| 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 ABC/DTG/3TC over 48 weeks in HIV-1 antiretroviral naïve participants. |
|
| E.2.2 | Secondary objectives of the trial |
-To demonstrate the antiviral and immunologic activity of switching to intramuscular CAB LA + RPV LA every 4 weeks (monthly) compared to continuation of ABC/DTG/3TC.
-To evaluate the safety and tolerability of switching to CAB LA + RPV LA every 4 weeks compared to continuation of ABC/DTG/3TC over time.
-To evaluate the effects of CAB LA + RPV LA every 4 weeks on fasting lipids over time compared to continuation of ABC/DTG/3TC over time.
-To assess the development of viral resistance in participants experiencing protocol-defined virologic failure.-
-To characterize CAB and RPV concentrations and population pharmacokinetics and identify important determinants of variability.
-To assess the acceptance of pain and injection site reactions following injections.
-To assess degree of health related QoL using the HIV/AIDS-targeted quality of life (HAT-QoL) questionnaire short form.
-Refer to protocol Section 3, "Objectives and Endpoints", for complete list of Secondary Objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants eligible for enrollment in the study must meet all of the following criteria:
AGE
1. HIV-1 infected, ART-naive men or women aged 18 years or greater at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. HIV-1 infection as documented by Screening plasma HIV-1 RNA ≥1000 c/mL;
3. Antiretroviral-naïve (≤10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection). Any previous exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase inhibitor will be exclusionary.
SEX
4. Female Participants:
A female participant is eligible to participate if she is not pregnant at Screening and first
day of Induction Phase (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), 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 Appendix 7.) 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.
ALL participants 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
Capable of giving signed informed consent as described in Section 6.2 which includes compliance with the requirements and restrictions listed in the consent form and in this
protocol.
OTHER
French participants: In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
|
| E.4 | Principal exclusion criteria |
A participant will not be eligible for inclusion in this study if any of the following criteria
apply:
Exclusionary Medical Conditions
1. Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed
during the study.
2. Any evidence at Screening of an active Centers for Disease and Prevention Control
(CDC) Stage 3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic therapy or historic or current CD4+ cell count <200 cells/mm3 are not exclusionary (local guidelines dictate).
3. Participants with known moderate to severe hepatic impairment.
4. Any pre-existing physical or mental condition (including substance abuse 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.
5. 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.
6. Participant who, in the investigator's judgment, poses a significant suicide risk. Participant’s recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
7. The participant has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
8. 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 (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.
9. 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 prior to Week 48 of the Maintenance Phase must be excluded. HCV treatment on study may be permitted post Week 48, following consultation with the Medical Monitor.
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, HCV is not advanced, and will not require treatment prior to the Week 48 visit. Additional information (where available) on participants with HCV co-infection 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 is inconclusive,
the Fib-4 score will be used to verify eligibility.
A 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 (√ALT))
10. Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
11. History of liver cirrhosis with or without hepatitis viral co-infection.
12. Ongoing or clinically relevant pancreatitis.
13. All participants will be screened for syphilis (rapid plasma reagin [RPR]). 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. 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; other localized malignancies require agreement between the investigator and the study Medical Monitor for inclusion of the participant prior to enrollment.
For complete exclusion Criteria please refer to section 5.2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants with a ‘virologic failure’ endpoint as per FDA Snapshot algorithm at Week 48 (Missing, Switch or Discontinuation = Failure, Intent-to-Treat Exposed [ITT-E] population). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 48 of Maintenance Phase |
|
| 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 <200 c/mL at Week 48 using the FDA Snapshot algorithm (ITT-E population).
• Proportion of participants with plasma HIV-1 RNA <200 c/mL and HIV-1 RNA <50 c/mL at Week 96 using the FDA Snapshot algorithm (ITT-E population).
• Proportion of participants with a 'virologic failure' endpoint as per FDA Snapshot algorithm at Week 96.
• Proportion of participants with confirmed virologic failure at Week 48 and Week 96.
• Absolute values and change from Baseline in plasma HIV-1 RNA at Week 48 and 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, 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 and Week 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 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 (e.g., "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 PIN questionnaire.
• 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 PIN questionnaire.
• 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 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 total "treatment satisfaction" score, and
individual item scores of the HIV Treatment Satisfaction Questionnaire
(status version) (HIVTSQs) at Week 4b, Week 24, Week 44, Week 96 (or
Withdrawal).
• Change in treatment satisfaction over time (using the HIVTSQ change
version [HIVTSQc]) at Week 48 (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 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 injections at Week 5, Week 40, Week 41, and Week 96 using the Numeric Rating Scale (NRS) within the CAB LA + RPV LA arm.
• Proportion of participants with HIV-1 RNA >= 50 c/mL at Week 124, with and without oral lead-in (FDA Snapshot algorithm, Extension Switch population).
• Proportion of participants with plasma HIV-1 RNA <50 c/mL and HIV-1 RNA <200 c/mL over time.
• Proportion of participants with confirmed virologic failure over time.
• Incidence of treatment emergent genotypic and phenotypic resistance to CAB and RPV over time.
• Absolute values and change from Baseline in CD4+ cell counts over time.
• Incidence and severity of AEs and laboratory abnormalities over time.
• Proportion of participants who discontinue treatment due to AEs over time.
• Absolute values and change in laboratory parameters over time.
• To evaluate plasma CAB and RPV concentrations over time (Week 100 [direct to inject without oral lead-in] and Week 104 [both direct to inject and optional oral lead-in participants])
|
|
| 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 |
|
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| 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 |
| Canada |
| Japan |
| Russian Federation |
| South Africa |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
|
| 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 | 6 |
| 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 | 6 |
| 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 |
Print
