Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04229290 |
| Other study ID # |
2SD |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
February 12, 2020 |
| Est. completion date |
September 16, 2021 |
Study information
| Verified date |
January 2022 |
| Source |
University of Nairobi |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Kenya has the 4th largest HIV burden in the world with about 1.6 million people living with
HIV. Of these, just over 1 million are on antiretroviral therapy (ART). Current national
guidelines recommend a first line regimen composed of 2 nucleoside reverse transcriptase
inhibitors (NRTI) plus an integrase strand transfer inhibitor (INSTI) or a non-nucleoside
reverse transcriptase inhibitor(NNRTI). Second line regimens are composed of 2 NRTI plus a
ritonavir boosted protease inhibitor(PIr). This is based on evidence showing good clinical
outcomes on this regimen. PIr are associated with side effects including an increase in
cardiovascular disease risk and, have significant drug to drug interactions that complicate
management of other conditions such as tuberculosis. INSTIs have been shown in one study to
be an alternative to PIr in second line regimens when combined with fully active NRTIs. It is
not clear if this would still be the case if the activity of the NRTIs was not known. The
investigators will evaluate the efficacy of switching from a PIr to a dolutegravir based
second line ART regimen.
Hypothesis: switching virologically suppressed patients from a PIr based second line to a
dolutegravir based second line is non-inferior to continuing on a PIr based second line.
Objectives: The primary objective will be to evaluate the non-inferiority of switching to a
DTG containing regimen relative to maintaining a PI/r containing second-line regimen in
virologically suppressed, INSTI-naive HIV-1 positive adults (≥ 18 years old) as determined by
having HIV-1 RNA ≥ 50 copies/ml at week 48. Secondary objectives will be to assess the impact
of such a switch on CD4 count, safety and tolerability.
Methods: Open-label, randomized, non-inferiority, multisite trial over 48 weeks, describing
the efficacy and safety of switching from a second-line ARV regimen containing a
ritonavir-boosted protease inhibitor (PI/r) plus 2 NRTIs to DTG plus 2 NRTIs in patients with
virological suppression (HIV-1 RNA < 50 copies/ml) for at least 12 weeks and with no prior
INSTI exposure. Adult participants will be randomized at baseline to remain on their
pre-enrollment PI/r or switch to DTG. Participants will continue the NRTIs from their
pre-enrollment regimen in both arms. A total of 766 participants(388 per arm) will be
recruited from 4 sites in Kenya Conclusion: This study seeks to inform guidelines around the
efficacy and safety of alternative second line regimens.
Description:
Background and Purpose of Research:
Current Kenya National Antiretroviral(ARV) Guidelines recommend that after failing an
NNRTI-based first-line regimen, patients should move to a ritonavir-boosted protease
inhibitor (PI/r) + 2 nucleoside reverse transcript inhibitors second-line regimen. Several
randomised trials support this sequencing, even without drug resistance testing results to
guide the choice of second-line NRTIs. The Kenya guidelines have recommended PI/r-based
second-line regimens for over a decade and essentially all second-line patients in Kenya are
currently on PI/r-based regimens with approximately 75% of these patients currently virally
suppressed.
The pill burden, long-term toxicities, tolerability challenges, drug-drug interactions and
higher cost of PI/r containing regimens are considerable disadvantages of the current
second-line regimens in Kenya and much of sub-Saharan Africa. In contexts with high
Tuberculosis (TB) prevalence, the impact of potential drug-drug interactions is considerable,
requiring either super boosting of the PI with ritonavir which is toxic and poorly tolerated
and only found to result in adequate drug levels for LPV/r but not for ATV/r or DRV/r or, use
of rifabutin which is not co-formulated with other anti-mycobacterial agents and leads to a
high pill burden affecting adherence. The supply of rifabutin has been unreliable in Kenya.
No study has evaluated a switch strategy from PI/r to DTG for virally suppressed treatment
experienced patients who have failed a prior first line regimen consisting of a NNRTI +
NRTIs. If such a strategy is found to be non-inferior to the current standard of care it
would have major implications for the current regimens distribution in Kenya and similar
settings, allowing a transition of almost 75% of current second-line patients from PI/r-based
to DTG-based second line with lower cost, improved tolerability, decreased risk of toxicity,
reduced risk of drug-drug interactions, and lower pill burden.
Summary of Previous Studies
A recent study has shown that a second-line regimen of dolutegravir (DTG) + 2 NRTIs is
superior to LPV/r + 2 NRTIs after failing a first line regimen of NNRTI + 2 NRTIs in the
presence of a fully active NRTI in the second line (Aboud 2019). The study excluded patients
who did not have a fully active NRTI for second line, so the results can only be directly
applied to scenarios where one can reliably predict activity of the NRTIs after first-line
failure or where DRT results are available.
The Kenya National ARV Guidelines also recommend that patients on an alternative first line
regimen, either NNRTI based or PI/r based, with virologic suppression should be switched to
DTG/TDF/3TC. The evidence for this strategy comes from two studies showing that switch of
virally suppressed patients to DTG-based first line regimens was associated with non inferior
viral suppression, improved patient satisfaction and improved lipid profiles
In the NEAT022 study, investigators enrolled older individuals or those with high
cardiovascular disease risk with the goal of analysing efficacy and impact of a change from a
boosted PI to dolutegravir. Participants had suppressed HIV RNA while taking a boosted PI and
two NRTIs, with no documented NRTI resistance mutations or previous virologic failure. All
participants were over the age of 50 or had Framingham estimated 10-year risk of
cardiovascular events greater than 10%. 415 individuals were randomised to continue two
NRTI's plus a boosted PI or switch to dolutegravir while maintaining the same NRTIs. After 48
weeks, 97.5% of individuals in the boosted PI arm maintained virologic suppression compared
to 94.5% in the dolutegravir switch arm (a non-statistically significant difference).
Notably, lipid parameters and cardiovascular risk improved significantly in the switch arm.
Hypothesis Switch of virologically suppressed, INSTI-naïve HIV-1 positive adults (≥ 18 years
old) on PI/r-based second line ARV regimens is non-inferior to continuing the PI/r-based
regimen, as determined by risk of developing virological failure by 48 weeks.
Primary Objective To evaluate the non-inferiority of switching to a DTG containing regimen
relative to maintaining a PI/r containing second-line regimen in virologically suppressed,
INSTI-naive HIV-1 positive adults (≥ 18 years old) as determined by having HIV-1 RNA ≥ 50
copies/ml at week 48.
Secondary Objectives To assess the impact of switching to DTG on development of virological
failure at week 24 To assess the impact of switching to DTG on maintenance of virological
suppression at weeks 24 and 48 To assess the impact of switching to DTG on change in CD4
count at weeks 24 and 48 To assess the impact of switching to DTG on change in cardiovascular
risk as determined by change in lipid values (total cholesterol, LDL, HDL, triglycerides and
TC:HDL ratio) at weeks 24 and 48 and change in fasting blood glucose at weeks 24 and 48 To
investigate the impact of switching to DTG on change in anthropometric measurements (weight,
body-mass index, waist-hip ratio, waist circumference) To investigate the impact of switching
to DTG on safety and tolerability To investigate the impact of switching to DTG on patient
satisfaction, as determined by the HIV Treatment Satisfaction Questionnaire To investigate if
outcomes differ based on the PI/r used To investigate if outcomes differ based on the NRTI
used (TDF, ABC, or AZT) To investigate if outcomes differ for patients who switch NRTIs for
clinical reasons during the study relative to patients who do not switch NRTIs during the
study To investigate if outcomes differ based on if the NRTIs were changed from first-line to
second-line To describe the genotypic resistance patterns for participants meeting
protocol-defined virological failure
Study Design This is an open-label, randomized, non-inferiority, multicenter trial over 48
weeks, describing the efficacy and safety of switching from a second-line ARV regimen
containing a ritonavir-boosted protease inhibitor plus 2 NRTIs to DTG plus 2 NRTIs in
patients having achieved virological suppression for at least 12 weeks and with no prior
INSTI exposure. Participants will be randomized at baseline to remain on their pre-enrollment
PI/r or switch to DTG. Participants will continue the NRTIs from their pre-enrollment regimen
in both arms.
Research Procedures Study visits will take place at screening, baseline, and weeks 4, 12, 24,
36, and 48 (with a 4-week extension as required for confirming HIV-1 RNA levels within the
FDA snapshot window).
HIV-1 RNA viral load will be performed at screening and weeks 4, 12, 24 and 48. If HIV-1 RNA
is ≥ 50 copies/ml then a repeat test will be performed at least two weeks after the
detectable result to confirm virological failure. A repeat HIV-1 RNA result of ≥ 50 copies/ml
is confirmed protocol-defined virological failure (PDVF) and genotypic resistance testing
will be performed.
Other routine study investigations will include CD4, complete blood count, serum Creatinine,
Alanine aminotransferase, Aspartate aminotransferase, total cholesterol, HDL, LDL,
triglycerides, HBsAg, serum glucose, patient satisfaction questionnaires (HIVTSQ), and urine
pregnancy test in women of child-bearing potential. In extenuating circumstances, such as
travel restrictions or facility closures due to risk of COVID-19 infection or other
unanticipated events, telephone calls may be used to complete as much information as possible
on the CRFs for the scheduled study visits, and arrangements ade for laboratory samples to be
taken at or near the subject's home.
A participant is free to withdraw from the study at any time. In addition, the investigators
may decide, for reasons of medical prudence, to stop study medications. These participants
will be followed to 48 weeks.
If any participants experience PDVF (two consecutive HIV-1 RNA levels of 50 copies/ml or more
taken at least 14 days apart), the study PI/co-PI must be informed immediately for management
recommendations, which will include genotypic drug resistance testing. Participants will be
asked to attend all study visits.
Study medication may also be discontinued in the following instances:
If the participant withdraws their consent If the participant requires a substitution of the
PI/r or DTG due to drug-drug interactions or toxicity. Changes to the NRTIs are allowed if
clinically indicated, and changes within the PI/r class (e.g. from LPV/r to ATV/r) are
allowed if it is required because of national supply chain limitations. Dose adjustments
required to manage drug-drug interactions are allowed, following the product monograph for
the drug If the investigators consider in the interest of the subject (i.e. intercurrent
illness, unacceptable toxicity) that it is best for them to stop study medication The subject
fails to comply with the protocol requirements, including poor adherence, or fails to
cooperate with investigators
A female subject receiving DTG who becomes pregnant during the study must immediately have
their DTG withdrawn to eliminate further exposure to the embryo/foetus. Exceptions may be
discussed with Ethics and ViiV in situations where the benefits of continuing the pregnant
woman on DTG outweigh the potential risks.
To minimize risk to subjects, study staff, and other staff at the study sites, precautions
will be taken to reduce the risk of COVID-19 transmission in-line with the Ministry of Health
guidelines and guidance from the Ethical Review Committee.
Source and Dose of the Products
Participants will be randomized to continue their pre-enrollment PI/r or switch from PI/r to
DTG while continuing the NRTIs from the pre-enrollment regimen. Changes to the NRTIs are
allowed throughout the study period only for clinical indications. Changes within the PI/r
class are allowed (e.g. from LPV/r to ATV/r) if required by limitations in the national
supply chain.
ARVs will be provided to all participants through the Kenya national ARV supply change
mechanism, which uses generic fixed-dose combinations when available. For participants who
are randomized to switch from PI/r+ABC/3TC to DTG+ABC/3TC, ViiV will provide the
single-tablet fixed-dose combination of DTG/ABC/3TC in the commercial form of Triumeq®.
Participants who are randomized to take DTG will take a 50 mg tablet once daily, either as a
single tablet in combination with a separate fixed-dose combination tablet of NRTIs or as
part of a fixed-dose combination of DTG 50 mg and the NRTIs, as available through the
national supply change or by ViiV (in the case of DTG/ABC/3TC).
Participants will be dispensed a 4 week supply of ARVs at baseline, an 8 week supply at week
4, and a 12 week supply at weeks 12, 24 and 36.
Number and Type of Participants
The anticipated sample size is 766 participants (383 per study arm). The sample size
calculation is based on the primary endpoint of HIV-1 RNA ≥ 50 copies/ml at week 48 using the
FDA snapshot method for the Intent-to-Treat Exposed (ITT-E) population. The sample size
calculation assumes that the true difference in efficacy between treatment arms is zero and
that overall virological failure rate is 3% at week 48. A total of 766 participants (383
participants per study arm) is required to provide at least 90% power to demonstrate
non-inferiority for the DTG arm, compared to the control arm, with a one-sided significance
level of 2.5% and non-inferiority margin of 4%.
Study Location:
All study sites are in Kenya and include: Kenyatta National Hospital, Thika Level 5 Hospital,
Kiambu Level 5 Hospital and Jaramogi Oginga Odinga Teaching and Referral Hospital.
