Clinical trial NCT04689737: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV-infected Participants With ESRD Undergoing Routine Hemodialysis
Keywords: HIV
ESRD
Doravirine
Lead sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2020-12-30
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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).
Primary purpose: OTHER

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentatge of Doravirine Dialysis Extraction Ratio (ER)
timeFrame: At day 6
Secondary outcomes:
measure: Percentage of Participants Developing Related Adverse Events Grade 3-4 Related to Doravirine
timeFrame: Baseline to day 20
measure: Doravirine Concentration (mg/dl)
timeFrame: At day 6
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Germans Trias i Pujol Hospital
state: Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: Universitario Bellvitge Hospital
state: Barcelona
city: Barcelona
country: Spain
facility: Valle Hebron Hospital
Study officials:
References:
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.