Primary:To demonstrate the non-inferior antiviral activity of CAB LA + RPV LA every two months compared to a BIK single tablet regimen administered once daily over 12 months in suppressed HIV-1 infected antiretroviral therapy (ART)-experienced…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To demonstrate the non-inferior antiviral activity of CAB LA + RPV LA every two
months compared to a BIK single tablet regimen administered once daily:
Proportion of participants with plasma HIV-RNA greater than or equal to 50
copies/mL as per Food and Drug Administration (FDA) Snapshot algorithm at Month
12 (OLI and BIK)/Month 11 (D2I) (Intent-to-Treat Exposed [ITT-E] population)
Secondary outcome
To demonstrate the antiviral and immunologic activity of CAB LA + RPV LA every
2 months compared to a BIK single tablet regimen administered once daily:
Proportion of participants with plasma HIV-1 RNA <50 c/mL (c/mL) at Month 6 and
Month 12 (OLI and BIK)/Month 5 and Month 11 (D2I) using the FDA Snapshot
algorithm (Intent-to-Treat Exposed [ITT-E] population)
Proportion of participants with protocol-defined confirmed virologic failure
(CVF) through Month 6 and Month 12 (OLI and BIK)/Month 5 and Month 11 (D2I).
Proportion of participants with HIV-RNA greater than or equal to 50 c/mL as per
FDA Snapshot algorithm at Month 6, and Month 12 (OLI and BIK)/Month 5 and Month
11 (D2I)
Absolute values and changes from Baseline in viral load and CD4+ cell count
over time including Month 6 and Month 12 (OLI and BIK)/Month 5 and Month 11
(D2I)
To assess viral resistance in participants experiencing protocol-defined
confirmed virologic failure:
Incidence of treatment emergent genotypic and phenotypic resistance to CAB,
RPV, BIC, FTC, and TAF through Month 6 and Month 12 (OLI and BIK)/Month 5 and
Month 11 (D2I).
To evaluate renal (in urine and blood) and bone (in blood) biomarkers in
participants treated with CAB LA + RPV LA compared to BIK: Change from Baseline
(Day 1) in renal and bone biomarkers at Months 6 and 12 (OLI and BIK)/Month 5
and Month 11 (D2I).
To evaluate Metabolic Syndrome for participants treated with CAB + RPV and BIK:
Change from Baseline in proportions of participants with Metabolic syndrome at
Months 6 and 12 (OLI and BIK)/Month 5 and Month 11 (D2I)
Change from Baseline in incident metabolic syndrome at Months 6 and 12 (OLI and
BIK)/Month 5 and Month 11 (D2I)
To evaluate insulin resistance in participants treated with CAB LA + RPV LA
compared to BIK: Change from Baseline (Day 1) in homeostasis model of
assessment-insulin resistance (HOMA-IR) at Months 6 and 12 (OLI and BIK)/Month
5 and Month 11 (D2I).
To assess preference for CAB LA + RPV LA administered every 2 months compared
to a BIK single tablet regimen administered once daily: Preference for CAB LA +
RPV LA every 2 months compared to a BIK single tablet regimen will be assessed
using a preference questionnaire at Month 12 (OLI and BIK)/Month 11 (D2I) (or
Withdrawal).
To assess patient reported treatment satisfaction, and injection tolerability:
Change from baseline (Day 1) in total *treatment satisfaction* score, and
individual item scores of the HIV Treatment Satisfaction Status Questionnaire
(HIVTSQs) at Month 6 and Month 12 (OLI and BIK)/Month 5 and Month 11 (D2I), (or
Withdrawal)
Change in treatment satisfaction over time using the HIV Treatment Satisfaction
Change Questionnaire HIVTSQc total score and individual item scores at Month 12
(OLI and BIK)/Month 11 (D2I) (or Withdrawal).
Change from Month 2 in Dimension scores (*Acceptance of ISRs*, *Bother of
ISRs*, *Leg movement*, *Sleep and individual item scores assessing pain during
injection, anxiety before and after injection, willingness to be injected in
the future and overall satisfaction with mode of administration over time will
be assessed using the Perception of injection questionnaire (PIN) at Months 2,
6, and 12 (OLI)/Months 1, 5, 11 (D2I) (or Withdrawal)
Safety:
Incidence and severity of AEs and laboratory abnormalities over time including
Month 6 and Month 12 (OLI and BIK)/Month 5 and Month 11 (D2I).
Proportion of participants who discontinue treatment due to AEs over time
including Month 6 and Month 12 (OLI and BIK)/Month 5 and Month 11 (D2I).
Change from Baseline in laboratory parameters over time including Month 6 and
Month 12 (OLI and BIK)/Month 5 and Month 11 (D2I).
Background summary
It is estimated that 37.9 million people are currently living with HIV/Acquired
Immunodeficiency Syndrome (AIDS) and that the worldwide epidemic continues to
grow at a rate of 1.7 million new infections and cause 770, 000 deaths per
year. Chronic HIV infection in adults continues to be characterized by
increased development of resistant virus, increasing transmission of resistant
virus and issues associated with long term toxicity of ART. The current
paradigm in the treatment of HIV involves life-long therapy with multiple
antiretrovirals. This dependency on medical therapy requires a need for
continuous improvement on the durability, tolerability and convenience of all
antiretroviral classes.
A study by the Antiretroviral Therapy Cohort Collaboration found that of more
than 21,000 patients in a European and North American cohort on their first
combination antiretroviral therapy (cART) regimen, 51% modified or interrupted
their first cART regimen during a median of 28 months of follow-up with one
third of interruptions occurring within the first 6 months of starting
therapy. Forty percent of all treatment interruptions were due to the
secondary side effects or toxicities of cART, 17% were due to the desire for
simplification of the regimen and 14% were due to patient choice. These
observations have led to numerous *switch* ART studies, designed to understand
the efficacy, safety, and tolerability of switching patients from one regimen
to another.
Previous studies have evaluated switches to ritonavir-boosted PI monotherapy in
virologically suppressed patients. These studies suggest that simplifying from
a three-drug dual class regimen to a single boosted protease inhibitor may be a
safe and effective option for the majority of participants studied, who have
effectively maintained viral suppression.
CAB LA + RPV LA is indicated as a complete regimen for the treatment of human
immunodeficiency virus type 1 (HIV-1) infection in adults to replace the
current antiretroviral regimen in those who are virologically suppressed on a
stable antiretroviral regimen with no history of treatment failure and with no
known or suspected resistance to either CAB or RPV.
Three Phase IIb studies (LATTE, LATTE-2 and POLAR) have been conducted with
oral CAB and/or IM CAB LA, evaluating an induction/maintenance simplification
approach. Three Phase III studies (FLAIR, ATLAS and ATLAS-2M) conducted with
CAB LA + RPV LA are ongoing.
Biktarvy (BIK) is a three-drug combination of bictegravir (BIC), a human
immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor
(INSTI), and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1
nucleoside analog reverse transcriptase inhibitors (NRTIs), and is indicated as
a complete regimen for the treatment of HIV-1 infection in adults who have no
antiretroviral treatment history or to replace the current antiretroviral
regimen in those who are virologically suppressed on a stable antiretroviral
regimen.
Long-acting 2-class therapy consisting of CAB LA + RPV LA as an IM regimen has
the benefit of being a NRTI-sparing regimen for long-term treatment of HIV
infection which will avoid known NRTI-associated adverse drug reactions and
long-term toxicities. Additionally, a 2-drug combination therapy with CAB LA
plus RPV LA may offer a better tolerability and resistance profile, as well as
improved adherence and treatment satisfaction in virologically suppressed
participants improving the quality of life for people living with HIV.
Study objective
Primary:
To demonstrate the non-inferior antiviral activity of CAB LA + RPV LA every two
months compared to a BIK single tablet regimen administered once daily over 12
months in suppressed HIV-1 infected antiretroviral therapy (ART)-experienced
participants
Secondary:
To demonstrate the antiviral and immunologic activity of CAB LA + RPV LA every
2 months compared to a BIK single tablet regimen administered once daily
To assess viral resistance in participants experiencing protocol-defined
confirmed virologic failure
To evaluate renal (in urine and blood) and bone (in blood) biomarkers in
participants treated with CAB LA + RPV LA compared to BIK
To evaluate Metabolic Syndrome for participants treated with CAB + RPV and BIK
To evaluate insulin resistance in participants treated with CAB LA + RPV LA
compared to BIK
To assess preference for CAB LA + RPV LA administered every 2 months compared
to a BIK single tablet regimen administered once daily
To assess patient reported treatment satisfaction, and injection tolerability.
SafetyL
To evaluate the safety and tolerability of CAB LA + RPV LA every 2 months
compared to a BIK single tablet regimen administered once daily
Study design
This study is a Phase IIIb, randomized, open-label, active-controlled,
multicenter, parallel-group, non-inferiority study designed to assess the
antiviral activity and safety of a two-drug regimen of CAB LA + RPV LA
administered every 2 months compared with maintenance of BIK. Approximately
654 adult HIV-1 infected patients who are on the stable ARV regimen BIK will be
randomized 2:1 to either be switched to the CAB LA + RPV LA regimen or continue
BIK through 12 months.
Intervention
IM Injections every 2 months (Oral Lead In):
Day 1 - CAB 30 mg + RPV 25 mg oral, administered once daily for 1 month
Month 1 - CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
Month 2 - CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
Month 4 and Q2M thereafter - CAB LA 600 mg + RPV LA 900 mg IM, every 2 months
until Month 12, each given as 1 X 3 mL IM injection
IM Injections every 2 months (Direct to Injections):
Day 1- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
Month 1 and Q2M thereafter- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X
3 mL IM injection
BIC/FTC/TAF (BIK)
Day 1 - BIC 50 mg + FTC 200 mg + TAF 25 mg oral, administered once daily until
Month 12.
Study burden and risks
Side effects associated with CAB (tablets and injections).
CAB when taken together with RPV
In more than 1 in 10 people- headache, pyrexia, injection site reaction
between 1 in 10 people and 1 in 100 people - Rash, diarrhoea or loose stools,
nausea, flatulence, Vomiting, Abdominal pain, upper abdominal pain, insomnia,
abnormal dreams/nightmares, feeling lightheaded, anxiety, depression, myalgia,
fatigue, asthenia, malaise
between 1 in 100 people and 1 in 1,000 people - somnolence (sleepiness or
Drowsiness), vasovagal reactions, lightheadedness, light-headedness or
fainting, during or following an injection, hepatotoxicity, transaminase
increase, weight increase
Hypersensitivity reactions have been reported with other drugs in the same
class as CAB (INSTI) with signs and symptoms including general feeling of being
sick, skin rash, a high temperature, lack of energy, swelling (sometimes of the
face or mouth, causing difficulty in breathing), blisters, mouth ulcers,
conjunctivitis, and muscle or joint aches.
Seizures/convulsions have been observed in a small number of HIV-infected study
participants receiving CAB (less than 1%). It is unlikely that CAB contributes
to seizures, although this cannot be ruled out entirely.
Abnormal liver tests. A small number of participants across CAB research
studies developed abnormal liver tests requiring them to stop treatment with
CAB. In some of the participants, the abnormal liver tests were explained by
other causes (e.g. a new virus infection), while a smaller number of
participants (less than 1% of all participants) did not have alternative
explanations, suggesting a mild form of liver damage suspected as due to CAB.
The liver tests improved after stopping CAB, suggesting that any damage was
temporary
RPV (EDURANT)(tablet and Injections):
The RPV tablet is a marketed drug and therefore the side effects are more
established than those of CAB, since many more people have received EDURANT.
Skin rash. Most rashes were mild or moderate, happened within the first 4 weeks
of taking RPV, and got better after one week after stopping RPV. However, some
types of moderate rash and all types of severe rash, which can be
life-threatening, will need participants to stop study medicines (either
temporarily or permanently) and come for additional study visits. Some
participants with rash may also have other signs and symptoms of allergic
reaction.
Abnormal liver tests. Other changes in blood tests have also been observed.
Participants with hepatitis B or C or with increases in liver tests showing
possible liver damage before starting RPV may have worse liver tests while
taking RPV. A few cases of liver problems have also been seen in participants
taking RPV who did not already have any liver problems.
Side effects associated with RPV injections:
between 1 in 10 people and 1 in 100 people: Feeling less hungry, sleep
disorders, depressed mood, abdominal, discomfort (belly ache), dry mouth
between 1 in 100 people and 1 in 1,000 people: Immune reconstitution syndrome
or *IRIS* (an inflammatory condition which may develop as the immune system
becomes stronger)
Side effects associated with Bikarvy:
more than 1 in 10 people: Diarrhoea
between 1 in 10 people and 1 in 100 people: headache, nausea, fatigue, joint
pain, back pain
Changes in the immune system, kidney problems, including kidney failure, severe
liver problems. Too much lactic acid in the subjects blood, which is a serious
but rare medical emergency that can lead to death.
Injection site reactions following an injection of CAB LA or RPV LA. The
subject may experience local reactions at the spot where he/she received
injections (termed *injection site reactions*). Very common side effects could
include pain or discomfort, which are usually mild or moderate. The subject may
also have redness, swelling, itching, bruising, lumps, infection complications
(cellulitis or abscess), and irritation where they get the injection(s). Most
reactions go away in a week or less.
The injections will be given in the muscles of the buttocks. The injection
could be given too deeply or not deeply enough, missing the muscle and entering
the skin, blood vessel, or a nerve.
The risks of this are not well understood but could make CAB or RPV levels too
low or too high. If too low the drug may not work against HIV. If RPV is too
high, there could be a change in the heart rate, which very rarely, in severe
cases, can be life-threatening and could lead to sudden death; however, to
date, no such severe changes in heart rate or sudden deaths have been observed
in clinical studies with RPV. In rare cases, high RPV levels immediately after
an injection have been associated with feeling lightheaded, numbness or
tingling, difficulty breathing, sweating, feeling nauseous and feeling anxious
Per visit 30-75 ml blood will be drawn. Blood drawl may cause mild pain or
bruising.
There is a risk that the virus will become resistant against the (study) drugs
against HIV. The risk of the HIV becoming resistant is unknown. It will depend
on how well the study drugs work against the virus and how well the subject
follows directions on how to take the study drugs
Mental health problems. Some people with chronic health conditions, including
HIV, sometimes have feelings of depression or may have thoughts of hurting or
killing themselves (suicide). A small number of people being treated with CAB
and RPV have had suicidal thoughts and actions, particularly those with a prior
history of depression or mental health problems.
980 Great West Road -
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980 Great West Road -
Brentford, Middlesex TW8 9GS
GB
Listed location countries
Age
Inclusion criteria
- 18 years or older
- Women not pregnant, not lactating, or having a Non-reproductive potential or
Postmenopausal
- Must be on the uninterrupted current regimen of BIK for at least 6 months
prior to
Screening with an undetectable HIV-1 viral load for at least 6 months prior to
Screening. Only a single prior INI regimen is allowed if BIK is a second line
regimen > 6 months prior to screening.
- Documented evidence of plasma HIV-1 RNA measurements <50 c/mL in the 6
months prior to Screening.
- Plasma HIV-1 RNA <50 c/mL at Screening.
Exclusion criteria
1. Within 6 months prior to Screening, any plasma HIV-1 RNA measurement
50 c/mL
2. Within the 6 to 12-month window prior to Screening, any plasma HIV-1 RNA
measurement >200 c/mL, or 2 or more plasma HIV-1 RNA measurements
50 c/mL.
3. History of prior treatment failure to any DHHS recommended ART regimen.
4. History of drug holiday >1 month for any reason prior to Screening visit,
except
where all ART was stopped due to tolerability and/or safety concerns
5. Any change to a second line regimen
7. Women who are pregnant, breastfeeding or plan to become pregnant or
breastfeed
during the study
8. Any evidence of a current Center for Disease Control and Prevention (CDC)
Stage 3 disease, except cutaneous Kaposi*s sarcoma not requiring systemic
therapy, and CD4+ counts <200 cells/mm3L are not exclusionary.
9. Participants with moderate to severe hepatic impairment
10. Any pre-existing physical or mental condition (including substance use
disorder)
which, in the opinion of the Investigator, may interfere with the participant*s
ability to comply with the dosing schedule and/or protocol evaluations or which
may compromise the safety of the participant
11. Participants with a high risk of seizures, including participants with an
unstable or poorly controlled seizure disorder.
12. Untreated secondary (late latent) or tertiary syphilis infection, defined
as a positive RPR and a positive treponemal test without clear documentation of
treatment
13. Participants who pose a significant suicide risk.
14. The participant has a tattoo, gluteal implant/enhancements or other
dermatological
condition overlying the gluteus region which may interfere with interpretation
of
injection site reactions
15. Evidence of Hepatitis B virus (HBV) infection
16. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection
will not
be excluded
17. Unstable liver disease
18. History of liver cirrhosis with or without hepatitis viral co-infection.
19. Ongoing or clinically relevant pancreatitis
20. Clinically significant cardiovascular disease
21. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell
carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or
cervical intraepithelial neoplasia;
22. Any condition which, may interfere with the absorption, distribution,
metabolism or excretion of the study drugs or render the participant unable to
receive study medication
23. History or presence of allergy or intolerance to the study drugs or their
components or drugs of their class.
24. Current or anticipated need for chronic anti-coagulation
25. Corrected QT interval for subjects with bundle branch block.
26. Known or suspected active COVID-19 infection OR has had contact with an
individual with known COVID-19, within 14 days of study enrolment.
27. Known or suspected presence of resistance mutations as defined by the
IAS-USA
to the individual components of BIK (BIC, FTC, TAF), RPV, and CAB by any
historical resistance test result.
28. Any verified Grade 4 laboratory abnormality.
29. Any acute laboratory abnormality at Screening
30. Participant has estimated creatine clearance <30mL/min per 1.73m2
31. Alanine aminotransferase (ALT) >=3 × ULN
32. Exposure to an experimental drug or experimental vaccine within either 30
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 Day 1 of this study
33. Treatment with any of the following agents within 28 days of Screening:
• radiation therapy
• cytotoxic chemotherapeutic agents;
• tuberculosis therapy with the exception of isoniazid
• anti-coagulation agents;
• Immunomodulators that alter immune
34. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of
Screening
35. Treatment with any agent, except recognized ART, with
documented activity against HIV-1 within 28 days of study Day 1.
36. Use of medications which are associated with Torsade de Pointes.
37. Participants receiving any prohibited medication
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 | EUCTR2020-002623-11-NL |
| CCMO | NL74638.028.20 |