PrimaryTo demonstrate the non-inferior antiviral activity of switching to DTG +3TC once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, ART therapy (ART)-experienced, virologically suppressed subjectsSecondary- To demonstrate…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
HIV-1 infection
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Virologic failure endpoint as per FDA snapshot category at Week 48
Secondary outcome
1) Proportion of subjects with plasma HIV-1 RNA <50 copies c/mL at Week 48
using the Snapshot algorithm for the ITT-E population
2) Virologic failure endpoint as per FDA snapshot category at Week 24, 96 and
144; Proportion of subjects with plasma HIV-1 RNA <50 c/mL at
Week 24 using the Snapshot algorithm for the ITT-E population
3) Change from Baseline in CD4+ cell count and in CD4+/CD8+ cell counts ratio
at Weeks 24 and 48, 96 and 144; Incidence of disease
progression (HIV-associated conditions, AIDS, and death) through Weeks 24 and
48, 96 and 144
4) Incidence and severity of AEs and laboratory abnormalities through 144
weeks; Proportion of subjects who discontinue treatment due to AEs through 144
weeks
5) Change from Baseline in fasting lipids at Weeks 24, 48, 96 and 144
6) Incidence of observed genotypic and phenotypic resistance to ARVs for
subjects meeting Virologic Withdrawal Criteria
7) Change from Baseline in renal and bone biomarkers at Weeks 24, 48, 96 and 144
8) Change from Baseline in health status using EQ-5D-5L at Weeks 24,
48, 96 and 144 (or Withdrawal from the study)
Background summary
Study 204862 is being conducted to establish if human immunodeficiency virus
type 1 (HIV-1) infected adult subjects with current virologic suppression on a
>=3-drug tenofovir alafenamide (TAF) based regimen (TBR) remain suppressed upon
switching to a two-drug regimen of dolutegravir (DTG) 50 mg + lamivudine (3TC)
300 mg. This study also will provide important information regarding the
safety of, and patient satisfaction with this two-drug regimen. This trial is
designed to demonstrate the non inferior antiviral activity of switching to DTG
+ 3TC once daily compared to continuation of TBR over 48 weeks. This study
also will characterize the long term antiviral activity, tolerability and
safety of DTG + 3TC compared to TBR through Week 144 and characterize the
longterm antiviral activity, tolerability and safety of DTG + 3TC through Week
200.
Study objective
Primary
To demonstrate the non-inferior antiviral activity of switching to DTG +3TC
once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, ART
therapy (ART)-experienced, virologically suppressed subjects
Secondary
- To demonstrate the antiviral activity of switching to DTG +3TC once daily
compared to continuation of TBR over 48 weeks
- To demonstrate the antiviral activity of switching to DTG+3TC once daily
compared to continuation of TBR over 24 weeks, 96 weeks and 144
weeks.
- To evaluate the immune effects of DTG+3TC once daily compared to continuation
of TBR over 24, 48, 96 and 144 weeks.
- To evaluate the safety and tolerability of DTG + 3TC once daily compared to
TBR over time
- To evaluate the effects of DTG + 3TC once daily on fasting lipids over time
compared to TBR
- To assess viral resistance in subjects meeting Virologic Withdrawal Criteria
- To evaluate renal (in urine and blood) and bone (in blood) biomarkers in
subjects treated with DTG + 3TC compared to TBR
- To assess health related quality of life for subjects treated with DTG + 3TC
compared to TBR
Study design
This is a 200-week, Phase III, randomized, open-label, active-controlled,
multicenter, parallel-group study to assess the non-inferior antiviral activity
and safety of replacing a TBR with a two-drug regimen of DTG + 3TC in
HIV-infected adults who are virologically suppressed and stable on a TBR. The
study will include a Screening Phase (up to 28 days), a Randomized Early Switch
Phase (Day 1 up to Week 148), a
Randomized Late Switch Phase (Week 148 up to Week 200), and a Continuation
Phase (post Week 200) if DTG + 3TC fixed dose combination (FDC) is not yet
approved and available locally. Approximately 550 HIV-1 infected adults who are
on a stable TBR will be randomized 1:1 to switch to DTG + 3TC once daily (DTG +
3TC arm) for up to 200 weeks, or to continue their TBR for 148 weeks, at which
time and if HIV-1 RNA
<50 c/mL at Week 144 (or upon retest by Week 148), these subjects will switch
to DTG + 3TC up to Week 200. For subjects randomized to the TBR, provisions
will be in place, as needed and after discussion with the study team, to assist
patients in obtaining their TBR during the study. For subjects who switch to
DTG + 3TC at Week 148, a separate Late Switch Phase Time and Events Table is
provided in Section 7.1.2 as these
participants will be monitored closely for the first 24 weeks post-switch.
Subjects who remain on DTG + 3TC will follow a separate Late Switch Phase Time
and Events Table in Section 7.1.3.
The primary endpoint for the study is the proportion of participants who meet
the Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat
Exposed (ITT-E) population. The Week 48 primary analysis will take place after
the last subject has had their Week 48 viral load assessed, including any
retests. Subjects randomized to DTG + 3TC will receive DTG + 3TC up to Week
200. Subjects randomized to TBR will
have a Week 148 switch visit, allowing approximately 4 weeks for subjects who
have a viral load >=50 c/mL at Week 144 to have a retest prior to switch. The
study will continue for at least 200 weeks.
Intervention
The study will include a Screening Phase (up to 28 days), a Randomized Early
Switch Phase (Day 1 up to Week 148), a Randomized Late Switch Phase (Week 148
up to Week 200) and a Continuation Phase (post Week 200). Subjects randomized
to DTG + 3TC will receive DTG + 3TC up to Week 200. Subjects randomized to TBR
will continue to take their current regimen up to Week 148, at which time and
if HIV-1 RNA <50 c/mL at Week 144 (or upon retest by Week 148), these subjects
will switch to DTG + 3TC up to Week 200. Randomization will be stratified by
baseline third agent class (protease inhibitor [PI], integrase inhibitor [INI],
or non-nucleoside reverse transcriptase inhibitor [NNRTI]).
Study burden and risks
Burden:
- Columbia Suicidality Severity Rating Scale: every visit, except screening, wk
148, wk 200 and follow up
- ECG: 1x
- Willingness to Switch treatment: 1x
- EQ-5D-5L: 7x
- Blood sampling: every visit, except wk 148
- Urine sampling: minimum 6x
- Pregnancy stest: every visit, except follow up
See also protocol section 7 (Time and Events Table) of the protocol
Dolutegravir (DTG)
The following adverse events are very common (could affect 1 in every 10 people
or more):
• Headache
• Nausea (feeling sick)
• Diarrhea or loose stools
These adverse events are common, (could affect between 1 in 100 and 1 in 10
people):
• Rash
• Itching
• Vomiting
• Stomach pain and discomfort
• Difficulty sleeping; abnormal dreams
• Dizziness
• Depression
• Fatigue
• Anxiety
• Flatulence
• Increase in the level of liver enzymes
• Increase in the level of enzymes produced in the muscles
These adverse events are uncommon (could affect between 1 in 1000 and 1 in 100
people):
• Allergic reaction: often include symptoms like feeling sick, rash, fever,
fatigue, swelling sometimes of the face or mouth causing difficulty in
breathing, blisters, mouth ulcers, sore eyes, and muscle or joint aches. If you
develop any of these signs then you must call your study doctor immediately.
The doctor may decide to carry out additional tests or tells you to stop taking
DTG.
• Liver toxicity : in case you experience liver toxicity, your study doctor can
decide to stop giving DTG to you. Your study doctor will follow up your status
and will make the decision if and when to re-start the study drug or change
your HIV-1 drug therapy. If you re-start the study drug, you will be asked to
sign an additional Informed Consent.
• Inflammatory condition which may develop as the immune system becomes
stronger (immune reconstitution syndrome or *IRIS*)
• Suicidal thoughts and behaviours (mainly in patients who have had depressive
or mental health problems before)
• Muscle aches
• Joint pain
• Weight gain
Other side effects that may show up in blood tests (frequency unknown):
• Increase in bilirubin (pigment produced from the breakdown of red blood
cells)
• Increase in enzymes produced in the kidney (creatinine)
Lamivudine (3TC)
The following adverse events are common (could affect between 1 in 100 and 1 in
10 people):
• Headache
• Nausea or vomiting
• Stomach pains
• Diarrhea or loose stools
• Rash
• Hair loss
• Joint and muscle pain
• Fatique
• General feeling of being unwell
• High temperature
These adverse events are uncommon (could affect between 1 in 1000 and 1 in 100
people):
• Low white blood cells
• Anemia (low red blood cell count)
• Decreased platelet count
• Increased levels of liver enzymes
• Increased fatty acids or sugar in the blood
These adverse events are rare (could affect between 1 in 10,000 and 1 in 1,000
people):
• Inflammation of the pancreas
• Increase in an enzyme called amylase in the blood
• Serious allergic reaction causing swelling of the face, tongue, or throat
which may cause difficulty in swallowing or breathing
• Muscle breakdown
• Lactic acidosis: life threatening condition caused by build up of lactic acid
in the blood and tissues. Some nonspecific symptoms that might indicate lactic
acidosis include: unexplained weight loss, stomach discomfort, nausea,
vomiting, fatigue, cramps, muscle pain, weakness, dizziness and shortness of
breath.
These adverse events are very rare (could affect less than 1 in 10,000 people):
• Failure of the bone marrow to produce new red blood cells
• Tingling or numbness of the arms, legs, hands or feet
Other possible risks are there to being in this study:
• When giving blood you may feel faint, or experience mild pain, bruising,
irritation or redness at the site. In rare cases, you may get an infection.
• When you have an electrocardiogram, you may have itching or get irritation of
the skin where the machine patches are placed.
• It is also important that while participating in the study, you do not take
any other prescription drugs or over-the-counter medications without first
talking to your doctor(s) or study nurse. There is the risk of serious and/or
life threatening side effects when non-study medications are taken with study
drugs.
• With any drug for HIV, there is a risk that the virus in your body will
become resistant, which means that the drug will be less effective or not
effective against your HIV. The risk that taking part in this study will cause
your HIV to develop resistance to the study drug is unknown and will depend on
how well the study drugs you will take work against your virus and whether
instructions are followed for taking study drugs.
Great West Road 980
Middlesex TW8 9GS
GB
Great West Road 980
Middlesex TW8 9GS
GB
Listed location countries
Age
Inclusion criteria
AGE
1. Aged 18 years or older (or older where required by local regulatory agencies), at the time of signing the informed consent.;TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. HIV-1 infected men or women.
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.
4. Plasma HIV-1 RNA <50 c/mL at Screening.
5. Must be on uninterrupted ART for at least 6 months prior to screening. Only the following regimens are allowed:
a. Subjects on a TAF-based regimen for at least 6 months as the initial regimen, or
b. Subjects who switched from a TDF first regimen to TAF, without any changes to the other drugs in their regimen, and have been on the TAF-based regimen for at least 3 months immediately prior to Screening, i.e., the only switch made is from TDF to TAF. This switch must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for suspected or established treatment failure. A switch from a PI boosted with RTV to the same PI boosted with cobicistat is allowed (and vice versa).;SEX
6. Male or Female
A female subject is eligible to participate if she is not pregnant [as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative urine hCG test at Randomization (a local serum hCG test at Randomization is allowed if it can be done, and results obtained, within 24 hours prior to randomization)], not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
• Pre-menopausal females with one of the following:
o Documented tubal ligation
o Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
o Hysterectomy
o Documented Bilateral Oophorectomy;• Post-menopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (see Protocol) from 30 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
All subjects participating in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.;INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 10.2, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Eligible subjects or their legal guardians must sign a written Informed Consent Form before any protocol-specified assessments are conducted.;OTHER
8. Subjects enrolled in France must be affiliated to, or a beneficiary of, a social security category.
Exclusion criteria
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. Women who are breastfeeding or plan to become pregnant or breastfeed during the study.
2. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease [CDC, 2014], EXCEPT cutaneous Kaposi*s sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/mm3 are NOT exclusionary.
3. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification (see Section 13.4).
4. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
5. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV DNA as follows:
• Subjects positive for HBsAg are excluded.
• Subjects negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
Note: Subjects positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded. Anti-HBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and NOT anti-HBc IgM.
6. Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study, or anticipated need for HCV therapy based on interferon or for any drugs that have a potential for adverse drug-drug interactions with study treatment throughout the entire study period.
7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Subjects who are at least 7 days post completed treatment are eligible.
8. History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
9. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia.
10. Subjects who in the investigator*s judgment, poses a significant suicidality risk. ;EXCLUSIONARY TREATMENTS PRIOR TO SCREENING OR DAY 1
11. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
12. Treatment with any of the following agents within 28 days of Screening
• radiation therapy
• cytotoxic chemotherapeutic agents
• any systemic immune suppressant
13. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
14. Use of any regimen consisting of single or dual ART.;LABORATORY VALUES OR CLINICAL ASSESSMENTS AT SCREENING
15. Any evidence of major NRTI mutation or presence of any major INSTI resistance associated mutation [Wensing, 2017] in any available prior resistance genotype assay test result, if known, must be provided to ViiV after screening and before randomization for review by ViiV Virology. Refer to the most recent version of IAS Guidelines, SRM, and Section 7.2.1 (Screening Assessments) for more information.
16. Any verified Grade 4 laboratory abnormality.
17. Alanine aminotransferase (ALT) >= 5 times the upper limit of normal (ULN) or ALT >= 3xULN and bilirubin >= 1.5xULN (with >35% direct bilirubin).
18. Creatinine clearance of <50 mL/min/1.73m2 via CKD-EPI method.;EXCLUSIONARY CRITERIA PRIOR TO SCREENING OR DAY 1
19. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.
20. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements >= 50 c/mL.
21. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement >= 50 c/mL.
22. Any drug holiday during the 6 months prior to Screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns.
23. Any history of switch to another regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV 1 RNA >= 400 c/mL. ;COUNTRY SPECIFIC REQUIREMENTS
24. Subjects enrolled in France (or in other countries as required by local regulations or Ethics Committee/Institutional Review Board [IRB]) who:
• participated in any study using an investigational drug or vaccine during the previous 60 days or 5 half-lives, or twice the duration of the biological effect of the experimental drug or vaccine, whichever is longer, prior to screening for the study, or
• participate simultaneously in another clinical study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004401-17-NL |
| CCMO | NL62030.078.18 |