Clinical trial NCT05156658: Pharmacokinetic Interactions of ENG Subdermal Implants with Long-Acting Cabotegravir (CAB-LA) and LA Rilpivirine (RPV-LA) (CARLA)
Official title: Pharmacokinetic Interactions of Etonogestrel (ENG) Subdermal Implants with Long-Acting (LA) Cabotegravir (CAB-LA) and LA Rilpivirine (RPV-LA) (CARLA) in Participants of Reproductive Potential
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: HIV-1-infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2021-12-14
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.

OR

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.

NOTE: The term "licensed" refers to a US FDA-approved kit or, for sites located in countries other than the United States, a kit that has been certified or licensed by an oversight body within that country and validated internally.

WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

* Body Mass Index (BMI) (kg/m2) available from weight/height measurements obtained within 30 days prior to study entry.

NOTE: Refer to the BMI Index calculator located on the Frontier Science website.

Group A-specific Additional Inclusion Criteria (Participants with HIV)

* Willingness to adhere to the following contraception requirements.

  a. Individuals who are participating in sexual activity that could lead to pregnancy must agree to use a non-hormonal method of contraception in addition to the ENG implant while participating in the study. Acceptable forms of contraception include:
  * Condoms (male or female) with or without a spermicidal agent
  * Diaphragm or cervical cap with spermicide
  * Non-hormonal intrauterine device (IUD)
  * Bilateral tubal ligation
  * Male partner vasectomy
* Receiving monthly CARLA for ≥24 weeks immediately prior to study entry.

NOTE A: Oral CAB+RPV bridging that was used to cover one or more missed injection(s) is acceptable. If the individual missed an injection within the 24 weeks prior to study entry without oral bridging of CAB+RPV until the next injection was received, this would be defined as a missed dose and is exclusionary. The last dose of oral CAB+RPV must have occurred more than 4 weeks prior to study entry, with an intervening injection of CARLA since that oral dose.

NOTE B: For individuals co-enrolling from a study through which they are receiving CARLA, sites must document the study number and the participant's identifier on that study.

* No documentation of HIV-1 plasma RNA of ≥200 copies/mL obtained within 90 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 is VQA certified.
* HIV-1 plasma RNA of \<200 copies/mL 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 is VQA certified.
* Agreement not to change ART regimen (CARLA) for the duration of the study including the frequency of CARLA administration from monthly to every 8 weeks.

Exclusion Criteria:

* 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).
* For Group B study candidates only, prior use of LA CAB or RPV.
* Acute or serious illness requiring systemic treatment and/or hospitalization within 14 days prior to study entry.
* Undiagnosed abnormal genital bleeding within 30 days prior to study entry.

Primary outcomes:
measure: ENG PK parameter Area under the concentration-time curve (AUC0-24weeks) based on ENG PK samples obtained from individual participants
timeFrame: PK samples at pre-insertion, and 1, 4, 12 and 24 weeks post implant insertion
Secondary outcomes:
measure: ENG PK parameter Area under the concentration-time curve (AUC0-12weeks) based on ENG PK samples obtained from individual participants
timeFrame: PK samples at pre-insertion, and 1, 4, and 12 weeks post implant insertion
measure: Probability of having ENG implant removed due to intolerance before 48 weeks
timeFrame: From insertion of implant to 48 weeks
measure: ENG PK parameter Area under the concentration-time curve (AUC0-48weeks) based on ENG PK samples obtained from individual participants
timeFrame: PK samples at pre-insertion, and 1, 4, 12, 24, 36 and 48 weeks post implant insertion
measure: ENG total concentration in serum
timeFrame: PK samples at pre-insertion, and 1, 4, 12, 24, 36 and 48 weeks post implant insertion
Other outcomes:
Locations:
Study officials:
affiliation: University of Colorado Hospital CRS
name: Adriana Weinberg, MD
role: STUDY_CHAIR
References: