Conditions: Severely Immunocompromised HIV Patients
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 186
Healthy volunteers: no

Brief summary:
The current available antiretroviral (ARV) agents make possible a successful treatment of virtually all HIV-infected patients, but some problems related to early mortality are still of concern, mainly in resources-limited settings. There are several published reports showing that such patients are at a significantly higher risk of death during the first months of treatment, in comparison with the observed outcomes in developed countries. One of the consistently detected risks for early mortality across these reports is the baseline low CD4 count, although it does not seem to be the only reason for such outcome. In Brazil and other developing countries, there is still a large proportion of AIDS patients who are diagnosed with AIDS, or only seek health care for HIV infection late in the course of disease. Dolutegravir (DTG), the first HIV-1 integrase inhibitor, is a potent and safe ARV drug. The available evidence suggest it promotes a faster decline in HIV-1 plasma viremia, and a higher increase in CD4 cells count, in comparison with those in Efavirenz (EFV) arm. The investigators propose to compare the impact of DTG versus EFV in the early mortality rates for severely ill (CD4+ cells count \<50 cells/mm3) patients starting ARV therapy.

Detailed description:

Arms:
arm 1: Intervention: Patients will receive ART regimen based on investigational drug Dolutegravir 50 mg QD + TDF 300 mg QD+ 3TC 150 mg BID arm 2: Intervention: Patients who received ART regimen based efavirenz (EFV 600 mg QD +TDF 300 mg QD+ 3TC 300 mg QD) for one year, befor the use of DTG as SOC for first-line therapy (historic controls)

Interventions: intervention 1: Dolutegravir 50 mg intervention 2: Efavirenz-based regimens
Intervention descriptions: intervention 1: Use of Dolutegravir -based regimens: patients will receive a Dolutegravir -based ART regimen (RAL 400 mg BID + TDF 300 mg QD + 3TC 150 mg BID) intervention 2: Efavirenz-based regimens: patients will receive an EFV-based regimen (EFV 600 mg QD + TDGF 300 mg QD + 3TC 300 mg QD)

Protocol document:
Prot_000.pdf: 
 
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FBaI 
 
Bahiana Foundation of Infectology 
CNPJ: 02.340.960/0001-26 
Rua João das Botas, 185, Room 705, 
Canela, 40110-160, Salvador-Bahia. 
Telephone: +55 (71) 3247-2756 
 
 
Impact of a Dolutegravir-based regimen on 
early mortality in participants with AIDS: a 
pilot study. 
 
Institution : 
Fundação Bahiana de Infectologia  
Investigator : 
• Carlos Brites 
Fundação Bahiana de Infectologia - FBaI 
Rua João das Botas, 185, Centro Médico João das Botas, Rooms 
703/704/705, 7th floor. Cinnamon. Salvador BA. CEP 40.110-160. 
Phone: (5571) 3247-2756 / 98643-7227 
Email: crbrites@gmail.com 
 
 
 


 
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Content 
Institution  ............................................................................................................................... 11 
Researcher 1 _ ........................................................................................................................... 1 
1.  Objectives  ....................................................................................................................... 33 
1.1.  
Primary  ............................................................................................................... 33 
1.2.  
Secondary  ........................................................................................................... 33 
2.  Clinical Hypotheses 3 _ ..................................................................................................... 3 
3.  Background and Rationale 3 ............................................................................................. 3 
4.  Study Design 4 _ .................................................................................................................  
5.  Location  ............................................................................................................................ 4 
6.  Size of A shows  .............................................................................................................. 55 
6.1.  
Primary outcome 5 _ ............................................................................................. 5 
6.2.  
Secondary Outcomes 5 _ ....................................................................................... 5 
7.  Inclusion Criteria 5 _ ...........................................................................................................  
7.1.  
Retrospective Group  ............................................................................................. 5 
7.2.  
Prospective Group  ................................................................................................ 5 
8.  Exclusion Criteria 6 _ ........................................................................................................ 6 
8.1.  
Retrospective Group  ............................................................................................. 6 
8.2.  
Prospective Group  ................................................................................................ 6 
9.  Study 6 Flowchart _ ............................................................................................................  
10.  
Study Procedures 7 _ .......................................................................................................  
10.1.  
Retrospective Group  ............................................................................................. 7 
10.2.  
Prospective Group  ................................................................................................ 7 
10.3.  
Baseline Critical Ratings  ...................................................................................... 8 
10. 4 .  
Initial Evaluation Period 8 _ _ .................................................................................  
10.5 .  
_ Evaluation of And ficacity  ................................................................................ 8 
10.6 .  
_ Safety Parameters 9 _ ...........................................................................................  
10.7 .  
_ Toxicity Control 9 _ ........................................................................................... 9 
10.8 .  
_ Follow -up of Participants 9 .................................................................................  
11.  
Duration of the  ................................................................................................... Study 9 
12.  
Statistical Analysis and Justification of Sample Size 10 _  ....................................... 10_ 
12.1.  
Justification for the Size of the Show  ............................................................. 1010 
12.2.  
Statistical Analysis Plan 11 _ _ ........................................................................... 10 
12.3.  
G eneral  ................................................................................. 10Considerations 11 
12.4.  
Disposition of  ............................................................................. 11Participants 11 
12.5.  
Demographic Characteristics and Disease ...................................................... 1112 
12.6.  
Security Endpoints .......................................................................................... 1213 
12.7.  
Severe Adverse Events 13 _ _ ............................................................................. 12 
12.8 .  
_ Report of Adverse Experiences 13 ................................................................... 12 
13.  
Bibliography ............................................................................................................ 1314 
14.  
Plan for Publication ................................................................................................. 1516 
 
 


 
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1. Goals 
1.1. Primary 
• To assess early (all-cause) mortality rates within the first year of treatment in 
participants symptomatic with AIDS who started antiretroviral therapy with 
regimens based on Dolutegravir (DTG) or Efavirenz (EFV). 
1.2. secondary 
• Evaluate the proportion of participants with suppression of plasma viremia 
(CV less than 50 copies/ml), at different times of the study; 
• Compare CD4+ gain over time for both groups; 
• Compare the frequency of adverse events in participants using regimens with 
DTG and EFV. 
2. Clinical Hypotheses 
• DTG-based regimens are most effective in rapidly recovering CD4+ cells within 
the first year of therapy; 
• DTG-based antiretroviral regimens are able to promote more rapid suppression 
of HIV plasma viremia than EFV; 
• The group of participants treated with DTG-based regimens will have a lower 
rate of early mortality than those treated with the comparator drug. 
3. Background and Justification  
Currently available antiretroviral agents (ARVs) have made it possible to successfully 
treat virtually all HIV-infected participants, but some problems related to early mortality 
are still a matter of concern, especially in countries with limited resources (1,2 ). There 
are several reports showing that these participants have a significantly higher risk of 
death during the first few months of treatment compared to results observed in 
developed countries (3-11). One of the consistently detected risks for early mortality 
across these reports is low baseline CD4+ counts, although it does not appear to be the 
only reason for such an outcome. Other factors associated with higher mortality rates for 
participants starting antiretroviral therapy (ART) are anemia, low body weight, and 
ongoing opportunistic infections (12,13). Mortality rates for participants starting 


 
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antiretroviral therapy are quite variable, ranging from 1.8%, as demonstrated by a study 
carried out in Baltimore/USA, to values as high as 54%, in some areas of the African 
continent (3- 13). 
A recent study comparing mortality rates between low-income and high-income 
countries in participants with AIDS starting ARV therapy demonstrated that the risk 
ratio for early death was 4.3 times higher (95% CI: 1.6 - 11 .8), in poorer countries, but 
dropped to 1.5 after seven months of therapy (6). Furthermore, another report 
comparing mortality rates among participants with AIDS in Brazil and the USA showed 
that individuals with CD4+ cell counts below 50 cells/mm³ had a 4.8 times greater risk 
of death after starting ART and the proportion of early deaths in the first three months 
was significantly higher for Brazilian participants compared to Americans (14). 
In Brazil and other developing countries, there is still a large proportion of participants 
with AIDS who are diagnosed with AIDS, or who only seek health care for HIV 
infection in the final course of the illness. While a median first CD4+ cell count below 
200 is a frequent finding for most countries in the world, it is expected to be even lower 
for participants living in resource-limited countries, making the problem of early 
mortality an issue. important concern. 
Dolutegravir (DTG), an HIV-1 integrase inhibitor, is a potent and safe antiretroviral 
drug (14). Available evidence suggests that drugs in this class promote a more rapid 
reduction in HIV-1 plasma viremia, and a greater increase in CD4+ cell count, 
compared to EFV (15,16). 
We propose to compare the impact of DTG versus EFV on early mortality rates in 
critically ill participants starting antiretroviral therapy (CD4+ <50 cells/mm³). 
4. Study Design  
This is a pilot, open-label study to prospectively assess the rate of early all-cause 
mortality in participants initiating ART with DTG-based regimens. Retrospectively, the 
medical records of participants who used EFV in the years 2014-2016 will be reviewed 
for comparison purposes. 


 
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5. Local 
The study will be conducted by FBaI - Fundação Bahiana de Infectologia (Bahia) - 
Investigator: Dr. Carlos Brites, and will include 4 additional sites in different Brazilian 
cities (Manaus, Natal, Florianópolis, and Porto Alegre) 
6. Sample size  
The total number of participants included in each study arm will be 92. The calculation 
of this sample size is detailed in the SAMPLE SIZE section. 
6.1. Primary outcome  
• The primary study endpoint will be the all-cause mortality rate in the first 
year of therapy for critically ill participants starting ART. 
6.2. Secondary Outcomes  
• The proportion of patients who achieved a Viral Load (CV) below 50 
copies/ml at weeks 4, 8, 12, 24 and 48; 
• Gain of CD4+ cells after 24 and 48 weeks 
• Frequency of adverse events in participants receiving DTG or EFV therapy. 
7. Inclusion criteria 
7.1. Retrospective Group 
• Participants with confirmed HIV-1 infection (Western Blot positive or HIV-1 
RNA > >1,000 copies/ml); 
• Having used EFV as initial therapy in the years 2013-2016; 
• Baseline CD4+ cell count equal to or less than 50 cells/mm³; 
• Age equal to or greater than 18 years; 
• Plasma viral load immediately prior to initiation of therapy ≥ 1000 HIV-1 RNA 
copies/ml. 
7.2. Prospective Group 
• Participants with confirmed HIV-1 infection (Western Blot positive or HIV-1 
RNA ≥ 1000 copies/ml); 
• Not having previously used any ARV (treatment-naïve participants); 
• Baseline CD4+ cell count equal to or less than 50 cells/mm³; 
• Age equal to or greater than 18 years; 


 
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• Plasma viral load ≥ 1,000 HIV-1 RNA copies/ml in the last 30 days. 
• The participant or his/her legal representative is willing and able to understand 
and provide signed and dated free and informed consent prior to any study 
procedure. 
8. Exclusion Criteria  
8.1. Retrospective Group 
• Asymptomatic individuals (at the beginning of ART). 
8.2. Prospective Group 
• Undetectable plasma viral load at screening; 
• CD4+ cell count > 50 cells/mm³; 
• Age less than 18 years old; 
• Asymptomatic individuals. 
 
9. Study Flowchart  
 
 
 
 
EFV / TDF / 3TC 
(dados retrospectivos) 
N=92 
DTG + TDF/3TC  
N=92 
HIV-1, virgem de 
tratamento, 
 ≥ 18 anos, 
CV >1.000 cp/ml, 
CD4 ≤50 cels/mm³, 
sintomáticos
 
N=184 
Baseline 
Semana 48 


 
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10. Study Procedures 
10.1. 
Retrospective Group 
 
Procedures 
*Basal 
Without 24 
Without 
48 
TCLE 
Not applicable 
Inclusion and Exclusion Criteria 
X 
 
 
Medical History 
X 
 
 
Adverse events 
During the 48 weeks 
CV HIV-1 
X 
X 
X 
CD4+ / CD8 count 
X 
X 
X 
Biochemistry 
X 
X 
X 
Hematology 
X 
X 
X 
NOTE: A window of -30/+30 days for each visit will be acceptable for collecting this 
data. 
*In the baseline visit, results of laboratory tests up to 90 days before screening 
will be accepted. 
10.2. 
Prospective Group 
Procedures 
Basal 
Without 
4 
Without 
8 
Without 
16 
Without 
24 
Without 
48 
TCLE 
X 
  
  
  
  
  
Inclusion and Exclusion 
Criteria 
X 
 
  
  
  
  
Medical History 
X 
  
  
  
  
  
Adverse events 
  
X 
X 
X 
X 
X 
CV HIV-1 
X 
X 
X 
X 
X 
X 
CD4+ / CD8 count 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Plasma Sample (Storage) 
X 
  
  
  
  
  
Vitamin D3 
X 
  
  
  
X 
X 
NOTE: A window of -30/+30 days for each visit will be acceptable for collecting this 
data. 


 
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10.3. 
Basal Critical Ratings 
The Informed Consent Form (TCLE) must be obtained from each potentially eligible 
individual (or their legal representative) by the study center staff before any study 
procedure . The TCLE must have been approved by the Research Ethics Committee (CEP). 
Upon signing up, participants will complete initial assessments to determine their eligibility. 
Each participant selected for evaluation of inclusion in the study will be assigned an 
allocation number, given sequentially in chronological order of inclusion. 
10.4. 
Initial Evaluation Period  
Participants who meet the eligibility criteria will be included after signing the TCLE. 
10.5. 
Efficacy Assessment 
Plasma samples will be collected at each evaluation point, according to table 10.2. The 
method used to measure VC will be real-time PCR, with a detection limit set at 40 
copies/ml. The CD4+ / CD8 cell count will be determined by flow cytometry. 
• Primary Efficacy Parameters 
▪ The all-cause mortality rate in the first year of therapy using an absence, 
switch, discontinuation = failure (MSDF) algorithm, as per the FDA 
algorithm. 
• Secondary Efficacy Parameters 
▪ Proportion of patients achieving VC < 50 copies/ml at 4, 8, 12, 24 and 48 
weeks; 
▪ CD4+ T cells gained at each assessment point; 
▪ Frequency of adverse events in participants receiving DTG or EFV therapy. 
Safety assessments will consist of monitoring and reporting of all adverse events 
and serious adverse events in participants receiving DTG. Safety will be assessed 
through regular physical examination, and laboratory monitoring of hematology, 
lipids, glucose, liver enzymes and creatinine levels . All abnormalities detected in 
laboratory results and clinical changes will be reported in the Clinical File (CRF). 
The laboratory parameters to be tested will be: 
• Complete blood count; 


 
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• Fasting Glucose, Total Cholesterol and Fractions, Triglycerides, Vitamin D3 
(25-OH), Creatinine, TGO/TGP and Alkaline Phosphatase. 
10.6. 
Security Parameters  
• Incidence and severity of adverse effects and laboratory abnormalities; 
• Absolute values and changes in results throughout the study; 
• Proportion of participants discontinuing therapy due to adverse events; 
• Changes in the initial physical examination. 
10.7. 
Toxicity Control  
The occurrence of an Adverse Event (AE) during the study period will be evaluated by 
the investigator and classified according to the Division of AIDS (DAIDS) toxicity 
scales. 
The safety of Dolutegravir as initial therapy in critically ill participants has not been 
fully defined and the investigational product may be discontinued by the investigator 
according to the severity of the AE. No reduction of DTG doses will be allowed. Any 
change in the use of DTG must be recorded in the CRF. In case there is a need to 
interrupt the DTG, the drug will be replaced by a PI/r. 
Participants who experience a grade 1 or 2 AE will continue to receive DTG at the 
Investigator's discretion. Subjects who experience a Grade 3 AE may continue to use 
DTG if the investigator is of the opinion that the toxicity was not caused by the drug, 
but if the AE is found to be caused by the DTG, or if it is classified as a Grade 4, the 
drug should be interrupted. 
10.8. 
Follow-up of Participants  
All participants included in the protocol in the Prospective Group will be evaluated at 
baseline and after 4, 8, 16, 24, 36 and 48 weeks. 
11. Study Duration  
We estimate to recruit 92 participants over a period of 10 months. Considering the need 
for follow-up to 48 weeks, the total duration of the study will be 22 months. An 
additional two months will be spent on data analysis and manuscript preparation, giving 
us a total of 24 months to complete the study. The retrospective study should be 


 
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completed within the same time period. The selection of patients will be carried out 
considering eligible participants, consecutively, until the predicted N is reached. 
12. Statistical Analysis and Justification of the Sample Size  
12.1. 
Sample Size Justification  
Mortality rates are quite variable, depending on region, specific study, and population. 
Most studies from African countries have shown that mortality in the first 3 months of 
ART for participants with CD4+ cells under the threshold of 50 cells/mm³ is generally 
greater than 30%, and may reach 52% in some reports. 
On the other hand, in developed countries, most deaths in such a population usually 
occur after 7 months of therapy and the mortality rate is just as low (1.8% for the first 
year of treatment). 
We estimated that early mortality for participants included in the EFV arm would be 
similar to the rates detected in African countries (around 30%). We hypothesize that 
participants using DTG-based regimens would benefit from faster recovery of CD4+ 
cell count and that they behave like those individuals starting antiretroviral therapy in 
developed countries (mortality rate around 2%). 
Considering a lower limit of 2% (DTG arm) and an upper limit of 25% (EFV arm), a 
95% CI and 80% power to detect differences between groups, it would be necessary to 
treat a total of 84 participants ( 42 on each arm). Adding 10% for dropouts, this would 
result in a total of 92 subjects (46 in each arm). 
With the recent changes in treatment recommendations, all 92 participants will receive 
DTG. Participants who used EFV will be retrospectively evaluated, through the review 
of medical records, in an identical number (92 participants). 
This will be an exploratory pilot study. 
12.2. 
Statistical Analysis Plan 
12.3. 
General considerations  
intent-to-treat population , defined as all participants who are randomized to treatment. 
With the exception of the Primary Efficacy Endpoint Analysis, percentage responders to 


 
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the intention-to-treat population, missing data will not be estimated or carried forward 
in any statistical analyses. 
All comparisons of treatment groups will be performed using two-tailed tests at a 
significance level of 0.05 (p< 0.05). The null hypothesis for all analyzes is that there is 
no difference between treatment groups. 
All summaries, statistical analyzes and individual participant registration data described 
below will be provided in separate attachments. Separate listings will be provided for 
each of the treatment groups in the intent-to-treat population. 
12.4. 
Disposition of Participants  
Summaries of the number of patients randomized, number completing the study, and 
incidence of protocol violations will be provided for each treatment group. The number 
(%) of participants with protocol violations that may affect the study objectives will be 
based on database analysis. This assessment will be made prior to determining the 
treatment allocation for all participants in the database. 
12.5. 
Demographic Characteristics and Disease  
The statistical analyzes described below will be completed for: 
• The participating intent-to-treat population; 
• The evaluable population of efficacy. 
Demographic Characteristics 
The table below identifies the demographic and disease characteristics used to 
determine the comparability of treatment groups and the methods used to analyze them. 
Table 1 - Variables analyzed to determine comparability 
Variable 
Analysis method 
Baseline age 
One-way 
ANOVA/KW 
baseline CV 
One-way 
ANOVA/KW 
basal CD4+ 
One-way 


 
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ANOVA/KW 
The primary efficacy endpoint is the number (%) of participants who met the primary 
endpoint (HIV-1 RNA Viral Load <50 copies/ml) at the week 48 visit (or 
discontinuation). Participants will be counted as non-responders if they do not show up 
by Week 48 (or termination). 
The DTG treatment group will be compared to the EFV group with respect to the 
percentage of responders using a chi-square test. Two-tailed 95% confidence intervals 
for the percentage of responders will be calculated for each treatment group. 
The following table identifies secondary efficacy endpoints and the methods used to 
analyze them. 
Table 2 - Variables analyzed at the main points of analysis 
Variable 
Analysis method 
Frequency of Adverse Events 
Chi-square test 
Proportion of participants achieving CV <50 
copies/ml at each analysis point 
Chi-square test 
proportion of deaths 
Chi-square test 
CD4+ count at each analysis point 
One-way ANOVA/KW 
 
12.6. 
security endpoints  
Summaries and statistical analyzes of safety endpoints will be completed for the 
intention-to-treat population. The incidence of at least one grade III or IV event will be 
the primary safety endpoint of the study. Treatment groups will be compared with 
respect to the percentage of participants with at least one grade III or IV adverse event 
using a Chi-square test. 
12.7. 
Serious Adverse Events  
Secondary safety endpoints are the incidence of adverse events categorized according to 
preferred term and body system, clinically significant laboratory test results, and 
changes in vital signs. Treatment groups will be compared with respect to the 
percentage of participants with clinically significant laboratory test results at Week 4, 8, 
16, 24, 36, or 48 visits using Chi-square. 


 
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Summaries of physical examination data, vital signs (actual value and change from 
baseline), and laboratory data (actual value and change from baseline) will be provided 
at each visit. 
12.8. 
Report of Adverse Experiences  
The investigator and the site team will be responsible for documenting, detecting and 
reporting events that meet the definition of Adverse Event is defined as any unwanted 
medical event occurring in a participant or individual involved in a clinical investigation 
protocol, which may be transiently associated with the use of a medical product, 
regardless of whether or not it is considered to be related to the investigational product. 
A serious adverse event (SAE) is defined as any medical occurrence, resulting in death, 
or life-threatening, requiring hospitalization, resulting in impairment/disability, being a 
congenital anomaly, or all liver injuries grade 3 or higher , caused by drugs. 
13. Bibliography 
1. Bartlett JA, Shao JF. Successes, challenges, and limitations of current antiretrovidGT 
therapy in low-income and middle-income countries. Lancet Infect Dis. 2009 Oct; 
9(10):637-49. 
2. Bekker LG, Egger M, Wood R. Early antiretroviDTG therapy mortality in resource-
limited settings: what can we do about it? Curr Opin HIV AIDS. 2007 Jul; 2(4):346-51. 
3. Mutevedzi PC, Lessells RJ, Rodger AJ, Newell ML. Association of age with 
mortality and virological and immunological response to antiretroviDTG therapy in 
ruDTG South African adults. PLoS One. 2011; 6(7):e21795. 
4. Barth RE, Tempelman HA, Moraba R, Hoepelman AI. Long-Term Outcome of an 
HIV-Treatment Program in RuDTG Africa: ViDTG Suppression despite Early 
Mortality. AIDS Res Treat. 2011; 2011:434375. 
5. May M, Boulle A, Phiri S, Messou E, Myer L, Wood R, Keiser O, Sterne JA, Dabis 
F, Egger M; IeDEA Southern Africa and West Africa. Prognosis of patients with HIV-1 
infection starting antiretroviDTG therapy in sub-Saharan Africa: a collaborative 
analysis of scale-up programmes. Lancet. 2010 Aug 7; 376(9739):449-57. 


 
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6. Grinsztejn B, Veloso VG, Friedman RK, Moreira RI, Luz PM, Campos DP, Pilotto 
JH, Cardoso SW, Keruly JC, Moore RD. Early mortality and cause of deaths in patients 
using HAART in Brazil and the United States. AIDS. 2009 Oct 23; 23(16):2107-14. 
7. Zachariah R, Harries K, Moses M, Manzi M, Line A, Mwagomba B, Harries AD. 
Very early mortality in patients starting antiretroviDTG treatment at primary health 
centers in ruDTG Malawi. Trop Med Int Health. 2009 Jul; 14(7):713-21. Epub 2009 
May 26. 
8. Etard JF, Ndiaye I, Thierry-Mieg M, Guèye NF, Guèye PM, Lanièce I, Dieng AB, 
Diouf A, Laurent C, Mboup S, Sow PS, Delaporte E. Mortality and causes of death in 
adults receiving highly active antiretroviral DTG therapy in Senegal: a 7-year cohort 
study. AIDS. 2006 May 12; 20(8):1181-9. 
9. Zachariah R, Fitzge DTGd M, Massaquoi M, Pasulani O, Arnould L, Makombe S, 
Harries AD. Risk factors for high early mortality in patients on antiretroviDTG 
treatment in a ruDTG district of Malawi. AIDS. 2006 Nov 28; 20(18):2355-60. 
10. Marazzi MC, Liotta G, Germano P, Guidotti G, Altan AD, Ceffa S, Lio MM, 
Nielsen-Saines K, Palombi L. Excessive early mortality in the first year of treatment in 
HIV type 1-infected patients initiating antiretroviDTG therapy in resource-limited 
settings. AIDS Res Hum Retroviruses. 2008 Apr; 24(4):555-60. 
11. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults 
accessing antiretroviDTG treatment programs in sub-Saharan Africa. AIDS. 2008 Oct 
1; 22(15):1897-908. 
12. Russell EC, ChaDTGambous S, Pemba L, Churchyard GJ, Grant AD, Fielding K. 
Low haemoglobin predicts early mortality among adults starting antiretroviral therapy 
in an HIV care program in South Africa: a cohort study. BMC Public Health. 2010 Jul 
23;10:433. 
13. Dillingham RA, Pinkerton R, Leger P, Severe P, Guerrant RL, Pape JW, 
FitzgeDTGd DW. High early mortality in patients with chronic acquired 
immunodeficiency syndrome diarrhea initiating antiretroviral therapy in Haiti: a case-
control study. Am J Trop Med Hyg. 2009 Jun; 80(6):1060-4. 


 
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14. The AntiretroviDTG Therapy in Lower Income Countries (ART-LINC) 
Collaboration and ART Cohort Collaboration (ART-CC) groups. Mortality of HIV-1-
infected patients in the first year of antiretroviDTG therapy: comparison between low-
income and high-income countries. Lancet 2006; 367: 817–24 
15. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, 
Xu X, Williams-Diaz A, Rodgers AJ, Barnard RJ, Miller MD, DiNubile MJ, Nguyen 
BY, Leavitt R, Sklar P; STARTMRK investigators. Safety and efficacy of raltegravir-
based versus efavirenz-based combination therapy in treatment-naïve patients with 
HIV-1 infection: a multicentre, double-blind randomized controlled trial. Lancet. 2009 
Sep 5; 374(9692):796-806. 
16. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, 
Prada G, MoDTGes-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller 
MD, Wenning LA, Teppler H ; Protocol 004 Part II Study Team. Rapid and durable 
antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination 
therapy in treatment-naive patients with HIV-1 infection: results of a 48-week 
controlled study. J Acquire Immune Defic Syndr. 2007 Oct 1;46(2):125-33. 
14. Plan for Publication  
We intend to have enough data to guarantee a scientific publication 3 months after the 
end of the protocol. We plan to have 2-4 abstracts submitted to international scientific 
meetings by the end of the research project. Finally, we think that at least 2 scientific 
papers will be published with the results of the project. 
 

SAP_001.pdf: 
FBaI 
 
 
Fundação Bahiana de Infectologia 
CNPJ: 02.340.960/0001-26 
Rua João das Botas, 185, Salas 703-705, 
Canela, 40110-160, Salvador-Bahia. 
Telefone: +55 (71) 3247-2756 
 
 
 
 
TITLE: IMPACT OF A DOLUTEGRAVIR-BASED REGIMEN ON 
EARLY MORTALITY OF SEVERELY IMMUNOCOMPROMISED AIDS 
PATIENTS: A PILOT STUDY 
 
 
 
 
 
 
NCT number: NCT01837277 
Date: 20 June 2018 
 
 
 


Statistical Analysis Plan 
 General Considerations 
All abstracts and statistical analyzes will be provided for the intended intention to treat 
population, defined as all participants who are randomized to treatment. With the 
exception of the Primary Efficacy Parameter Analysis, percentage of responders for the 
intent-to-treat population, missing data will not be estimated or transported in any 
statistical analyzes. 
All comparisons of treatment groups will be performed using two-tailed tests at a 
significance level of 0.05 (p <0.05). The null hypothesis for all analyzes is that there is 
no difference between the treatment groups. 
All abstracts, statistical analyzes and individual record data of participants described 
below will be provided in separate annexes. Separate listings will be provided for each of 
the treatment groups in the intention-to-treat population. 
Arrangement of participants 
Summaries of the number of randomized patients, number of those completing the study, 
and incidence of protocol violations will be provided for each treatment group. The 
number (%) of participants with protocol violations that may affect study objectives will 
be based on database analysis. This evaluation will be done before determining the 
allocation of treatment for all participants in the database. 
Demographic Characteristics and Disease 
The statistical analyzes described below will be completed to: 
• The population of intention to treat participant; 
• The evaluable population of effectiveness. 
Demographic Characteristics 


The table below identifies the demographic and disease characteristics used to determine 
the comparability of treatment groups and the methods used to analyze them. 
Table 1 - Variables analyzed to determine comparability 
Variable 
Analysis method 
Basal age 
One-way 
ANOVA/KW 
Basal VL 
One-way 
ANOVA/KW 
CD4 + basal 
One-way 
ANOVA/KW 
 
The primary efficacy endpoint is the number (%) of participants who achieved the 
primary endpoint (HIV-1 Viral Load RNA <50 copies / ml) at week 48 (or 
discontinuation) visit. Participants will be counted as non-responders if they do not attend 
Week 48 (or term). 
The DTG treatment group will be compared to the EFV group with respect to the 
percentage of responders using a chi-square test. Two-tailed, 95% confidence intervals 
for the percentage of responders will be calculated for each treatment group. 
The following table identifies the secondary endpoints of effectiveness and the methods 
used to analyze them. 
 
 
Table 2 - Variables analyzed in the main points of analysis 
Variable 
Analysis method 
Frequency of Adverse Events 
chi-square test 
Proportion of participants achieving VL <50 
copies / ml at each point of analysis 
chi-square test 
Proportion of deaths 
chi-square test 


CD4 + count at each point of analysis 
One-way ANOVA/KW 
 
Security Endpoints 
Summaries and statistical analyzes of safety parameters will be completed for the 
population by intention to treat. The incidence of at least one grade III or IV event will 
be the primary safety objective of the study. Treatment groups will be compared to the 
percentage of participants with at least one grade III or IV adverse event using a Chi-
square test. 
Serious Adverse Events 
Secondary safety endpoints are the incidence of adverse events classified according to the 
preferred term and body system, the results of clinically significant laboratory tests and 
changes in vital signs. Treatment groups will be compared with the percentage of 
participants with clinically significant laboratory test results at Week 4, 8, 16, 24, 36 or 
48 visits using Chi-square. 
Summaries of physical examination data, vital signs (actual value and baseline change) 
and laboratory data (real value and change of baseline) will be provided at each visit. 
Report of Adverse Experiences 
The investigator and local staff will be responsible for documenting, detecting and 
reporting events that correspond to the definition of Adverse Event, which is defined as 
any undesired medical event occurring in a participant or individual involved in a clinical 
investigation protocol, which may be transiently associated with the use of a medical 
product, whether or not it is considered to be related to the test product. A serious adverse 
event (SAE) is defined as any medical event that results in death or life-threatening, 
hospitalization, disability, congenital anomaly, or all grade 3 or higher liver damage 
caused by drugs.