Conditions: HIV Infections Tuberculosis
Keywords: Antiretroviral therapy Dolutegravir Rifampicin Tuberculosis Drug-drug interaction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
The investigators propose to conduct a phase 2 randomised (1:1) double-blind placebo-controlled trial of the dolutegravir-lamivudine-tenofovir fixed dose combination tablet daily with an additional 50 mg dose of dolutegravir/matching placebo taken 12 hours later in ART-naïve or fisrt-line interrupted HIV-infected patients on rifampicin-based anti-tuberculosis therapy. The hypothesis is that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based anti-tuberculosis therapy.

Detailed description:
Dolutegravir is being rolled out to replace efavirenz in first-line antiretroviral therapy (ART) in low-middle income countries (LMICs) because it is more effective, better tolerated, and has a considerably higher genetic barrier to resistance.

Tuberculosis is the commonest cause of HIV-related morbidity and mortality in LMICs. Rifampicin, which is a key component of anti-tuberculosis therapy, induces genes that are important in the metabolism and transport of dolutegravir. The resulting drug-drug interaction between dolutegravir and rifampicin significantly reduces dolutegravir exposure, which can be overcome by increasing the dose of dolutegravir to 50 mg 12 hourly.

The additional dose of dolutegravir will be difficult to implement in high burden settings. Furthermore, the additional dolutegravir tablet increases pill burden and costs. If standard dose dolutegravir is shown to be effective in patients with tuberculosis this would sweep away one of the major barriers to its implementation in LMICs. There are three lines of evidence to support studying standard dose dolutegravir in patients with HIV-associated tuberculosis.

First, there are compelling pharmacokinetic and pharmacodynamic data supporting the therapeutic efficacy of lower dolutegravir exposure. Second, the investigators have conducted a drug-drug interaction study of dolutegravir dosed at 50 mg or 100 mg once daily in healthy volunteers with rifampicin. Although, as expected, concomitant rifampicin significantly reduced dolutegravir exposure at both doses, all dolutegravir trough concentrations on rifampicin were above the protein-adjusted 90% inhibitory concentration (PA IC90). Third, exposure to the first-generation integrase inhibitor raltegravir is also significantly reduced with concomitant rifampicin. A phase 2 study in patients with HIV-associated tuberculosis showed that virologic outcomes were similar with standard and double dose raltegravir. It is plausible that findings could be similar with dolutegravir.

The hypothesis is that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based anti-tuberculosis therapy. If the proportion of participants who achieve virological suppression on standard dose dolutegravir is acceptable, this would pave the way for a phase 3 trial of dolutegravir 50 mg daily versus an appropriate standard of care regimen, like efavirenz-based ART, in patients with HIV-associated tuberculosis.

Arms:
arm 1: Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later. arm 2: Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with placebo taken 12 hours later.

Interventions: intervention 1: Placebo intervention 2: Dolutegravir 50 mg
Intervention descriptions: intervention 1: Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg. intervention 2: Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.

Protocol document:
Prot_SAP_000.pdf: 
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Standard versus double dose dolutegravir in patients with 
HIV-associated tuberculosis: a phase 2 non-comparative 
randomised controlled trial 
 
CLINICALTRIALS.GOV NCT03851588 
 
CORE STUDY TEAM 
Gary Maartens (principal investigator) 
 
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town 
 
gary.maartens@uct.ac.za 
Graeme Meintjes (co-investigator) 
Institute of Infectious Diseases and Molecular Medicine and Department of Medicine, 
University of Cape Town 
graemein@mweb.co.za 
Andrew Hill (study statistician) 
 
Department of Pharmacology and Therapeutics, University of Liverpool, UK 
 
ahill.IC@clintonhealthaccess.org; microhaart@aol.com  
PI contact details: 
 
Prof Gary Maartens 
 
Division of Clinical Pharmacology,  
University of Cape Town Health Sciences Faculty 
Anzio Road 
Observatory 7925 
Phone: 021-4066286/083-4085685 
 
ADDITIONAL STUDY TEAM MEMBERS 
Dr Rulan Griesel (lead-investigator) 
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town 
Grsrul001@myuct.ac.za 
Dr Claire Keene (co-investigator) 
Médecins Sans Frontières, 8 Mzala street, Khayelitsha 
msfocb-khayelitsha-hivmam@brussels.msf.org 


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SPONSOR 
University of Cape Town 
FUNDER 
Wellcome Trust 
 
 
 
 
 
 


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Summary 
Rifampicin induces genes involved in the metabolism and transport of dolutegravir, resulting in 
significantly lower dolutegravir exposure. This drug-drug interaction can be overcome by doubling the 
dose of dolutegravir to 50 mg 12 hourly, which was well tolerated with good rates of virologic 
suppression in a phase 2b study of patients with HIV-associated tuberculosis. However, the additional 
dose of dolutegravir will be difficult to implement in high burden settings; for this reason, the South 
African national guidelines on dolutegravir continue to recommend an efavirenz-based ART regimen 
for ART-naive patients with tuberculosis. 
Three lines of evidence support studying standard dose dolutegravir in patients with HIV-associated 
tuberculosis. First, the phase 2b study (SPRING-1) of dolutegravir plus dual nucleoside reverse 
transcriptase inhibitors showed similar rates of virologic suppression with dolutegravir dosed at 10 
mg, 25 mg, or 50 mg daily and no pharmacokinetic-pharmacodynamic relationships between 
dolutegravir exposure and virologic outcomes could be established. Second, we conducted a drug-
drug interaction study of dolutegravir dosed at 50 mg or 100 mg once daily in healthy volunteers with 
rifampicin and showed that concomitant rifampicin significantly reduced dolutegravir exposure at 
both doses, as expected, but all dolutegravir trough concentrations on rifampicin were above the 
protein-adjusted IC90. Furthermore, the geometric mean ratio of the area under the curve (AUC) of 
dolutegravir 50 mg once daily with rifampicin (versus 50 mg daily without rifampicin) was similar to 
the geometric mean ratio AUC of 10 mg dolutegravir (versus 50 mg dolutegravir), which performed as 
well as 50 mg daily in the SRING-1 study. Third, exposure to the first-generation integrase inhibitor 
raltegravir is also significantly reduced with concomitant rifampicin and, as is the case with 
dolutegravir, the induction can be overcome by doubling the dose of raltegravir. However, a phase 2 
study (ANRS 12 180 Reflate TB) in patients with HIV-associated tuberculosis showed that virologic 
outcomes were similar with standard and double dose raltegravir.  It is plausible that findings could 
be similar with dolutegravir. 
We propose to conduct a phase 2 randomised (1:1) double-blind placebo-controlled trial of the 
dolutegravir-lamivudine-tenofovir fixed dose combination tablet daily with an additional 50 mg dose 
of dolutegravir/matching placebo taken 12 hours later in ART-naïve or first-line ART treatment 
interrupters (either on ART for <6 months at the time of interruption or a suppressed viral load [<50 
copies/mL or LDL] <6 months before the time of interruption) HIV-infected patients with CD4 counts 
>100 cells/µL on rifampicin-based anti-tuberculosis therapy. The primary endpoint is virologic 
suppression at week 24. Key secondary endpoints include the emergence of antiretroviral resistance 
mutations and dolutegravir trough concentrations. 
The main risk to participants will be the emergence of antiretroviral resistance mutations, which will 
be mitigated by frequent viral load monitoring, close monitoring by a data safety monitoring 
committee, performing genotypic antiretroviral testing in participants with virologic failure, and 
providing antiretroviral therapy directed by the resistance test results. 
 
 


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CONTENTS 
1.0 
Background and rationale ............................................................................................................... 5 
2.0  Study design ............................................................................................................................................ 6 
2.1 Study sites: ........................................................................................................................................... 6 
2.2 Recruitment and enrolment: ............................................................................................................... 6 
2.3 Screening visit: ..................................................................................................................................... 7 
2.4 Baseline visit: ....................................................................................................................................... 7 
2.5 Follow up visits: ................................................................................................................................... 7 
2.6 End of study visit .................................................................................................................................. 7 
2.7 Data management: .............................................................................................................................. 7 
2.8 Withdrawal and loss to follow up: ....................................................................................................... 8 
2.9 Study treatments: ................................................................................................................................ 8 
2.10 Adverse events / Safety procedures: ................................................................................................. 9 
2.10.1 Collection and documentation of adverse events: ..................................................................... 9 
2.10.2 Management of suspected drug-induced liver injury: ............................................................... 9 
2.10.3 Viral load monitoring and detection of antiretroviral resistance ............................................... 9 
2.10.3 Independent Data and Safety Monitoring Committee (IDSMC): .............................................. 10 
2.11 Pharmacokinetic analyses ................................................................................................................ 10 
3.0 Statistical considerations and analyses .................................................................................................. 12 
3.1 Sample size: ....................................................................................................................................... 12 
3.2 Primary endpoint: .............................................................................................................................. 12 
3.3 Secondary endpoints: ........................................................................................................................ 12 
3.4 Analysis plan ...................................................................................................................................... 12 
4.0 Study monitoring ................................................................................................................................... 12 
5.0 
Ethical Considerations and informed consent ............................................................................... 13 
5.1 Ethical Conduct .................................................................................................................................. 13 
5.2  
Compliance with the protocol ................................................................................................... 13 
5.3  
Protocol amendments ............................................................................................................... 13 
5.4  
Informed consent and procedures ............................................................................................ 13 
5.5  
Use of Placebo ........................................................................................................................... 14 
6.0 
Confidentiality of data .................................................................................................................... 14 
7.0 References ............................................................................................................................................. 15 
Appendix A: Gantt chart .............................................................................................................................. 16 
Appendix B:  ADVANCE Sleep assessment questionnaire ............................................................................ 17 
Appendix C:  ADVANCE Mental Health questionnaire ................................................................................. 17 
Appendix D: Sample Informed Consent ....................................................................................................... 17 
 


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1.0 BACKGROUND AND RATIONALE 
Dolutegravir is being rolled out to replace efavirenz in first-line antiretroviral therapy (ART) in low-middle income 
countries (LMICs) because it is more effective, better tolerated, and has a considerably higher genetic barrier to 
resistance.  
Tuberculosis is the commonest cause of HIV-related morbidity and mortality in LMICs, and continues to occur at 
a higher incidence than in the general population despite normalisation of CD4 counts on ART. Rifampicin, which 
is a key component of anti-tuberculosis therapy, induces the following genes that are important in the 
metabolism and transport of dolutegravir: UGT1A1, ABCB1 (which encodes for P-glycoprotein), ABCG2 (which 
encodes for breast cancer resistance protein (BCRP)), and CYP3A4. The resulting drug-drug interaction between 
dolutegravir and rifampicin significantly reduces dolutegravir exposure, which can be overcome by increasing 
the dose of dolutegravir to 50 mg 12 hourly [Dooley 2013]. Interim 24-week data from the INSPIRING study, a 
randomised controlled trial (RCT) of double dose dolutegravir versus efavirenz in patients with tuberculosis, 
reported double dose dolutegravir was well tolerated and rates of virologic suppression were similar in both 
arms, but the study wasn’t powered for efficacy comparisons [Dooley 2018].  
The additional dose of dolutegravir will be difficult to implement in high burden settings where nurses prescribe 
ART, making complex regimens undesirable, and pharmacies would need to stock dolutegravir as a single tablet 
as well as the fixed dose combination formulation (dolutegravir-lamivudine-tenofovir), increasing the risks of 
stock outs. Furthermore, the additional dolutegravir tablet increases pill burden and costs. Our experience is 
that double dose lopinavir-ritonavir, which is recommended with rifampicin-based antituberculosis therapy, is 
often not implemented in ART programs. For this reason, the draft South African national guidelines for the 
dolutegravir roll out in 2019 are recommending that efavirenz continue to be used in patients with tuberculosis 
who are starting ART.  
If standard dose dolutegravir is shown to be effective in patients with tuberculosis this would sweep away one 
of the major barriers to its implementation in low-middle income countries (LMICs). There are three lines of 
evidence to support studying standard dose dolutegravir in patients with HIV-associated tuberculosis. 
First, there are compelling pharmacokinetic and pharmacodynamic data supporting the therapeutic efficacy of 
lower dolutegravir exposure. Dolutegravir trough concentrations were found to be the key pharmacokinetic 
parameter for virologic efficacy in a phase 2a study of different doses of dolutegravir monotherapy [Min]. 
However, no pharmacokinetic-pharmacodynamic relationships between dolutegravir exposure (including 
trough concentrations) and virologic outcomes could be established in the phase 2b study (SPRING-1) of 
different doses of dolutegravir given as part of a combination ART regimen together with dual nucleoside reverse 
transcriptase inhibitors (NRTIs) [Van Lunzen]. In SPRING-1 all doses of dolutegravir (10 mg, 25 mg, and 50 mg 
daily) resulted in similar, high rates of virologic suppression [Van Lunzen]. The trough concentrations of 
dolutegravir 50 mg daily are 19 times above the protein-adjusted IC90 [Van Lunzen], indicating that the drug has 
a lot of “forgiveness”. An important pharmacodynamic characteristic of dolutegravir may mitigate against the 
emergence of resistance in patients with potentially sub-therapeutic dolutegravir trough concentrations: 
dolutegravir binds avidly to its receptor, integrase, with a dissociative half-life of 71 hours [Hightower]. 
Therefore, the pharmacokinetic-pharmacodynamic data and the SPRING-1 study results indicates that lower 
exposures of dolutegravir have a high likelihood of success. 
Second, we have conducted a drug-drug interaction study (RADIO) of dolutegravir dosed at 50 mg or 100 mg 
once daily in healthy volunteers with rifampicin [Wang]. Although, as expected, concomitant rifampicin 
significantly reduced dolutegravir exposure at both doses, all dolutegravir trough concentrations on rifampicin 
were above the protein-adjusted IC90 and the median trough concentrations were 2.3 times and 4.3 times above 
the protein-adjusted IC90 for the 50 mg and 100 mg dolutegravir doses respectively. The geometric mean trough 
concentration of the 10 mg dose in SPRING-1 was 0.3 µg/mL; and 0.156 and 0. 251 µg/mL for the 50 mg and 100 
mg dolutegravir doses on rifampicin respectively in RADIO. The geometric mean ratio of the area under the curve 
(AUC) of dolutegravir 50 mg once daily with rifampicin versus dolutegravir 50 mg once daily without rifampicin 
was 44% (90%CI 37, 52), which is similar to the geometric mean ratio of 40% reported for 10 mg versus the 50 
mg dolutegravir dose in the SRING-1 study [Van Lunzen]. As noted above, 10 mg dolutegravir performed as well 
as 50 mg in SPRING-1 [Van Lunzen].   
Third, exposure to the first-generation integrase inhibitor raltegravir is also significantly reduced with 
concomitant rifampicin. A study in healthy volunteers showed that double dose raltegravir overcame the 


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pharmacokinetic drug-drug interaction with rifampicin [Wenning], but a subsequent phase 2 study (ANRS 12 180 
Reflate TB) in patients with HIV-associated tuberculosis showed that virologic outcomes were similar with 
standard and double dose raltegravir [Grinsztejn].  It is plausible that findings could be similar with dolutegravir. 
Finally, a recent retrospective cohort study from Botswana reported virologic outcomes in patients with 
tuberculosis on rifampicin-based anti-tuberculosis therapy who were on a dolutegravir-based ART regimen; the 
dolutegravir dose was not doubled while on antituberculosis therapy in 44% [Modongo]. Virologic suppression 
was achieved in 204/214 (95.3%) and 241/254 (94.9%) in those on standard and double dose dolutegravir 
respectively. In a multivariable analysis virologic suppression was more likely with CD4 counts >100 cells/µL. 
Our hypothesis is that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in 
patients on rifampicin-based anti-tuberculosis therapy. If the proportion of participants who achieve virological 
suppression on standard dose dolutegravir is acceptable, this would pave the way for a phase 3 trial of 
dolutegravir 50 mg daily versus an appropriate standard of care regimen, like efavirenz-based ART, in patients 
with HIV-associated tuberculosis. A variety of safety measures will be put in place to ensure that no harm will 
come to participants. 
 
2.0 STUDY DESIGN 
Phase 2 randomised (1:1, computer generated) double-blind placebo-controlled trial of the dolutegravir-
lamivudine-tenofovir fixed dose combination tablet daily with an additional 50 mg dose of dolutegravir or 
matching placebo taken 12 hours later in HIV-infected patients on rifampicin-based antituberculosis therapy.  
2.1 STUDY SITES: 
The study will primarily be conducted at Site B/Ubuntu community health clinic in Khayelitsha, Cape Town and 
will receive referrals for recruitment from 2 satellite sites – Michael Mapongwana and Nolungile/Site C 
community health clinics.  
2.2 RECRUITMENT AND ENROLMENT: 
108 ART-naïve or first-line ART treatment interrupters with HIV-associated tuberculosis attending the study 
clinics will be approached by study staff to obtain written consent for study screening. If they are eligible for the 
study (see inclusion and exclusion criteria below) they will be invited to participate in the study and provided 
with the patient information leaflet and informed consent documents. 
Inclusion criteria:  
• 
≥18 years old  
• 
HIV-1 infection as documented by screening plasma HIV-1 RNA >1000 c/mL; 
• 
ART-naïve (short-term antiretroviral use for prevention of mother-to-child transmission will be allowed)  
or 
ART treatment interrupters (see rationale below):  
o 
on ART <6 months prior to interruption or  
o 
virologically suppressed (<50 copies/mL or LDL) <6 months prior to interruption  
• 
On rifampicin-based therapy for tuberculosis for <3 months  
• 
CD4 counts >100 cells/µL  
• 
Women of child-bearing potential willing to use adequate contraception (defined as either an IUCD or 
hormonal contraception as per national guidelines) 
Our rationale for enrolling first-line ART treatment interrupters into the study is to make the study findings more 
generalizable – the majority (~70%) of HIV-positive patients with TB who aren’t on ART have interrupted ART 
rather than being ART-naïve. There is a potential risk of impaired virologic response in participants who are 
treatment interrupters as they may harbour NRTI resistance mutations – however, this risk will be mitigated by 
only selecting participants who have a low risk of NRTI viral resistance mutations (either on ART for <6 months 
at the time of interruption or a suppressed viral load <6 months before the time of interruption). As per the 
study schedule we are doing frequent viral load measurements and resistance testing for participants with 
virological failure – those who develop resistance will be placed on an appropriate regimen.  


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Exclusion criteria:  
• 
Pregnant/breastfeeding 
• 
Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (calculated by the Modification of Diet 
in Renal Disease (MDRD) study) 
• 
ALT >3 times upper limit of normal (ULN) 
• 
Allergy or intolerance to one of the drugs in regimen 
• 
Concomitant medication known to significantly reduce or increase dolutegravir exposure (except 
rifampicin) 
• 
Active psychiatric disease or substance abuse 
• 
On treatment for active AIDS-defining condition other than tuberculosis (participants on maintenance 
therapy may be enrolled) 
• 
Malignancy 
• 
Any other clinical condition that in the opinion of an investigator puts the patient at increased risk of 
participating in the study. 
2.3 SCREENING VISIT: 
Should occur within 8 weeks before the commencement of ART (Baseline). All eligible patients (see inclusion 
and exclusion criteria below) will sign informed consent. Medical history, method of diagnosis of tuberculosis, 
physical exam, safety blood monitoring will be done, as well as a urine pregnancy test for women of childbearing 
potential. 
2.4 BASELINE VISIT: 
Participants who are eligible for the study will return for a baseline visit (within 8 weeks of screening).  A mental 
health questionnaire and sleep assessment will be conducted.  All eligibility criteria will be checked, and, at the 
investigator’s discretion, the participant will be enrolled into the study.  A blood sample for storage will be taken 
if the participant consents to stored samples.  The participant will be randomised, and drug will be dispensed by 
a registered pharmacist according to the randomisation. Randomisation will be done with a computer-generated 
randomisation plan and stratified by baseline ART-naïve or first-line ART treatment interrupter status. Site 
pharmacists will manage a system of sealed envelopes with all participants assigned a unique randomisation 
number based on the randomisation plan. Participants will be assigned 1:1 to either dolutegravir-lamivudine-
tenofovir fixed dose combination tablet daily with an additional 50 mg dose of dolutegravir or matching placebo 
taken 12 hours later. The trial will be double-blind. Only the study statistician will have access to the 
randomisation code. We do not anticipate that breaking the randomisation code will be necessary as the 
intervention and control arms differ only by dolutegravir lower dose. 
2.5 FOLLOW UP VISITS: 
The participant will return every 4 weeks for a physical exam, adverse event check, sleep assessment, mental 
health questionnaire (every 12 weeks) and serum biochemical tests (ALT, creatinine, potassium and albumin). 
HIV-1 viral loads will be done at weeks 4, 8, 12, 24 and 48. An additional sample for storage will be taken with 
each viral load sample, this will be for antiretroviral resistance testing should it become necessary. Contraception 
use will be checked at every visit for women of child-bearing potential. Dolutegravir trough concentrations and 
tenofovir-diphosphate dried blood spot testing will be done at weeks 4, 8, 12, 24 and 48 only (note that these 
assays will be done batched at the end of the study). 
2.6 END OF STUDY VISIT 
After 48 weeks, the participant will return to the site for a final study visit.  They will be referred out to their 
local clinic and dispensed with one month of medication.  A follow up call to the participant will be made to 
ensure that they have accessed continuing care.  
2.7 DATA MANAGEMENT: 
Upon screening, participants will receive a screening number, the screening document will identify the patient 
based on his/her hospital folder number only. At the enrolment visit participants will receive a randomisation 
number, completely deidentifying the participant. From this point the randomisation number will be the only 


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identifier. Blood samples taken will be identified only by the assigned randomisation number given to each 
participant. This will be attached with a sticker to each blood sample. 
The study visit case record form (CRF) will be completed as soon as possible after the study visit. Data will be 
captured for this study on an electronic data capture system using a password protected platform.  The principal 
investigator has overall responsibility for ensuring the data collected are complete, accurate, and recorded in a 
timely manner.  Confidentiality of records must be protected, respecting the privacy and confidentiality rules in 
accordance with the applicable regulatory requirements. 
Once the CRF is completed the document needs to be signed and dated. Corrections can only be done by study 
staff and must be signed and dated. 
2.8 WITHDRAWAL AND LOSS TO FOLLOW UP: 
Participants reserve the right to withdraw from the study at any stage, without an obligation to provide reasons 
for their withdrawal. Should a participant voluntarily withdraw their consent after receiving study treatment, 
the study team will attempt to ascertain the reason for withdrawal and encourage the patient to complete a 
withdrawal/final study visit as soon as possible, while respecting the participants decision.  
Participants who fail to keep a study visit or appointment will be contacted telephonically and the visit 
rescheduled (if feasible). If, in the opinion of the investigator, a participant’s continued participation in the study 
poses unacceptable risks to themselves, a withdrawal/final study visit should be performed whenever possible.  
Participants who develop adverse events deemed related to dolutegravir that requires discontinuation will be 
withdrawn from the study. Participant safety will be ensured by continued follow-up after withdrawal from the 
study. Their data will be part of the primary and secondary outcomes in the intention-to-treat analysis. Switches 
of one or both of the dual NRTIs for toxicity will be allowed. 
Participants who become pregnant on the study will be withdrawn and the dolutegravir switched to efavirenz. 
Pregnancy outcomes for the participant and the infant will be recorded. This is especially important in this study 
as a recent report has implicated dolutegravir as a cause of neural tube defects [Zash]. 
All participants who withdraw from the study will be referred to their local HIV clinic for ongoing care. 
Participants who miss two consecutive visits will be deemed lost to follow up and withdrawn from the study. All 
possible efforts will be made to ensure participants attend the final safety assessment. These include contacting 
participants telephonically and rescheduling a visit if feasible. 
Data from participants who do not complete the study will be used for secondary endpoint analyses. 
 
2.9 STUDY TREATMENTS: 
Dolutegravir 50 mg tablet (Myltega®, Mylan) or matching placebo will be administered 12 hours after the 
morning dose of fixed dose combination dolutegravir-tenofovir-lamivudine from the start of the study until 2 
weeks after stopping anti-tuberculosis therapy. The study pharmacist will prepare, package, and label 
dolutegravir/placebo for each participant according to the randomisation code and dispense a month’s supply 
to be taken together with fixed dose combination dolutegravir-tenofovir-lamivudine.  
The ingredients of the placebo will be the standard excipients found in dolutegravir 50 mg tablet without the 
active ingredient. None of these have any biological effect. 
Anti-tuberculosis therapy and fixed dose combination dolutegravir-tenofovir-lamivudine will be supplied by the 
clinics as part of standard of care.  
Dolutegravir has recently been implicated as a cause of neural tube defects [Zash]. As per the exclusion criteria 
above, women of child-bearing potential must be on adequate, reliable contraception, defined as an IUCD or 
hormonal contraception as per national guidelines. Women of child-bearing potential in the study who do not 
have an IUCD will be given hormonal contraception on site for the duration of the study. As rifampicin is a known 
potent inducer, thereby reducing the effectiveness of oral contraceptives by enhancing their metabolism, we 


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recommend the use of injectable progesterone-only contraceptives such as medroxyprogesterone acetate 
(Depo-Provera® 150 mg 12 weekly). 
2.10 ADVERSE EVENTS / SAFETY PROCEDURES: 
An adverse event is any untoward medical occurrence developing in participants from the first dose of study 
drugs until the end of the study or developing after this period and thought to be not related, possibly, probably, 
or likely related to the study drug. 
Drug-related adverse events reported by participants or observed by the investigator, and any remedial actions, 
will be recorded in the source documents and the participant’s CRF. The nature of the event, the time of onset, 
duration, severity (rated according to the Division of AIDS [DAIDS] table for grading the severity of adult and 
pediatric adverse events vs 2, Nov 2014, DAIDS, NIH) and causality assessment will be recorded in the individual 
CRFs and included in the study report.  
Any serious adverse events (SAE; defined as resulting in death, being life threatening, requiring hospitalization, 
resulting in significant or persistent disability/incapacity, or jeopardizing the participant, or requiring 
intervention to prevent significant or persistent damage or disability) will be reported to the principal 
investigator immediately. SAEs and all unexpected adverse events suspected to be related to the study drugs, 
will be reported to UCT’s Human Research Ethics Committee (HREC) and SAHPRA according to their current 
guidelines and in line with Good Clinical Practice (GCP) guidelines. 
2.10.1 COLLECTION AND DOCUMENTATION OF ADVERSE EVENTS: 
The occurrence of adverse events will be solicited from participants at each study visit using a standardized 
adverse events collection tool with which participants will be encouraged to report any untoward change in their 
condition and questioned about specific adverse events related to insomnia (using a sleep assessment 
questionnaire developed by the ADVANCE study team – ADVANCE is a randomised controlled trial of 
dolutegravir versus efavirenz for ART-naïve patients being conducted in Johannesburg, PI Francois Venter), new 
or worsening neuropsychiatric symptoms (using a mental health questionnaire developed by the ADVANCE 
study team), and symptoms of hepatotoxicity. Participants will also be asked to contact the study team 
immediately should they develop any untoward changes in their medical condition. 
All laboratory reports will be reviewed by clinical investigators, with the review signed and dated. 
If the eGFR declines to <50 mL/min then tenofovir will be discontinued and replaced with abacavir as per national 
guidelines. Tenofovir may be reintroduced if there is an alternative explanation for the decline in renal function 
once the eGFR has increased to >60 mL/min. 
2.10.2 MANAGEMENT OF SUSPECTED DRUG-INDUCED LIVER INJURY: 
Dolutegravir, cotrimoxazole, and several antituberculosis drugs (isoniazid, rifampicin, and pyrazinamide) can 
cause drug-induced liver injury. 
Liver chemistry threshold stopping criteria have been designed to assure participant safety and to evaluate liver 
event aetiology during administration of dolutegravir and the follow-up period. Dolutegravir, cotrimoxazole, and 
antituberculosis therapy (if the participant is still taking this) will be stopped if any of the following liver 
chemistry criteria are met: 
• 
ALT ≥3 x ULN (or 3 x baseline ALT if this was above ULN) and bilirubin ≥2 x ULN  
• 
ALT ≥3 x ULN (or 3 x baseline ALT if this was above ULN) with symptoms of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, or 
rash; 
• 
ALT ≥5 x ULN irrespective of bilirubin and symptoms 
Participants who develop ALT ≥5 x ULN should be followed weekly until resolution or stabilization (ALT <5 x ULN 
on 2 consecutive evaluations). 
Participants should not restart dolutegravir due to the risk of a recurrent reaction unless an alternative 
diagnosis is made for the liver chemistry abnormalities (e.g. viral hepatitis).   
2.10.3 VIRAL LOAD MONITORING AND DETECTION OF ANTIRETROVIRAL RESISTANCE 


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Frequent viral load monitoring will be done during the study as per the schedule of events table. 
Antiretroviral resistance testing will be done in participants who do not have virologic suppression at week 24 
or in participants who suppress their viral loads and then subsequently rebound. Resistance testing will also be 
done on stored plasma from the baseline visit in participants who have antiretroviral resistance mutations to 
distinguish emergent from pre-treatment resistance. Participants who have antiretroviral resistance mutations 
will have an appropriate ART regimen, using antiretrovirals available in national guidelines (which includes 
efavirenz, zidovudine, and lopinavir-ritonavir). Currently no other analyses of stored blood samples are planned. 
Blood samples will be kept for a period of 3 years after the end of the study and then destroyed. 
2.10.4 INDEPENDENT DATA AND SAFETY MONITORING COMMITTEE (IDSMC): 
An IDSMC will be established consisting of three experienced HIV clinical researchers and the study statistician 
(quorum will be two HIV clinical researchers). The IDSMC will review study data 6 monthly. The IDSMC will 
discuss in closed session whether the study should be stopped, modified or continued, and will communicate a 
recommendation to the principal investigator. As this is a non-comparative study, there are no formal stopping 
rules – a decision to stop the study for serious harm will be at the discretion of the IDSMC. The findings from the 
research will be published even if the trial is terminated early based on an IDSMC recommendation.  
2.11 PHARMACOKINETIC ANALYSES 
Dolutegravir trough concentrations and tenofovir-diphosphate in dried blood spots will be determined at regular 
intervals as outlined in the schedules of events (note that these assays will be batched and done after study 
completion). The Clinical Pharmacology Laboratory at UCT has developed validated assays for both of these 
analytes on liquid chromatography-mass spectrometry. We will use thresholds of tenofovir-diphosphate 
concentrations in dried blood spots that have been determined to predict different adherence levels [Castillo-
Mancilla].   
 


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Table: Schedule of events (WOCBP = women of child-bearing potential) 
Visit 
Screening 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 48 
Wk 52 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Inclusions & 
exclusions 
X 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Mental health 
questionnaire 
 
X 
 
 
X 
 
 
X 
X 
 
Sleep 
assessment 
questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study 
drug and  
accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test 
 
X 
(urine β-
HCG) 
X 
(urine 
β-HCG) 
X 
(urine 
β-HCG) 
X 
(urine 
β-HCG) 
X 
(urine 
β-HCG) 
X 
(urine 
β-HCG) 
X 
(urine 
β-HCG) 
X 
(urine 
β-HCG) 
X 
 
Contraception 
use (for 
WOCBP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Creatinine, 
potassium, ALT, 
& bilirubin 
X 
 
X 
X 
X 
 
 
X 
X 
 
HIV viral load 
X 
 
X 
X 
X 
 
 
X 
X 
 
CD4 count 
X 
 
 
 
 
 
 
X 
X 
 
DTG trough 
 
 
X 
X 
X 
 
 
X 
X 
 
Tenofovir-
diphosphate 
dried blood 
spots 
 
 
X 
X 
X 
 
 
X 
X 
 
Plasma for 
storage  
 
X 
X 
X 
X 
 
 
X 
X 
 
Antiretroviral 
resistance 
testing 
 
If viral load is >1000 copies/mL at week 24 or if viral load was suppressed and then 
rebounded to >1000, resistance testing will be performed on a stored plasma sample, and 
compared to the baseline stored sample to determine pre-treatment vs emergent resistance 
mutations. 
Referral to 
public sector 
care 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


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3.0 STATISTICAL CONSIDERATIONS AND ANALYSES 
3.1 SAMPLE SIZE: 
We assume that 85% of participants will achieve virologic suppression at week 24. With 49 patients per group 
the lower 95% confidence interval (CI) of virological suppression at week 24 would exceed 70% (actual value is 
73%) with power of 80% and α of 5% (one-sided test). We selected this lower 95% CI of virologic suppression 
based on the outcomes in two randomised controlled trials with efavirenz-based ART in patients with HIV-
associated tuberculosis, which achieved suppression of 74% and 70% at 48 weeks [Bonnet, Havlir].  Assuming a 
10% rate of loss to follow we plan to enroll 54 participants per arm. The study is not powered for formal 
comparison of efficacy between the two arms. 
3.2 PRIMARY ENDPOINT:  
Proportion with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT), which 
includes all participants who received at least one dose of dolutegravir, and according to the FDA snapshot 
algorithm. The FDA snapshot algorithm regards the following categories of participants as failures: HIV viral load 
≥50 copies/ml, missing HIV viral load within the visit window, or those who have discontinued ART. Switching of 
the NRTI component of the ART regimen for intolerance or adverse event will not be regarded as failure, but 
switching or stopping of dolutegravir will be regarded as failure. Switching due to pregnancy will not be regarded 
as failure. 
3.3 SECONDARY ENDPOINTS:  
• 
Proportion with HIV viral load <50 copies/mL at 12 weeks analysed ITT 
• 
Proportion with HIV viral load <50 copies/mL at 48 weeks analysed ITT 
• 
Proportion with HIV viral load <50 copies/mL at 12, 24 and 48 weeks analysed per protocol 
• 
Primary and secondary virological endpoints stratified by baseline ART-naïve or treatment interruption 
status 
• 
Change in CD4 count from screening at week 24 
• 
Proportion with dolutegravir trough concentrations above the protein-adjusted IC90 at weeks 4, 8, 12, 
24, and 48. 
• 
Tenofovir-diphosphate in dried blood spots, which is an objective medium-term ART adherence 
measure, at weeks 4, 8, 12 ,24 and 48. 
• 
Grade 3 or 4 drug-related adverse events 
• 
Change from baseline of sleep assessment and mental health questionnaires  
• 
Serious adverse events 
• 
Adverse events requiring discontinuation of any drug in the ART regimen 
• 
Emergence of antiretroviral resistance mutations in participants with virologic failure (resistance testing 
will be done on stored plasma at baseline in those with on study antiretroviral resistance mutations to 
distinguish emergent from pre-treatment resistance – see schedule of events) 
3.4 ANALYSIS PLAN 
The proportions of participants with virologic suppression will be determined with 95% CIs. Intention to treat 
and per protocol analyses will be performed as outlined in the primary and secondary endpoints above. 
Between-group differences for secondary endpoints will be analysed with chi-squared tests (or Fisher’s exact 
tests if the number in any cell is ≤5) for categorical data and with Wilcoxon rank sum tests for continuous data. 
As noted above in the sample size section, no formal between group comparisons will be made of the primary 
endpoint as we do not have sufficient power. 
4.0 STUDY MONITORING 
Monitoring systems with procedures to maximise the quality of every aspect of the study will be implemented. 
On site monitoring will be performed by independent study monitors on a regular basis. The monitors will: 
o 
verify completeness of the investigator site file 


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o 
confirm adherence to protocol 
o 
review eligibility verification and consent procedures 
o 
look for missed clinical event reporting 
o 
verify completeness, consistency, and accuracy of data being entered on CRFs  
o 
verify completeness, consistency, and accuracy of pharmacokinetic study data and samples 
o 
evaluate drug accountability  
o 
provide additional training as needed  
o 
document findings in a formal feedback letter (monitoring report) to the site 
5.0 ETHICAL CONSIDERATIONS AND INFORMED CONSENT 
5.1 ETHICAL CONDUCT 
This study will be conducted in accordance with the ethical principles laid out in the National Statement on 
Ethical Conduct in Research Involving Humans, the Declaration of Helsinki (most current version issued, available 
at www.wma.net), and will be consistent with GCP and applicable regulatory requirements.  
The rights, safety, and wellbeing of the study participants are the most important considerations and should 
prevail over interests of science and society.  All personnel involved in conducting this study will be qualified by 
education, training, and experience to perform their respective task(s). 
Institutional review board/independent ethics committee (IRB/IEC) and local regulatory approval will be 
documented and kept in the investigator site file, specifying the version number of the protocol and informed 
consent as well as the date of approval. Any amendments will require IRB/IEC and regulatory approval.   
The principal investigator will comply with all IRB/EC and regulatory authorities, reporting requirements for all 
safety reporting, annual updates, safety updates, end of study reports and any other important information 
relevant to the conduct of the study.  
5.2  
COMPLIANCE WITH THE PROTOCOL  
The study will be conducted as described in this protocol.  The principal investigator will not implement any 
deviation or change to the protocol without prior review and documented approval/favourable opinion from 
the IRB/IEC and regulatory authorities of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study participants. Any significant deviation will be reported to sponsor, IRB/IEC, and local 
regulatory authority. 
5.3  
PROTOCOL AMENDMENTS 
When revisions to the protocol are made by the sponsor, if the revision is an administrative letter, the principal 
investigator will submit this for the information of their IRB/IEC.  Study documents will be updated in line with 
the changes required in the protocol amendment. 
5.4  
INFORMED CONSENT AND PROCEDURES 
A study specific informed consent will include all elements required by GCP as well as all local ethics and 
regulatory requirements.   
The principal investigator will ensure that participants are clearly and fully informed about the purpose, potential 
risks and other critical issues regarding clinical trials in which they participate and that their participation is 
voluntary.  A copy of the informed consent will be given to the participant in a language of their choice.  Informed 
consent process will be conducted as per the trials site standard operating procedures.  A copy of the signed 
informed consent will be given to the participant.  
If the patient is illiterate, an impartial witness will be present during the entire consent discussion. A thumb print 
may be used as a signature.    


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The informed consent document will be updated with any pertinent information that becomes available during 
the study. 
5.5  
USE OF PLACEBO 
The use of a 50 mg dolutegravir vs placebo in this study will indicate whether the additional 50 mg dose is 
adequate to achieve and maintain viral suppression. All participants will be on the fixed dose combination 
antiretroviral tablet of dolutegravir-lamivudine-tenofovir. The phase 2 INSPIRING study [Dooley], although 
proving that the additional dolutegravir dose was well tolerated, was not powered to evaluate the efficacy of 
the additional dose versus the control arm (efavirenz-based ART) and has therefore not been adopted as 
standard of care. 
6.0 CONFIDENTIALITY OF DATA 
The site principal investigator agrees that the University of Cape Town and sponsor, IRB/EC or regulatory 
authorities may consult and/or copy study documents to verify information in the CRF. By signing the consent 
form the participant agrees to these processes.   
Participant confidentiality will be maintained at all times and no documents containing the participant’s name 
or other identifying information will be collected by the sponsor.  It may be necessary for the sponsor’s 
representatives, the IRB/EC and regulatory authority representatives to have direct access to the participant’s 
medical records. If study documents need to be photocopied during the process of verifying CRF data, the 
participant will be identified by a unique code only; full names and other identifying information will be masked.  
The principal investigator also agrees to maintain confidentiality with all study information and only divulge 
necessary information to the staff, ethics committee and regulatory authorities.  The data generated by this 
study will be considered confidential, except where it is included in a publication as agreed in the publication 
policy of this protocol. 


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7.0 REFERENCES 
Bonnet M, Bhatt N, Baudin E, et al. Nevirapine versus efavirenz for patients co-infected with HIV and 
tuberculosis: a randomized non-inferiority trial. Lancet Infect Dis 2013; 13: 303–12. 
Castillo-Mancilla JR, Morrow M, Coyle RP, Coleman SS, Gardner EM, Zheng J, et al. Tenofovir Diphosphate in 
Dried Blood Spots Is Strongly Associated With Viral Suppression in Individuals With Human Immunodeficiency 
Virus Infections. Clin Infect Dis 2018; Epub ahead of print. 
Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase 
inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study 
among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21-7.  
Dooley K, Kaplan R, Mwelase N, et al. Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults 
at week 24. 25th Conference on Retroviruses and Opportunistic Infections, Boston, 4-7 March 2018. 
Grinsztejn B, De Castro N, Arnold V, et al. Raltegravir for the treatment of patients co-infected with HIV and 
tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. 
Lancet Infect Dis 2014 Jun;14(6):459-67. 
Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J 
Med. 2011 Oct 20;365(16):1482-91.  
Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, Tomberlin GH, Carter HL 3rd, Broderick T, Sigethy 
S, Seki T, Kobayashi M, Underwood MR. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation 
than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA 
complexes. Antimicrob Agents Chemother. 2011 Oct;55(10):4552-9.  
Mfinanga SG, Kirenga BJ, Chanda DM, et al. Early versus delayed initiation of highly active antiretroviral therapy 
for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, 
randomised, placebo-controlled trial. Lancet Infect Dis. 2014 Jul;14(7):563-71.  
Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Stroder R, Chen S, Underwood M, Fujiwara T, Piscitelli 
S, Lalezari J. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day 
monotherapy in HIV-1-infected adults. AIDS. 2011 Sep 10;25(14):1737-45. 
Modongo C, Wang Q, Dima M, et al. Clinical and Virological Outcomes of TB/HIV Coinfected Patients Treated 
With Dolutegravir-Based HIV Antiretroviral Regimens: Programmatic Experience From Botswana. J Acquir 
Immune Defic Syndr. 2019 Oct;82(2):111–5. 
van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in 
antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, 
randomised, phase 2b trial. Lancet Infect Dis. 2012 Feb;12(2):111-8.  
Wang X, Cerrone M, Ferretti F, Castrillo N, Maartens G, McClure M, Boffito M. Pharmacokinetics of dolutegravir 
100 mg once daily with rifampicin. 19th International Workshop on Clinical Pharmacology, Baltimore, 22-24 May 
2018. 
Wenning LA, Hanley WD, Brainard DM, et al. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, 
on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009;53: 2852–56. 
Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. 
N Engl J Med. 2018 Sep 6;379(10):979-981. doi: 10.1056/NEJMc1807653. Epub 2018 Jul 24. 
 
 
 
 
 


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APPENDIX A: GANTT CHART 
 
Year 1  
Year 2 
Year 3 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Preparation of CRFs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staff recruitment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Public engagement and institutional meetings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training of clinical staff and counsellor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Engagement with laboratory staff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient recruitment and follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis of results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preparation and submission of manuscripts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RADIANT-TB GANNT chart 
 
 


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APPENDIX B:  ADVANCE SLEEP ASSESSMENT QUESTIONNAIRE 
APPENDIX C:  ADVANCE MENTAL HEALTH QUESTIONNAIRE 
APPENDIX D: SAMPLE INFORMED CONSENT