| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus type 1 (HIV-1) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Human Immunodeficiency Virus type 1 (HIV-1) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003582 |
| E.1.2 | Term | Asymptomatic human immunodeficiency virus type I infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To demonstrate the non-inferior antiviral activity of CAB LA + RPV LA every 8
weeks (every two months) compared to CAB LA + RPV LA every 4 weeks (monthly) over 48 weeks in suppressed HIV-1 infected antiretroviral therapy
(ART)-experienced participants |
|
| E.2.2 | Secondary objectives of the trial |
-To demonstrate the antiviral and immunologic activity of CAB LA + RPV
LA every 8 weeks compared to CAB LA + RPV LA every 4 weeks
-To evaluate the safety and tolerability of CAB LA + RPV LA every 8 weeks
compared to CAB LA + RPV LA every 4 weeks
-To assess viral resistance in participants experiencing protocol-defined confirmed virologic failure
-To characterize CAB and RPV concentrations and population pharmacokinetics and identify important determinants of variability
- To assess preference for CAB LA + RPV LA every 8 weeks or CAB LA +
RPV LA every 4 weeks LA compared to oral antiretroviral (ARV)
- To assess preference for CAB LA+ RPV LA every 8 weeks compared to
CAB LA + RPV LA every 4 weeks
-To assess patient reported health-related quality of life, treatment satisfaction,
injection tolerability, and treatment acceptance.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged 18 years or older (or ≥19 where required by local regulatory agencies), at
the time of signing the informed consent.
2. A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotropin (hCG) test at screen and a negative urine hCG test at 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:
Documented tubal ligation Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
-Hysterectomy
-Documented Bilateral Oophorectomy
-Postmenopausal 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) from 30 days prior to the first dose of study
medication, throughout the study, for at least 30 days after discontinuation of all
oral study medications, and for at least 52 weeks after discontinuation of CAB LA
and RPV LA.
The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception.
3. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Eligible participants or their legal guardians (and next of kin when locally
required), must sign a written Informed Consent Form before any protocol specified assessments are conducted. Enrolment of participants who are unable to provide direct informed consent is optional and will be based on local
legal/regulatory requirements and site feasibility to conduct protocol procedures.
4. Participants enrolled in France must be affiliated to, or a beneficiary of, a social
security category.
5. Must be on uninterrupted current regimen (either the initial or second ARV
regimen) for at least 6 months prior to Screening. Any prior switch, defined as a
change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for treatment failure (HIV-1 RNA ≥400 c/mL).
Acceptable stable (initial or second) ARV regimens prior to Screening include 2
NRTIs plus:
INI (either the initial or second cART regimen)
NNRTI (either the initial or second cART regimen)
Boosted PI (or atazanavir [ATV] unboosted) (must be either the initial cART regimen or one historical within class switch is permitted due to safety/tolerability)
The addition, removal, or switch of a drug(s) that has been used to treat HIV
based on antiretroviral properties of the drug constitutes a change in ART with the following limited exceptions:
Historical changes in formulations of ART drugs or booster drugs will not
constitute a change in ART regimen if the data support similar exposures
and efficacy, and the change must have been at least 3 months prior to
Screening.
Historical perinatal use of an NRTI when given in addition to an ongoing
HAART will not be considered a change in ART regimen.
A change in dosing scheme of the same drug from twice daily to once
daily will not be considered a change in ART regimen if data support
similar exposures and efficacy.
6. 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;
7. Plasma HIV-1 RNA <50 c/mL at Screening;
8. Must have been on CAB LA 400 mg + RPV LA 600 mg Q4W or “Current ART”
regimen through at minimum Week 52 of the ATLAS study as per ATLAS protocol dosing requirements and until Day 1 of the ATLAS-2M study. Any disruptions in dosing during ATLAS must be discussed with the Medical Monitor for a final determination of eligibility.
9. Plasma HIV-1 RNA <50 c/mL at Screening |
|
| E.4 | Principal 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. Any drug holiday during the window between initiating first HIV ART
and 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
4. Any switch to a second line 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 measurement
≥200 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen)
5. A history of use of any regimen consisting of only mono or dual HIV-1
therapy (even if only for peri-partum treatment).
6.Participants who are currently
participating in or anticipate to be selected for any other interventional study with the exception of the 201585 (ATLAS) study.
7. During participation in ATLAS, consecutive (2 or more sequential)
plasma HIV-1 RNA measurements ≥ 50 c/mL
8. During participation in ATLAS, any HIV-1 RNA measurement ≥ 200 c/mL
9. More than two total measurements of plasma HIV-1 RNA ≥ 50 c/mL
during participation in the ATLAS trial will require direct approval by
the ATLAS-2M Medical Monitor and Study virologist for study participation.
10. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study
11. Any evidence of a current Center for Disease Control and Prevention
(CDC) stage 3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma
not requiring systemic therapy, and CD4+ counts <200 cells/μL are not exclusionary.
12. Participants with moderate to severe hepatic impairment
13. 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
14. Participants determined by the Investigator to have a high risk of
seizures, including participants with an unstable or poorly controlled
seizure disorder. A participant with a prior history of seizure may be
considered for enrolment if the Investigator believes the risk of
seizure recurrence is low. All cases of prior seizure history should be
discussed with the Medical Monitor prior to enrolment
15. All participants will be screened for syphilis. Participants with
untreated secondary (late latent) or tertiary syphilis infection,
defined as a positive RPR and a positive treponemal test without clear
documentation of treatment, are excluded. Participants with a false
positive RPR (with negative treponemal test) or serofast RPR result
(persistence of a reactivenontreponemal syphilis test despite history of
adequate therapy and no evidence of re-exposure) may enroll after
consultation with the Medical Monitor. Participants with primary syphilis
or early latent secondary syphilis (acquiredwithin the preceding year)
who have a positive RPR test and have not been treated may be treated
during the screening period and if completion of antibiotic treatment
occurs during the screening period, may be allowed entry after
consultation with the Medical Monitor. Ifantibiotic treatment cannot be
completed before the screening window ends, subjects may be
rescreenedonce following completion of antibiotic therapy for primary
or early latent secondary syphilis.
16. Participants who, in the investigator's judgment, pose a significant suicide risk. Participant’s recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk
17. The participant has a tattoo or other dermatological condition overlying the
gluteus region which may interfere with interpretation of injection site reactions
18. 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 antibody (anti-HBs) and HBV DNA as follows:
a. •Participants positive for HBsAg are excluded;
b. •Participants negative for anti-HBs but positive for anti-HBc (negative
HBsAg status) and positive for HBV DNA are excluded
Note: Participants 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.
For a full list of exclusion criteria refer to Section 5.2 of the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of participants with plasma HIV-RNA greater than or equal to 50 copies/mL (Virologic Failure ) as per Food and Drug Administration (FDA)
Snapshot algorithm at Week 48 (Intent-to- Treat Exposed [ITT-E] population) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Proportion of participants with plasma HIV-1 RNA <50 c/mL (c/mL) at
Week 24, Week 48 and Week 96 and Week 152 using the FDA Snapshot algorithm
(Intent-to-Treat Exposed [ITT-E] population)
-Proportion of participants with protocol defined confirmed virologic failure (CVF) through Week 24,Week 48, Week 96 and Week 152
-Proportion of participants with HIV-RNA greater than or equal to 50 c/mL as per
FDA Snapshot algorithm at Week 24, Week 96 and Week 152
-Absolute values and changes from Baseline in viral load and CD4+ cell counts over time including Week 48, Week 96 and Week 152
-Incidence and severity of AEs and laboratory abnormalities over time
including Week 24, Week 48, Week 96 and Week 152
-Proportion of participants who discontinue treatment due to AEs over time including Week 24, Week 48, Week 96 and Week 152
-Change from Baseline in laboratory parameters over time including Week 48,
Week 96 and Week 152
-Incidence of treatment emergent genotypic and phenotypic resistance to CAB, RPV through Week 24, Week 48, Week 96 and Week 152
-Plasma PK parameters for CAB LA and RPV LA (when evaluable, Ctrough,
concentrations post dose [~Cmax], and area under the curve [AUC])
-Demographic parameters including, but not limited to, age, sex, race, body weight, body mass index, and relevant laboratory parameters will be evaluated as potential predictors of inter- and intra-participant variability for pharmacokinetic parameters
-Preference for CAB LA + RPV LA every 8 weeks or CAB LA + RPV LA
every 4 weeks compared to oral ARV and preference for CAB LA + RPV
LA every 8 weeks compared to CAB LA + RPV LA every 4 weeks will be
assessed using a preference questionnaire at week 48 (or Withdrawal).
-Change from Baseline (Day 1) in HRQoL at Week 24, and Week 48 (or Withdrawal)
-Change from baseline (Day 1) in total “treatment satisfaction” score, and
individual item scores of the HIV Treatment Satisfaction Status Questionnaire (HIVTSQs) at Week 24, 48, and 152(or Withdrawal)
-Change in treatment satisfaction over time using the HIV Treatment Satisfaction
-Change Questionnaire HIVTSQc at Week 48 (or Withdrawal).
-Change from Week 8 in Dimension scores (“Bother of ISRs”, “Leg movement”,
“Sleep”, and “Injection Acceptance”) 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 Weeks 8, 24, 48, and 152 (or Withdrawal)
-Change from Baseline (Day 1) in treatment acceptance at Week 24, Week 48 and Week 152 (or Withdrawal) will be assessed using the “General acceptance” dimension of the Chronic Treatment Acceptance (ACCEPT) questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time points of evaluation are included within endpoint above. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| CAB LA + RPV LA Q4W and CAB LA + RPV LA Q8W |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Korea, Democratic People's Republic of |
| Mexico |
| South Africa |
| United States |
| France |
| Sweden |
| Spain |
| Germany |
| Italy |
| Russian Federation |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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