A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study
Phase: PHASE2
Conditions: HIV, Tuberculosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
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ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems, Inc., a DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
 
 
 
LETTER OF AMENDMENT #1 
 
DATE:  
June 22, 2023 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5362 Protocol Team  
 
SUBJECT: 
Letter of Amendment #1 for Protocol A5362, Version 2.0 
 
 
The following information affects the A5362 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) should be implemented 
immediately, prior to IRB/EC approval, to eliminate immediate hazard to participants.  
 
The following information also affects the Sample Informed Consent (SIC). A letter 
informing participants about the contents of this LOA and an addendum to the SIC were 
provided electronically to sites on 16Jun2023.  
 
Sites should implement the LOA immediately and inform IRB/EC and any other applicable 
regulatory entities of the LOA. Sites are still required to submit an LOA registration packet 
to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support Center (RSC). 
Sites will receive a registration notification for the LOA once the DAIDS PRO verifies that 
all required LOA registration documents have been received and are complete. An LOA 
registration notification from the DAIDS PRO is not required prior to implementing the 
LOA. A copy of the LOA registration notification, along with this letter and any IRB/EC 
correspondence, should be retained in the site’s regulatory file. 
 
In April 2023, the study temporarily closed to screening and accrual due to an unanticipated 
trend in outcome events, which triggered review by the National Institute of Allergy and 
Infectious Diseases (NIAID) Therapeutic and Prevention Data and Safety Monitoring Board 
(DSMB), which met on 01Jun2023 to review all available safety and efficacy data from A5362. 
The DSMB recommended that A5362 permanently close to accrual because of the high rate of 
treatment failure and TB recurrence. There were no other safety concerns related to study 
regimen. The A5362 team, NIAID and DAIDS leadership, and ACTG leadership concur with the 
following DSMB recommendations for implementation: 
• 
Permanently close A5362 to accrual. 

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• 
Participants currently receiving treatment in the experimental arm (Arm 1) should finish 
their 3-month experimental regimen 
[rifapentine/isoniazid/pyrazinamide/ethambutol/clofazimine (PHZEC)] and then be placed 
on an additional 3 months of continuation phase rifampicin/isoniazid (RH) regimen. 
• 
Participants in Arm 1 who have already finished the experimental regimen in Arm 1 
without an unfavorable outcome, should be followed closely for the duration of the trial. 
The DSMB suggests that the investigators consider strategies for more intensive follow-
up of these participants to ascertain recurrences, and that those diagnosed with 
recurrence be referred for 6 months of SOC treatment. 
• 
Participants in Arm 1 follow-up will be extended to 117 weeks, as outlined below. 
 
As referenced in the investigator and IRB/EC letters sent to A5362 sites on 16Jun2023, this 
LOA formally outlines changes to Version 2.0 of A5362, dated 08Jul2022, given the 
abovementioned DSMB recommendations.  
 
There are no changes to the Sample Informed Consent (SIC) in this LOA. Refer to the SIC 
addendum for the updated information to provide to participants and for reconsenting 
participants. 
 
This LOA also includes revisions from the 26Sep2022 DSMB review, in which the DSMB 
requested that the team specify the monitoring of the unfavorable composite outcome per 
definition 10.2.4A. 
 
 

A5362, Version 2.0 LOA #1 (22Jun2023) 
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TABLE OF CONTENTS 
 
1. 
Section SCHEMA, DESIGN ............................................................................................ 4 
2. 
Section SCHEMA, DURATION ....................................................................................... 5 
3. 
Section SCHEMA, REGIMEN ......................................................................................... 5 
4. 
Section 1.4, Exploratory Objectives ................................................................................ 5 
5. 
Section 3.0, STUDY DESIGN ......................................................................................... 5 
6. 
Section 6.1, Schedule of Evaluations ............................................................................. 6 
7. 
Section 6.2.3 Post-Entry Evaluations .............................................................................. 7 
8. 
Section 6.3, Instructions for Evaluations ......................................................................... 7 
9. 
Section 10.5.1, Interim Monitoring Guidelines ................................................................. 7 
10. 
Section 10.5.2, Interim Analysis Plan ............................................................................. 7 
11. 
Appendix I-C, ADDENDUM TO SAMPLE INFORMED CONSENT ................................. 8 
12. 
Protocol Signature Page (PSP) ...................................................................................... 8 
 
 
 
 

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The following are changes (noted in bold or strikethrough) to A5362, Version 2.0, 08Jul2022, 
titled A “Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening 
Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study.” These changes will be 
included in the next version of the A5362 protocol if it is amended at a future date. Changes that 
have already been made (Clarification Memo #1) have been incorporated in the excerpted text 
shown below (and are no longer presented in bold or strikethrough).  
 
1. Section SCHEMA, DESIGN 
 
The following information has been added to reference the change in study design due to a 
DSMB review. 
 
Per the June 1, 2023 DSMB review, and permanent closure of accrual, the follow-
up schedules for Arm 1 participants will be revised as follows: 
 
• 
Participants currently on Arm 1 study treatment should complete the 3-
month regimen and then be placed on an additional 3 months of 
continuation phase rifampicin/isoniazid (RH). Based on the DSMB 
recommendations, an additional 3 months of treatment is necessary to 
decrease the likelihood of treatment failure and TB relapse in study 
participants.  
 
• 
Participants who have already completed Arm 1 treatment should be seen 
for a follow-up visit within the next 4 weeks of the date of this LOA, at a 
scheduled or unscheduled visit, to assess whether further treatment is 
needed.  
 
• 
Additional extended follow-up visits for participants in Arm 1 will be added 
at weeks 30, 38, 60, 91 and 117 unless the participant has already been 
referred for, or already received, 6 months of SOC through the local TB 
program. The additional visits at weeks 30, 38, and 60 may be performed by 
telephone only; these calls are to assess the participant’s TB symptoms 
and determine if it is clinically indicated that the participant should come in 
for an in-person visit to assess the need for possible poor treatment 
response (PPTR) assessments and/or referral to SOC treatment.  
 
• 
If the site investigator diagnoses TB recurrence at any time during Arm 1 
follow up, the participant should be referred to 6 months of SOC treatment 
by the national TB program. For study purposes, such participants should 
continue to be followed in the study for outcome determination, unless the 
participant withdraws consent. 
 
Participants in Arm 2 and Arm C should complete their treatment and follow-up 
schedule as planned; no additional visits are planned for these groups.  
 

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2. Section SCHEMA, DURATION  
 
Arm 1: 
• 
Up to 117 weeks. 
• 
65 weeks for participants who are or have been diagnosed with TB 
treatment failure or recurrence and are or have been referred to six months 
of local SOC treatment by the national/local TB program.  
 
Arm 2: 65 weeks 
 
Arm C: 65 weeks 
 
3. Section SCHEMA, REGIMEN  
 
The following paragraph has been included to add three months of rifampicin/isoniazid for 
Arm 1 participants who are currently receiving the experimental 3-month treatment regimen 
as of 16Jun2023. The treatment regimen for all other participants will remain the same. 
 
Arm 1 participants receiving the experimental 3-month treatment regimen as of 
16Jun2023: 
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 300 mg 
once daily for 2 weeks; then PHZE + CFZ 100 mg once daily for 6 weeks; then 
rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg once daily for 5 weeks; 
then rifampicin/isoniazid (RH) for 13 weeks for a total of 26 weeks of study 
treatment.  
 
4. Section 1.4, Exploratory Objectives 
 
The following objective has been added to align with the addition of Drug-Susceptibility 
Testing and Sputum AFB Smear and Culture at weeks 91 and 117: 
 
1.4.8 To explore long term outcomes in Arm 1 participants through 117 weeks 
after randomization. 
 
5. Section 3.0, STUDY DESIGN  
 
The following update to the Arm 1 regimen and follow-up has been added to the end of the 
section:  
 
Updates following the DSMB reviews in April and June 2023 
Following the DSMB reviews in April and June 2023, and the premature closure to 
accrual of the study, Arm 1 treatment duration and follow-up was revised for 
participants who are currently on or have completed Arm 1 study treatment 
without experiencing treatment failure or TB recurrence, and have not already 
been referred to six months local SOC treatment. Participants in Arm 1 who have 
not already been referred to six months local SOC treatment will have follow-up 
extended through week 117.  

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6. Section 6.1, Schedule of Evaluations 
 
A new Table 6.1-2 has been inserted for the additional visits and assessments for Arm 1 after week 26. The SOE table for Arm C has been 
renumbered to Table 6.1-3. 
 
Table 6.1-2: Schedule of Evaluations for Arm 1 Who Have Not Been Referred to Local SOC, Additional Visits and Assessments After 
Week 26 
Evaluation 
Follow-up 
After Week 65 
Visit Window is ±7 days 
Visit Window is 
±14 days 
Time of 
Suspected 
Treatment Failure 
or Recurrence or 
Poor Treatment 
Response 
Premature 
Treatment/Study 
Discontinuation 
304 
34 
384 
42 
52 
604 
65 
91 
117 
Targeted Physical Exam 
(X) 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
X 
X 
X 
X 
Concomitant Medications 
(X) 
(X) 
(X) 
X 
X 
X 
X 
Pregnancy Testing 
As clinically indicated 
Sputum AFB Smear and Culture1 
(X) 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
X 
X 
X 
X 
Molecular Assay to Detect Mtb INH- and RIF- 
Resistance 
(X) 
(X) 
(X) 
X 
X 
X 
X 
Whole Genome Sequencing2 
 
 
 
 
 
X 
X 
Drug-Susceptibility Testing3 
(X) 
(X) 
(X) 
X 
X 
X 
X 
TB Symptom Assessment (See Section 6.3.18) 
X 
X 
X 
 
 
 
 
(X) = If clinically indicated. 
 
1 
Two sputum samples for AFB smear microscopy and culture in liquid and solid media will be collected at each time point. Sputum 
specimens and culture isolates will be stored for targeted deep sequencing and phenotypic drug-susceptibility testing in the event of TB 
treatment failure or TB recurrence.   
2 
For participants with suspected recurrence, whole genome sequencing performed on the baseline and recurrent isolate pair. 
3 
See section 6.3.9. 
4  Telephone visit for Arm 1 participants who did not receive 6 months of SOC. If concerning symptoms are reported in the opinion of the site 
investigator, the patient should be seen in person and the conditional evaluations noted in the SOE performed. 

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7. Section 6.2.3 Post-Entry Evaluations 
 
The revision below has been made to update the study duration for follow-up:  
 
Post-Treatment Evaluations  
Arm 1: The window for study visits during weeks 17-26 is ±3 days. The window for study 
visits during weeks 34-65 is ±7 days. The window for study visits during weeks 66 -
117 is ±14 days.   
 
8. Section 6.3, Instructions for Evaluations 
 
The following evaluation has been added: 
 
6.3.18 TB Symptom Assessment 
 
At weeks 30, 38, and 60, participants in Arm 1, who have not already been referred 
for 6 months of SOC, will have telephone follow-up visits to assess participants’ 
TB symptoms and determine if it is clinically indicated that the participant should 
come in for an in-person visit and further TB treatment. If the participant has 
symptoms concerning for TB in the opinion of the site investigator, an 
unscheduled in-person visit should be conducted within 1 week to determine if 
PPTR reporting and evaluations are appropriate, and whether the participant 
should be referred to the local TB program for 6 months of SOC treatment. 
 
9. Section 10.5.1, Interim Monitoring Guidelines 
 
The first and last sentences have been updated as follows: 
 
Unfavorable Composite Outcome Monitoring in Arm 1 
Monitoring for unfavorable composite clinical efficacy outcome (per definition 
10.2.4A) will begin approximately 1 month after the first participant completes treatment 
in Arm 1 and will continue approximately monthly and for each DSMB review until the 
end of the study. Two-sided 95% confidence bands for the cumulative probability of 
unfavorable outcome over time will be generated. If the lower confidence band for the 
cumulative probability exceeds 12% at any time, this will trigger a DSMB review. At all 
DSMB reviews, the DSMB will also be provided with the cumulative probability of 
unfavorable composite outcome (and corresponding two-sided 95% confidence 
interval) according to definition 10.2.4B. 
 
10. Section 10.5.2, Interim Analysis Plan 
 
The first and third sentences have been revised to read: 
 
Confidence Bands for Unfavorable Composite Outcome Probabilities 
Monitoring of the unfavorable composite outcome will be according to definition 
10.2.4A. only include treatment failures, treatment extensions, loss to follow-up while 
culture positive, recurrences, and deaths. Two-sided 95% confidence bands will be 

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generated for the cumulative unfavorable composite outcome probability in Arm 1. Since 
Arm 2 data will be lagging 3 months behind Arm 1, the data will be presented alongside 
historical unfavorable proportions for SOC on the REMox, OFLOTUB, and RIFAQUIN 
trials, and A5362 SOC data as it becomes available. There will be no adjustment to the 
confidence bands for multiple looks. 
 
11. Appendix I-C, ADDENDUM TO SAMPLE INFORMED CONSENT 
 
An addendum to the Sample Informed Consent has been added as Appendix I-C. Appendix 
I-C is included in this LOA on pages 9-12. 
 
12. Protocol Signature Page (PSP)  
 
A PSP is appended for submission to DAIDS Protocol Registration System (DPRS) as part 
of the LOA registration packet. 
 
 
 

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APPENDIX I-C: ADDENDUM TO SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For protocol A5362 
 
A5362, FINAL Version 2.0, 08Jul2022, A Phase IIc Trial of Clofazimine- and 
Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible 
Tuberculosis: The CLO-FAST Study  
 
SHORT TITLE FOR THE STUDY: A5362, FINAL Version 2.0, 08Jul2022, 
Clofazimine and Rifapentine for Drug-Susceptible Tuberculosis 
 
We have important information to share with you about the A5362 (CLO-FAST) 
study. This study is reviewed by the National Institute of Allergy and Infectious 
Diseases (NIAID) Therapeutic and Prevention Data and Safety Monitoring Board 
(DSMB) at least every 6 months. This Board is a group of people who are experts 
in the fields of medicine and statistics, none of whom are directly involved with 
the study. Their role is to review the conduct of the study and ensure the safety of 
participants. 
  
The DSMB met on June 1, 2023 to review the A5362 study.  
  
DSMB RECOMMENDATIONS 
 
After looking at the information about how participants who were receiving the 3-
month experimental treatment (Arm 1) were doing, the DSMB concluded that 
participants who were treated with 3-months of experimental treatment were not 
doing as well as people who were treated with standard of care [SOC] (Arm 2). 
Because of this, the DSMB recommended that the study close to enrollment, and 
recommended that participants currently receiving the 3-month experimental 
treatment continue to finish the treatment and then receive an additional 3 
months of SOC rifampicin/isoniazid treatment. The Board did not find any safety 
concerns, so there is no concern about harm if you received the 3-month 
experimental treatment.  
 
WHAT WILL HAPPEN TO ME NOW? 
 
Participants randomized to Arm 1 and are still on study treatment  
• If you are currently completing the 13 weeks of study treatment, you will 
complete your current course of 
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 

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300 mg for 2 weeks; then PHZE + CFZ 100 mg for 6 weeks; then 
rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg for 5 weeks, for a 
total of 13 weeks of study treatment. 
• Once you have completed the 13 weeks of study treatment, you will take 
rifampicin/isoniazid (RH) for 12 weeks. 
• You will complete all study visits and follow-up through 117 weeks.  
 
Participants randomized to Arm 1 and have completed study treatment 
• You will be contacted by study staff to discuss how you are feeling and 
decide whether further TB treatment is needed. 
• You will attend an additional 5 follow-up visits through 117 weeks. Three of 
these visits will be conducted by telephone.  
 
Participants randomized to Arm 2  
• Study treatment and follow-up visit schedule is not changing. 
• You will complete your current course of 
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then 
rifampicin/isoniazid (RH) for 18 weeks, for a total of 26 weeks of study 
treatment. Thus, the standard of care for TB treatment. 
•  You will complete all study visits and follow-up through 65 weeks. 
 
Participants randomized to Arm C  
• Study treatment and follow-up visit schedule is not changing. 
• You will complete your course of 
rifapentine/isoniazid/pyrazinaminde/ethambutol (PHZE) + clofazimine (CFZ) 
100 mg daily for 4 weeks. This will be followed by standard of care TB 
treatment (received from your health care provider) that will include 4 
weeks of rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) and 18 
weeks of rifampicin/isoniazid (RH). 
• You will complete all study visits and follow-up through 65 weeks. 
 
WHAT DO I HAVE TO DO IF I STAY ON THE STUDY? 
 
If you are in Arm 1 and stay on study, you will have up to 5 additional follow up 
visits than you were previously scheduled for, to make sure you are safe and 
well. Three of these follow up visits may occur on the telephone. If you are on 
Arm 2 or Arm C, you will continue with the current study visits and follow-up 
schedule.  
 
You may also choose to stop being followed on the study at any time as well, but 
we encourage you to discuss this with your health care provider. Once you leave 
the study, you will not be able to return to the study.  
 

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We appreciate your efforts and thank you for being a part of this study and for 
your continued participation.  
 
WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study contact: 
• Site add Name and telephone number for the investigator or other study staff. 
 
 
 
 

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SIGNATURE PAGE 
 
 
I have been notified of the new study findings and have discussed these findings 
and my treatment options.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
Participant Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
 
 
Study Staff Signature and Date 
Consent Discussion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name 
 
 
 
 
Witness Signature and Date 
 
 
 

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A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in 
Drug-Susceptible Tuberculosis: The CLO-FAST Study 
 
 
SIGNATURE PAGE 
 
 
I will conduct the 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 Conference on Harmonization 
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. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title