Pharmacokinetic Interactions of ENG Subdermal Implants with Long-Acting Cabotegravir (CAB-LA) and LA Rilpivirine (RPV-LA) (CARLA)

NCT05156658 | Withdrawn Phase 4 DMC FDA Drug

• 2 other identifiers: ACTG A5392UM1AI068636
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this pharmacokinetic (PK) trial is to evaluate whether the ENG implant, a long-acting birth control method, is tolerable and effective for adults with HIV who are taking long-acting cabotegravir (CAB-LA) and long-acting rilpivirine (RPV-LA). Access to safe and effective birth control for adults with HIV is important because it may result in fewer infants exposed to HIV in the womb or born with HIV. Researchers believe that people of childbearing potential need access to birth control options that do not need to be negotiated with a partner.

Conditions

HIV-1-infection

Outcome Measures

Primary Outcomes (1)

• ENG PK parameter Area under the concentration-time curve (AUC0-24weeks) based on ENG PK samples obtained from individual participants

  AUC for each participant will be calculated from all available ENG concentrations measured over 24 weeks using the linear interpolation version of trapezoidal rule (i.e., noncompartmental technique) using the software package Phoenix WinNonLin (Certara®). This version of the trapezoidal rule uses linear interpolation between untransformed data up through Clast. Assay lower limit of quantification (LLoQ) for ENG is 0.025 ng/mL; values \< LLoQ were imputed as 0 (if pre-dose) or as ½ the LLoQ, 0.0125 ng/mL (if post-dose).

  PK samples at pre-insertion, and 1, 4, 12 and 24 weeks post implant insertion

Secondary Outcomes (4)

• ENG PK parameter Area under the concentration-time curve (AUC0-12weeks) based on ENG PK samples obtained from individual participants

  PK samples at pre-insertion, and 1, 4, and 12 weeks post implant insertion

• Probability of having ENG implant removed due to intolerance before 48 weeks

  From insertion of implant to 48 weeks

• ENG PK parameter Area under the concentration-time curve (AUC0-48weeks) based on ENG PK samples obtained from individual participants

  PK samples at pre-insertion, and 1, 4, 12, 24, 36 and 48 weeks post implant insertion

• ENG total concentration in serum

  PK samples at pre-insertion, and 1, 4, 12, 24, 36 and 48 weeks post implant insertion

Study Arms (2)

Group A: With HIV receiving Monthly CARLA: ENG subcutaneous implant

ACTIVE COMPARATOR

Participants with HIV-1 receiving monthly cabotegravir-long acting and rilpivirine-long acting (CARLA) (not provided by the study) will receive ENG implant immediately after enrollment.

Drug: Etonogestrel (ENG) Subdermal Implants

Group B: Without HIV: ENG subcutaneous implant

ACTIVE COMPARATOR

Participants without HIV-1 will receive ENG implant immediately after enrollment.

Drug: Etonogestrel (ENG) Subdermal Implants

Interventions

Etonogestrel (ENG) Subdermal Implants DRUG

Etonogestrel is available as a single, white/off-white, soft, radiopaque, flexible, ethylene vinyl acetate copolymer implant, 4 cm in length and 2 mm in diameter containing 68 mg of etonogestrel. Store at 25°C (77°F); excursions permitted between 15 and 30°C (59-86°F) \[see USP Controlled Room Temperature\]. Avoid storing ENG at temperatures above 30°C (86°F).

Group A: With HIV receiving Monthly CARLA: ENG subcutaneous implant; Group B: Without HIV: ENG subcutaneous implant

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Last menstrual period started ≤35 days prior to study entry. If the start of the last menstrual period was \>35 days prior to study entry, and the individual has been using hormonal contraception for at least 30 days prior to study entry, individual is eligible. If the start of the last menstrual period was \>35 days prior to study entry, and the individual has not been using hormonal contraception for at least 30 days prior to study entry, serum follicle-stimulating hormone (FSH) must be ≤40 mIU/mL.
• Negative serum or urine pregnancy test (urine test must have a sensitivity of ≤25 mIU/mL) within 48 hours prior to study entry by any US clinic or laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or is using a point-of-care (POC)/ CLIA-waived test, or at any network-approved non-US laboratory or clinic that operates in accordance with Good Clinical Laboratory Practice (GCLP) and participates in appropriate external quality assurance programs.
• Willingness and ability to have ENG implant placed per section 5.1.2.
• The following laboratory values obtained within 30 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with GCLP and participates in appropriate external quality assurance programs.
• Hemoglobin ≥8.0 g/dL
• Creatinine clearance \>60 mL/min/1.73m2
• o Refer to the calculator located on the Frontier Science website (at www.frontierscience.org): Calculated Creatinine Clearance - Cockcroft-Gault Equation (Adult).
• Aspartate transaminase (AST; serum glutamic oxaloacetic transaminase \[SGOT\]) \<2.5 x upper limit of normal (ULN)
• Alanine transaminase (ALT; serum glutamic pyruvic transaminase \[SGPT\]) \<2.5 x ULN
• Total bilirubin \<1.5 x ULN
• Platelet count ≥50,000 platelets/mm3
• Ability and willingness of the individual to provide informed consent.
• HIV status, documented by one of the following, based on group:
• Group A: Presence of HIV-1 Infection Documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
• Group B: Absence of HIV-1 infection Documented by any licensed rapid HIV test or HIV E/CIA test kit obtained within 30 days prior to study entry.

You may not qualify if:

• Hysterectomy or bilateral oophorectomy.
• Within 30 days postpartum at study entry.
• Currently breastfeeding or planning to become pregnant during the study.
• Participated in sexual activity that could lead to pregnancy in the 14 days prior to study entry without contraception, as reported by individual.
• Plans to use sex hormonal therapy, including but not limited to hormonal contraceptives, other than the ENG implant, during the study.
• The study puts the individual at unacceptable risk based on the judgment of the site investigator.
• Current or past history of thrombosis or thromboembolic disorder(s).
• Current or past history of breast, liver, or cervical cancer.
• Unstable liver disease (as defined by presence of ascites, encephalopathy, coagulopathy, esophageal or gastric varices, or persistent jaundice), cirrhosis, and/or known biliary abnormalities.
• Poorly controlled hypertension defined as ≥160 mmHg systolic or ≥100 mmHg diastolic measurements taken within 30 days prior to study entry.
• Known allergy/sensitivity or any hypersensitivity to components of ENG or its formulation.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Current use of drugs known to be contraindicated with ENG (see A5392 Prohibited and Precautionary Medications document on the PSWP).
• Use of any drugs known to: 1) induce CYP3A4 system within 30 days prior to study entry or 2) inhibit the CYP3A4 system within 1 week immediately prior to study entry (see A5392 Prohibited and Precautionary Medications document on the PSWP).
• Plans to use prohibited medications during the study (see A5392 Prohibited and Precautionary Medications document on the PSWP).

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Related Links

• Related Info

MeSH Terms

Interventions

etonogestrel; Endoglin

Intervention Hierarchy (Ancestors)

Receptors, Cell Surface; Membrane Proteins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Adriana Weinberg, MD

  University of Colorado Hospital CRS

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2021
• First Posted: December 14, 2021
• Study Start: January 1, 2024
• Primary Completion: August 2, 2024
• Study Completion: August 2, 2024
• Last Updated: December 13, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group. * For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group. * By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.