Clinical trial NCT02652793
Conditions: Human Immunodeficiency Virus
Sponsor: Judit Pich
Start date: 2015-11-01; Completion date: 2018-11-01
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A 48-week, open label, non comparative prospective trial in stable chronic human immunodeficiency virus-infected patients having achieved complete virological suppression for more than 24 weeks (human immunodeficiency virus-1 RNA \<50 c/ml) switching from an antiretroviral regimen containing tenofovir and lamivudine or emtricitabine and boosted protease inhibitor to boosted atazanavir and lamivudine Study visits will take place at screening, baseline, weeks 4, 12, 24, and 48.

Detailed description:

Arms: arm 1: All participants will switch their current antiretroviral regimen to a boosted atazanavir and lamivudine once daily.
Interventions: intervention 1: Boosted atazanavir intervention 2: Lamivudine
Intervention descriptions: intervention 1: Atanazir 300 mg once dailly boosted with 100 mg of ritonavir once dailly intervention 2: Lamivudine 300 mg once dailly

Protocol documents:
Prot_SAP_000.pdf: 
Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
 
 
Simplification from Tenofovir plus Lamivudine or Emtricitabine plus 
Ritonavir-Boosted-Protease Inhibitor to Ritonavir-Boosted-
Atazanavir plus Lamivudine in Virologically-Suppressed-HIV-
Infected Adults with Osteopenia: a pilot study 
 
 
 
 
 
 
Primary investigator: 
J.L Blanco 
Co-investigators:  
J.F. Rojas, E. Martinez, J.M. Gatell 
 
 
 
Sponsor's Protocol Code Number: Osteosimply014 
EudraCT number: 2014-002720-27 
Protocol Version:  1.0 
 
Date of Protocol:  06 Oct,2014, 2014 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
TABLE OF CONTENTS 
4 
1. STUDY SYNOPSIS 
4 
2. GENERAL STUDY INFORMATION 
7 
3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
8 
4. FLOW CHART OF ASSESSMENTS 
9 
5. BACKGROUND 
10 
5.1. 
Management of low bone mineral density in HIV-infected adults 
10 
5.2. 
Rationale for Performing the Study 
10 
6. STUDY OBJECTIVES 
11 
6.1. 
Primary Objective 
11 
6.2. 
Secondary Objectives 
11 
7. SELECTION CRITERIA 
11 
7.1. 
Total Number of patients 
11 
7.2. 
Inclusion criteria: 
11 
7.3. 
Exclusion criteria: 
11 
8. STUDY DESIGN 
12 
8.1. 
Design 
12 
8.2. 
Interventions and Assessments 
12 
9. STUDY INVESTIGATIONAL MEDICINAL PRODUCTS 
14 
9.1. 
Provision of Antiretroviral drugs during the Study 
14 
10. VISIT SCHEDULE 
14 
ELIGIBILITY SCREENING FORM 
14 
ELIGIBILITY OF PARTICIPANTS 
14 
Study Visit Windows 
17 


Osteosimply014 
EudraCT number: 2014-002720-27 
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11. ADVERSE EVENTS 
18 
11.1 Definitions 
18 
11.2 
Assessment of Intensity 
18 
11.3 
Assessment of Causality 
19 
11.4 
Collection and follow up of Adverse Events 
19 
11.5 
Serious Adverse Events (SAE) 
19 
12. SAMPLE SIZE AND STATISTICAL ANALYSIS 
21 
12.2 
Statistical analysis 
21 
12.3 
Sample size 
21 
13. DATA QUALITY, ETHICS, PATIENT PROTECTION 
21 
13.1 Data recording 
21 
13.2 
Data transfer to Study Sponsor 
21 
13.3 
Confidentiality and Personal Data 
22 
13.4 Monitoring Arrangements 
22 
13.5 Ethics Approval 
22 
13.6 
Regulatory 
22 
13.7 
Insurance Provisions 
22 
13.8 
Funding 
22 
14 PUBLICATIONS AND PRESENTATIONS 
22 
15 REFERENCES 
24 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
TABLE OF CONTENTS 
 
 
1. STUDY SYNOPSIS 
 
Protocol Number: 
Osteosimply014 
EudraCT Number: 
2014-002720-27 
Investigational Medicinal 
Products: 
Atazanavir, ritonavir, lamivudine  
Study Title: 
Simplification from Tenofovir plus Lamivudine or 
Emtricitabine plus Ritonavir-Boosted-Protease 
Inhibitor to Ritonavir-Boosted-Atazanavir plus 
Lamivudine in Virologically-Suppressed-HIV-
Infected Adults with Osteopenia: a pilot study 
 
Phase of Study: 
Phase IV 
Objectives: 
 
 
Primary: To assess the change in BMD by dual-
energy X-ray (DXA) absorptiometry in HIV-infected 
adults with hip or spine T-score < -1.0 by DXA at 
week 48 after switching to r/ATV plus lamivudine. 
Secondary: 
To assess the effects of switching on: 
o Proportion of patients free of virologic 
failure (confirmed VL≥ 50 copies/mL) at 48 
weeks 
o Adverse effects at 48 weeks 
o Bone turnover markers (BTMs):  urinary N-
terminal telopeptide of type-1 collagen 
(NTX), and bone-specific alkaline 
phosphatase at 48 weeks. 
o Estimated glomerular filtration rate (eGFR) 
and phosphorus in blood sample; (ii) 
proximal tubule dysfunction parameters: 
glucose, protein, albumin, creatinin, 
phosphorus, beta-2 microglobuline and NAG 
in urine samples. at week 48 when 
compared to baseline 
 
Study Design 
A 48-week, open label, non comparative 
prospective trial in stable chronic HIV-infected 
patients having achieved complete virological 
suppression for more than 24 weeks (HIV-1 RNA 
<50 c/ml) switching from an ARV regimen 
containing TDF+3TC or FTC+r/PI to r/ATV+3TC 
Study visits will take place at screening, baseline, 


Osteosimply014 
EudraCT number: 2014-002720-27 
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Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
Page 5 of 24 
weeks 4, 12, 24, and 48. 
 
Indication: 
Chronic HIV-1 infection 
Planned Sample Size: 
45 
Summary of Eligibility Criteria: 
Inclusion criteria: 
o Adult (≥18 years old) HIV-1-infected 
subjects. 
o Provision of written, informed consent 
o Hip or spine T-scores <-1.0 measured by 
dual-energy X-ray absorptiometry (DXA) (in 
the previous 24 weeks) 
o On stable cART based on TDF+3TC or 
FTC+r/PI for at least 24 weeks. 
o Having plasma HIV-1 RNA <50 copies/mL 
for at least the previous 24 weeks, including 
at least two samples. 
Exclusion criteria: 
o Pregnancy, breast-feeding status or plans 
for pregnancy in the short term. 
o Primary genotypic resistance mutations 
and/or previous virological failures to ATV 
or 3TC/FTC 
o Chronic hepatitis B infection 
o Patients with indication for therapy for the 
prevention of bone fractures.  
o 25-OH vitamin D deficiency (< 10ng/mL), 
o Hypogonadism (low total testosterone 
according to local reference range), 
untreated.  
o Hypothyroidism (low T4 and increased 
thyroid stimulating hormone levels 
according to local reference ranges)  
o Hyperparathyroidism (increased parathyroid 
hormone level with hypercalcaemia 
according to local reference ranges) 
o Having received oral corticosteroids or 
inhaled fluticasone (daily doses higher than 
5 mg/d prednisone equivalent for 3 months 
or more) 
o Using anti-resorptive therapy (Calcium and 
vitamin D supplements are encouraged but 
not mandated) 
o BMI lower than 19. 
o A patient with a history or current evidence 
of any condition, therapy, or laboratory 
abnormality, or other circumstance that 
might confound the results of the study, or 
interfere with the patient’s participation for 


Osteosimply014 
EudraCT number: 2014-002720-27 
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Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
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the full duration of the study 
o Unable to complete study procedures 
 
Number of Study Centres 
o 1 
Duration of Treatment: 
o 48 weeks 
Dose and Route of 
Administration: 
o All patients will switch to the following 
regimen: atazanavir 300 mg plus ritonavir 
100 mg plus lamivudine 300 mg, once daily, 
orally for 48 weeks. 
o  
Criteria for Evaluation: 
o Virological suppression, safety, physical 
examination, and laboratory parameters.  
 
Primary Endpoint: 
o Change in BMD by dual-energy X-ray (DXA) 
absorptiometry at week 48. 
 
Secondary Endpoints: 
o Proportion of patients free of virologic 
failure (confirmed VL≥ 50 copies/mL) at 48 
weeks 
o Proportion of patients with adverse effects 
at 48 weeks 
o Changes in bone turnover markers (BTMs): 
urinary N-terminal telopeptide of type-1 
collagen (NTX), and bone-specific alkaline 
phosphatase at 48 weeks. 
o Changes from baseline to week 48 in: (i) 
estimated glomerular filtration rate (eGFR) 
and phosphorus in blood sample; (ii) 
proximal tubule dysfunction parameters: 
glucose, protein, albumin, creatinin, 
phosphorus, beta-2 microglobuline and NAG 
in urine samples. 
 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
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Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
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2.  
 
 
 
GENERAL STUDY INFORMATION 
 
Sponsor: 
Fundació Clínic per a la Recerca Mèdica 
Rosselló, 149 
08036 Barcelona, Spain 
 
Primary Investigator: 
José Luis Blanco 
Hospital Clínic de Barcelona 
Villarroel 170, 
08036 Barcelona, Spain  
Telephone number: +34 93 2275430 
 
Co-investigators 
Esteban Martínez MD, PhD 
José M Gatell MD, PhD 
Jhon F Rojas MD 
Statistics and Data Management: 
Elisa De Lazzari, Statistician 
 
Monitor: 
Joan Albert Arnaiz MD, PhD 
CTU Clinic 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
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Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
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3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
3TC 
Lamivudine 
ATV 
Atazanavir 
ACTG 
AIDS Clinical Trial Group 
AE 
Adverse event 
ALT 
Alanine transaminase 
cART 
Combined Antiretroviral therapy 
ARV 
Antiretroviral 
AST 
Aspartate transaminase 
BMD 
Bone mineral density 
BTM 
Bone turnover marker 
CRF 
Case report form 
CYP450 
Cytochrome P450 
DXA 
Dual-energy X-ray absorptiometry 
FTC 
Emtricitabine 
HAART 
Highly Active Antiretroviral therapy 
HBV 
Hepatitis B Virus 
HIV 
Human Immunodeficiency Virus 
ICH GCP 
International conference of harmonization good clinical practice 
LDH 
Lactate dehydrogenase 
NRTI 
Nucleoside reverse transcriptase inhibitor 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
NAG 
N-acetyl-beta-D-glucosaminidase 
NTX 
N-terminal telopeptide 
OD 
Once daily 
r/PI 
Ritonavir-boosted Protease inhibitor 
RTV 
Ritonavir 
SAE 
Serious adverse event 
TDF 
Tenofovir disoproxil fumarate 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
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Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
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4. FLOW CHART OF ASSESSMENTS 
 
Time of Visit 
Screen Baseline 
Follow-up visits 
Week 
-4 
0 
4 
12 
24 
36 
48 
Clinical 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
Inclusion / exclusion criteria 
x 
x 
 
 
 
 
 
Demographic data 
x 
 
 
 
Physical examination / Vital signs 
x 
 
 
 
 
 
 
Targeted physical examination  
 
x 
x 
x 
x 
x 
x 
Concomitant medication  
 
x 
x 
x 
x 
x 
x 
Safety/ Adverse events 
 
x 
x 
x 
x 
x 
x 
Switching to r/ATV+3TC 
 
x 
 
 
 
 
 
Other tests 
 
 
 
 
 
 
 
DXA 
x 
 
 
 
x 
 
x 
Laboratory (blood) 
 
 
 
 
 
 
 
Total and free testosterone, TSH 
and free-T4 
x 
 
 
 
 
 
 
HIV RNA viral load  
x 
x 
x 
x 
x 
x 
x 
Biochemistry* 
 
x 
x 
x 
x 
x 
x 
Blood test to exclude pregnancy 
x 
 
 
 
 
 
 
Full blood count 
 
x 
x 
x 
x 
x 
x 
CD4/CD8+  cell count  
 
x 
 
 
 
 
x 
Calcium/phosphate** 
x 
 
 
 
 
 
 
eGFR and phosphorus 
 
x 
 
x 
x 
 
x 
bone-specific alkaline phosphatase 
 
x 
x 
 
x 
 
x 
Laboratory (urine) 
 
 
 
 
 
 
 
BTMs*** 
 
x 
x 
 
x 
 
x 
glucose, protein, albumin, creatinin, 
phosphorus, beta-2 microglobuline 
and NAG 
 
x 
 
x 
x 
 
x 
* 
Biochemistry: urea, electrolytes (including sodium, potassium, chloride, bicarbonate,calcium, magnesium and 
phosphate), creatinine, liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
albumin, total protein, bone-specific alkaline phosphatase [ALP], gamma glutamyltransferase [GGT], bilirubin),  
 
**If abnormal, determine parathyroid hormone 
 
***BTMs: NTX 
 
 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
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5.  BACKGROUND 
5.1. 
Management of low bone mineral density in HIV-infected adults  
The increased life expectancy for a majority of patients with access to combined antiretroviral 
therapy (cART) treatment has shown up that HIV infected patients continue to suffer many 
conditions, not all directly related to untreated HIV infection. Multiple factors contribute to non-
AIDS conditions, with lifestyle, continued immunosuppression (despite cART), immune activation, 
inflammation, co-infections (e.g.HCV), and long term exposure to ART all implicated. These co-
morbidities are becoming increasingly important for HIV-infected persons because are the major 
barrier to the goal of ‘normal’ life expectancy for cART-treated, HIV-infected patients. (1). Among 
these conditions, bone disease, particularly osteoporosis, has attracted increasing attention, 
particularly as the HIV infected population ages. Low bone mineral density (BMD) predisposes to 
fractures of the hip, spine and forearm - all more prevalent in HIV-infected adults (2). 
Antitretroviral therapy is associated with significantly greater loss of BMD (3). Tenofovir (TDF) 
particularly induces a greater decline in BMD–and increases bone turnover markers (BTMs)- than 
other ARV drugs -that trends to stabilize after 1 year of treatment- (4), and a large, retrospective 
cohort study reported more minimal trauma fractures with TDF based ART (5). Optimal 
management of low BMD in HIV-infected adults remains unclear. Potential strategies include 
bisphosphonate therapy and ART switch strategies. Switching TDF to abacavir (6) or to raltegravir 
(7) have been proposed.  
Once started, lifelong cART continuation is recommended, however concerns about long-term 
toxicity and sustainability of cART have been raised. Recently, new simpler therapeutic approaches 
that may limit the number of drugs have been evaluated both as initial therapy as well as 
maintenance therapy after virologic control. Maintenance monotherapy with a ritonavir-boosted PI 
(r/PI), the drugs with higher genetic barrier to resistance, is the most widely investigated strategy 
(8,9). A novel strategy based on dual therapy with a r/PI plus lamivudine (3TC) has been recently 
evaluated due to the finally lower efficacy of monotherapy with ritonavir-boosted Darunavir or 
Lopinavir compared to standard cART. 
Simplification strategy is widely referred into the Spanish Guidelines for the Use of Antiretroviral 
Treatment  in HIV-infected Individuals (15).   Ritonavir-boosted atazanavir is a once daily r/PI that 
has shown good tolerability with limited impact on lipid and glucose metabolism. In dual therapy 
with 3TC is the only rPI so far that has recently proven, in simplification strategy, to be safe, well 
tolerated and with rare virological failure without resistance selection (10,11). This combination is 
supported by a recent analysis of prevalence of transmitted drug resistance in Spain that have 
shown the very low rate of primary resistance for these specific drugs (3TC – 0.7% and ATV- 
0.1%) (16) 
5.2. 
Rationale for Performing the Study 
The aim of this pilot study is to evaluate if the strategy of switching from a stable triple therapy 
based on TDF plus lamivudine/emtricitabine (3FTC) plus rPI to a dual therapy of 3TC plus r/ATV in 
HIV-infected adults is safe, maintains a good control of HIV replication, increases BMD and 
decreases BTMs. 
 
 
 
 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
Page 11 of 24 
 
6. STUDY OBJECTIVES 
6.1. 
Primary Objective 
o To assess the change in BMD by dual-energy X-ray (DXA) absorptiometry in HIV-infected 
adults with hip or spine T-score < -1.0 by DXA at week 48 after switching to r/ATV plus 
lamivudine. 
6.2. 
Secondary Objectives 
To assess the effects of switching on: 
 
o Proportion of patients free of virologic failure (confirmed VL≥ 50 copies/mL) at 48 weeks 
o Adverse effects at 48 weeks 
o bone turnover markers (BTMs):  urinary N-terminal telopeptide of type-1 collagen (NTX), 
and bone-specific alkaline phosphatase at weeks 4, 24 and 48. 
o (i) estimated glomerular filtration rate (eGFR) and phosphorus in blood sample; (ii) 
proximal tubule dysfunction parameters: glucose, protein, albumin, creatinin, phosphorus, 
beta-2 microglobuline and NAG in urine samples. at week 48 when compared to baseline. 
 
7. SELECTION CRITERIA 
7.1. 
Total Number of patients 
A pilot study including forty-five (45) eligible participants. 
7.2. 
Inclusion criteria: 
o HIV-1-infected subjects with age ≥18 years old. 
o Provision of written, informed consent 
o Hip or spine T-scores <-1.0 by dual-energy X-ray absorptiometry (DXA) (in the previous 24 
weeks) 
o Stable cART based on TDF+3TC or FTC+r/PI for at least 24 weeks. 
o Having plasma HIV-1 RNA <50 copies/mL for at least the previous 24 weeks, including at 
least two samples. 
7.3. 
Exclusion criteria: 
o Pregnancy, breast-feeding status or plans for pregnancy in the short term. 
o Primary genotypic resistance mutations and/or previous virological failures to ATV or 
3TC/FTC 
o Chronic hepatitis B infection 
o Patients with indication for therapy for the prevention of bone fractures.  
o 25-OH vitamin D deficiency (< 10ng/mL), 
o Hypogonadism (low total testosterone according to local reference range),  
o Hypothyroidism (low T4 and increased thyroid stimulating hormone levels according to 
local reference ranges) 
o Hyperparathyroidism (increased parathyroid hormone level with hypercalcaemia according 
to local reference ranges) 
o Having received oral corticosteroids or inhaled fluticasone (daily doses higher than 5 mg/d 
prednisone equivalent for 3 months or more) 
o Using anti-resorptive therapy (Calcium and vitamin D supplements are encouraged but not 
mandated) 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
Page 12 of 24 
o BMI lower than 19. 
o A patient with a history or current evidence of any condition, therapy, or laboratory 
abnormality, or other circumstance that might confound the results of the study, or 
interfere with the patient’s participation for the full duration of the study 
o Unable to complete study procedures. 
 
8. STUDY DESIGN 
8.1. 
Design 
This is an open-label, 48-week prospective, non comparative clinical trial. Forty five (45) eligible 
subjects will be allocated to switch their current cARV regimen to r/ATV + 3TC. 
 
8.2. 
Interventions and Assessments 
Once the individual has fulfilled the inclusion/exclusion criteria, has understood the study aims and 
procedures, accepted its terms and signed the informed consent, he/she will be included in the 
study. The study will then start following the schedule detailed below. 
Virological failure was defined as the first of two consecutive HIV-RNA levels >37 copies/mL. A 
GRT will be performed in these patients. After VF, treatment will be modified at the investigator’s 
decision. 
A trial stopping rule was planned by assuming that an acceptable total virological failure rate 
should not have exceeded 12.5% (six patients). Therefore, study termination was planned if more 
than six virological failures were observed. 
 
Assessments 
 
Clinical visit: safety, adverse events, full blood count, biochemistry and HIV viral load, will be 
assessed at baseline, weeks 4, 12, 24, 36 and 48. (CD4/CD8 at baseline and w48)  
 
Bone: Parathyroid hormone levels will only be determined after screening if serum calcium or 
phosphate levels are abnormal. Total and free testosterone, TSH and free-T4 will be performed at 
prescreening (week: -4). DXA will be performed at pre-screening, weeks 24 and 48. BTMs will be 
assessed at baseline and weeks 4, 24 and 48 : urinary N-terminal telopeptide of type-1 collagen 
(NTX) (a peptide fragment released during bone resorption), bone-specific alkaline phosphatise 
(an isoform of alkaline phosphatase (ALP), a serum marker of bone formation). The 10-year risks 
of osteoporotic and hip fractures will be estimated at screening using the WHO FRAX(R) algorithm 
(using Spain-specific dataset) 
 
Kidney: eGFR, and phosphorus in blood sample; and, proximal tubule dysfunction parameters: 
glucose, protein, albumin, creatinin, phosphorus, beta-2 microglobuline and NAG in urine samples 
will be performed at baseline and weeks 12, 24 and 48. 
 
Plasma samples will be stored for possible subsequent testing of viral load if necessary after each 
visit. 
 
Study conduction, recruitment and follow-up: 
 
The study will be conducted at a single center: Infectious Diseases Department, Hospital Clinic, 
University of Barcelona  
 


Osteosimply014 
EudraCT number: 2014-002720-27 
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Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
Page 13 of 24 
Recruitment will take 24 weeks and duration of patient follow-up will be 48 weeks 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
Page 14 of 24 
 
9. STUDY INVESTIGATIONAL MEDICINAL PRODUCTS 
All participants will switch their current ARV regimen to a r/ATV + 3TC once daily. Medication will 
be used under the approved conditions detailed in the Summary of Product Characteristics 
(SmPC). 
For the management of Drug-drug interactions, contraindications and drug-related adverse events 
, please refer to the SmPC. 
 
Any changes in the ARV regimen will be made by the investigator and recorded in the CRF.  
9.1. 
Provision of Antiretroviral drugs during the Study  
All ARV drugs will be obtained by prescription from the study participant’s treating doctor. 
 
The budget impact of this simplification strategy, usually done in our clinical practice in candidate 
patients, is associated with net savings on hospital ARV drug budget, since all 45 patients will be 
switched from a triple to a double therapy regiment thus reducing acquisition costs. 
 
10. VISIT SCHEDULE 
 
Screening Visit (week -4) 
 
Eligibility Screening Form 
An eligibility screening form should be completed at the screening visit. Participant details will be 
entered on the study participant identification log including whether or not the participant was 
included, and if excluded, the reason why. 
 
Eligibility of participants 
Prior to screening, participants must be on stable and well-tolerated ART including a TDF+3TC or 
FTC+r/PI for at least 24 weeks prior to randomisation.   
 
Informed consent should be obtained and forms signed and dated by the participant prior to any 
study-related procedures being performed. 
 
The screening procedures will be completed in one visit.  
 
Assessments (results to be recorded in the CRF) 
Clinical eligibility will be measured by inclusion criteria and exclusion criteria as listed below.  
 
Inclusion criteria: 
 
o Provision of written, informed consent 
o HIV-1-infected subjects with age ≥18 years old. 
o Hip or spine T-scores <-1.0 by dual-energy x-ray absorptiometry (DXA) (in the previous 24 
weeks) 
o Stable cART based on TDF+3TC or FTC+r/PI for at least 24 weeks. 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
Page 15 of 24 
o Having plasma HIV-1 RNA <50 copies/mL for at least the previous 24 weeks, including at 
least two samples. 
 
Exclusion criteria: 
 
o Pregnancy, breast-feeding status or plans for pregnancy in the short term. 
o Primary genotypic resistance mutations and/or previous virological failures to ATV or 
3TC/FTC 
o Chronic hepatitis B infection 
o Patients with indication for therapy for the prevention of bone fractures.  
o 25-OH vitamin D deficiency (< 10ng/mL), 
o Hypogonadism (low total testosterone according to local reference range), untreated.  
o Hypothyroidism (low T4 and increased thyroid stimulating hormone levels according to 
local reference ranges)  
o Hyperparathyroidism (increased parathyroid hormone level with hypercalcaemia according 
to local reference ranges) 
o Having received oral corticosteroids or inhaled fluticasone (daily doses higher than 5 mg/d 
prednisone equivalent for 3 months or more) 
o Using anti-resorptive therapy (Calcium and vitamin D supplements are encouraged but not 
mandated) 
o BMI lower than 19. 
o A patient with a history or current evidence of any condition, therapy, or laboratory 
abnormality, or other circumstance that might confound the results of the study, or 
interfere with the patient’s participation for the full duration of the study 
o Unable to complete study procedures 
 
Other screening assessments: 
 
Demographic data: date of birth, age, gender, race,  
Full physical examination, medical history concomitant medications information will be obtained by 
the study doctor  
DXA (obtained in the previous 24 weeks) 
Blood and urine samples will be taken for lab test 
 
Safety 
 
For potentially child-bearing female participants a blood test will be done to exclude pregnancy.  
 
HIV antibodies/Western blot/proviral DNA (if report not available prior to study entry) 
HIV RNA viral load 
Biochemistry – urea, electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium 
and phosphate), creatinine, liver function tests (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], albumin, total protein, alkaline phosphatase [ALP], gamma 
glutamyltransferase [GGT], bilirubin, creatine kinase 
 
Fasting metabolic parameters 
total cholesterol, triglycerides, HDL/LDL cholesterol and calculated VLDL cholesterol 
Lab results will be recorded on the screening page of the CRF. 
 


Osteosimply014 
EudraCT number: 2014-002720-27 
________________________________________________________________________________ 
 
 
Simplification to RTV-Boosted-ATV + 3TC in Virologically-Suppressed HIV-Infected Adults with Osteopenia 
 
Version 1.0 
June 30, 2014 
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Baseline Visit (week 0)  
 
Baseline assessments will be recorded in the CRF: vital signs, physical examination, new 
concomitant medications, and adverse events  
 
Blood samples will be taken for full blood count, biochemistry – urea, electrolytes (sodium, 
potassium, chloride, bicarbonate, calcium, magnesium and phosphate), creatinine, liver function 
tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total protein, , 
gamma glutamyltransferase [GGT], bilirubin, creatine kinase, bone-specific alkaline phosphatase 
[ALP],CD4+/CD8+ lymphocyte count,  total cholesterol, triglycerides, HDL and LDL cholesterol, 
glucose. 
 
Urine samples will be collected for BTMs and glucose, protein, albumin, creatinin, phosphorus, 
beta-2 microglobuline and NAG 
 
Study participants will be provided with one (1) month’s supply of study medication, sufficient to 
cover 4 weeks 
 
Week 4  
 
Week 4 assessments will be recorded in the CRF: vital signs, physical examination, new 
concomitant medications, and adverse events  
 
Blood samples will be taken for full blood count, biochemistry – urea, electrolytes (sodium, 
potassium, chloride, bicarbonate, calcium, magnesium and phosphate), creatinine, liver function 
tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total protein, 
alkaline phosphatase [ALP], gamma glutamyltransferase [GGT], bilirubin), creatine kinase, bone-
specific alkaline phosphatase [ALP], CD4+ lymphocyte count, HIV RNA viral load ,total cholesterol, 
triglycerides, HDL and LDL cholesterol.  
 
Urine samples will be collected for BTMs and glucose, protein, albumin, creatinin, phosphorus, 
beta-2 microglobuline and NAG. 
 
At Week 4, study participants will be provided with study medication for at least two (2) months 
plus an additional two (2) weeks supply to allow for the allowable study window (±7 days).  
 
Weeks 12, 24, 36 and 48 
 
All clinical assessments will be recorded in the CRF: vital signs, physical examination, new 
concomitant medications, and adverse events. 
 
Blood samples will be taken for full blood count, biochemistry – urea, electrolytes (sodium, 
potassium, chloride, bicarbonate, calcium, magnesium and phosphate), creatinine, liver function 
tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total protein, 
alkaline phosphatase [ALP], gamma glutamyltransferase [GGT], bilirubin, creatine kinase, bone-
specific alkaline phosphatase [ALP] (weeks 24 and 48),CD4+ lymphocyte count, HIV RNA viral 
load, total cholesterol, triglycerides, HDL and LDL cholesterol.  
 
Urine samples will be collected for BTMs (weeks 24 and 48) and glucose, protein, albumin, 
creatinin, phosphorus, beta-2 microglobuline and NAG when specified. 
 


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DXA will be performed on weeks 24 and 48. 
Bone-specific alkaline phosphatase [ALP] will be determined at baseline and at week 48. 
Study Visit Windows 
 
Baseline and Week 4 visits have a visit window of ±2 days. 
 
Week 12, 24, 36 and 48 visits have a visit window of ±7 days. 
 
 
Pregnancy 
 
Despite the known effects of the study drugs (atazanavir, ritonavir and lamivudine), and their 
relative safety during pregnancy, women should avoid becoming pregnant during the course of 
this trial.  If a participant becomes pregnant, she will be monitored until the end of the pregnancy.  
The pregnancy must be followed up to determine outcome (including premature termination) and 
status of mother and child which must be reported to the sponsor(BMS)  
 
 
Blood and Urine Specimen Management 
  
Safety parameters will be assessed by the local laboratory.  Local laboratory reference ranges will 
apply. Safety parameter blood samples will be transported according to the local laboratory 
requirements for measurement of: urea, electrolytes (including, sodium, potassium, chloride, 
bicarbonate, calcium, magnesium and phosphate), creatinine, liver function tests - alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin, total protein, bone-
specific alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), bilirubin and creatine 
kinase. Lipids: triglycerides, total cholesterol, HDL, LDL, VLDL cholesterol, glucose 
 
HIV parameters will be assessed by Local laboratory and local reference ranges will apply. HIV 
parameter blood samples will be transported to according to the local laboratory requirements for 
measurement of: full blood count, CD4/CD8+ lymphocyte count and percentage and HIV viral 
load.  
 


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11. 
ADVERSE EVENTS 
 
11.1 Definitions 
 
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a casual relationship with the study treatments. An 
adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product. 
 
Adverse events observed by the Investigator, or reported by the subject, and any remedial action 
taken, will be recorded in the subject’s CRF and should be verifiable in the subject’s notes 
throughout the study.  The nature of each event, time of onset after drug administration, duration 
and severity will be documented together with the Investigator’s opinion of the causal relationship 
to the treatment (unrelated, unlikely, possible, probable, and definite). 
All subjects experiencing adverse events, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline, or until there is a satisfactory explanation 
for the changes observed. 
Procedures such as surgery should not be reported as adverse events.  However, the medical 
condition for which the procedure was performed should be reported if it meets the definition of 
an adverse event.  For example, an acute appendicitis that begins during the adverse event 
reporting period should be reported as the adverse event and the resulting appendectomy noted 
on the CRF. 
Planned procedures such as surgery planned prior to the subject’s enrolment into the study need 
not be reported as adverse events if these are documented as planned at the screening visit. 
 
Clinically significant changes in physical examination and blood safety profiles should also be 
recorded as adverse events. 
 
11.2 
Assessment of Intensity 
 
Severity should be recorded and graded according to the AIDS Clinical Trial Group (ACTG) Grading 
Scale.  
 
Note: There is a distinction between the gravity and the intensity of an adverse event. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious adverse event. For 
example, a headache may be severe in intensity but would not be classified as serious unless it 
met one of the criteria for serious events. 
 
All events deemed to be Grade 4 (potentially life threatening) according to the ACTG grading scale 
should be routinely reported as a serious adverse event. However there may be occasions where 
in the investigator’s clinical judgement they do not consider the event to be life threatening 
therefore they do not consider the event to meet the definition of an SAE. In these cases the 
investigator must document clearly in the participants source documentation that the Grade 4 
event has been assessed and why in their clinical judgement they do not consider the event to be 
life threatening.   


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11.3 
Assessment of Causality 
 
The relationship to study drug of each adverse event will be assessed using the following 
definitions: 
DEFINITE: 
distinct temporal relationship with drug treatment. Known reaction to agent or 
chemical group, or predicted by known pharmacology. Event cannot be explained by subject’s 
clinical state or other factors. 
PROBABLE: 
reasonable temporal relationship with drug treatment. Likely to be known reaction 
to agent or chemical group, or predicted by known pharmacology. Event cannot easily be 
explained by subject’s clinical state or other factors. 
POSSIBLE: 
reasonable temporal relationship with drug treatment. Event could be explained by 
subject’s clinical state or other factors. 
UNLIKELY: 
poor temporal relationship with drug treatment. Event easily explained by subject’s 
clinical state or other factors. 
UNRELATED: the event occurs prior to dosing. Event or intercurrent illness is due wholly to 
factors other than drug treatment. 
 
11.4 
Collection and follow up of Adverse Events  
 
All adverse events, however minor, will be documented in the CRF whether or not the Investigator 
concludes the event to be related to drug treatment. 
 
The adverse event reporting period will be from consent  until the subjects final study visit.  In 
addition, any untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as possibly, probably or definitely related to the study drug medication 
should also be reported as an Adverse Event. 
 
Adverse events may be directly observed, reported spontaneously by the subject or by questioning 
the subject at each study visit. 
 
All adverse events should be followed up until they are resolved or the subject’s participation in 
the study ends (i.e. until the final CRF is completed for that subject).  In addition, all serious and 
non-serious adverse events assessed by the Investigator as possibly related to the investigational 
medication should continue to be followed even after the subject’s participation in the study is 
over.  Such events should be followed until resolution, or until no further change can reasonably 
be expected.  Deaths occurring more than 30 days after the final dose, which are considered to be 
unrelated to the study medication, should not be reported as a Serious Adverse Event. 
 
Rash and any associated symptoms should be reported as adverse events (see section 4.3) 
 
11.5 
Serious Adverse Events (SAE) 
 
A serious adverse event is any untoward medical occurrence that at any dose: 
i) 
Results in death 
ii) 
Is life threatening 
iii) 
Requires in patient hospitalisation or prolongation of existing hospitalisation 


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iv) 
Results in persistent or significant disability/ incapacity 
or 
v) 
Is a congenital anomaly/ birth defect. 
 
Additionally, important medical events that may not results in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical 
judgment, the may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Example of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-patient hospitalization, or the development of 
drug dependency or drug abuse.  
 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.  
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs.  An overdose is defined as the accidental or intentional 
administration of any dose of a product that is considered both excessive and medically important. 
All occurrences of overdose must be reported as an SAE 
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE. 
 
The SAE should be reported immediately to the sponsor and BMS (study supported). 
 
NOTE: bilirubin fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and 
suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin 
≥2xULN, then the event should still be reported as an SAE.  If INR is obtained, include values on 
the SAE form. INR elevations >1.5 suggest severe liver injury.. 
 
Deadline for SAE notification 
All SAEs, whether or not deemed drug-related or expected, and pregnancies must be 
reported to BMS within 24 hours of first becoming aware of the event. All SAEs related related to 
the use of Atazanavir must be emailed to Bristol-Myers Squibb: SAE Email Address: 
Worldwide.Safety@BMS.com 
SAEs must be recorded on a SAE form (BMS can provide), MEDWATCH or CIOMS form; 
Pregnancies on a Pregnancy Surveillance Form. 
All SAEs should be also reported to local Ethic Committee. 
Pharmacovigilance aspects will be conducted according to Appendix 3 described in this protocol.  
  
SAE Reconciliation 
 
The investigator will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (GPV&E). Frequency of reconciliation will be determined prior to study 
commencement but will occur no less than once prior to study database lock. BMS GPV&E will e-
mail upon request from the investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on the 
GPV&E reconciliation report will be used for case identification purposes. If the investigator 
determines a case was not transmitted to BMS GPV&E, the case will be sent immediately. 
 


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12. 
Sample size and Statistical analysis 
12.2 
Statistical analysis 
 
This is an open-label pilot study. All patients included in the study will be included in the safety 
population. All analyses will be performed after all participants have completed the study, 
permanently withdrawn or been lost to follow-up.  
 
Descriptive statistics will be used for continuous and ordinal variables. For continuous data, mean 
change from baseline will be calculated for participants with baseline and at least 1 follow-up visit. 
 
Changes on BMD from baseline at week 48 (and 24), will be assessed using random-effects 
regression model. Patient’s characteristics (age, sex, weight, BMI, smoking, units of alcohol), 
antiretroviral therapy, tenofovir duration, concomitant medication, hepatitis C coinfection and 
laboratory markers will be assessed using a linear regression as a potential predictors of changes 
in bone mineral density. Those that were associated (p<0.05) will then be tested for their 
independent association with greater increase in BMD using stepwise regression. Correlations 
between changes in BTMs and changes in BMD at week 48 will be calculated using Spearman's 
rank correlation coefficient. An additional multivariate model will be constracted including the 
changes in the BTMs at weeks 4 and 24 as a covariates. 
 
Analyses will be primarily by intent-to-treat. As this study is designed to evaluate the biological 
effects of an intervention, a per-protocol analysis will also be performed. An interim analysis will be 
done at week 24, study will be stopped if more than six virological failures were observed. 
 
12.3 
Sample size 
This is a non-comparative pilot study planning to include 45 patients. Switching from TDF to RAL in 
osteopaenic HIV-infected patients virological suppressed achieved a 2.5% increase in BMD at 48 
weeks (7). Assuming a standard deviation (SD) of 3.5%, in order to detect a 2% increase from 
baseline with 90% power and α=0.025 in two-sides, 45 patients would be required (allowing for 
10% losses to follow-up). 
 
13. 
Data Quality, Ethics, Patient protection 
 
The study will be conducted guided by the Declaration of Helsinki and under the ICH GCP 
guidelines on clinical research with medicines. 
13.1 Data recording 
The investigators will be provided with CRF folders for the input of study data. These should be 
completed according to the printed set of instructions accompanying these folders. Participants will 
not be identified by name on any CRFs, but rather by a site-specific ‘Study Identifier’ and ‘Name 
Code’. 
13.2 
Data transfer to Study Sponsor 
The completed study CRFs should be transferred to the Study Sponsor Statistician once source 
data verification has been performed. 
 


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Any data queries generated will be addressed in consultation with study monitor. 
 
13.3 
Confidentiality and Personal Data 
 
All data will be managed in accordance with the ICH GCP guidelines and under Spanish regulations 
on protection of personal data (LEY ORGÁNICA 15/1999, DE 13 DE DICIEMBRE, DE PROTECCIÓN 
DE DATOS DE CARÁCTER PERSONAL) 
 
 
13.4 Monitoring Arrangements  
 
The purpose of monitoring is to verify the rights and wellbeing of human subjects are protected; 
that trial data is accurate, complete and verifiable with source data; that the trial is conducted in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
A monitor will conduct regular site visits for the purpose of monitoring various aspects of the 
study.  The Investigator must agree to allow the study monitor and authorised representatives of 
the Sponsor, to inspect all CRF and corresponding source documents, e.g. original medical records, 
subject records and laboratory raw data, access to the clinical supplies, dispensing and storage 
areas and agree to assist with their activities if requested.  The Investigator should provide 
adequate time and space for monitoring visits. 
The monitor will query any missing or spurious data with the Investigator, which should be 
resolved in a timely manner.  A monitoring log will be maintained recording each visit, the reason 
for the visit, the monitor’s signature and Investigator’s or designee’s confirmation signature. 
13.5 Ethics Approval 
 
The study protocol, subject information and consent form, the Investigator brochure, or other 
reference safety information, subject recruitment procedures, information about payments and 
compensation available to the subjects and documentation evidencing the Investigator’s 
qualifications should be submitted to the Ethics Committee for ethical review and approval 
according to local regulations, prior to the study initiation. Any changes, which may need to be 
made, will be submitted in the form of numbered and dated protocol amendments in accordance 
with local regulations.  
13.6 
Regulatory  
As required by Spanish regulations, authorisation by the Spanish competent Authorities (AEMPS) 
will be obtained, prior to study initiation. 
13.7 
Insurance Provisions  
The sponsor will take out appropriate insurance cover for this trial in accordance with Spanish 
regulations.  
13.8 
Funding 
The study conduction is funded by a grant provided by BMS. 
 
14 
Publications and presentations 
 


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The study will be registered in a publicly available data base before the inclusion of the first 
patient. The final data will be presented at one or more scientific meetings and published in a 
peer-reviewed journal. No patient data will be presented that could permit identification of any 
study participant. No other publication will be made before the primary manuscript has been 
agreed upon and accepted for publication and without prior approval of the principal investigator. 


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15 
REFERENCES 
 
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3-. El-Sadr WM, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 
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4-. McComsey GA, et al. Bone mineral density and fractures in antiretroviral-naive persons 
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A5202. J Infect Dis. 2011;203:1791-1801 
5-. Bedimo R, et al. Osteoporotic fracture risk associated with cumulative exposure to tenofovir 
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6-. Martin A, et al. Simplification with tenofovir-emtricitabine causes less, serious non-AIDS events 
than with abacavir-lamivudine: a randomized, 96-week trial. Clin Infect Dis 2009; 49: 1591-1601 
7-. Bloch M, et al. Switch from tenofovir to raltegravir increases low bone mineral density and 
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11-. Perez Molina et al. SALT study. EACS 2013; Brussels, Belgium. Abstract PE7/1 
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13-. Stellbrink H-J, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. 
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14-.  McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone mineral density 
and fractures in antiretroviral-naive persons randomized to receive abacavirlamivudineor tenofovir 
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16-. Monge S, Guillot, Alvarez M, et al. Clinically relevant transmitted drug resistance to first line 
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