A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Bedaquiline (BDQ) Given in Combination With an Individualized Rifampin-Resistant Tuberculosis (RR-TB) Therapy in Infants, Children, and Adolescents With RR-TB Disease, Living With or Without HIV
Phase: PHASE1
Conditions: Tuberculosis, HIV
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Letter of Amendment #1 
Page 1 of 6 
2 May 2023 
IMPAACT P1108 Protocol Version 2.0 
Letter of Amendment #1 for: 
 
IMPAACT P1108 
A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability of Bedaquiline (BDQ) Given in Combination with an 
Individualized Rifampin-Resistant Tuberculosis (RR-TB) Therapy in Infants, 
Children, and Adolescents with RR-TB Disease, Living with or without HIV  
 
Version 2.0, dated 21 September 2022 
 
 DAIDS Study ID #11884 
IND #131,832 Held By DAIDS 
 
Letter of Amendment Date: 2 May 2023 
 
 
Table of Contents 
Table of Contents .......................................................................................................................................... 1 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications and Rationale .................................................................................................... 3 
Implementation ............................................................................................................................................. 3 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT P1108 study and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed. 
 
Upon obtaining all required IRB/EC and regulatory entity approvals, each site should begin implementing 
this LoA. Sites are required to submit an LoA registration packet to the DAIDS Protocol Registration 
Office (DAIDS PRO) at the Regulatory Support Center (RSC). Sites will receive a registration 
notification for the LoA after the DAIDS PRO verifies that all required registration documents have been 
received and are complete. Sites should not await this notification before implementing this LoA. 
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT P1108. If the IMPAACT P1108 
protocol is amended in the future, applicable contents of this LoA will be incorporated into the next 
version of the protocol. 
 
 

Letter of Amendment #1 
Page 2 of 6 
2 May 2023 
IMPAACT P1108 Protocol Version 2.0 
IMPAACT P1108 
A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and 
Tolerability of Bedaquiline (BDQ) Given in Combination with an Individualized Rifampin-
Resistant Tuberculosis (RR-TB) Therapy in Infants, Children, and Adolescents with RR-
TB Disease, Living with or without HIV  
 
 DAIDS Study ID #11884 
 
Version 2.0, Letter of Amendment #1 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Council on Harmonisation Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 

Letter of Amendment #1 
Page 3 of 6 
2 May 2023 
IMPAACT P1108 Protocol Version 2.0 
Summary of Modifications and Rationale 
 
The primary purpose of this LoA is to remove accrual requirements for participants living with HIV in 
each cohort to minimize delays in study completion due to a general decline in potential participants 
living with HIV presenting for RR-TB treatment. This LoA also incorporates the contents of protocol 
Version 2.0 Clarification Memorandum #1, dated 29 March 2023; clarifies expectations for confirming 
BDQ adherence prior to the Week 2 visit; and updates the protocol team and study site rosters to reflect 
current membership. 
 
 
Implementation 
 
Modifications of protocol text are presented below. Where applicable, modified text is shown using 
strikethrough for deletions and bold type for additions. 
 
1. Schema, Sample Size: 
 
Up to 84 participants total (24 for Cohort 1; 30 for Cohort 2; 30 for Cohort 3) to achieve 54 evaluable 
participants (18 per age cohort): 
Cohort 1: Age ≥ 6 to < 18 years  
Cohort 2: Age ≥ 2 to < 6 years  
Cohort 3: Age ≥ 0 to < 2 years 
 
In each cohort, at least three participants living with HIV will be enrolled. 
 
2. Section 3.1, Cohort Approach, second paragraph: 
 
Up to 24 participants in Cohort 1, up to 30 participants in Cohort 2, and up to 30 participants in 
Cohort 3 will be enrolled to achieve at least 18 evaluable participants in each cohort. In Cohort 1, up 
to 12 participants will be enrolled in each of the two weight bands (15 to < 30 kg and ≥30 kg) to 
achieve approximately nine evaluable participants in each weight band. In each cohort, at least three 
participants living with HIV will be enrolled. See Section 9.4 for further details on participant 
evaluability and replacement of non-evaluable participants. 
 
3. Section 4.3, Determination of HIV Status, the first paragraph is removed: 
 
At least nine participants living with HIV (at least three per cohort) will be enrolled in the study. In 
consultation with the DAIDS and Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) Medical Officers, if there is agreement regarding the need for 
additional data in participants living with HIV (e.g., possible differences are observed in BDQ 
exposure related to drug-drug interactions) additional participants living with HIV (e.g., up to 5-10) 
may be enrolled across all cohorts, unless the maximum cohort sample size has been reached.  
 

Letter of Amendment #1 
Page 4 of 6 
2 May 2023 
IMPAACT P1108 Protocol Version 2.0 
4. Section 6.3, Week 1 Visit, Participants who received non-study BDQ doses prior to Entry and will 
have intensive PK sampling at the Week 1 visit, last paragraph: 
 
BDQ TIW dosing will be initiated after the intensive PK sampling is completed (see Section 5.3). At 
the Week 1 visit, applicable reminders should be provided for the scheduled Week 2 visit (see Section 
6.4). The date, time, and dose amount administered for the two BDQ daily doses preceding the 
Week 2 visit should be confirmed prior to the visit. If this dosing information is not confirmed 
for the last BDQ dose taken prior to the Week 2 visit, the visit should be rescheduled within the 
allowable visit window, with adherence support provided to help ensure appropriate dose 
administration on days preceding the rescheduled visit date. The participant and/or 
caregiver/guardian should be reminded not to administer BDQ at home on the day of sparse PK 
sampling at the Week 2 visit. 
 
5. Section 9.4, Sample Size and Accrual, second paragraph: 
 
Total accrual will depend on the number of participants who must be enrolled to achieve a 
minimum of 18 participants in each of the three age cohorts with evaluable PK data, including 
approximately nine participants with evaluable PK data in each weight band in Cohort 1. At least 
three participants living with HIV will be enrolled in each cohort. 
 
6. Section 9.6.1, Primary Safety Analyses, first paragraph:  
 
The primary safety analyses will focus on the 24-week time period during BDQ treatment and will 
include only participants whose total exposure to BDQ has been was at the final BDQ dose 
recommended implemented dose for their cohort for the protocol-specified period of BDQ 
administration. Participants who have been removed from treatment, or who have had their doses 
reduced as part of cohort management due to toxicities, will be included and treated as safety failures 
in the primary safety analysis (note that such participants may have to be excluded from any 
secondary analyses which require complete follow-up at the optimal dose). Participants whose doses 
have been adjusted on the basis of PK results will be excluded from these primary analyses, 
regardless if the participant initiated BDQ at the final recommended implemented dose, and 
sensitivity analyses performed in an attempt to determine whether the exclusion of these participants 
creates a selection bias which impacts upon any results. These primary analyses will be performed 
after the last participant of the last cohort has completed the study drug regimen over the 24-week 
dosing period.  
 
7. Section 9.6.1, Primary Safety Analyses, fourth paragraph:  
 
In addition, if possible, a primary evaluation of safety across the 24 weeks of study treatment will be 
performed on the data from participants who have been started at the final recommended dose for a 
given cohort and have remained on that dose for the 24-week period or have left the study or had a 
dose modification due to safety failure prior to 24 weeks of exposure (in which case the participant 
will be analyzed as a failure). Note that such an analysis may not be possible, since the PK modeling 
procedure which will determine the final recommended dose will not guarantee that an adequate 
number of participants be on that dose. However, secondary safety analyses will include all safety 
data collected from first participant exposure to the end of the study, with results broken down by 
dose. This will include data representing the final implemented dose for each cohort, as well as data 
gathered during the dose finding stage, which may represent exposure to doses which have failed. 

Letter of Amendment #1 
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2 May 2023 
IMPAACT P1108 Protocol Version 2.0 
8. Section 9.6.2.1, Safety, first paragraph: 
 
The 24-week analyses described above for the primary analysis will be repeated as secondary 
analyses at 72 weeks after BDQ discontinuation and by HIV status. Of note, precision may be limited 
for participants living with HIV, and for cohorts with few participants living with HIV (e.g., one 
or two participants), estimation with confidence limits will not be feasible particularly if only the 
required minimum number of participants living with HIV are enrolled. In addition, descriptive and 
exposure-related analyses will present safety data from participants whose doses have undergone 
individual adjustment or who were treated on doses other than the final recommended implemented 
dose for their cohorts. 
 
9. Section 9.6.2.2, TB Treatment Outcomes: 
 
This Phase I/II study will only be able to describe treatment response in participants; this is not an 
efficacy trial. The proportions of participants classified at the end of their RR-TB treatment regimen 
as having exhibited bacteriological cure (defined under Section 8.5), and clinical (probable) cure, will 
be presented, bounded with 95% CIs. The proportions of participants classified at the end of study 
(Week 96/End of Study or Early Study D/C visits) as having exhibited bacteriological cure with no 
TB recurrence (defined under Section 8.5), and clinical (probable) cure with no TB recurrence, will 
be presented, bounded with 95% CIs. Participants who were classified as lost to follow-up will be 
excluded from the analysis set used to compute these proportions and CIs. The time to culture-
conversion (in weeks, months) in participants with bacteriological confirmation will be presented. 
Descriptive analyses will compare those who convert their bacteriology with those who fail to do so 
over pre-specified time periods with respect to overall exposure to study drug as estimated by PK 
modeling. Similar analyses will also be performed by HIV status, as data allow. Of note, precision 
may be limited for participants living with HIV, and for cohorts with few participants living with 
HIV (e.g., one or two participants), estimation with confidence limits will not be feasible 
particularly if only the required minimum number of participants living with HIV are enrolled.  
 
10. Section 10.2.1, Number of Participants: 
 
Each cohort will enroll a minimum of 18 participants. Based on existing information on the dose-
exposure relationship for BDQ in adults (58) and a simulation study to evaluate the expected power 
and parameter precision with the suggested sampling schedule and number of participants (see 
Appendix X), this number is expected to be sufficient to estimate the main PK parameter, clearance 
(CL), with acceptable precision (85). The simulation study also showed that this sample size, 
including six participants living with HIV in each age group of 18, will have almost 90% power to 
detect a 30% difference between participants living with and without HIV in either CL or 
bioavailability (F) with the selected design. A minimum of three participants living with HIV will be 
enrolled in each cohort. If less than six participants living with HIV are enrolled in a cohort, then the 
power will be reduced.  
 
 

Letter of Amendment #1 
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2 May 2023 
IMPAACT P1108 Protocol Version 2.0 
11. To reflect current protocol team membership, Sarah Buisson, Madison Cooper, and Mats Karlsson 
are removed from the protocol team roster (deletions not shown). Andrea McMunn is added, and 
Kelly Dooley’s contact information is updated as shown below. 
 
Protocol Pharmacist 
Andrea McMunn, PharmD, BCPPS 
NIH, NIAID, DAIDS, PAB  
5601 Fishers Lane, Room 9E28 
Rockville, MD 20892-9829 
Phone: 240-571-1945 
Email: andrea.mcmunn@nih.gov 
 
Protocol Pharmacologist 
Kelly Dooley, MD, PhD 
Vanderbilt University Medical Center 
1161 21st Avenue South, A2200 MCN 
Nashville, TN  37232 
Phone: 615-343-6160 
Email: kelly.e.dooley@vumc.org 
 
12. To reflect current membership at site 31441, Uday Rajput and Nishi Suryavanshi are removed from 
the study site roster (deletions not shown) and Aarti Kinikar and Mandar Paradkar have been added. 
 
Site 31441, Byramjee Jeejeebhoy Medical College (BJMC)  
Aarti Kinikar, MD 
Investigator of Record 
BJMC and Sassoon General Hospitals 
Infosys Building, 2nd Floor, Room No. 6 
Jai Prakash Narayan Road 
Pune, Maharashtra 411001 
India 
Phone: 91 98 500 39063 
Email: aarti.kinikar63@gmail.com 
Mandar Paradkar, MBBS, MPH 
Study Coordinator 
BJMC and Sassoon General Hospitals 
Infosys Building, 2nd Floor, Room No. 6 
Jai Prakash Narayan Road 
Pune, Maharashtra 411001 
India 
Phone: 91 98 234 57325 
Email: mparadk1@jhu.edu