| 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 switching to intramuscular CAB LA
+ RPV LA every 4 weeks (monthly) compared
to continuation of current first line
antiretroviral regimen over 48 weeks in HIV-1
infected antiretroviral therapy (ART)-
experienced participants |
|
| E.2.2 | Secondary objectives of the trial |
Refer to protocol (section 3) for complete list of Secondary Endpoints
-To demonstrate the antiviral and immunologic
activity of switching to intramuscular CAB LA
+ RPV LA every 4 weeks (monthly) compared
to continuation of current ART
-To evaluate the safety and tolerability of
switching to CAB LA + RPV LA every 4 weeks
(monthly) compared to continuation of current
ART
-To assess viral resistance in participants
experiencing protocol-defined virologic failure
-To assess the impact of Baseline third agent
treatment class (INI, NNRTI, or PI) on
efficacy, safety, tolerability, and viral
resistance of CAB LA + RPV LA compared to
continuation of current ART
-To characterize CAB and RPV concentrations
and population pharmacokinetics and identify
important determinants of variability.
-To evaluate the antiviral and immunologic
effects, safety, tolerability, and viral resistance
of CAB LA + RPV LA for participants during
the Extension Phase |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
AGE
1. Aged 18 years or older (or ≥19 where required by local regulatory
agencies), at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. 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 with the exception of ABC/DTG/3TC (either the initial or second cART regimen)
-NNRTI (either the initial or second cART regimen)
-Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based cART regimen)
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;
SEX
5. A female participant 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), 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) (see Section 12.7.1, Appendix 7) from 30 days prior to the first dose of study medication and until from 30 days prior to the first dose of study medication throughout the study, and 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.
INFORMED CONSENT
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 participants or their legal guardians must sign a written Informed
Consent Form before any protocol-specified assessments are conducted.
OTHER
Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.
All participants participating in the study should be counselled 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. |
|
| E.4 | Principal exclusion criteria |
Exclusionary Criteria prior to Screening or Day 1
1. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement >or=50 c/mL
2. 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, or 2 or more plasma HIV-1 RNA measurements >or=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
5. Abacavir/dolutegravir/lamivudine, (ABC/DTG/3TC) as current ART regimen
6. A history of use of any regimen consisting of only single NNRTI therapy, or only single or dual NRTI therapy prior to starting cART
7. Participants who are currently participating in or anticipate to be selected for any other interventional study
Exclusionary medical conditions
8. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study
9. Any evidence of an active Center for Disease Control and Prevention (CDC) Stage 3 disease, except cutaneous Kaposi’s sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells/mm3
10. Participants with moderate to severe hepatic impairment
11. Any pre-existing physical or mental condition 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
12. 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
13. All participants will be screened for syphilis. Participants with untreated syphilis infection, defined as a positive RPR without clear documentation of treatment, are excluded. Participants with a positive RPR test who have not been treated may be rescreened at least 30 days after completion of antibiotic treatment for syphilis
14. 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
15. The participant has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions
16. 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:
-Participants positive for HBsAg are excluded;
-Participants negative for anti-HBs but positive for anti-HBc and positive for HBV DNA are excluded
17. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; participants who are anticipated to require HCV treatment within 12 months must be excluded.
Participants with HCV co-infection will be allowed entry into phase 3 studies if:
-Liver enzymes meet entry criteria
-HCV Disease has undergone appropriate work-up, and is not advanced, and will not require treatment prior to the Week 48 visit.
Additional information (where available) on participants with HCV coinfection at screening should include results from any liver biopsy, Fibroscan, ultrasound, or other fibrosis evaluation, history of cirrhosis or other decompensated liver disease, prior treatment, and timing/plan for HCV treatment.
-In the event that recent biopsy or imaging data is not available or inconclusive, the Fib-4 score will be used to verify eligibility
-Fib-4 score > 3.25 is exclusionary
-Fib-4 scores 1.45 – 3.25 requires Medical Monitor consultation
Fibrosis 4 Score Formula:
( Age x AST ) / ( Platelets x ( sqr [ ALT ])
18. Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis), known biliary abnormalities
19. History of liver cirrhosis with or without hepatitis viral co-infection.
20. Ongoing or clinically relevant pancreatitis
Please refer to the protocol for the following criteria:
-Exclusionary medical conditions (21-25)
-Exclusionary Laboratory Values or Clinical Assessments at Screening
-Concomitant Medications
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants with a ‘virologic failure’ endpoint 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 at Week 48 using the FDA Snapshot algorithm (ITT-E population).
•Proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 48 using the FDA Snapshot algorithm (ITT-E population).
•Proportion of participants with plasma HIV-1 RNA <50c/mL over time including week 96 (Observed Case).
•Proportion of participants with confirmed virologic failure at Week 48 and through Week 96.
•Absolute values and change from Baseline in plasma HIV-1 RNA at Week 48 and over time including Week 96.
•Absolute values and changes from Baseline in CD4+ cell counts over time including Week 48 and Week 96
•Incidence of disease progression (HIV-associated conditions, acquired immunodeficiency syndrome [AIDS] and death).
•Incidence and severity of AEs and laboratory abnormalities over time including Week 48 and Week 96.
•Proportion of participants who discontinue treatment due to AEs over time including Week 48 and Week 96.
•Absolute values and changes in laboratory parameters over time including Week 48 and Week 96.
•Change from Baseline in fasting lipids over time including Week 48 andWeek 96.
•Incidence of treatment emergent genotypic and phenotypic resistance to CAB, RPV, and other on-study ART at Week 48 and Week 96. • 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.
•Change from Week 5 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 using the Perception of iNjection questionnaire (PIN)
•Proportion of participants considering pain and local reactions following injection to be extremely or very acceptable based on the acceptability score over time using the Perception of iNjection questionnaire (PIN).
•Change from Baseline in HR QoL using the HIV/AIDS-targeted quality of life questionnaire (HAT QoL) short form at Week 24, Week 48, Week 96 (or Withdrawal).Change from Baseline in health status at Week 24, Week 48, and Week 96 (or Withdrawal) using the 12-item Short Form Survey (SF-12). .
•Change from baseline in total “treatment satisfaction” score, and individual items scores of the HIVTSQs at Weeks 4b, 24, 44, 96 (or Withdrawal)
•Change in treatment satisfaction over time using the HIVTSQc at Week 48 (or Withdrawal)
•Change from Baseline in treatment acceptance at Week 8, Week 24, Week 48, Week 96 (or Withdrawal) using the “General acceptance” dimension of the Chronic Treatment Acceptance (ACCEPT) questionnaire
•Change from Week 4b in tolerability of injection at Week 5, Week 40, Week 41, and Week 96 using the Numeric Rating Scale (NRS) within the CAB + RPV LA arm
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time points of evaluation are included within endpoint above. Primary analyses at Week 48, Secondary analyses at Week 96. Following completion of ATLAS Week 52, eligible participants will be offered an optional rollover to the 207966 (ATLAS-2M) study designed to demonstrate the non-inferior antiviral activity of CAB LA 600 mg + RPV LA 900 mg administered every 8 weeks compared with CAB LA 400 mg + RPV LA 600 mg administered every 4 weeks (Q4W; monthly) over a 48-week treatment period. ATLAS-2M will also provide comparative data on antiviral activity, safety, tolerability, and patient satisfaction through Week 96 |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 |
| current antiretroviral regimen (CAR) |
|
| 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 | 41 |
| 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 | 10 |
| 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 | 8 |
| 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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