be determined 
after data from at least 6 subjects from Group 3 in 
Trial 232 are available)
Patient age group and dosing will be determined at the time of 
enrollment into Trial 232 and will not change during rollover into 
Trial 233
2)
Group 2 (6 to 11 years, inclusive):  adult formulation 
delamanid 50 mg BID (administered as 1 x 50-mg tablet BID) 
+ OBR
3)
Group 3 (3 to 5 years, inclusive):  pediatric formulation 
delamanid 25 mg BID (administered as 1 x 25-mg tablet BID) 
+ OBR
4)
Group 4 (birth to 2 years, inclusive):  pediatric formulation 
delamanid based on body weight  + OBR. Children with 
weight > 10 kg will be given delamanid pediatric formulation 
(DPF) 10 mg BID (administered as 2 x 5-mg dispersible 
tablet) + OBR; Children with weight > 8 and ≤ 10 kg will be 
given DPF 5 mg BID (administered as 1 x 5-mg dispersible 
tablet) + OBR, and children with weight ≤ 8 kg will be given 
DPF delamanid 5 mg QD (administered as 1 x 5-mg 
dispersible tablet) + OBR.    
Patient age group and dosing (Groups 1, 2 and 3) will be 
determined at the time of enrollment into Trial 232 and will not 
change during rollover into Trial 233.  Dosing for Group 4 will be 
determined during baseline visit and will be adjusted based on weight 
measurement during specific study visits (Visits 5, 7, 9, 11 and 12).
Table 3.4.3-1
2. Children with a positive test for HIV or who have been 
previously identified as having HIV or with laboratory evidence 
of hepatitis B or C
2.Children with a positive test for HIV or who have been previously 
identified as having HIV or with laboratory evidence of hepatitis B or 
C
3. Children with body weight < 5.5 kg.
4. For patients with HIV co-infection, CD4 cell count ≤ 1000/mm3 
for children 1-5 years old, and ≤ 1500/mm3 for children less than 1
year old.
Table 3.4.3-1
Minor revisions on number sequence.
Table 3.4.3-1
Use of rifampicin and/or moxifloxacin within 1 week prior to the 
first dose of IMP 
Use of rifampicin and/or moxifloxacin within 1 week prior to the first 
dose of IMP and/or any prior concurrent use of bedaquiline


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Table 3.4.3-1
Lansky Play Performance Score < 50 or Karnofsky Score < 50
Lansky Play Performance Score < 50 (not applicable for children < 1 
year old) or Karnofsky Score < 50
Section 3.4.3
Patients ages 12 to 17 years excluded for a positive drug/alcohol 
screen are not eligible to be rescreened for participation in the 
trial.  
Patients ages 6 to 17 years excluded for a positive drug/alcohol screen 
are not eligible to be rescreened for participation in the trial.  
Section 3.5.1.1
Safety and tolerability of delamanid will be assessed by the 
following variables:

Reported TEAEs 

Physical examination including visual testing and 
audiometry  

Vital signs

ECGs

Clinical laboratory assessments (hematology, serum 
chemistry, urinalysis, and other laboratory tests [see 
Table 3.7.3.1-1])
Safety and tolerability of delamanid will be assessed by the following 
variables:

Reported TEAEs 

Physical examination including visual testing and audiometry  

Vital signs

ECGs

Holter monitoring (if applicable)

Clinical laboratory assessments (hematology, serum chemistry, 
urinalysis, and other laboratory tests [see Table 3.7.3.1-1])
Section 3.5.2.3
The palatability of the pediatric formulation will be assessed 
using an-age appropriate visual hedonic scale and clinical 
assessment.
The palatability of the pediatric formulation will be assessed using an-
age appropriate visual hedonic scale and clinical assessment (Groups 3 
and 4 only).
Section 3.7
Delamanid will be administered twice daily with a standard meal 
for the duration of the trial.  OBR will be administered as 
prescribed, under the DOTS guidelines of the WHO.  
Delamanid will be administered twice daily with a standard meal for 
the duration of the trial.  OBR will be administered as prescribed, under 
the DOTS guidelines of the WHO.  
Table 3.7.1
Numerous updates to assessments and schedule
Updates include:
-
ACTH test, Adrenal function and Thyroid function in 
Visit 13 was moved to Visit 14. 
-
Minor revisions in reference to footnote  
Table 3.7.1
Additional footnotes
t For Group 4 only, delamanid dose will be adjusted based on the 
subject’s weight measurement during study visit
u Twenty-four-hour Holter monitor tracing if QTcF > 490 msec.
v Not required if patient had a documented HIV test and result 
within 1 year prior to the screening visit AND there is no known 
exposure to HIV. 


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Updated Text
w Screening CD4 cell count test will only be performed for 
patients with positive HIV test results unless the patient has 
documented CD4 cell count test and results within 3 months 
prior to screening visit.
Section 3.7.1.1

Laboratory assessments including serum chemistry, 
hematology and coagulation, urinalysis, HIV, hepatitis 
B surface antigen (HBsAg), antibody to hepatitis C virus 
(anti-HCV), adrenocorticotropic hormone (ACTH), 
adrenal function (cortisol), C-reactive protein (Groups 1 
and 2 only), and thyroid function tests (T4 and thyroid 
stimulating hormone [TSH])

Laboratory assessments including serum chemistry, 
hematology and coagulation, urinalysis, HIV, CD4 cell count 
(if HIV test is positive), hepatitis B surface antigen (HBsAg), 
antibody to hepatitis C virus (anti-HCV), adrenocorticotropic 
hormone (ACTH), adrenal function (cortisol), C-reactive 
protein (Groups 1 and 2 only), and thyroid function tests (T4 
and thyroid stimulating hormone [TSH])
Section 3.7.1.3

Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be 
administered twice daily (morning and evening)

Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice 
daily (morning and evening). For Group 4, delamanid 
dosing will be determined based on weight measurement 
during baseline visit.  
Section 3.7.1.3
Added text

Obtain twenty-four-hour Holter monitor tracing if QTcF >
490 msec following the first dosing of delamanid pediatric 
formulation. 
Section 3.7.1.4

Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be 
administered twice daily (morning and evening).

Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice 
daily (morning and evening).
Section 3.7.1.5

Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be 
administered twice daily (morning and evening)

Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed 
by investigator). Delamanid will be administered twice 
daily (morning and evening). For Group 4 only, delamanid 
dosing will be adjusted as needed based on weight 
measurement during this visit.  Study personnel must 
determine whether or not delamanid dosing will be adjusted 
prior to IWRS drug dispensation.  
Section 3.7.1.5
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 3.7.1.6
Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
Delamanid dispensed (plus OBR administration either one hour before 
or one hour after delamanid dosing, as prescribed by investigator).  


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investigator).  Delamanid will be administered twice daily 
(morning and evening).
Delamanid will be administered twice daily (morning and evening).
Section 3.7.1.7
Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
Delamanid dispensed (plus OBR administration either one hour before 
or one hour after delamanid dosing, as prescribed by investigator).  
Delamanid will be administered twice daily (morning and evening). 
For Group 4 only, delamanid dosing will be adjusted as needed based 
on weight measurement during this visit.  Study personnel must 
determine whether or not delamanid dosing will be adjusted prior to 
IWRS drug dispensation.  
Section 3.7.1.7
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 3.7.1.8
Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
Delamanid dispensed (plus OBR administration either one hour before 
or one hour after delamanid dosing, as prescribed by investigator).  
Delamanid will be administered twice daily (morning and evening).
Section 3.7.1.9
Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
Delamanid dispensed (plus OBR administration either one hour before 
or one hour after delamanid dosing, as prescribed by investigator).  For 
Group 4 Delamanid dosing will be adjusted as needed based on 
weight measurement during this visit.  Study personnel must 
determine whether or not delamanid dosing will be adjusted prior to 
IWRS drug dispensation.  
Section 3.7.1.9
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 
3.7.1.10
Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).
Delamanid dispensed (plus OBR administration either one hour before 
or one hour after delamanid dosing, as prescribed by investigator).
Delamanid will be administered twice daily (morning and evening).
Section 
3.7.1.11
Delamanid dispensed (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
Delamanid dispensed (plus OBR administration either one hour before 
or one hour after delamanid dosing, as prescribed by investigator).
Delamanid will be administered twice daily (morning and evening).


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(morning and evening)
For Group 4 only, delamanid dosing will be adjusted as needed based 
on weight measurement during this visit.  Study personnel must 
determine whether or not delamanid dosing will be adjusted prior to 
IWRS drug dispensation.  
Section 
3.7.1.11
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 
3.7.1.12

Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be 
administered twice daily (morning and evening)

Delamanid dispensed (plus OBR administration either one 
hour before or one hour after delamanid dosing, as prescribed 
by investigator).  Delamanid will be administered twice 
daily (morning and evening).  For Group 4 only, delamanid 
dosing will be adjusted as needed based on weight 
measurement during this visit.  Study personnel must 
determine whether or not delamanid dosing will be adjusted 
prior to IWRS drug dispensation.  
Section 
3.7.1.12
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 
3.7.1.13

Delamanid dispensed (plus OBR administration either 
one hour before or one hour after delamanid dosing, as 
prescribed by investigator).  Delamanid will be 
administered twice daily (morning and evening).  
NOTE:  This is the last day of delamanid dosing

Delamanid dosing (plus OBR administration either one hour 
before or one hour after delamanid dosing, as prescribed by 
investigator).  Delamanid will be administered twice daily 
(morning and evening).  NOTE:  This is the last day of 
delamanid dosing
Section 
3.7.1.13
Deleted text

Blood draw for ACTH and adrenal function (cortisol)

Blood draw for thyroid function tests (T4 and TSH) for 
patients taking ethionamide or PAS
Section 
3.7.1.13
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 
3.7.1.14
Added text

Blood draw for ACTH and adrenal function (cortisol)

Blood draw for thyroid function tests (T4 and TSH) for 
patients taking ethionamide or PAS
Section 
3.7.1.17
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 
Section 
3.7.1.19
Added text
Obtain twenty-four-hour Holter monitor tracing if QTcF > 490 msec 


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Table 3.7.3.1-1
Other Laboratory Tests
Morning cortisol
Thyroid function tests (serum thyroid stimulating hormone and 
free T4)
Urine pregnancy test (for female patients who have reached 
menarche)
Adrenocorticotropic (screening only)
HIV (screening only)
Hepatitis B surface antigen (screening HBsAg only)
Antibody to hepatitis C virus (screening only)
C-reactive protein (Groups 1 and 2 only
Other Laboratory Tests
-
Morning cortisol
-
Thyroid function tests (serum thyroid stimulating hormone 
and free T4)
-
Urine pregnancy test (for female patients who have reached 
menarche)
-
Adrencorticotropic hormone (screening only)
-
HIV (screening onlya) 
-
CD4 cell count (screening onlyb)
-
Hepatitis B surface antigen (screening HBsAg only)
-
Antibody to hepatitis C virus (screening only)
-
C-reactive protein (Groups 1 and 2 only)
a Not required if patient had a documented HIV test and result 
within 1 year prior to the screening visit AND there is no known 
exposure to HIV. 
b Screening CD4 cell count test will only be performed for patients 
with positive HIV test results unless the patient has documented CD4
cell count test and results within 3 months prior to screening visit.
Section 3.7.4
Approximately 3 mL of blood will be collected per PK sample in 
the 12- to 17-year-old group (Group 1) and 2 mL per PK sample 
for children ages 11 years and younger (Groups 2, 3, and 4).  
Delamanid data from this trial are to be combined with PK data 
from Trial 232 for the POPPK analysis.
Approximately 3 mL of blood will be collected per PK sample in the 
12- to 17-year-old group (Group 1); 2 mL per PK sample for in the 3-
to 11-year-old children (Groups 2 and 3) and 0.6 mL per PK sample 
for children ages 2 years and (Group 4). Delamanid data from this 
trial are to be combined with PK data from Trial 232 for the POPPK 
analysis.
Section 3.8.1
2. Occurrence of QTcF > 500 msec
2. Occurrence of QTcF > 500 msec or occurrence of proarrhythmic 
events
Section 4.1
Table 4.1-1
List of Medications Prohibited Prior to and 
During the Treatment Period of the Trial
Anti-Arrhythmic medications with potential for QT interval 
prolongation
1.
Quinidine
2.
Procainamide
3.
Disopyramide
4.
Encainide
Table 4.1-1
List of Medications Prohibited Prior to and During 
the Treatment Period of the Trial
Anti-Arrhythmic medications with potential for QT interval 
prolongation
1.
Quinidine
2.
Procainamide
3.
Disopyramide
4.
Encainide


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5.
Flecainide
6.
Sotalol
7.
Amiodarone
8.
Digitalis
Other Medications With Potential For QT Interval Prolongation
1.
Moxifloxacin
Other Medications
1.
Antiretroviral Medications
2.
Rifampicin
3.
Bedaquiline
5.
Flecainide
6.
Sotalol
7.
Amiodarone
8.
Digitalis
Other Medications With Potential For QT Interval Prolongation
1.
Moxifloxacin
Other Medications
1.
Rifampicin
2.
Bedaquiline
Section 5.1
QTcF interval prolongation > 500 msec
QTcF interval prolongation > 500 msec or occurrence of 
proarrhythmic event
Section 5.2.3
QTcF interval prolongation > 500 msec
QTcF interval prolongation > 500 msec or occurrence of 
proarrhythmic event
Section 5.2.3
E-mail:  
Fax:  
Phone:  
 (PVRE Blackberry 24h/7d)
E-mail:  
Fax:  
Phone:  
 (PVRE Blackberry 24h/7d)
Section 6.2
Pharmacokinetic/pharmacodynamic relationship analysis will be 
conducted for delamanid and DM-6705 plasma concentrations 
and QTcF prolongation. 
Delamanid and DM-6705 plasma concentrations will be examined 
in conjunction with QTcF data to explore if there is a PK/PD 
correlation.
Section 7.3.2
The quantitative change in clinical chemistry, hematology, 
coagulation, and urinalysis assessment results will be calculated 
relative to baseline.  Baseline is defined as the last measurement 
before the first administration of delamanid.  Thyroid function 
tests and ACTH will be measured at baseline only.  Summary 
statistics for quantitative laboratory assessment results will be 
presented by treatment (age) group and visit for the change from 
baseline (Day −1) will be provided.  Shift tables will be produced 
for assessing changes from baseline in clinical laboratory 
measurements.
The quantitative change in clinical chemistry, hematology, coagulation, 
and urinalysis assessment results will be calculated relative to baseline.  
Baseline is defined as the last measurement before the first 
administration of delamanid.  Thyroid function tests and ACTH will 
be measured at baseline only.  Summary statistics for quantitative 
laboratory assessment results will be presented by treatment (age) 
group and visit for the change from baseline (Day −1) will be provided.  
Shift tables will be produced for assessing changes from baseline in 
clinical laboratory measurements.
Section 14
Otsuka Maryland Research Institute.  OPC-67683 Investigator's 
Otsuka Maryland Research Institute.  OPC-67683 Investigator's 


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Drug Brochure, edition 10.  Otsuka Report, issued May 2014.
Drug Brochure, edition 12.  Otsuka Report, issued April 2016.
References
45
Pawlowski A, Johnson M, Skold M, Rottenberg ME, 
Kallenius G. Tuberculosis and HIV co-infection. PLoS  Path. 
1012;8:1-5.
46
Reid A, Scano F, Getahun H, et al. Towards universal access 
to HIV prevention, treatment, care, and support: the role of 
TB/HIV collaboration. Lancet Infect Dis 2006; 6:483-95.
127
World Health Organization (WHO). Global tuberculosis 
control - surveillance, planning, financing. WHO Document, 
2008, Geneva, Switzerland. WHO/HTM/TB/2008.393.
130
Salazar-Vergara RML, Sia IG, Tupasi TE, Alcneses MR, et 
al. Tuberculosis infection and disease in children living in 
households of Filipino patients with tuberculosis: a 
preliminary report. Int J Tuberc Lung Dis. 2003;7:S494-
S500.
131
Schaaf H, Vermuelen H, Gie R, Beyers N, Donald P. 
Evaluation of young children in household contact with adult 
multidrug-resistant pulmonary tuberculosis cases. Pediatr 
Infect Dis. 1999;18:494-500
Removed  references 45- 46, 129-131. Revised the number sequence.
45
Pawlowski A, Johnson M, Skold M, Rottenberg ME, Kallenius 
G. Tuberculosis and HIV co-infection. PLoS  Path. 1012;8:1-5.
46
Reid A, Scano F, Getahun H, et al. Towards universal access to 
HIV prevention, treatment, care, and support: the role of 
TB/HIV collaboration. Lancet Infect Dis 2006; 6:483-95.
127
World Health Organization (WHO). Global tuberculosis 
control - surveillance, planning, financing. WHO Document, 
2008, Geneva, Switzerland. WHO/HTM/TB/2008.393.
130
Salazar-Vergara RML, Sia IG, Tupasi TE, Alcneses MR, et al. 
Tuberculosis infection and disease in children living in 
households of Filipino patients with tuberculosis: a 
preliminary report. Int J Tuberc Lung Dis. 2003;7:S494-S500.
131
Schaaf H, Vermuelen H, Gie R, Beyers N, Donald P. 
Evaluation of young children in household contact with adult 
multidrug-resistant pulmonary tuberculosis cases. Pediatr 
Infect Dis. 1999;18:494-500
Appendix 1
Report Immediately Reportable Events to:
Otsuka Europe Development and Commercialisation, Ltd 
(OEDC) 
Pharmacovigilance Region Europe (PVRE)
Fax:  
Phone:  
 (24h/7d PVRE Blackberry)
E-mail:  
Report Immediately Reportable Events to:
Otsuka Europe Development and Commercialisation, Ltd (OEDC) 
Pharmacovigilance Region Europe (PVRE)
Fax:  
Phone:  
(24h/7d PVRE Blackberry)
E-mail:  
Appendix 1
Deleted text
For Medical Emergencies in the Philippines
Otsuka (Philippines) Pharmaceutical Inc.
3F King's Court II Building 
2126 Chino Roces Avenue
Makati City, Philippines
Phone:  


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Fax:  
E-mail:  
Appendix 3
Blood (2 - 3 mL) will be collected into green-top Vacutainer
tubes containing sodium heparin anticoagulant.  The tubes must 
be gently inverted 3 to 4 times and then centrifuged at 2500 rpm 
for at least 10 minutes at 4°C.  The separated plasma from each 
tube should then be divided equally between the 2 barcode-
labeled polypropylene tubes.  The PK sample must be stored at 
−65°C or below.
One PK tube (primary sample) will be shipped on dry ice to the 
central lab.  Following confirmation that the first tube arrived 
safely, the second tubes (backup samples) can also be shipped to 
the central lab.
Blood (0.6 - 3 mL) will be collected into green-top Vacutainertubes 
containing sodium heparin/lithium heparin anticoagulant.  The tubes 
must be gently inverted 3 to 4 times and then centrifuged at 2500 rpm 
for at least 10 minutes at 4°C.  The separated plasma from each tube 
should then be divided equally between the 2 barcode-labeled 
polypropylene tubes (Groups 1-3). For Group 4, the separated plasma 
should be transferred to a single barcode-labeled polypropylene tube.   
The PK sample must be stored at −65°C or below.
One PK tube (primary sample) will be shipped on dry ice to the central 
lab (Groups 1-4).   Following confirmation that the first tube arrived 
safely, the second tubes (backup samples) can also be shipped to the 
central lab (Groups 1-3).  There will be no backup samples for Group
4.
ADDITIONAL RISK TO THE SUBJECT:
This amendment will not affect the safety of patients, the scope of the investigation, or the scientific quality of the trial.


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Amendment 5, 28 February 2019
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Amendment Number: 5
Issue Date:
28 February 2019
PURPOSE: The purpose of this amendment is to add an interim analysis to the protocol.
BACKGROUND:  In the previous protocol, no interim analysis was included and now it 
has been added. To get preliminary safety information about the adult formulation of
delamanid in children 6 to 17 years of age the interim analysis is focusing on those 
groups (Groups 1 and 2) treated with the adult formulation.
MODIFICATIONS TO PROTOCOL:
Bold and underlined text:
Changed Text
Bold and strike through text:
Deleted Text
Bold and italicized text:
Added Text
Global Changes:

Corrected minor typographical, grammatical, and formatting errors.

Added an interim analysis in children 6 to 17 years of age treated with the adult 
formulation of delamanid.


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Sectional Revisions:
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Title Page
Added text.
Amendment 5 Issue Date
28 February 2019
Synopsis
Statistical Methods:
No power calculation was performed for this trial because of the 
limited number of patients expected to be enrolled in the population of 
interest (ie, pediatrics).  No formal statistical analysis is planned due to 
the small sample sizes; all statistical presentations will be descriptive.
Statistical Methods:
No power calculation was performed for this trial because of the 
limited number of patients expected to be enrolled in the population of 
interest (ie, pediatrics).  No formal statistical analysis is planned due to 
the small sample sizes; all statistical presentations will be descriptive.
An interim analysis review of safety, tolerability, PK, and efficacy of 
delamanid will be conducted with complete follow-up data in
children 6 to 17 years of age.
Section 
7.6
Added text
7.6
Interim Analysis
An interim analysis of safety, tolerability, PK, and efficacy of 
delamanid in children 6 to 17 years of age is planned in the 1st 
quarter of 2019.
ADDITIONAL RISK TO THE SUBJECT:
This amendment will not affect the safety of patients, the scope of the investigation, or the scientific quality of the trial.


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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Research Agreement.
I will provide copies of the protocol to all physicians, nurses and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, delamanid (OPC-67683), the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) responsible for such matters in the clinical trial facility where 
delamanid (OPC-67683) will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in Paragraph I of the 
sponsor's Clinical Research Agreement, at which time I agree to adhere strictly to the protocol as 
amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any protocol amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within 5 working days. Administrative 
changes to the protocol will be transmitted to the IRB/IEC for informational purposes only.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Research Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and sub-
investigators in accordance with the terms of the relevant regional regulation(s). I understand that 
participation in the protocol involves a commitment to publish the data from this trial in a 
cooperative publication prior to publication of efficacy and safety results on an individual basis.
________________________________________________
Principal or Coordinating Investigator Signature and Date


This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: Protocol_242-12-233_Amendment 5
Document Number: 0000843868
Document Version: 12.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
02-Mar-2019
01:44:10
Clinical Pharmacology
Approval
01-Mar-2019
15:58:11
Biostatistics Approval
28-Feb-2019
23:21:58

SAP_001.pdf: 
Official Title: 
Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Delamanid (OPC 67683) in Pediatric 
Multidrug-resistant Tuberculosis Patients on Therapy with an Optimized 
Background Regimen of Antituberculosis Drugs over a 6-Month 
Treatment Period 
NCT Number: 
NCT01859923 
Document Date: 
SAP Version Final: 03 July 2019 


Statistical Analysis Plan                                        1 of 33
Version Date: 3 July 2019
    
Investigational New Drug OPC-67683 (Delamanid)
Protocol No. 242-12-233
IND No.  76,728
Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Delamanid (OPC 67683) in Pediatric 
Multidrug resistant Tuberculosis Patients on Therapy with an Optimized 
Background Regimen of Antituberculosis Drugs over a 6 Month Treatment 
Period
Investigational Medicinal Product  
Delamanid (OPC-67683)
Statistical Analysis Plan
Version: Final
Date: 3 July 2019
Protocol Version Amendment 5: 28 February 2019
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


Protocol: 242-12-233
Statistical Analysis Plan                                        2 of 33
Version Date: 3 July 2019
Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................4
List of In-text Figures....................................................................................5
List of Appendices .........................................................................................6
List of Abbreviations and Definitions of Terms.........................................7
1
Introduction ..........................................................................................9
2
Study Objectives...................................................................................9
2.1
Primary Objectives............................................................................................. 9
2.2
Secondary objectives:......................................................................................... 9
3
Study Design..........................................................................................9
4
Sample Size and Power Justification............................................... 11
5
Statistical Analysis............................................................................. 11
5.1
General Principles ............................................................................................ 11
5.2
Datasets for Analysis........................................................................................ 12
5.3
Definition of Baselines..................................................................................... 12
5.4
Handling of Missing Data ................................................................................ 12
5.5
Demographic and Baseline Characteristics...................................................... 12
5.6
Medical History................................................................................................ 12
5.7
Primary Outcome Analysis............................................................................... 13
5.7.1
Safety Outcome Variables ............................................................................. 13
5.7.1.1
Adverse Events........................................................................................... 13
5.7.1.2
Clinical Laboratory Data............................................................................ 14
5.7.1.3
Drug Induced Liver Injury (DlLI) .............................................................. 15
5.7.1.4
Physical Examination and Vital Signs ....................................................... 15
5.7.1.5
Electrocardiogram Results ......................................................................... 15
5.7.1.6
Additional Safety Assessments.................................................................. 16
5.8
Extent of Exposure to Trial Medication........................................................... 16
5.9
Treatment Compliance ..................................................................................... 16
5.10
Protocol Deviation............................................................................................ 16


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Statistical Analysis Plan                                        3 of 33
Version Date: 3 July 2019
5.11
Pharmacokinetic Analysis of Plasma ............................................................... 16
5.11.1
Pharmacokinetic Assessment of Cerebral Spinal Fluid (CSF)...................... 17
5.12
Secondary Outcome Analysis........................................................................... 17
5.12.1
Pharmacokinetics/Phamacodynamics............................................................ 17
5.12.2
Efficacy Outcome Analysis ........................................................................... 17
5.12.3
Palatibility...................................................................................................... 18
5.12.4
Final Treatment Outcomes Assessed by the Principal Investigator............... 18
5.13
Concomitant Medications................................................................................. 18
5.14
Patient Disposition, Completion Rate and Reasons for Discontinuation......... 18
5.15
Discontinuation ................................................................................................ 18
6
Table of Contents for Table and Listings ....................................... 20
7
Bibliography....................................................................................... 28


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Statistical Analysis Plan                                        4 of 33
Version Date: 3 July 2019
List of In-text Tables
Table 3-1
Subject Population ........................................................................ 10


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Statistical Analysis Plan                                        5 of 33
Version Date: 3 July 2019
List of In-text Figures
Figure 3-1
Trial Design Schematic................................................................. 11


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Statistical Analysis Plan                                        6 of 33
Version Date: 3 July 2019
List of Appendices
Appendix 1
Serum Chemistry, Hematology and Urinalysis Lab Test 
Results Clinical Significant Criteria Based on Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events .............................................................. 29
Appendix 2
Criteria for Potentially Clinical Significant Vital Sign 
Abnormalities................................................................................ 32
Appendix 3
Criteria for Potentially Clinical Significant ECG 
Abnormalities................................................................................ 33


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ACTH
Adrenocorticotropic hormone
ADAM
Analysis data model
ADSL
Subject-level analysis dataset
AE
Adverse event
AFB
Acid-fast bacilli
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ARV
Antiretroviral
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the plasma-time concentration curve
AUC0-24
Area under the plasma-time concentration curve from time zero to 24 hours
BID
Dosing twice per day
BMI
Body mass index
BP
Blood pressure
CA
Competent authority
CDISC
Clinical Data Interchange Standards Consortium
CFU
Colony Forming Units
CI
Confidence interval
Cmax
Peak (maximal) concentration of drug in plasma/serum
CRO
Contract Research Organization
CSF
Cerebral Spinal Fluid
CYP
Cytochrome P-450
DILI
Drug Induced Liver Injury
DOTS
Directly-observed therapy short-course
DST
Drug susceptibility testing
DS-TB
Drug-susceptible tuberculosis
EB
Ethambutol
EBA
Early bactericidal activity
EC
Ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EFV
Efavirenz
EU
European Union
FDA
(United States) Food and Drug Administration
FOCBP
Female of child-bearing potential
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s brochure
IC
Inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
ID
Identification
IDM
Interval duration measurement
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INH
Isoniazid


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INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
ISR
Immediate Safety Report
LMP
Last menstrual period
LPV
Lopinavir
LTBI
Latent TB infection
MedDRA
Medical Dictionary for Regulatory Activities
MD
Medical doctor
MDR-TB
Multidrug-resistant tuberculosis
MTB
Mycobacterium tuberculosis
NTBP
National Tuberculosis Program
OBR
Optimized background regimen
PD
Pharmacodynamic
P-gp
P-glycoprotein
PIP
Pediatric Investigational Plan
PK
Pharmacokinetics
PO
Oral route of administration
POPPK
Population pharmacokinetics
PT
Preferred term
PZA
Pyrazinamide
QD
Once daily
QTc
Corrected QT interval
QTcB
QTc corrected by Bazett formula
QTcF
QTc corrected by Fridericia formula
RR
Respiratory rate
RTV
Ritonavir
SAE
Serious adverse event
SCC
Sputum culture conversion
SD
Standard deviation
SMC
Safety Monitoring Committee
SOC
System organ class
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TFV
tenofovir
t1/2
Elimination half-life
t1/2z
Terminal elimination half-life
TSH
Thyroid stimulating hormone
TST
Tuberculin skin test
ULN
Upper limit of normal
WHO
World Health Organization
XDR-TB
Extensively Drug Resistant TB


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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
safety, tolerability, pharmacokinetics (PK) and efficacy of Otsuka Pharmaceutical 
Development and Commercialization (Otsuka) Trial 242-12-233.  All amendments to the 
protocol are taken into consideration in developing this SAP.
2
Study Objectives
2.1
Primary Objectives

Safety and tolerability: To evaluate the long-term safety and tolerability of delamanid 
and its metabolites in combination with an OBR during a 6-month treatment period in 
pediatric patients with MDR-TB for the age-specific delamanid doses determined in 
Trial 232.

Pharmacokinetics: To report delamanid and metabolite plasma concentrations at each 
visit by age groups and to conduct population pharmacokinetics (POPPK) anlaysis of 
delamanid when delamanid is administered in combination with an OBR during a 
6-month treatment period in pediatric patients with MDR-TB. 
2.2
Secondary objectives:

To evaluate the pharmacokinetic (PK)/ pharmacodynamics (PD) relationship of
delamanid and its metabolite DM-6705 plasma concentrations and change in QTc 
when delamanid is administered in combination with OBR during a 6-month 
treatment period in pediatric patients with MDR-TB.

Efficacy: To evaluate the efficacy of delamanid when administered in combination 
with an OBR during a 6-month treatment period in pediatric patients with MDR-TB.

To determine the palatability of the delamanid pediatric formulation.
3
Study Design
This is a Phase 2, open-label, multi-dose, age de-escalation multicenter trial to assess the
long-term safety, tolerability, PK, and efficacy of delamanid plus OBR over a 6-month 
treatment period in pediatric patients with MDR-TB who have successfully completed 
Trial 232. Since the trial is an extension of Trial 242-12-232 (Trial 232), patients must 
complete Trial 232 to roll-over to the current Trial 242-12-233 (Trial 233). Those patients 
who have completed Trial 232 and choose to enter Trial 233 must rollover from Trial 232 
within 30 days after completing that Trial. If any patients terminate Trial 232 early or 
choose not to enter Trial 233, patients will be recruited to enter and complete Trial 232 


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first, and then rollover into Trial 233. However, patients who terminate Trial 233 early 
will not be replaced. Subject population is listed in Table 3-1 and study design schematic
is illustrated in Figure 3-1.
Patients who enter Trial 233 will retain the same unique identification number and the 
same age group assigned to them in Trial 232:
Table 3-1
Subject Population
Group
Category
Sample Size (N)
Administration
1†
Age 12 -17 years
6+
Adult formulation of delamanid 100 mg 
BID + OBR for 6 months
2‡
Age 6 -11 years
6+
Adult formulation of delamanid 50 mg 
BID + OBR for 6 months
3‡
Age 3 -5 years
12+
Pediatric formulation of delamanid
(DPF) 25 mg BID + OBR for 6 months 
4‡
Age 0 -2 years
12+
Pediatric formulation of delamanid
based on body weight + OBR:

Patient > 10 kg will receive 
DPF 10 mg BID + OBR

Patient > 8 and <= 10 kg will 
receive DPF 5 mg BID + OBR

Patient <= 8 kg will receive 
DPF 5 mg QD + OBR

Delamanid dose will be 
adjusted as needed for Group 4 
patients based on the weight 
measurement at specified study 
visits (Visits 5, 7, 9, 11 and 12)
†: Group 1 must include at least 2 but no more than 5 females. 
‡: Group 2, 3, 4 must include both genders.


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Figure 3-1
Trial Design Schematic
4
Sample Size and Power Justification 
Since patients are rolled over directly from Trial 232, no power/sample size calculation 
was performed for this trial and no formal statistical hypothesis test is planned due to the 
small sample size. All statistical presentations will be descriptive. 
5
Statistical Analysis
5.1
General Principles
All data processing, summarization and analyses will be performed using version of 9.4
or higher of SAS-statistical software packages. Data will be presented in summary 
tables by age groups, and by study time points if applicable. 
Without distinction, Descriptive Continuous Statistics will include the number of patients 
/ observations (N), mean, standard deviation (SD), min and max by default;  Descriptive 
Categorical Statistics will include frequency counts and percentages [n (%)].  The 
denominator for percentage calculations will be the total number of patients in the 
analysis sample, or the subset of the analysis sample if the analyses are restricted for the 
subset of the analysis sample only, as defined in section 5.2, unless specified otherwise. 
No formal statistical hypothesis testing will be performed.


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When a measurement is repeated for the same visit, the last of repeat values will be used 
for production of summary tables. International System of Units (SI) will be applied for 
all analyses unless specified otherwise.
5.2
Datasets for Analysis
For safety and PK summaries, the following study samples are defined in Analysis Data 
Model [ADaM] subject-level analysis dataset [ADSL] and naming conventions will 
follow Clinical Data Interchange Standards Consortium [CDISC] standards.

Safety Sample: comprises the patients who have received any amount of study 
medication in Trial 233, regardless of any protocol deviation or violation. 

Efficacy Sample:  comprises all patients with at least one efficacy endpoint available, 
the efficacy end points include: 1) chest radiograph result; 2) investigator assessed 
clinical signs and symptoms of tuberculosis; 3) microbiologic assessment of sputum;
4) evaluable change from baseline in body weight or height at treatment period.
5.3
Definition of Baselines 
Baseline is in general defined as the latest evaluation prior to the first dose in study 233,
from both scheduled and unscheduled visits in either Trial 233, or Trial 232 if not 
applicable from Trial 233.  
5.4
Handling of Missing Data
All analyses are performed on the observed data and no missing data imputation is 
needed. 
5.5
Demographic and Baseline Characteristics
Baseline demographic characteristics including age, gender, race, ethnicity, height, height 
percentile for age, weight, weight percentile for age, body mass index (BMI) and 
menstruation will be summarized by age group for the Safety and Efficacy samples 
respectively using the baseline assessments. Descriptive statistics will be tabulated by age 
groups. 
5.6
Medical History
General medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 18.0 (or a later version if updated during the study).  All 
medical history will be listed, and Descriptive Categorical Statistics for patients with any 
medical history will be tabulated for safety sample by system organ class (SOC) and 
preferred term (PT) by age groups.  


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5.7
Primary Outcome Analysis
5.7.1
Safety Outcome Variables
Safety and Tolerability was assessed by adverse events (AEs), physical examination
including visual and audiometry assessments, vital signs, electrocardiograms, clinical 
laboratory tests (serum chemistry, hematology, urinalysis and other laboratory tests), .
Safety parameters will be summarized by incidence rates and their change from baseline 
if applicable.  Change from baseline is summarized for observed cases at each scheduled 
post-baseline visit and for the last visit. 
5.7.1.1
Adverse Events
All adverse events (AEs) recorded will be classified by SOC and PT according to the 
most recent version of the Medical Dictionary for Regulatory Activities (MedDRA)
available at the time of analysis. 
Treatment emergent AE (TEAE) is defined as any new adverse event experienced by a 
study subject that occurs after the initiation of (investigational) Medicinal Product 
((I)MP) administration; an event or pre-existing medical problem that has changed 
adversely in nature or severity from baseline in a patient/subject while receiving (I)MP.
The seriousness of AEs is assessed as “Death”, “Life-threatening condition”, “Persistent 
or significant incapacity”, “Hospitalization- initial or prolonged”, “Congenital anomaly or 
birth defect”, “Medically significant condition” and “Non-serious”.
The severity of all AEs is recorded as “Mild”, “Moderate” and “Severe”. 
The relationship between an AE and study drug is assessed as “Related”, “Possibly 
Related”, “Unlikely Related” and “Not Related”.
Action taken for AEs is recorded as “Drug Interrupted”, “Drug Withdrawn”, “Dose Not 
Changed”, “Not Applicable” and “Unknown”.
Adverse event outcome is assessed as “Recovered/Resolved”, “Recovering/Resolving”, 
“Recovered/Resolved with sequelae”, “Not recovered/Not resolved”, “Fatal” and 
“Unknown”.
The number and percentage of the TEAEs will be summarized overall by SOC (sorted 
alphabetically) and PT (sorted by descending overall total). 
Patients with more than one AE within a particular SOC or PT are counted only once for 
that PT and the maximum severity will be selected. AEs with missing intensity/severity 


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will be included in the overall count of patients with AEs, but will not be included in the 
counts in summary for severity.

Incidence of TEAEs

Incidence of TEAEs by severity

Incidence of potentially drug-related TEAEs (including ‘related’ and ‘possibly 
related’)

Incidence of TEAEs with an outcome of death

Incidence of treatment-emergent serious adverse events

Incidence of drug-discontinuations (drug withdrawn) due to TEAEs

Incidence of non-serious AEs [NSAE] with incidence rate 5% or higher by System 
Organ Class and MedDRA Preferred Term.
5.7.1.2
Clinical Laboratory Data
Data for the hematology, blood chemistry and urinalysis analytes received will be 
analyzed. The quantitative change in hematology, blood chemistry, and urinalysis 
analytes assessment results will be calculated relative to baseline. Laboratory tests with 
character results that cannot be quantitated by change from baseline will presented in 
tables with counts and percentages. Data obtained in the eCRF for additional analytes not 
required by the protocol will not be summarized, but will be included in listings.
Shift tables will be produced for assessing changes from baseline in clinical laboratory 
measurements using an ordinal scale (ie, low, normal, high based on lab normal range 
criteria). 
Summary for frequency and percentage of laboratory tests that are newly occurred clinical 
significant during the study will be summarized for each laboratory parameter by age 
group. The clinical significant lab test result criteria is based on Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events[1]. Lab 
results with severity grade 3 or above is defined as clinical significant for this study and 
the criteria are listed in Appendix 1.
Listings of lab test results that are clinically significant will be presented. 
A listing of all patients’ lab result will be presented for each lab test and the values that 
are abnormal will be flagged as low (L) or high (H) in data listings.
If there are repeats for a certain lab test at a visit, then the last repeat value will be used in 
summaries. Post-baseline data from all unscheduled visits will not be included in the 


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summary tables by visits, but will be included in clinical notable change table and 
listings.
5.7.1.3
Drug Induced Liver Injury (DlLI)
The potential DILI case will be presented in tables and listings: 

AST or ALT ≥3 x ULN and total bilirubin to >= 2 ULN
5.7.1.4
Physical Examination and Vital Signs 
Vital signs will be listed and summarized by age groups and by visits:

Weight (kg);

Weight percentile for age.

Height (cm); 

Height percentile for age

Body temperature (°C);

Heart rate (beats/min);

Respiratory rate (breaths/minute);

Systolic and diastolic blood pressure (mm Hg);

BMI (kg/m2).
Physical examination [HEENT; Thorax; Abdomen; Urogenital; Extremities;
Neurological; Skin and Mucosae] and vital signs data and changes from baseline in vital 
signs will be summarized by age group using Descriptive Continuous Statistics. 
In addition, a listing of patients with at least one potentially clinically significant vital 
signs result will be presented for each vital sign parameter. Criteria for potentially 
clinically significant vital sign abnormalities are listed in Appendix 2. Summary for 
potentially clinically significant vital signs by visit, and newly acquired potentially 
clinically significant result during the treatment period will be presented for each vital 
sign by age group. 
Post-baseline data from all unscheduled visits will not be included in the summary tables 
by visits, but will be included in clinical notable change table and listings.
5.7.1.5
Electrocardiogram Results
Continuous ECG parameters, including Heart rate, PR interval, QRS interval, QT 
intervals and QTc (including both QTcB and QTcF) will be summarized for:

Descriptive Continuous Statistics on actual measurements and change from baseline. 


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
Summary table for patients with potentially clinically significant results. Criteria for 
potentially clinically significant vital sign abnormalities are listed in Appendix 3.

Number and percentage of subjects with new qualitative abnormalities in rate, 
rhythm, conduction, morphology, including myocardial infarction, ST Segment, T 
Wave or U Wave abnormalities. 

Listing of patients with at least one potentially clinically significant ECG 
abnormalities result during the treatment period.
Data from all unscheduled visits will not be included in the summary tables for the 
changes from baseline by visits, but will be included in summary tables for the incidence 
of potentially clinically significant abnormalities and all listings.
5.7.1.6
Additional Safety Assessments
Visual and audiometry assessment results will be summarized and listed by study visits.
5.8
Extent of Exposure to Trial Medication
Number of days patients were exposed to IMP will be summarized by duration categories 
using counts and frequencies for the Safety Sample. 
Duration of exposure to study drug will be defined as (date of last dose - date of first dose 
+1). 
5.9
Treatment Compliance
Acceptability of delamanid will be summarized by visit by age group. And the dose 
administration of delamanid will be listed and DOT plan compliance is shown in the 
listing. 
5.10
Protocol Deviation
Protocol deviations, as a measure of quality of study conduct, are summarized by type of 
deviation, and by age group for the safety sample, using Descriptive Categorical 
Statistics. Protocol deviations collected from CRF and generated from programmable 
cross-checks of data will be pooled together and listed by type of deviation, and by 
patient respectively. Nature of the violation, specified as either major or minor, will be 
included in the listing.
5.11
Pharmacokinetic Analysis of Plasma
Delamanid and metabolite plasma concentrations will be reported with descriptive 
statistics at each visit day per age group.  In addition, delamanid data from this trial will 


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be combined with PK data from Trial 232 for a separate population PK analysis and 
report and will be conducted by Clinical Pharmacology group.
5.11.1
Pharmacokinetic Assessment of Cerebral Spinal Fluid (CSF) 
In patients where a lumbar puncture is clinically indicated during the routine management 
of a child enrolled in the trial, CSF concentrations of delamanid will be measured and 
reported. The delamanid CSF concentration will be listed by patient together with the 
timing of the lumbar puncture in relation to the timing of the dose.  If adequate data is 
available, the concentrations will be summarized using descriptive statistics.
5.12
Secondary Outcome Analysis
5.12.1
Pharmacokinetics/Phamacodynamics
PK/PD analysis will be performed by Clinical Pharmacology group to determine the 
relationship of delamanid and DM-6705 plasma concentrationsto any changes in QTc 
interval.
5.12.2
Efficacy Outcome Analysis
Descriptive Categorical Statistic will be summarized for each efficacy endpoint and 
presented in listings by patient, no formal statistical inference performed.

Chest radiography results;

Body weight/height

Investigator-assessed signs and symptoms of tuberculosis:
1) Cough; 
2) Fever; 
3) Weight loss; 
4) Failure to thrive;
5) Hemoptysis;
6) Dyspnea;
7) Chest pain;
8) Night sweats;
9) Loss of appetite;

Sputum culture conversion (SCC) will be assessed in patients with culture-positive 
and able to produce sputum or provide other biological specimens or with investigator 
order for purpose of routine management of the patient;


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5.12.3
Palatibility
The palatability of the pediatric formulation will be assessed using an age-appropriate 
visual hedonic scale and clinical assessment (Group 3 and 4 only). The counts and 
percentages will be tabulated in frequency tables.
5.12.4
Final Treatment Outcomes Assessed by the Principal 
Investigator
Final treatment outcomes will be assessed by the investigator at 24 months of initial IMP 
dose, according to the WHO outcome definitions for treating patients with MDR TB.
Treatment outcome (Cured, Treatment Completed, Died, Treatment Failed, Lost to 
follow-up, Not evaluated) will be provided by treatment group.  Frequency and 
percentage of patients achieving a favorable treatment outcome (cured or treatment 
completed) will be summarized by age group, using descriptive categorical statistics.
Listing of treatment outcome will also be provided by age group.
5.13
Concomitant Medications
Medications received concomitantly with study drug will be collected in the database and 
coded using the most recent WHO Drug Dictionary , Anatomical Therapeutic Chemical 
(ATC) Classification codes. 
Descriptive Categorical Statistics will be tabulated by drug classification according to age 
group for the following periods:

Prior to taking trial therapy; 

During the trial therapy; 

During the scheduled follow-up period after trial therapy complete.
5.14
Patient Disposition, Completion Rate and Reasons for 
Discontinuation
The number and percentage of patients who complete the trial and who discontinue early, 
including a breakdown of the primary reasons for discontinuation, will be summarized 
using Descriptive Categorical Statistics. Patients who are evaluated at the last scheduled 
visit of the trial, the follow-up visit (Visit 19, Day 365), will be defined as trial 
completers. The discontinuation by primary reasons will be summarized by age group for 
Enrolled and PK samples. 
5.15
Discontinuation
A patient disposition table will be presented including the following categories: 


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Safety (Treated)
Efficacy
PK
Early discontinued
Completed study treatment
The number and percentage of patients who complete the trial and who discontinue early, 
including a breakdown of the primary reasons for discontinuation, will be summarized 
using Descriptive Categorical Statistics. The discontinuation by primary reasons will be 
summarized by age group for Enrolled and PK samples: 
Lost to follow-up
Adverse events
Sponsor discontinued study
Subject met withdrawal criteria
Subject was withdrawn from participation by the investigator
Subject withdrew consent to participate
Protocol deviation
5.16
Interim Analysis
Safety, tolerability, PK, and efficacy of delamanid in children 6 to 17 years of age will be 
reviewed when a full complete data is available.


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6
Table of Contents for Table and Listings
CT-1   PATIENT DISPOSITION   ENROLLED SAMPLE
CT-2   REASONS FOR DISCONTINUATION   ENROLLED SAMPLE
CT-3.1   DEMOGRAPHIC CHARACTERISTICS: AGE, WEIGHT, HEIGHT, BMI, 
GENDER, ETHNICITY, RACE AND COUNTRY   SAFETY SAMPLE
CT-3.2.1   AUDIOMETRY, CHEST X-RAY, AND VISUAL ASSESSMENT AT 
BASELINE   SAFETY SAMPLE
CT-3.2.2   INVESTIGATOR-ASSESSED SIGNS AND SYMPTOMS OF 
TUBERCULOSIS AT BASELINE   SAFETY SAMPLE
CT-3.2.3   ANTI-TB TREATMENT HISTORY   SAFETY SAMPLE
CT-3.2.4   SUMMARY OF MEDICAL HISTORY   SAFETY SAMPLE
CT-4.1.1   CONCOMITANT MEDICATIONS (EXCLUDING ANTI-TB 
MEDICATIONS):  MEDICATIONS TAKEN PRIOR TO START OF TRIAL 
THERAPY   SAFETY SAMPLE
CT-4.1.2   CONCOMITANT MEDICATIONS(EXCLUDING ANTI-TB 
MEDICATIONS): MEDICATIONS TAKEN DURING STUDY THERAPY   SAFETY 
SAMPLE
CT-4.1.3   CONCOMITANT MEDICATIONS (EXCLUDING ANTI-TB 
MEDICATIONS): MEDICATIONS TAKEN AFTER END OF STUDY THERAPY   
SAFETY SAMPLE
CT-4.2.1   CONCOMITANT ANTI-TB MEDICATIONS: MEDICATIONS TAKEN 
PRIOR TO START OF TRIAL THERAPY   SAFETY SAMPLE
CT-4.2.2   CONCOMITANT ANTI-TB MEDICATIONS: MEDICATIONS TAKEN 
DURING STUDY THERAPY   SAFETY SAMPLE
CT-4.2.3   CONCOMITANT ANTI-TB MEDICATIONS: MEDICATIONS TAKEN 
AFTER END OF STUDY THERAPY   SAFETY SAMPLE
CT-5.1   PHARMACOKINETIC PARAMETERS   SAFETY SAMPLE
CT-5.2   SUMMARY OF FINAL OUTCOME AT THE END OF TREATMENT AS 
ASSESSED BY PRINCIPAL INVESTIGATOR AT 24 MONTHS   SAFETY SAMPLE
CT-5.3   SUMMARY OF PALATABILITY OF DELAMINID   SAFETY SAMPLE


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CT-5.4   SUMMARY OF AUDIOMETRY, CHEST X-RAY, AND VISUAL 
ASSESSMENTS   SAFETY SAMPLE
CT-5.5   SUMMARY OF INVESTIGATOR-ASSESSED SIGNS AND SYMPTOMS OF 
TUBERCULOSIS   SAFETY SAMPLE
CT-5.6   SUMMARY OF PERCENTILE OF WEIGHT AND HEIGHT   SAFETY 
SAMPLE
CT-6.1   PHARMACODYNAMIC ENDPOINTS   SAFETY SAMPLE
CT-6.2   LISTING OF CORRECTED QT INTERVALS AND PK PARAMETERS BY 
VISIT   SAFETY SAMPLE
CT-7.1   EXTENT OF EXPOSURE TO STUDY MEDICATION   SAFETY SAMPLE
CT-7.2   ADHERENCE TO STUDY MEDICATION   SAFETY SAMPLE
CT-8.1   ADVERSE EVENTS (ALL CAUSALITIES)   SAFETY SAMPLE
CT-8.2.1   INCIDENCE OF ALL TREATMENT-EMERGENT ADVERSE EVENTS 
BY SYSTEM ORGAN CLASS   SAFETY SAMPLE
CT-8.2.2   INCIDENCE OF ALL TREATMENT-EMERGENT ADVERSE EVENTS 
BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   SAFETY 
SAMPLE
CT-8.2.3   INCIDENCE OF ALL TREATMENT-EMERGENT ADVERSE EVENTS 
BY SYSTEM ORGAN CLASS, MEDDRA PREFERRED TERM AND SEVERITY   
SAFETY SAMPLE
CT-8.3.1   INCIDENCE OF POTENTIALLY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS   SAFETY 
SAMPLE
CT-8.3.2   INCIDENCE OF POTENTIALLY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND MEDDRA 
PREFERRED TERM   SAFETY SAMPLE
CT-8.3.3   INCIDENCE OF POTENTIALLY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS, MEDDRA 
PREFERRED TERM AND SEVERITY   SAFETY SAMPLE
CT-8.4.1   INCIDENCE OF DEATH DUE TO TREATMENT-EMERGENT ADVERSE 
EVENTS BY SYSTEM ORGAN CLASS   SAFETY SAMPLE


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CT-8.4.2   INCIDENCE OF DEATH DUE TO TREATMENT-EMERGENT ADVERSE 
EVENTS BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
SAFETY SAMPLE
CT-8.4.3   INCIDENCE OF DEATH BY SYSTEM ORGAN CLASS, MEDDRA 
PREFERRED TERM AND SEVERITY  SAFETY SAMPLE
CT-8.5.1   INCIDENCE OF SERIOUS TREATMENT-EMERGENT ADVERSE 
EVENTS BY SYSTEM ORGAN CLASS   SAFETY SAMPLE
CT-8.5.2   INCIDENCE OF SERIOUS TREATMENT-EMERGENT ADVERSE 
EVENTS BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
SAFETY SAMPLE
CT-8.5.3   INCIDENCE OF SERIOUS TREATMENT-EMERGENT ADVERSE 
EVENTS BY SYSTEM ORGAN CLASS, MEDDRA PREFERRED TERM AND 
SEVERITY   SAFETY SAMPLE
CT-8.6.1   INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS 
RESULTING IN DISCONTINUATION FROM STUDY MEDICATION BY SYSTEM 
ORGAN CLASS   SAFETY SAMPLE
CT-8.6.2   INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS 
RESULTING IN DISCONTINUATION FROM STUDY MEDICATION BY MEDDRA 
PREFERRED TERM   SAFETY SAMPLE
CT-8.6.3   INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS 
RESULTING IN DISCONTINUATION FROM STUDY MEDICATION BY MEDDRA 
PREFERRED TERM AND SEVERITY   SAFETY SAMPLE
CT-8.7.1   INCIDENCE (> 5%) OF NON-SERIOUS ADVERSE EVENTS BY SYSTEM 
ORGAN CLASS AND MEDDRA PREFERRED TERM   SAFETY SAMPLE
CT-8.8.1   LISTING OF DEATHS   SAFETY SAMPLE
CT-8.8.2   LISTING OF SERIOUS ADVERSE EVENTS   SAFETY SAMPLE
CT-8.8.3   LISTING OF DISCONTINUATIONS DUE TO ADVERSE EVENTS   
SAFETY SAMPLE
CT-9     SUMMARY OF PHYSICAL EXAMINATION   SAFETY SAMPLE
CT-10.1.1   MEAN CHANGE FROM BASELINE IN LABORATORY TEST 
RESULTS: SERUM CHEMISTRY   SAFETY SAMPLE


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CT-10.1.2   MEAN CHANGE FROM BASELINE IN LABORATORY TEST 
RESULTS: HEMATOLOGY   SAFETY SAMPLE
CT-10.1.3   MEAN CHANGE FROM BASELINE IN LABORATORY TEST 
RESULTS: URINALYSIS   SAFETY SAMPLE
CT-10.1.4   MEAN CHANGE FROM BASELINE IN LABORATORY TEST 
RESULTS: OTHERS   SAFETY SAMPLE
CT-10.1.5   SUMMARY OF CATEGORICAL LABORATORY TEST RESULTS: 
URINALYSIS   SAFETY SAMPLE
CT-10.2.1   SHIFT TABLES OF CLINICAL LABORATORY TEST RESULTS: 
SERUM CHEMISTRY   SAFETY SAMPLE
CT-10.2.2   SHIFT TABLES OF CLINICAL LABORATORY TEST RESULTS: 
HEMATOLOGY   SAFETY SAMPLE
CT-10.2.3   SHIFT TABLES OF CLINICAL LABORATORY TEST RESULTS: 
URINALYSIS   SAFETY SAMPLE
CT-10.2.4   SHIFT TABLES OF CLINICAL LABORATORY TEST RESULTS: 
OTHERS   SAFETY SAMPLE
CT-10.3.1   LISTING OF LABORATORY TEST VALUES OUTSIDE NORMAL 
RANGES, BY AGE GROUP:  SERUM CHEMISTRY   SAFETY SAMPLE
CT-10.3.2   LISTING OF LABORATORY TEST VALUES OUTSIDE NORMAL 
RANGES, BY AGE GROUP:  HEMATOLOGY   SAFETY SAMPLE
CT-10.3.3   LISTING OF LABORATORY TEST VALUES OUTSIDE NORMAL 
RANGES, BY AGE GROUP:  URINALYSIS   SAFETY SAMPLE
CT-10.3.4   LISTING OF LABORATORY TEST VALUES OUTSIDE NORMAL 
RANGES, BY AGE GROUP: OTHERS   SAFETY SAMPLE
CT-10.3.5   CRITERIA FOR LABORATORY TEST VALUES OUTSIDE NORMAL 
RANGES   SAFETY SAMPLE
CT-10.4.1   INCIDENCE OF CLINICALLY SIGNIFICANT LABORATORY TEST 
ABNORMALITIES:  SERUM CHEMISTRY   SAFETY SAMPLE
CT-10.4.2   INCIDENCE OF CLINICALLY SIGNIFICANT LABORATORY TEST 
ABNORMALITIES: HEMATOLOGY   SAFETY SAMPLE


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CT-10.4.3   INCIDENCE OF CLINICALLY SIGNIFICANT LABORATORY TEST 
ABNORMALITIES: URINANALYSIS   SAFETY SAMPLE
CT-10.5.1   INCIDENCE OF NEWLY ACQUIRED CLINICALLY SIGNIFICANT 
LABORATORY TEST ABNORMALITIES FROM BASELINE: SERUM CHEMISTRY   
SAFETY SAMPLE
CT-10.5.2   INCIDENCE OF NEWLY ACQUIRED CLINICALLY SIGNIFICANT 
LABORATORY TEST ABNORMALITIES FROM BASELINE: HEMATOLOGY   
SAFETY SAMPLE
CT-10.5.3   INCIDENCE OF NEWLY ACQUIRED CLINICALLY SIGNIFICANT 
LABORATORY TEST ABNORMALITIES FROM BASELINE: URINANALYSIS   
SAFETY SAMPLE
CT-10.5.4   CRITERIA FOR POTENTIALLY CLINICAL SIGNIFICANT 
LABORATORY TEST ABNORMALITIES   SAFETY SAMPLE
CT-10.6.1   LISTING OF CLINICALLY SIGNIFICANT LABORATORY 
ABNORMALITIES: SERUM CHEMISTRY   SAFETY SAMPLE
CT-10.6.2   LISTING OF CLINICALLY SIGNIFICANT LABORATORY 
ABNORMALITIES: HEMATOLOGY   SAFETY SAMPLE
CT-10.6.3   LISTING OF CLINICALLY SIGNIFICANT LABORATORY 
ABNORMALITIES: URINANALYSIS   SAFETY SAMPLE
CT-10.7.1   INCIDENCE AND PERCENTAGE OF ELEVATED LIVER ENZYMES 
AND POTENTIAL DRUG INDUCED LIVER INJURY   SAFETY SAMPLE
CT-10.7.2   LISTING OF AST OR ALT >= 3 x ULN WITH >= 2 x  ULN IN 
BILIRUBIN   SAFETY SAMPLE
CT-11.1   MEAN CHANGE FROM BASELINE IN VITAL SIGN PARAMETERS   
SAFETY SAMPLE
CT-11.2   INCIDENCE OF CLINICALLY SIGNIFICANT ABNORMALITY IN VITAL
SIGN   SAFETY SAMPLE
CT-11.3   LISTING OF POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITY IN VITAL SIGNS   SAFETY SAMPLE
CT-11.4   CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITY IN VITAL SIGNS   SAFETY SAMPLE


Protocol: 242-12-233
Statistical Analysis Plan                                        25 of 33
Version Date: 3 July 2019
CT-12.1   MEAN CHANGE FROM BASELINE IN ELECTROCARDIOGRAM 
PARAMETERS   SAFETY SAMPLE
CT-12.2   INCIDENCE OF CLINICALLY SIGNIFICANT ELECTROCARDIOGRAM 
TEST ABNORMALITIES   SAFETY SAMPLE
CT-12.3   LISTING OF POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITY IN ELECTROCARDIOGRAM   SAFETY SAMPLE
CT-12.4   CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITY IN ELECTROCARDIOGRAM   SAFETY SAMPLE
PDATA-1   ENTRANCE CRITERIA
PDATA-2   ELIGIBILITY: INCLUSION-EXCLUSION CRITERIA
PDATA-3.1   SUBJECT DISPOSITION
PDATA-3.2   STUDY COMPLETION STATUS AND REASONS FOR 
DISCONTINUATION
PDATA-4.1   DEMOGRAPHIC CHARACTERISTICS: AGE, SEX, HEIGHT, 
WEIGHT, BMI, RACE, AND ETHNICITY
PDATA-4.2   AUDIOMETRY, CHEST X-RAY,  AND VISUAL  ASSESSMENTS
PDATA-4.3   INVESTIGATOR-ASSESSED SIGNS AND SYMPTOMS OF 
TUBERCULOSIS
PDATA-4.4   PREGNANCY TEST RESULTS
PDATA-4.5   SPECIMEN COLLECTION FOR MICROBIOLOGY TEST RESULTS
PDATA-4.6   PALATABILITY ASSESSMENT
PDATA-5   GENERAL MEDICAL HISTORY
PDATA-6.1   CONCOMITANT MEDICATIONS: MEDICATIONS TAKEN PRIOR TO 
START OF STUDY THERAPY
PDATA-6.2   CONCOMITANT MEDICATIONS: MEDICATIONS TAKEN DURING 
STUDY THERAPY
PDATA-6.3   CONCOMITANT MEDICATIONS: MEDICATIONS TAKEN AFTER 
END OF STUDY THERAPY


Protocol: 242-12-233
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PDATA-6.4   CONCOMITANT ANTI-TB MEDICATIONS: MEDICATIONS TAKEN 
PRIOR TO START OF STUDY THERAPY
PDATA-6.5   CONCOMITANT ANTI-TB MEDICATIONS: MEDICATIONS TAKEN 
DURING STUDY THERAPY
PDATA-6.6   CONCOMITANT ANTI-TB MEDICATIONS: MEDICATIONS TAKEN 
AFTER END OF STUDY THERAPY
PDATA-7.1   DOSE ADMINISTRATION
PDATA-7.2   STUDY MEDICATION
PDATA-7.3   STUDY MEDICATION ACCOUNTABILITY
PDATA-7.4   OBR ACCEPTABILITY
PDATA-8.1   PHYSICAL EXAMINATION
PDATA-8.2   MENSTRUATION
PDATA-9   VITAL SIGNS
PDATA-10.1   ELECTROCARDIOGRAM RESULTS
PDATA-10.2   ELECTROCARDIOGRAM RESULTS - DIAGNOSIS
PDATA-11   ADVERSE EVENTS
PDATA-12   PK BLOOD SAMPLING
PDATA-13   LAST DOSE OF DELAMANID PRIOR TO PK SAMPLING
PDATA-14   LISTING OF TUBERCULOSIS DIAGNOSIS RESULT
PDATA-15   TREATMENT OUTCOME
DEMOG-1   LISTING OF DEMOGRAPHIC CHARACTERISTICS
DREAS-1   DISCONTINUED SUBJECTS AND REASON FOR DISCONTINUATION
SMED-1   STUDY MEDICATION COMPLIANCE OF OPC-67683
AE-1   ADVERSE EVENTS
LAB-1   LABORATORY TEST RESULTS: SERUM CHEMISTRY
LAB-2   LABORATORY TEST RESULTS: HEMATOLOGY
LAB-3   LABORATORY TEST RESULTS:  URINALYSIS


Protocol: 242-12-233
Statistical Analysis Plan                                        27 of 33
Version Date: 3 July 2019
LAB-4   LABORATORY TEST RESULTS: OTHERS
PDEV-1   SUMMARY OF PROTOCOL DEVIATIONS BY AGE GROUP AND TYPE 
OF DEVIATION
PDEV-2   PROTOCOL DEVIATIONS BY DEVIATION TYPE
PDEV-3   LISTING OF PROTOCOL DEVIATIONS
PDEV-4   PROTOCOL DEVIATIONS CRITERIA


Protocol: 242-12-233
Statistical Analysis Plan                                        28 of 33
Version Date: 3 July 2019
7
Bibliography
1
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Version 2.1. July 2017


Statistical Analysis Plan                                        29 of 33
Version Date: 3 July 2019
Appendix 1
Serum Chemistry, Hematology and Urinalysis Lab Test Results Clinical Significant Criteria Based on 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events
LAB GROUP
TEST
UNITS
SEX
AGE Group
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Chemistry
Albumin, Low
g/dL
Male/Female
All
< 2.0
NA
Chemistry
Albumin, Low
g/L
Male/Female
All
< 20
NA
Chemistry
Alkaline Phosphatase, High
Male/Female
All
5.0 to < 10.0 x ULN
≥ 10.0 x ULN
Chemistry
ALT or SGPT, High
Male/Female
All
5.0  to < 10.0 x ULN
≥ 10.0 x ULN
Chemistry
AST or SGOT, High
Male/Female
All
5.0  to < 10.0 x ULN
≥ 10.0 x ULN
Chemistry
Total Bilirubin, High
Male/Female
> 28 days of age
2.6 to < 5.0 x ULN
≥5.0 x ULN
Chemistry
Calcium, High
mg/dL
Male/Female
≥ 7 days of age
12.5 to < 13.5
≥13.5
Chemistry
Calcium, High
mmol/L
Male/Female
≥ 7 days of age
3.13  to < 3.38
≥3.38
Chemistry
Calcium, Low
mg/dL
Male/Female
≥ 7 days of age
6.1  to < 7.0
< 6.1
Chemistry
Calcium, Low
mmol/L
Male/Female
≥ 7 days of age
1.53  to < 1.75
< 1.53
Chemistry
Creatinine, High
Male/Female
All
> 1.8 to < 3.5 x ULN
≥ 3.5 x ULN
Chemistry
Glucose, High
mg/dL
Male/Female
All
> 250 to 500
≥500
Chemistry
Glucose, High
mmol/L
Male/Female
All
13.89 to < 27.75
≥ 27.75
Chemistry
Glucose, Low
mg/dL
Male/Female
≥ 1 month of age
30 to < 40
< 30
Chemistry
Glucose, Low
mmol/L
Male/Female
≥ 1 month of age
1.67 to < 2.22
< 1.67
Chemistry
Cholesterol, High
mg/dL
Male/Female
All
≥300
NA
Chemistry
Cholesterol, High
mmol/L
Male/Female
All
≥7.77
NA
Chemistry
Inorganic Phosphorus, Low
mg/dL
Male/Female
> 14 years of age
1.0 to < 1.4
< 1.0
Chemistry
Inorganic Phosphorus, Low
mmol/L
Male/Female
> 14 years of age
0.32 to < 0.45
< 0.32
Chemistry
Inorganic Phosphorus, Low
mg/dL
Male/Female
<1 to 14 years of age
1.5  to < 2.5
< 1.5
Chemistry
Inorganic Phosphorus, Low
mmol/L
Male/Female
<1 to 14 years of age
0.48 to < 0.81
< 0.48
Chemistry
Magnesium, Low
mEq/L
Male/Female
All
0.6  to < 0.9
< 0.6
Chemistry
Magnesium, Low
mmol/L
Male/Female
All
0.30 to < 0.45
< 0.30
Chemistry
Potassium, High
mEq/L
Male/Female
All
6.5  to < 7.0
≥ 7.0
Chemistry
Potassium, High
mmol/L
Male/Female
All
6.5  to < 7.0
≥ 7.0


Protocol: 242-12-233
Statistical Analysis Plan                                        30 of 33
Version Date: 3 July 2019
LAB GROUP
TEST
UNITS
SEX
AGE Group
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Chemistry
Potassium, Low
mEq/L
Male/Female
All
2.0  to < 2.5
< 2.0
Chemistry
Potassium, Low
mmol/L
Male/Female
All
2.0  to < 2.5
< 2.0
Chemistry
Sodium, High
mEq/L
Male/Female
All
154  to < 160
≥ 160
Chemistry
Sodium, High
mmol/L
Male/Female
All
154  to < 160
≥ 160
Chemistry
Sodium, Low
mEq/L
Male/Female
All
121  to < 125
≤ 120
Chemistry
Sodium, Low
mmol/L
Male/Female
All
121  to < 125
≤ 120
Chemistry
Triglycerides, High
mg/dL
Male/Female
All
>500 to < 1,000
> 1,000
Chemistry
Triglycerides, High
mmol/L
Male/Female
All
>5.7 to 11.4
> 11.4
Chemistry
Uric Acid, High
mg/dL
Male/Female
All
12.0 to < 15.0
≥ 15.0
Chemistry
Uric Acid, High
mmol/L
Male/Female
All
0.71 to < 0.89
≥ 0.89
Hematology
Activated Partial Thromboplastin 
Time, High
Male/Female
All
2.33 to < 3.00 x ULN
≥3.00 x ULN
Hematology
Absolute CD4+ Count, Low
cell/mm3
Male/Female
All> 5 years of age
(not HIV infected)
100 to < 200
< 100
Hematology
Absolute CD4+ Count, Low
cells/L
Male/Female
> 5 years of age
(not HIV infected)
100 to < 200
< 100
Hematology
Absolute Lymphocytes, Low
cell/mm3
Male/Female
> 5 years of age
(not HIV infected)
350 to < 500
< 350
Hematology
Absolute Lymphocytes, Low
cells/L
Male/Female
> 5 years of age
(not HIV infected)
0.350 x 109 to < 0.500 x 109
< 0.350 x 109
Hematology
Absolute Neutrophil Count, Low
cell/mm3
Male/Female
> 7 days of age
400 to 599
<400
Hematology
Absolute Neutrophil Count, Low
cells/L
Male/Female
> 7 days of age
0.400 x 109 to < 0.599 x 109
< 0.400 x 109
Hematology
Hemoglobin, Low
g/dL
Male
≥ 13 years of age
7.0 to < 9.0
< 7.0
Hematology
Hemoglobin, Low
mmol/L
Male
≥ 13 years of age
4.34 to < 5.57
< 4.34
Hematology
Hemoglobin, Low
g/dL
Female
≥ 13 years of age
6.5 to < 8.5
< 6.5
Hematology
Hemoglobin, Low
mmol/L
Female
≥ 13 years of age
4.03 to < 5.25
< 4.03
Hematology
Hemoglobin, Low
g/dL
Male/Female
57 days of age to
< 13 years of age
6.5 to < 8.5
< 6.5
Hematology
Hemoglobin, Low
mmol/L
Male/Female
57 days of age to
< 13 years of age
4.03 to < 5.25
< 4.03
Hematology
Platelet Count, Decreased
cells/mm3
Male/Female
All
25,000 to < 50,000
< 25,000
Hematology
Platelet Count, Decreased
cells/L
Male/Female
All
25.000 x 109 to < 50.000 x 109
< 25.000 x 109
Hematology
Prothrombin Time, High
Male/Female
All
1.50 to < 3.00 x ULN
≥3.00 x ULN


Protocol: 242-12-233
Statistical Analysis Plan                                        31 of 33
Version Date: 3 July 2019
LAB GROUP
TEST
UNITS
SEX
AGE Group
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Hematology
Partial Thromboplastin Time, High
Male/Female
All
2.33 to < 3.00 x ULN
≥3.00 x ULN
Hematology
White Blood Cell, Decreased
cells/mm3
Male/Female
> 7 days of age
1,000 to 1,499
< 1,000
Hematology
White Blood Cell, Decreased
cells/L
Male/Female
> 7 days of age
1.000 x 109 to 1.499 x 109
< 1.000 x 109
Urinalysis
Urine Glucose
Male/Female
All
> 2+ or >500 mg
NA
Urinalysis
Urine Blood
Male/Female
All
Gross OR Presence of RBC casts 
OR Intervention indicated
Life-threatening consequences
Urinalysis
Urine Protein
Male/Female
All
3+ or higher
NA
RBC = red blood cell; ULN=upper normal limit


Statistical Analysis Plan                                        32 of 33
Version Date: 3 July 2019
Appendix 2
Criteria for Potentially Clinical Significant Vital Sign 
Abnormalities
Variable
Change Relative to Baseline
Weight
Decrease of >=5% in body weight 
Increase of >=5% in body weight        
Note: In order to be identified as “potentially clinical significant abnormal,” an on-drug 
value must represent a change from the patient’s baseline value of at least the magnitude
shown in the “Change Relative to Baseline column. 


Protocol: 242-12-233
Statistical Analysis Plan                                        33 of 33
Version Date: 3 July 2019
Appendix 3
Criteria for Potentially Clinical Significant ECG 
Abnormalities
Classification
Criterion Value
Change Relative to Baseline
HR Outliers    
               
< 50 bpm              
Decrease of >= 25%    
> 100 bpm             
Increase of >= 25%    
PR Outliers    
> 200 msec             
Increase of >= 25%   
QRS Outliers   
> 100 msec             
Increase of >= 25%   
QT             
New Onset (> 500 msec) §
                     
QTcB           
New Onset (> 450 msec) §
New Onset (> 480 msec) §
New Onset (> 500 msec) §
Increase of >= 30 msec and <=60 msec
Increase of >60 msec
QTcF
New Onset (> 450 msec) §
New Onset (> 480 msec) §
New Onset (> 500 msec) §
Increase of >= 30 msec and <=60 msec
Increase of > 60 msec
U Waves        
New Abnormal U Waves   
ST Segment     
New ST Segment Changes 
T Waves        
New T Wave Changes     
Rhythm         
New Abnormal Rhythm    
Conduction
New Conduction  Abnormality  
Note: In order to be identified as “potentially clinical significant abnormal,” an on-drug value must meet 
the “Criterion Value” and also represent a change from the patient’s pretreatment value of at least the 
magnitude shown in the “Change Relative to Baseline column. 
§ New Onset is defined as “not present on baseline ECG but present on on-treatment ECG”.  New Onset 
(> 450 msec), or New Onset (> 480 msec), or New Onset (> 500 msec) means a patient who attains a 
value >450 msec, or >480 msec, >500 msec respectively during treatment period but not at baseline 
visit.


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Biostatistics Approval
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