Darunavir and Rilpivirine Interactions With Levonorgestrel Implant (DRIVE-2)

A Pharmacokinetic Evaluation of Levonorgestrel Implant in HIV-Infected Women on Darunavir Versus Rilpivirine-based Antiretroviral Therapy

This study will evaluate the pharmacokinetic properties of Rilpivirine and Darunavir when used in combination with Levonorgestrel

Study Overview

• Status: Unknown
• Conditions: Contraception; HIV-1-infection
• Intervention / Treatment: Drug: Levonorgestrel two rod sub-dermal implant; Drug: Rilpivirine; Drug: Darunavir+Ritonavir

Detailed Description

Despite the benefits of hormonal contraceptives, significant drug-drug interactions (DDIs) with some antiretroviral therapies (ART) represent a barrier to effective family planning methods for HIV-infected women. It is therefore critical to generate data on the combined use of hormonal contraceptives and ART. This study is a prospective, non-randomized, open-label, parallel, two-group, sparse-sampling pharmacokinetic (PK) study to describe levonorgestrel (LNG) PK parameters in two treatment groups (rilpivirine or darunavir- based ART) in 60 HIV-1 infected women. The primary endpoint is the comparison of the mean LNG concentrations at month 6 between the rilpivirine or darunavir treatment groups versus historical controls. This study will provide information on effective ART options for HIV positive women who opt for the contraceptive implant as a family planning method of choice.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Senior Research Manager; Phone Number: 0704817590; Email: sokoboi@idi.co.ug

Study Locations

• Uganda
  • Kampala, Uganda, 256
    • Recruiting
    • Infectious Diseases Institue

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Women age 18 years to 45 years
4. Diagnosed with HIV infection
5. Medically eligible for the LNG subdermal implant as a contraceptive method based on the WHO Medical Eligibility Criteria for Contraceptive Use11
6. Receiving EFV- or LPV/r-based ART for a minimum of 1 year
7. If not abstinent, must agree to use an effective non-hormonal method of contraception for the duration of the study including male and female condoms or the copper-T intrauterine device.

8. Participants must have a negative urine pregnancy test at entry and report no unprotected sex since the last menstrual period or in the last two weeks.

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Exclusion Criteria:

1. HIV RNA greater than 50 copies/mL at the screening visit
2. CD4 count below 200 cells/mm3 at the screening visit
3. History of virologic failure on the current regimen (two consecutive viral load results equal to or greater than 400 copies/mL)
4. Serum hemoglobin less than 9.0 g/dl at screening
5. Elevations in serum levels of alanine transaminase (ALT) above 5 times the upper limit of normal
6. Elevations in serum creatinine above 2.5 times the upper limit of normal
7. Use of drugs known to be contraindicated with LNG, RPV (for women taking EFV-based ART), or DRV (for women taking LPV-based ART) within 30 days of study entry. Due to the dynamic nature of drug interactions related to antiretroviral therapy, the study team will review all concomitant medications at screening based on the US Department of Health and Human Services drug interaction table 14 and the University of Liverpool HIV drug interaction tables (www.hiv-druginteractions.org)
8. Currently pregnant or postpartum <30 days at study entry.
9. Breastfeeding women within 6 months of delivery.
10. Patients with a history of hypersensitivity to LNG implant, undiagnosed vaginal bleeding, diagnosed or suspected sex hormone dependent neoplasia, benign or malignant liver tumor, or thromboembolic disease.

11. Presence of any active clinically significant disease or life-threatening disease that, in the investigator's opinion, would compromise the subject's safety or outcome of the study.

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rilpivirine arm; All subjects will be administered oral rilpivirine 25mg once daily together with the rest of their oral antiretroviral combination plus a levonorgestrel two-rod subdermal implant (75mg/rod) through out the study period	Drug: Levonorgestrel two rod sub-dermal implant; Levonorgestrel (75 mg/rod), 2 rods (150 mg) inserted subdermally; Other Names: Jadelle; Levonorgestrel; Drug: Rilpivirine; Oral ripilvirine 25mg once daily; Other Names: Edurant
Experimental: Darunavir arm; All subjects will be administered oral darunavir/ritonavir 600/100mg twice daily together with the rest of their oral antiretroviral combination plus a levonorgestrel two-rod subdermal implant (75mg/rod) through out the study period	Drug: Levonorgestrel two rod sub-dermal implant; Levonorgestrel (75 mg/rod), 2 rods (150 mg) inserted subdermally; Other Names: Jadelle; Levonorgestrel; Drug: Darunavir+Ritonavir; Oral DRV/r 600/100mg twice daily; Other Names: DRV/r

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levonorgestrel concentrations: Change in mean levonorgestrel (LNG) concentrations	Comparison of the mean levonorgestrel (LNG) concentrations at month 6 between the rilpivirine (RPV) or darunavir (DRV) treatment groups versus historical controls	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean rilpivirine concentration	Rilpivirine mean concentration change prior to implant placement and then over the duration of the study time period.	12 months
Change in mean darunavir concentration	Darunavir mean concentration change prior to implant placement and then over the duration of the study time period.	12 months
Adverse events	Any signs and symptoms related to hormone exposure, including abnormal vaginal bleeding and local or systemic adverse events observed during the study period in both study groups.	12 months

Collaborators and Investigators

• Sponsor: Makerere University
• Collaborators: University of Pittsburgh; University of Nebraska; University of Liverpool

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2018
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: May 29, 2018
• First Submitted That Met QC Criteria: July 16, 2018
• First Posted (Actual): July 17, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2019
• Last Update Submitted That Met QC Criteria: March 26, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; HIV Protease Inhibitors; Viral Protease Inhibitors; Levonorgestrel; Ritonavir; Darunavir; Rilpivirine
• Other Study ID Numbers: PK22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No