protocol SAP redacted - ClinicalTrials.gov

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Lopinavir/ritoP15-452 Prot

17 August 201

n Identifier rsion of

er Number

ceuctnce

ber horisation

ion and

f Study

This study

sure outside A

onavir and Lamtocol

15

ProSpectivEffectiveneTreatment-Settings of

P15-452

17 Aug 20

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To assess t(lopinavir/treatment-eplasma HIVtimepoint oFederation

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ion 01, dated 1

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17 August 201

Authorisa

horisation Hol

Person

onavir and Lamtocol

15

ation Ho

lder(s) AL

N

mivudine

lder(s)

AbbVie DeutscLudwigshafen,

Not applicable

chland GmbH Germany

& Co. KG, KKnollstrasse 67

2

7061

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1.0

1.02.03.04.05.06.07.07.17.28.08.18.29.09.19.29.39.49.59.69.79.89.99.109.109.109.119.129.139.149.159.16

ion 01, dated 1

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4


17 August 201

Table

Table of AbbreviaResponsiAbstractAmendmMilestonRationalBackgrounRationale .ResearchPrimary ObSecondaryResearchStudy DesiProduct SuSetting .....Program DInvestigatoInclusion CExclusion DescriptionTerminatioEndpoints Primary EnSecondaryData SourcStudy SizeData ManaData AnalyQuality CoLimitation

onavir and Lamtocol

15

of Conte

Contentsations .....ible Partit ..............

ments andnes ...........le and Bacnd .................................

h Questionbjective ..... Objectives h Methodign .............upply ............................

Duration ......or selection Criteria ......Criteria .....n of Activiton of the Pro..................ndpoint ...... Endpointsces .............e .................agement .....ysis ............ontrol .........ns of the Res

mivudine

ents

s ...............................ies ............................ Updates.................ckground....................................n and Ob....................................s ......................................................................................criteria ..........................................

ties .............ogram ........................................................................................................................................................search Meth

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bjectives ...........................................................................................................................................................................................................................................................................................................................................................................................

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Versi

9.1710.011.011.111.111.111.111.111.111.111.211.211.212.0

13.0

ion 01, dated 1

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17 August 201

Other AspeProtectioManagemMedical CAdverse EvSeverity ...RelationshSerious AdSerious AdPregnancyProduct CoDefinition Reporting .Plans forResults ..Referenc

onavir and Lamtocol

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................

................

4

...... 25

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.... 31

Versi

2.0

3TC

AID

AE

ART

CI

CRA

CRO

CVD

eCR

EDC

GPV

HAA

HIV

IEC

LPV

MA

Med

NC=

NRT

PI

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RNA

SAE

ion 01, dated 1

C

DS

T

A

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AH

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17 August 201

Abbre

onavir and Lamtocol

15

eviations

Lamivacqui

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Cardi

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Globa

Highl

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Ribon

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mivudine

vudine red immune d

rse event

etroviral Ther

idential Interv

cal Research A

ract Research

iovascular Dis

ronic Case rep

ronic Data Cap

al Pharmacovi

ly Active Anti

an Immunodef

pendent Ethics

navir/ ritonavir

keting Applicat

cal Dictionary

completer=Fa

eoside Reverse

ase Inhibitor

Marketing Ob

nucleic acid

us adverse eve

deficiency synd

rapy

val

Associate

Organization

sease

port form

pture

igilance

i-Retroviral Th

ficiency Virus

s Committee

r

tion Holder

y for Regulato

ailure algorithm

e Transcriptas

bservational St

ent

drome

herapy

s

ry Activities

m

se Inhibitor

tudy

5

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3.0Abb

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ion 01, dated 1

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tract Resear


17 August 201

Respo

rch Organiz

onavir and Lamtocol

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onsible P

zation (CRO

mivudine

Parties

O)

6

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Title

(Lopi

Clinic

Ratio

assoc

nucle

exam

didan

abaca

that h

antivi

patien

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GAR

effica

maint

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overw

treatm

ion 01, dated 1

: Prospective

inavir/ritonavi

cal Settings of

onale and B

ciated with th

eos(t)ide analo

mple, some NR

nosine) and ki

avir in some c

has been wide

iral potency o

nts in a numbe

/r+3TC dual

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acy and comp

tenance therap

acy data for L

whelmingly fro

ment-experien


17 August 201

Abstra

, Multi-Center

ir + Lamivudin

f the Russian F

Background: he use of a

ogues (NRTIs

RTIs can caus

idney dysfunc

ohort studies

ely used as a f

of LPV/r (lop

er of different

therapy has b

E studies resp

parable safety

py in virologic

LPV/r+3TC d

om OLE study

nced HIV-1 inf

onavir and Lamtocol

15

act

r, Observation

ne) in Treatme

Federation

Standard o

a triple antire

s) (4). NRTIs

se anemia (zid

ction (tenofovi

(5 - 7). Lamiv

first line drug

pinavir/ritonav

clinical trials,

been studied

pectively (1-3)

to LPV/r + 2

cally suppresse

dual therapy da

y (1) whereas

fected patients

mivudine

nal Program to

ent-Experienc

of care treatm

etroviral ther

s are not alwa

dovudine), neu

ir). Cardiovas

vudine (3TC)

for the treatm

vir) has been

, for periods o

in HIV-1-naï

). Over 48 we

2 NRTIs, as f

ed patients in

ata from treatm

no data exists

s in routine cli

o Assess the E

ced HIV-1 Infe

ment of HIV-

rapy (ART)

ays well tolera

urotoxicity an

scular disease

is an effective

ment of HIV in

clearly demon

of up to seven y

ïve and HIV-

eeks, LPV/r +

first line regim

OLE study (1

ment-experien

s on that effect

inical settings

ffectiveness o

ected Patients

-1-infected pa

with regimen

ated (short an

nd lipodystroph

e (CVD) is als

e NRTI with g

nfected adults

nstrated in a

years (13-14).

-1 experience

3TC demonst

men in GARD

-3).

nced HIV-1 po

tiveness of LP

of the Russian

of Dual Therap

in the Routine

atients is usu

ns including

nd long term).

hy (stavudine

so associated

good safety pr

and children.

wide spectrum

.

ed patients in

trated non-infe

DEL study an

opulations are

PV/r + 3TC in

n Federation.

7

py

e

ually

two

. For

and

with

rofile

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m of

n the

ferior

nd as

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2

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as me

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1

2

3

4

5

ion 01, dated 1

arch Question

ary Objective

ssess the virolo

lation of treat

(for at least 6

ian Federation

ndary Objectiv

1. To evalua

2. To evalua

3. To assess

4. To evalua

5. To evalua

y Design: Thi

ol group.

ulation: HIV-

ma HIV-1 RNA

edically appro

points

ary endpoint

1. Proportion

level at we

ndary endpoin

1. Proportion

week 24 o

2. Absolute v

the baselin

3. Absolute v

baseline.

4. Proportion

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17 August 201

n and Object

ogic effectiven

tment-experien

6 months) at th

n. ves

ate virologic ef

ate immune rec

the developm

ate metabolic

ate the safety a

is is a non-inte

-1 infected pat

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priate to LPV

n of patients o

eek 48 of the o

nts

n of patients o

of the observat

values of HIV

ne (untransfor

values of CD4

n of patients w

values at week

umference in

onavir and Lamtocol

15

tives:

ness of dual th

nced HIV-1 in

he 48 week ti

ffectiveness of

constitution on

ment level of dr

and anthropom

and tolerability

erventional, pr

tients aged 18

least 6 months

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on dual therap

observational

on dual therap

tional period.

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rmed and base

4+ T-cell coun

who develop re

ks 24 and 48 a

cm) as compa

mivudine

herapy (lopina

nfected patien

imepoint of tr

f dual therapy

n the dual ther

rug resistance

metric parame

y of dual thera

roduct-focused

years and old

s (two consequ

he routine clini

py (LPV/r + 3

period.

py (LPV/r + 3

al loader at we

e-10 logarithm

nts at weeks 2

esistance to ea

and changes of

ared to the base

avir/ ritonavir

nts with an un

eatment in the

y at week 24.

rapy at weeks

over 48 week

eters change ov

apy (LPV/r + 3

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der on any tripl

uently plasma

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3TC) with und

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ach drug in the

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eline.

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24 and 48.

ks of treatment

ver 48 weeks o

3TC)

l and multi-ce

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ndetectable pla

detectable HIV

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data).

d the change a

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mivudine (3TC

asma HIV-1 R

ical settings o

t.

of treatment.

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with undetectab

levels) transfe

asma HIV-1 R

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nge as compare

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th no

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total chol

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at 48 weeks,

rvational prog

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of Data Colle

of Data Collec

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17 August 201

values at wee

lesterol, LDL-

n of patients

reatment disco

ta for the study

at the center. S

tal records, cli

er records, rec

OLE study (1

emained suppr

with non-inf

ram, it is estim

plasma HIV-1

a Simple Asym

n will extend

expected prop

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ince this is an

riptive summa

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d 95% confide

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ction: 1

ction: 1

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onavir and Lamtocol

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eks 24 and 48

- and HDL-ch

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ontinuations],

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constitute 216

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ence intervals w

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6 October 201

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om automated

at 87.8% of p

ectable plasma

he LPV/r plu

similar percent

at week 48. W

sided 95% con

width of the

%. Considerin

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es of metaboli

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nical interview

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d instruments,

pre-suppressed

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tage of the pa

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ng an approxi

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ariables will b

quartile, mini

and proportion

ated for param

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creatinine) as

eously reporte

at cause deaths

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ments, data and

nformation, ph

etc.

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ontrol arm. T

atients among

ple size witho

val for a single

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imate dropout

alyses will prim

be summarized

imum and max

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compared to

ed [including

s] ) over the s

ent and from

d records. This

harmacy

xperienced HI

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study sample

out a considera

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from the obse

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ndard of care

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didanosine

ciated with

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ractions wit

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17 August 201

Amend

by now.

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lestones and

lection: ection:

Report:

he EU PAS regStudy Results:

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e treatment

oviral therap

NRTIs are n

an cause ane

e) and kidn

abacavir in

e selection

th drugs for

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tive. And fin

ses may not

onavir and Lamtocol

15

dments a

ones

d their plann

gister

nale and

round

of HIV-1 in

py (ART) w

not always w

emia (zidov

ney dysfun

some cohor

of drugs in

r the treatm

g these inter

nally, the d

be available

mivudine

and Upda

ned dates ar

16 October 14 April 20N/A 15 NovembN/A 10 Decembe

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nfected pati

with regimen

well tolerat

vudine), neu

nction (teno

rt studies (5

n the regim

ment of com

ractions as

drugs includ

e for use for

ates

e as follows

2015 17

ber 2016

er 2017

ound

ents is usua

ns including

ed (short an

urotoxicity a

ofovir), car

5 - 7).

mens of AR

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treatment f

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s:

ally associat

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nd long ter

and lipodys

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RT should t

diseases suc

for HIV and

tandard tripl

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ted with the

os(t)ide ana

rm). For ex

strophy (stav

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take into a

ch as tuberc

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use of

alogues

ample,

vudine

is also

ccount

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iseases

gimens,

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supp

load

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limit

first

susc

rend

antiv

spec

year

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the

dem

line

patie

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for t

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gene

ion 01, dated 1

TI-sparing s

boosted wi

ies reportin

pression, the

d is usually

ntaining or

tation. 3TC

line drug

eptible to a

ders lamivud

viral potenc

ctrum of pat

rs (13-14).

V/r+3TC dua

GARDEL

monstrated n

regimen in

ents in OLE

cost of anti

the health sy

C may signif

eric ARV.


17 August 201

studies have

ith ritonavir

ng non-infer

e proportion

y higher in

adding lam

is an effect

for the tre

a single poi

dine inactiv

cy of LPV/r

tients in a n

al therapy w

and OLE

on-inferior

GARDEL

E study (1-3)

iretroviral th

ystems (12)

ficantly red

onavir and Lamtocol

15

e historically

r (lopinavir

riority of th

n of patients

n the grou

mivudine (o

ive drug wi

atment of

int mutation

ve but also

r (lopinavir/

number of

was studied

studies res

efficacy an

study and a

).

herapy and

). As an add

duce the cos

mivudine

y focused o

r or darunav

his strategy

s showing o

ups treated

or 3TC) to

th good safe

HIV-1 infe

n in the HI

o impacts t

/ritonavir) h

different cl

d in HIV-1-

spectively (

nd comparab

as maintena

its cost imp

ded value, s

st of treatm

n monother

vir) (8, 9).

when used

one or more

d with boo

this strateg

ety profile t

ected adults

IV-1 genom

he viral re

has been cle

linical trials

naïve and H

(1-3). Over

ble safety t

ance therapy

plications ar

simplifying

ment, especia

rapy with a

However, a

following

e episodes o

osted PI m

gy could he

that has been

s and childr

me (M184V

plicative ca

early demon

s, for period

HIV-1 expe

r 48 week

to LPV/r +

y in virolog

re also incre

triple thera

ally as 3TC

protease in

although the

HAART-led

of detectabl

monotherapy

elp overcom

n widely use

ren. This d

V mutation)

apacity (11

nstrated in a

ds of up to

erience patie

s, LPV/r +

2 NRTIs, a

gically supp

easingly imp

apy to LPV

C is an estab

11

nhibitor

ere are

d viral

le viral

y (10).

me this

ed as a

drug is

which

). The

a wide

seven

ents in

+ 3TC

as first

pressed

portant

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blished

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7.2

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settin

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8.0

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lami

an un

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ion 01, dated 1

cacy data

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ld effectiven

routine clini

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ngs could le

additional an

assess the

ivudine (3T

ndetectable

eatment in t

1. To evalu

2. To evalu

3. To asses

4. To eval

of treatm

5. To eval


17 August 201

Rationa

for LPV/r+

overwhelm

ness of LPV

ical settings

using the dua

ead to its ad

nd less expe

Resea

Primary

virologic e

TC)) in popu

plasma HIV

the routine c

Second

uate the viro

uate the imm

ss the develo

uate the me

ment.

uate the saf

onavir and Lamtocol

15

ale

+3TC dual

mingly from

V/r + 3TC i

of the Russ

al therapy (L

ddition to th

ensive regim

arch Que

y Objectiv

effectivenes

ulation of tr

V-1 RNA le

clinical setti

dary Objec

ologic effect

mune recons

opment leve

etabolic and

fety and tole

mivudine

therapy da

m OLE study

in treatment

sian Federat

LPV/r+3TC

he National

men of choic

stion and

ve

s of dual

reatment-ex

evel (for at l

ings of the R

ctives

tiveness of d

stitution on

el of drug re

anthropome

erability of d

ata from tr

y (1) where

t-experience

tion.

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guidelines

ce for stakeh

d Object

therapy (lo

xperienced H

least 6 mon

Russian Fed

dual therapy

the dual the

esistance ov

etric parame

dual therapy

reatment-ex

as no data e

ed HIV-1 in

in the Russi

and provide

holders.

tives

opinavir/ rito

HIV-1 infec

nths) at the 4

deration.

y at week 24

erapy at wee

ver 48 weeks

eters change

y (LPV/r + 3

xperienced

exists on th

nfected patie

an routine c

e the advant

onavir (LPV

cted patient

48 week tim

4.

eks 24 and 4

s of treatme

e over 48 w

3TC)

12

HIV-1

hat real

ents in

clinical

tage of

V/r) +

ts with

mepoint

48.

nt.

weeks

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9.0

9.1

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cont

This

3TC

plasm

the r

9.2

As t

supp

presc

9.3

For p

15 n

9.4

Enro

LPV

label

telep

will

ion 01, dated 1

s is a non-in

trol group.

s study desi

C) in populat

ma HIV-1 R

routine clini

this is a pos

ply since the

cribed by th

purpose of

national and

ollment wil

V/r + 3TC w

l to all enr

phone conta

be organize


17 August 201

Resea

Study D

nterventiona

gn will be

tion of treat

RNA level (

ical settings

Produc

st-marketing

e drug is be

he physician

Setting

this program

regional AI

Program

l start from

will be adm

rolled subje

act at 30 da

ed according

onavir and Lamtocol

15

arch Meth

Design

al, product-f

used to acc

ment-exper

(for at least

of the Russ

ct Supply

g observatio

eing used a

n under usua

g

m participan

IDS centers

m Duratio

m 16 Octob

ministrated a

ects. All en

ays after the

g to routine

mivudine

hods

focused, lon

cess the effe

rienced HIV

6 months) a

sian Federat

onal study, A

ccording to

al and custom

nts will be r

.

n

ber 2015 an

according to

nrolled patie

eir last dose

clinical pra

ngitudinal an

ectiveness o

V-1 infected

at the 48 we

tion.

AbbVie is N

o the approv

mary practi

recruited an

nd continue

o physician

ents will be

e in the stud

actice (appro

nd multi-cen

of the dual

patients wit

eek time poi

NOT involv

ved market

ce of physic

nd observed

e approxim

n’s prescript

e followed

dy. All visi

oximately ev

nter study w

therapy (LP

th an undete

int of treatm

ved in the p

label and is

cian prescrip

d in approxim

mately 6-8 m

tion and the

by a perso

its of the pr

very 3 mont

13

with no

PV/r +

ectable

ment in

product

s to be

ption.

mately

months

e local

onal or

rogram

ths).

Versi

9.5

In or

durin

9.6

ART

Patie

+ 3T

inter

wish

the f

1. A

2. Hcopias mclini(LPV

3. Cu

4. A

ion 01, dated 1

rder to assur

ng the recru

Physicia

Physicia

Availabi

Ability t

T therapy w

ent can be in

TC) due to

ractions, sid

h to simplify

following cr

ge 18 years

HIV-1 infectes/mL for a

medically apical settingsV/r + 3TC) n

umulative H

uthorization


17 August 201

Investig

re credibilit

uitment proc

an licensed i

an is workin

ility of patie

to appropria

Inclusio

will be presc

ncluded in t

any reason

de effects, p

y regimen, a

riteria:

and older (

ted patientsat least 6 moppropriate ts. OR HIVno more tha

HAART exp

n (Consent)

onavir and Lamtocol

15

gator sele

ty of the fina

cess of phys

in infection

ng at a nation

ent populati

ately conduc

on Criteria

cribed by p

the study, if

n such as do

prevention o

actual regim

(male and fe

s on any tronths (two cto LPV/r +-1 infected an 60 days a

perience at l

for Use/Dis

mivudine

ction crite

al results th

sician/invest

diseases;

nal or region

on fulfilling

ct the observ

a

physician ac

f he/she will

ocumented

of long-term

men no long

emale).

riple HAARconsequently+ 3TC as d

patients wago.

least 6 mont

sclosure of D

eria

he below list

tigators:

nal AIDS ce

g the inclusi

vational pro

ccording to

l be switche

toxicity, m

m toxicity (

er recomme

RT with play plasma HI

decided by who were sw

ths.

Data signed

ted criteria w

enter;

ion/exclusio

ogram.

the routine

ed on the du

management

(pre-emptiv

ended, etc, a

asma HIV-1IV-1 RNA lthe physiciwitched on

d by the pati

will be cons

on criteria;

e clinical pr

ual therapy (

of potentia

ve switch), p

and will be

1 RNA levelevels) transian in the r

the dual th

ient.

14

sidered

ractice.

(LPV/r

al drug

patient

satisfy

el <50 sferred routine herapy

Versi

9.7

A pa

1

2

9.8

The consmonfollointer

ion 01, dated 1

atient will n

1. Has con(please s

2. Previous

patient visisulting physnths) when dow-up visit/rvals of pati


17 August 201

Exclusi

ot be eligibl

ntraindicatiosee the lates

s participati

Descrip

its will be ssician. Howdual therapy/terminationent visits w

onavir and Lamtocol

15

ion Criteri

le for this P

ons for the st versions o

on in this pr

ption of Ac

cheduled bawever, it wy (LPV/r + n contact.

will not const

mivudine

ia

MOS if he/

treatment wof the locally

rogram.

ctivities

ased on rouwould be 5

3TC) will Failure to titute a brea

she fulfils th

with lopinay approved

utine clinica observatiobe adminisobserve th

ach or violat

he following

avir/ritonavilabels).

al practice anonal visits strated to thhese 3-montion of the p

g criterion:

ir and lamiv

nd prescript(approx. ev

he patient annth usual pprotocol.

15

vudine

tion of very 3 nd one ractice

Versi

Obs

ion 01, dated 1

Assignm

digit pat

Inclusion

Last ava

Last ava

Collectio

Last ava

Registra

Collectio

circumfe

Collectio

choleste

(mmol/L

SAEs m

ervational

Last ava

Last ava

was don

Last ava

level is d

was und

after 1 m

HIV-1 d

designat

Registra


17 August 201

ment of pati

tient individ

n/exclusion

ailable CD4+

ailable HIV-

on of releva

ailable resist

ation of start

on of anth

erence in cm

on of labor

rol (mmol

L), creatinin

monitoring

visits 2 and

ailable CD4+

ailable HIV-

ne or planned

ailable resis

detectable a

detectable, d

month. If the

drug resistan

ted these tes

ation of pres

onavir and Lamtocol

15

ient’s identi

dual enrollm

n criteria ver

+ T-cell cou

-1- RNA tes

ant medical

tance test re

t date and do

hropometric

m).

ratory tests

/L), LDL-

ne(μmol/L),

d 4

+ T-cell cou

-1- RNA tes

d both test a

stance test r

at a given vi

data of conf

e confirmat

nce genotyp

sts and the s

scribed med

mivudine

ification num

ment number

rification

unt test resu

st result

history

esult for LPV

oses of pres

c parameter

results (glu

and HDL

ALT (u/l),

unt test resu

st result. If

and re-test r

result for L

isit and at th

firmatory pl

ory plasma

ing test will

such informa

ications

mber (two-

r)

ult

V/r and 3TC

scribed LPV

rs measure

ucose (mmo

L-cholestero

AST (u/l)).

ult

last test res

results will b

LPV/r and 3

he previous

lasma HIV-

HIV-1 RNA

l be collecte

ation is avai

digit center

C, if any

V/r and 3TC

ement (arm

ol/L), insuli

ol (mmol/L

ult was dete

be collected

3TC (if pla

visit the pla

1 RNA test

A is >400 c

ed, if the con

ilable)

r number +

m, hip and

in (μEq/ml)

L), trigclyc

ectable and

d

asma HIV-1

asma HIV-1

t will be co

copies/mL, d

nsulting phy

17

three-

waist

), total

cerides

re-test

1 RNA

1 RNA

llected

data of

ysician

Versi

Obs

Follo

cont

9.9

Deci

parti

treat

ion 01, dated 1

Monitor

causing

ervational

Last ava

Last ava

was don

Last ava

Registra

Collectio

circumfe

Collectio

choleste

(mmol/L

Monitor

causing

ow-up Visi

tact

Monitor

causing

Complet

patient p

will be c

ision regard

icipant will

tment discon


17 August 201

ring of AE

treatment d

visits 3 and

ailable CD4+

ailable HIV-

ne or planned

ailable resist

ation of pres

on of anth

erence in cm

on of labor

rol (mmol

L), creatinin

ring of AE

treatment d

it/Terminat

ring of AE

treatment d

tion form of

prematurely

collected

Termin

ding the di

be ultimate

ntinuation w

onavir and Lamtocol

15

Es (non-seri

discontinuati

d 5

+ T-cell cou

-1- RNA tes

d both test a

tance test re

scribed med

hropometric

m)

ratory tests

/L), LDL-

ne(μmol/L),

Es (non-seri

discontinuati

tion or Ear

Es (non-seri

discontinua

f eCRF has

y discontinu

ation of th

iscontinuatio

ely based on

will be colle

mivudine

ious AEs s

ions], SAEs

unt test resu

st result. If

and re-test r

esult for LPV

ications

c parameter

results (glu

and HDL

ALT (u/l),

ious AEs s

ions], SAEs

rly Termin

ious AEs s

ations], SAE

to be comp

ued the study

he Program

on of the

n the treatin

cted and sum

spontaneous

s, [including

ult

last test res

results will b

V/r and 3TC

rs measure

ucose (mm

L-cholestero

AST (u/l))

spontaneous

s, [including

ation Cont

spontaneous

Es, [includi

leted at the

y. Reason f

m

dual therap

ng physician

mmarized in

sly reported

g SAEs that

ult was dete

be collected

C

ement (arm

ol/L), insul

ol (mmol/L

sly reported

g SAEs that

tact - Perso

sly reported

ng SAEs th

end of the s

for prematur

py (LPV/r

n’s judgmen

n the study

d) [includin

cause death

ectable and

d

m, hip and

lin (μEq/ml

L), trigclyc

d) [includin

cause death

onal or tele

d) [includin

hat cause d

study and al

re discontin

+ 3TC) for

nt. The reas

report.

18

ng AE

hs]

re-test

waist

l), otal

cerides

ng AE

hs]

ephone

ng AE

deaths]

lso if a

nuation

r each

son for

Versi

Abb

done

9.10

9.10

1

9.10

1

2

3

4

5

6

7

ion 01, dated 1

Vie may sto

e to particip

0

0.1

1. Proporti

RNA lev

0.2

1. Proporti

RNA lev

2. Absolute

change

transform

3. Absolute

compare

4. Proporti

regimen

5. Absolute

measure

baseline

6. Absolute

(glucose

creatinin

7. Proport

[includin


17 August 201

op the prog

ants if they

Endpoi

Primary

on of patien

vel at week

Second

on of patie

vel at week

e values of

as compar

med data).

e values of

ed to the bas

on of patien

n.

e values a

ements (arm

.

e values at

e, insulin,

ne, ALT, AS

ion of pat

ng AE cau

onavir and Lamtocol

15

gram in case

continue to

ints

y Endpoin

nts on dual

48 of the ob

dary Endp

ents on dual

24 of the ob

f HIV-1- R

red to the

CD4+ T-ce

seline.

nts who dev

at the wee

m, hip and

the weeks

total chole

ST) as comp

tients with

using treatm

mivudine

e there is ev

o participate

nt

l therapy (L

bservational

oints

l therapy (L

bservational

RNA viral lo

baseline (

ell counts at

velop resist

eks 24 and

waist circu

24 and 48

sterol, LDL

pared to the

AEs (non

ment discont

vidence of h

.

LPV/r + 3TC

l period.

LPV/r + 3T

l period.

oader at th

(untransform

t the weeks

ance to eac

d 48 and

umference

8 and chang

L- and HD

baseline.

n-serious A

tinuations],

harm that is

C) with und

TC) with un

he weeks 24

med and b

24 and 48

ch class of d

changes o

in cm) as

ges of meta

DL-choleste

AEs spontan

SAEs, [inc

done or co

detectable H

ndetectable

4 and 48 a

base-10 log

and the cha

drugs in the

of anthropo

compared

abolic para

rol, triglyc

neously rep

cluding SAE

19

ould be

HIV-1-

HIV1-

nd the

garithm

ange as

e study

ometric

to the

meters

cerides,

ported)

Es that

Versi

9.11

Data

docu

This

phar

9.12

The

infec

LPV

arm.

the p

Whe

two-

exten

for a

num

9.13

For

eCR

and

subje

prog

ion 01, dated 1

cause d

(SOCs)

1

a for the stu

ument at the

s may includ

rmacy dispe

2

OLE study

cted patient

V/r plus 3TC

. Therefore,

patients amo

en the samp

-sided 95%

nd 5% (i.e.

an expected

mber of enrol

3

this progra

RF data man

reviewed/ap

ect enrolled

gram data fo


17 August 201

eaths], with

and by frequ

Data So

udy will be

e center. So

de hospital

ensing and o

Study S

y (1) reporte

ts remained

C arm at 48

for this obs

ong study sa

ple size wit

confidence

half width

d proportion

lled patients

Data Ma

m electroni

nagement pla

pproved by

d in this pr

or AbbVie (

onavir and Lamtocol

15

h AEs orga

uency

ources

collected w

ource docum

records, clin

other records

Size

ed that 87.8

suppressed

weeks, wit

servational

ample will h

thout a cons

interval fo

of the 95%

of 85%. Co

s will consti

anagemen

ic Case rep

an and data

y AbbVie re

rogram. The

(or a CRO f

mivudine

anized acco

within clinic

ments will b

nical and of

s, recorded

8% of pre-s

d (undetect

th non-infer

program, it

have undete

sideration o

r a single p

% confidence

onsidering a

itute 216.

nt

port forms (

a validation

epresentativ

ese forms w

for data man

ording to S

cal interview

be original d

ffice charts,

data from au

suppressed t

table plasma

riority to the

is estimate

ctable plasm

of dropout i

proportion u

e interval) f

an approxim

(eCRF) will

specificatio

ve(s). eCRF

will be used

nagement)

System Org

w with the p

documents,

, laboratory

utomated in

treatment-ex

a HIV-1 RN

e LPV/r plu

d that a sim

ma HIV-1 R

is 196, a Si

using norma

from the ob

mate dropou

l be used. P

on will be d

F will be co

d to transm

and regulato

gan Classifi

patient and

data and re

data/inform

nstruments,

xperienced

NA level))

us 2 NRTi c

milar percent

RNA at week

imple Asym

al distributio

bserved prop

ut rate abou

Prior to set

eveloped by

ompleted fo

mit and colle

ory authorit

20

fication

source

ecords.

mation,

etc.

HIV-1

on the

control

tage of

k 48.

mptotic

on will

portion

t 10%,

t-up of

y CRO

or each

ect the

ties, as

Versi

appl

must

for

auto

infor

The

his/h

princ

subje

revie

9.14

The

Sinc

gene

with

mini

Qual

each

appr

Data

The

ion 01, dated 1

icable. Elec

t be entered

site staff

matically. D

rmation ente

investigato

her routine p

cipal investi

ect’s set of

ewed period

4

principal fe

ce this is an

eration of d

h number o

imum and

litative vari

h category.

ropriate.

a Analysis S

following a


17 August 201

ctronic CRF

d by trained

during site

Data discrep

ered in the e

or will store

practice. Th

igator will r

f eCRFs b

dically for c

Data An

eatures of th

n open-label

descriptive s

f patients,

maximum

iables will b

Graphs m

Set

analysis pop

onavir and Lamtocol

15

Fs will be se

d and author

e initiation.

pancies dete

eCRFs must

e subject d

hese subject

review the e

y electronic

ompletenes

nalysis

he statistica

, non-rando

summary st

mean, stan

values, and

be summari

may be gene

pulations wil

mivudine

et by CRO d

rized person

. eCRF tra

ected by eCR

t also be ref

data in his/h

files will se

eCRFs for c

c signature

s, legibility

al analysis o

omized trial

tatistics. Qu

ndard deviat

d 95% CI

ized with th

erated for

ll be defined

designee as

n only. eCR

acks all ch

RF will be a

flected in th

her source

erve as sour

completenes

e where ind

and accepta

of the data

, the analys

uantitative v

tion, media

for mean

he number a

visual inter

d:

web based s

RF training w

hanges to

addressed to

e patient so

documents

rce data for

ss and accur

dicated. Th

ability by A

are describe

ses will prim

variables wi

an, 1st quar

or median

and proport

rpretation o

site. In eCR

will be perf

the entered

o investigat

urce docum

in accorda

the program

racy and sig

e eCRFs w

AbbVie/CRO

ed in this s

marily invol

ill be summ

rtile, 3rd qu

(as approp

tion of patie

of the resu

21

RF data

formed

d data

tor. All

ments.

ance to

m. The

gn each

will be

O.

ection.

lve the

marized

uartile,

priate).

ents in

ults, as

Versi

All

Use/

Enro

The

No i

Base

Base

statis

Ana

Num

HIV

asym

Ana

1. N

HIV

asym

2. A

chan

data)

gene

untra

ion 01, dated 1

Enrolled S

/Disclosure

olled Set be

primary and

imputations

eline Demo

eline demog

stics mentio

alysis of prim

mber and pro

V-1- RNA le

mptotic two-

alysis of seco

Number and

V-1- RNA le

mptotic two-

Absolute val

nge as comp

) will be s

erated for

ansformed d


17 August 201

Set will inc

of Data for

used for all

d secondary

for missing

ographic an

graphic and

oned above.

mary endp

oportion of p

vel at week

-sided 95%

ondary end

proportion

evel at wee

-sided 95%

lues of HIV

pared to the

summarized

transforme

data.

onavir and Lamtocol

15

clude all p

rm to partic

l study analy

y effectivene

g data will b

nd Clinical C

d clinical ch

point

patients on

k 48 of the o

confidence

dpoints

of patients

ek 24 of the

confidence

V-1- RNA v

e baseline (

d with desc

d data an

mivudine

patients wh

cipate in the

yses.

ess analyses

be performed

Characteri

haracteristic

dual therapy

bservationa

interval for

on dual th

e observatio

interval for

viral load a

(untransform

cribed abov

nd 95% CI

ho signed A

e study and

s will be per

d.

istics

cs will be s

y (LPV/r +

al period wil

r a single pro

herapy (LPV

onal period

r a single pro

at baseline,

med and ba

ve statistics.

I for med

Authorizatio

have any c

rformed on t

summarized

3TC) with u

ll be present

oportion wi

V/r + 3TC)

will be pre

oportion wi

at weeks 2

ase-10 logar

. 95% CI f

dian will b

on (Consen

collected da

the observe

d with desc

undetectable

ted. A simp

ill be genera

with undete

esented. A

ill be genera

4 and 48 a

rithm transf

for mean w

be generate

22

nt) for

ata. All

d data.

criptive

e

le

ated.

ectable

simple

ated.

and the

formed

will be

ed for

Versi

3. A

chan

abov

4. N

prese

deve

num

enro

will

5. A

(arm

with

6. A

(mm

(mm

co

statis

7. N

repo

caus

prop

with

treat

code

ion 01, dated 1

Absolute val

nge as com

vementioned

Number and

ented separ

elops the re

mber of patie

olled in the s

be generate

Absolute val

m, hip and w

h described w

Absolute val

mol/L), insu

mol/L), trig

mpared to th

stics. 95% C

Number and

orted) [inclu

se deaths]wi

portion will

h non-seriou

tment disco

ed by Prefer


17 August 201

lues of CD4

mpared to

d statistics.

d proportion

rately. The t

esistance div

ent who dev

study. An e

ed.

lues at wee

waist circum

with abovem

lues at wee

ulin (μEq/m

clycerides

he baseline

CIs for mean

d proportion

uding AE ca

ill be presen

be generate

us AEs, SA

ntinuations

rred Terms

onavir and Lamtocol

15

4+ T-cell c

the basel

95% CIs for

n of patien

two proport

vided on nu

velops the r

exact two-si

eks 24 and

mference in c

mentioned s

eks 24 and

ml), total ch

(mmol/L),

e will be s

ns will be g

n of patien

ausing treatm

nted. An ex

ed. The com

AEs, SAE in

will be pre

(PTs) cons

mivudine

ounts at the

line will b

r means wil

nts who de

tions will b

umber of p

resistance d

ided 95% co

48 and ch

cm) as comp

tatistics. 95

48 and cha

holesterol (

creatinine

summarized

generated.

nts with all

ment discon

xact two-sid

mmon table

ncluding SA

esented. Th

istent with

e baseline,

be summa

ll be generat

evelop resis

be presented

patients who

divided on n

onfidence in

hanges of an

pared to the

% CIs for m

anges of m

(mmol/L),

(μmol/L),

d with desc

l AEs (non

ntinuations]

ded 95% con

with all AE

AEs that cau

he tables of

the latest ve

at weeks 2

arized with

ted.

stance to ea

d: (1) numb

o had the re

number of p

nterval for a

nthropomet

baseline w

means will b

etabolic par

LDL- and

ALT (u/l)

cribed with

n-serious A

, SAEs, [inc

nfidence int

Es as well a

use deaths,

f AEs will b

ersion of M

24 and 48 a

h described

ach drug w

ber of patien

esistance te

patients who

a single prop

ric measure

will be summ

be generated

rameters (g

HDL-chol

, AST (u/

h abovemen

Es spontan

cluding SAE

terval for a

as separated

and AEs c

be generate

MedDRA (M

23

and the

d with

will be

nt who

est; (2)

o were

portion

ements

marized

d.

glucose

esterol

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17 August 201

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17 August 201

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25

multi-

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ntity of

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Versi

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omplaint is ted to the phability, safetribution.

mplaints assoorted to the Stions 11.1.1

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adverse evens not necessaefore be anying), symptother or not t

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17 August 201

Manag

any writtenhysical charaty, effectiven

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Medica

AdversCatego

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can result frotentional ovndition or ill

vent meets a

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onavir and Lamtocol

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gement a

n, electronicacteristics, iness, or per

h any compoection 11.2.2.1.6. For pr

al Complai

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defined as ana causal relale and unintase temporaconsidered

om use of thverdose, drulness is cons

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Definition a

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event that re

event that, iuld have resurvention hadude an evenurred in a m

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in the opinioulted in immd not been tnt that would

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n a patient, wadverse eve

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serious adv

patient.

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26

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2.

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The colle

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17 August 201

on:

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Significantcapacity:

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definitions wendpoint/da

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ability/incapntaneous abortant mediude allergictment in an crasias or coatient hospitendency or

to rate the sthe study an

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medical evenfe-threatenin but based o

patient and mention to pree., death of p prolongatio

maly, or perpacity). Addortion or stical event. E

c bronchospaemergency

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severity for nd for all ser

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e the study pthe patient's

after birth,

ondition thaes of daily lintended to in

minor medicavomiting, drauma (e.g.,

nt that may nng or result on medical jmay requireevent any ofpatient, life on of hospitrsistent or siditionally, anillbirth is coExamples ofasm requirinroom or at

that do not rr the develo

any adverserious advers

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diarrhea, , sprained

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27

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11.1

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17 August 201

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adverse event's usual ac

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17 August 201

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17 August 201

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Cahn et atherapy winhibitorsresults ofDis. 2014

ThompsoInternatio

Gallant Jassociatereverse-tr

D:A:D Sttranscriptenrolled i(9622): 1

Brinkmannucleosidpathogen354:1112

Arribas Jlopinaviranalysis.

Arribas Jor withouAIDS, 20

Paton et a2014 Abs

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17 August 201

al Dual therawith lopinavs in antiretrof the random4 Jul;14(7):5

on MA, Abeonal AIDS S

JE, Parish Med with tenoranscriptase

tudy Grouptase inhibitoin the D:A:D

1417-26

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JR, Delgador-ritonavir anJ Acquir Im

JR, Horban Aut nucleosid010; 24: 223

al RCT of Pstract 550LB

M and Fauldsokinetic pro". Drugs, 19

onavir and Lamtocol

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apy with lopvir and ritonoviral-therap

mised, open 572-80

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, Sabin CA,ors and risk D study: a m

nk JA, Rome reverse-traretroviral-th

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PI monotherB

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mivudine

pinavir and navir plus twpy-naive adlabel, non-i

n P, et al. ASA Panel. 20

JC, Moore Rroxil fumarareatment". C

, Worm SWof myocard

multi-cohort

mijn JA, Reianscriptase iherapy-relate

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vudine: A retherapeutic, no4, pp. 6

ritonavir plwo nucleosiddults with Hinferiority G

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hondrial toxa key facto

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antiviral actn the manage

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endations ofA.

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27 July 2006

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