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

NCT04689737 | Completed Phase 4 Results

• 1 other identifier: Dora-HD
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 3

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

Conditions

HIV-infected Participants With ESRD Undergoing Routine Hemodialysis

Keywords

HIV; ESRD; Doravirine

Outcome Measures

Primary Outcomes (1)

• Percentatge of Doravirine Dialysis Extraction Ratio (ER)

  The haemodialysis extraction ratio (ER) for doravirine was calculated as: ER(%) = ((Cin - Cout)/ Cin) × 100 where Cin is the pre-dialyser doravirine concentration (i.e. blood entering the dialyser) and Cout is the post-dialyser doravirine concentration (i.e. blood leaving the dialyser). Post-dialyser doravirine concentrations (Cout) were corrected for haemoconcentration by a factor F based on total protein (TP) concentration pre- and post-dialyser: F = TPin / TPout.

  At day 6

Secondary Outcomes (2)

• Percentage of Participants Developing Related Adverse Events Grade 3-4 Related to Doravirine

  Baseline to day 20

• Doravirine Concentration (mg/dl)

  At day 6

Study Arms (1)

Experimental group

EXPERIMENTAL

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

Drug: Doravirine

Interventions

Doravirine DRUG

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

Also known as: Pifeltro

Experimental group

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

Germans Trias i Pujol Hospital

Badalona, Barcelona, 08916, Spain

Location

Universitario Bellvitge Hospital

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Valle Hebron Hospital

Barcelona, 08035, Spain

Location

Related Publications (1)

• 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.

  PMID: 35425985 DERIVED

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

doravirine

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Jose Molto Marhuenda
• Organization: Fundació de Lluita contra la SIDA, les Malalties Infeccioses i la Promoció de la Salut i La Ciència

jmolto@lluita.org

+34 934657897

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: December 29, 2020
• First Posted: December 30, 2020
• Study Start: March 20, 2021
• Primary Completion: June 14, 2021
• Study Completion: June 14, 2021
• Last Updated: August 27, 2024
• Results First Posted: August 27, 2024

Record last verified: 2023-08

Locations

ES (3)