Administration of the BCL-2 antagonist, venetoclax, to promote apoptosis of HIV-infected cells and reduce the size of the HIV reservoir: An investigator-initiated phase I/IIb clinical trial in people living with HIV on antiretroviral therapy (The AMBER Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Region Midtjylland

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02], Diseases [C] - Immune System Diseases [C20]

Trial duration

28 Oct 2022 → ongoing

Decision date (initial)

2024-10-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518873-32-00

EudraCT number

2022-001677-31

ClinicalTrials.gov

NCT05668026

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To determine the safety of venetoclax in PLWH on ART

Conditions and MedDRA coding

HIV-1 disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Documented HIV-1 infection
2. Age 18-65 years, both included
3. Receiving combination ART for at least 2 years and being on the same ART regimen for at least 4 weeks at the screening visit
4. HIV-1 plasma RNA <50 copies/mL for >2 years (documented on at least 2 occasions within the 2 years) and <20 copies/mL at screening. Episodes of a single HIV plasma RNA 50-500 copies/mL will not exclude participation if the subsequent HIV plasma RNA was <50 copies/mL
5. CD4+ T cell count >500 cells/μL at screening and at least two CD4+ T cell counts >500 cells/μL in the 24 months prior to screening
6. Ability and willingness to provide informed consent and to continue ART throughout the study
7. For potential study participants who anticipate receiving a SARS-CoV-2 vaccine within the study period, enrolment and commencement of study therapy will be postponed until 4 weeks after completing SARS-CoV-2 vaccination, whereas screening procedures can be initiated before or concurrently with SARS-CoV-2 vaccination.
8. A female, may be eligible to enter and participate in the study if she: o Is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or, o Is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the specified methods of contraception to avoid pregnancy
9. All participants must agree not to participate in a conception process (e.g. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, egg donation) during the study
10. Heterosexually active male if they are o willing to use an effective method of contraception (anatomical sterility in self that is confirmed prior to study entry) or o agree on the use of an effective method of contraception with an effective failure rate of < 1% by his partner (hormonal contraception, intra-uterine device (IUD), or anatomical sterility) from the day prior to the first dose and for at least 2 weeks after discontinuation of study drug.

Exclusion criteria 24

1. An individual who meets any of the following criteria will be excluded from participation in this study. Study participants receiving cobicistat or a protease inhibitor may opt to switch their ART regimen away from those drugs to allow study participation if this is deemed reasonable by their treating physician but will need to maintain their new regimen for at least 4 weeks prior to enrolling in the study.
2. Current or previous use of a BCL-2 antagonist or other pro-apoptotic agent used as cancer therapy
3. Any concomitant disease where venetoclax treatment is indicated
4. Current use of any moderate or strong CYP3A4 inhibitors (such as ketoconazole, voriconazole, posaconazole, itraconazole, ritonavir, cobicistat and clarithromycin)
5. Current use of any HIV protease inhibitor (due to CYP3A4 inhibition)
6. Current use of any strong inhibitor of the P-gp drug efflux pump (this includes cobicistat, ritonavir, azithromycin and clarithromycin)
7. Current use of strong CYP3A4 inducers (such as carbamazepine, phenytoin, rifampicin and St. John’s wort); moderate CYP3A4 inducers (such as bosentan, efavirenz, etravirine, modafinil and nafcillin) may be used but should be avoided as much as possible
8. Receipt of immunomodulating agents (excluding immunisation) or systemic chemotherapeutic agents within 28 days prior to study entry
9. Any other current or prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study
10. Known hypersensitivity to the components of venetoclax or its analogues
11. Any significant acute medical illness in the past 4 weeks
12. Any evidence of an active AIDS-defining opportunistic infection
13. Individuals who intend to modify their ART regimen within the study period
14. Current or recent gastrointestinal disease or gastrointestinal surgery that may impact the absorption of the investigational drug
15. Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy or procedures
16. Unable or unwilling to adhere to protocol procedures
17. History of malignancy or transplantation, excluding adequately treated basal cell carcinoma
18. Co-infection with hepatitis B or C (Individuals with prior hepatitis C infection that is now cleared are eligible for enrolment)
19. Impaired liver function with AST or ALT >3 times upper limit of normal
20. Severe hepatic impairment (Class C) as determined by Child-Pugh classification
21. Impaired renal function with estimated creatinine clearance (eGFR) <50 mL/min
22. Significant cardiac dysfunction
23. Women who are pregnant or breastfeeding or Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy as specified in the inclusion criteria
24. The specified laboratory values at screening (lab tests may be repeated, as clinically indicated, to obtain acceptable values before failure at screening is concluded but supportive therapies are not to be administered within the week prior to screening tests)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety defined as treatment-emerging adverse events (AEs) >=grade 3 (as cited as dose limiting toxicities section 4.2) probably or definitely related to study treatment
2. Safety defined as all other treatment-emerging AEs, graded according to severity and assessed as either not related or possibly, probably or definitely related to study treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Region Midtjylland

Sponsor organisation

Region Midtjylland

Address

Palle Juul-Jensens Boulevard 99

City

Aarhus N

Postcode

8200

Country

Denmark

Scientific contact point

Organisation

Aarhus University Hospital

Contact name

Jesper D. Gunst

Public contact point

Organisation

Aarhus University Hospital

Contact name

Jesper D. Gunst

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications