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Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-stage Renal Disease (ESRD)

Primary Purpose

HIV-infected Participants With ESRD Undergoing Routine Hemodialysis

Status
Completed
Phase
Phase 4
Locations
Spain
Study Type
Interventional
Intervention
Doravirine
Sponsored by
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for HIV-infected Participants With ESRD Undergoing Routine Hemodialysis focused on measuring HIV, ESRD, Doravirine

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Males and females* aging ≥ 18 years.
  2. Documented HIV infection).
  3. Stable antiretroviral treatment for at least 2 weeks prior to enrolment.
  4. Optimal adherence to antiretroviral treatment, defined as less than 2 missed doses within the previousweek.
  5. End-stage renal disease in renal replacement therapy with periodic hemodialysis.
  6. Agree with the study procedures and signature of the informed consent. *Women of childbearing potential must have a negative pregnancy test prior to randomization into the study and commitment to useat least one of these birth control methods: male or female condom with or without spermicide, cap, diaphragm or sponge with orwithout spermicide, intrauterine device, bilateral tubal occlusion, vasectomized partner, sexual abstinence during the study. Condomuse is considered as an additional method of contraception only and cannot be the only method of contraception used as not beenconsidered an effective method by the Clinical Trial Facilitation Group (CTFG) guidelines.

Based on ICH, M3 (R2) 2009 a woman is considered of childbearing potential: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include tubal ligation, hysterectomy, bilateral oophorectomy.

Exclusion Criteria:

  1. Evidence or clinical suspicion that the patient will not be able to comply with the study protocol.
  2. Hypersensitivity to doravirine

  3. Concomitant therapy within the previous 4 weeks with any of the following drugs:

    • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
    • Androgen receptor inhibitor: enzalutamide
    • Antimycobacterials: rifampin, rifapentine
    • Cytotoxic agent: mitotane
    • St. John's wort (Hypericum perforatum)
  4. Females who are pregnant or breastfeeding.
  5. ALT and/ or AST ≥ 4 times the upper limit of normal (ULN) at screening.
  6. Hemoglobin < 7,5 g/dL at screening.

Sites / Locations

  • Germans Trias i Pujol Hospital
  • Universitario Bellvitge Hospital
  • Valle Hebron Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental group

Arm Description

Doravirine (Pifeltro, MSD) will be added to participant's cART (100 mg once daily) for 5 days

Outcomes

Primary Outcome Measures

Doravirine hemodialysis extraction ratio
% doravirina in blood samples entering ('Cin') and leaving ('Cout') the dialyzer collected during the dialysis session
Doravirine Concentration in plasma at the beginning of dialysis session
mg/dl
Percentage of participants developing related adverse events grade 3-4 related to doravirine

Secondary Outcome Measures

Full Information

First Posted
December 29, 2020
Last Updated
July 6, 2021
Sponsor
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04689737
Brief Title
Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-stage Renal Disease (ESRD)
Official Title
Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-Stage Renal Disease (ESRD)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
March 20, 2021 (Actual)
Primary Completion Date
June 14, 2021 (Actual)
Study Completion Date
June 14, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with HIV infection in phase III clinical trials. Doravirine achieved non- inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Doravirine is mainly metabolized and eliminated by the liver, with only 6% of the drug being excreted unchanged through the urine.In a study comparing 8 subjects with severe renal disease to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal function impairment.However, according to prescribing information, no dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. On the other hand, data on doravirine pharmacokinetics in patients with ESRD on dialysis are lacking. This may be of special interest because doravirine has a relatively low molecular weight and it is only 76% bound to proteins in plasma. These characteristics could make possible for hemodialysis to remove doravirine from plasma, potentially leading to subtherapeutic concentrations of doravirine after the dialysis sessions. On the contrary, doravirine volume of distribution is about 60 liters,15 what could limit extraction of doravirine by hemodialysis. Since data on doravirine pharmacokinetics in PLWH with ESRD on dialysis are lacking, our aim is to evaluate the effect of intermittent hemodialysis on doravirine concentrations in HIV-infected patients with ESRD
Detailed Description
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with HIV infection in phase III clinical trials. Doravirine achieved non- inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Doravirine is mainly metabolized and eliminated by the liver, with only 6% of the drug being excreted unchanged through the urine.In a study comparing 8 subjects with severe renal disease to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal function impairment.However, according to prescribing information, no dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. On the other hand, data on doravirine pharmacokinetics in patients with ESRD on dialysis are lacking. This may be of special interest because doravirine has a relatively low molecular weight and it is only 76% bound to proteins in plasma. These characteristics could make possible for hemodialysis to remove doravirine from plasma, potentially leading to subtherapeutic concentrations of doravirine after the dialysis sessions. On the contrary, doravirine volume of distribution is about 60 liters,15 what could limit extraction of doravirine by hemodialysis. Since data on doravirine pharmacokinetics in PLWH with ESRD on dialysis are lacking, our aim is to evaluate the effect of intermittent hemodialysis on doravirine concentrations in HIV-infected patients with ESRD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV-infected Participants With ESRD Undergoing Routine Hemodialysis
Keywords
HIV, ESRD, Doravirine

7. Study Design

Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Model Description
This is a multi-centre, single-arm, open-label, pilot study in HIV-infected participants with ESRD undergoing routine hemodialysis. All participants will receive doravirine 100 mg once daily during the study (5 days).
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Experimental group
Arm Type
Experimental
Arm Description
Doravirine (Pifeltro, MSD) will be added to participant's cART (100 mg once daily) for 5 days
Intervention Type
Drug
Intervention Name(s)
Doravirine
Other Intervention Name(s)
Pifeltro
Intervention Description
Participants will be told to take one tablet of doravirine (Pifeltro, MDS) once daily, with or without food, approximately at the day time that they usually finish the hemodialysis sessions. The rest of their antiretroviral regimen and concomitant medications will remain unchanged
Primary Outcome Measure Information:
Title
Doravirine hemodialysis extraction ratio
Description
% doravirina in blood samples entering ('Cin') and leaving ('Cout') the dialyzer collected during the dialysis session
Time Frame
At day 6
Title
Doravirine Concentration in plasma at the beginning of dialysis session
Description
mg/dl
Time Frame
At day 6
Title
Percentage of participants developing related adverse events grade 3-4 related to doravirine
Time Frame
Baseline to day 20

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females* aging ≥ 18 years. Documented HIV infection). Stable antiretroviral treatment for at least 2 weeks prior to enrolment. Optimal adherence to antiretroviral treatment, defined as less than 2 missed doses within the previousweek. End-stage renal disease in renal replacement therapy with periodic hemodialysis. Agree with the study procedures and signature of the informed consent. *Women of childbearing potential must have a negative pregnancy test prior to randomization into the study and commitment to useat least one of these birth control methods: male or female condom with or without spermicide, cap, diaphragm or sponge with orwithout spermicide, intrauterine device, bilateral tubal occlusion, vasectomized partner, sexual abstinence during the study. Condomuse is considered as an additional method of contraception only and cannot be the only method of contraception used as not beenconsidered an effective method by the Clinical Trial Facilitation Group (CTFG) guidelines. Based on ICH, M3 (R2) 2009 a woman is considered of childbearing potential: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include tubal ligation, hysterectomy, bilateral oophorectomy. Exclusion Criteria: Evidence or clinical suspicion that the patient will not be able to comply with the study protocol. Hypersensitivity to doravirine Concomitant therapy within the previous 4 weeks with any of the following drugs: Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin Androgen receptor inhibitor: enzalutamide Antimycobacterials: rifampin, rifapentine Cytotoxic agent: mitotane St. John's wort (Hypericum perforatum) Females who are pregnant or breastfeeding. ALT and/ or AST ≥ 4 times the upper limit of normal (ULN) at screening. Hemoglobin < 7,5 g/dL at screening.
Facility Information:
Facility Name
Germans Trias i Pujol Hospital
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Universitario Bellvitge Hospital
City
Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08907
Country
Spain
Facility Name
Valle Hebron Hospital
City
Barcelona
ZIP/Postal Code
08035
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
35425985
Citation
Molto J, Graterol F, Curran A, Ramos N, Imaz A, Sandoval D, Perez F, Bailon L, Khoo S, Else L, Paredes R. Removal of doravirine by haemodialysis in people living with HIV with end-stage renal disease. J Antimicrob Chemother. 2022 Jun 29;77(7):1989-1991. doi: 10.1093/jac/dkac126.
Results Reference
derived

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Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-stage Renal Disease (ESRD)

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