Trial on Efficacy and Safety of Pritelivir Tablets for Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects

HSV Infection Clinical Trial

— PRIOH-1  

Official title:

A Randomized, Open Label, Multi-center, Comparative Trial, to Assess the Efficacy and Safety of Pritelivir for the Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects (PRIOH-1)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03073967
• Other study ID #: AIC316-03-II-01
• Status: Recruiting
• Phase: Phase 3
• Start date: May 8, 2017
• Est. completion date: April 2025

Study information

• Verified date: June 2024
• Source: AiCuris Anti-infective Cures AG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Randomized, open-label, multi-center, comparative trial to assess the efficacy and safety in immunocompromised subjects with acyclovir resistant or acyclovir susceptible mucocutaneous HSV infection, treated with pritelivir 100 mg once daily (following a loading dose of 400 mg as first dose to rapidly reach steady-state plasma concentration) or investigators choice, which can be either foscarnet 40 mg/kg every 8 hours or 60 mg/kg every 12 hours, or Cidofovir iv 5 mg/kg body weight given once weekly, or Cidofovir 1% or 3% topical applied 2 to 4 times daily, or Imiquimod 5% topical 3 times per week) (provided the drug is nationally approved).

Description:

The trial comprises 5 Parts, Part A, B, C, D, E and F. Part A and Part B (Phase 2) have been finalised. - Part A is a randomized, open-label, multi-center, comparative design to assess the efficacy and safety in subjects with ACV-resistant mucocutaneous HSV infection, treated with oral pritelivir or intravenous foscarnet. - Part B is an open-label, multi-center design to assess the efficacy and safety of pritelivir in subjects with ACV-resistant-mucocutaneous HSV and who either: 1. present with foscarnet-resistance/intolerance, or 2. developed foscarnet resistance/intolerance during treatment in Part A (no improvement after at least 5 days of foscarnet therapy or intolerance to foscarnet requiring cessation of foscarnet treatment). Parts C, D, E and F (Phase 3). - Part C is a randomized, open-label, multi-center, comparative design to assess the efficacy and safety of oral pritelivir in subjects with acyclovir resistent (ACV-R) mucocutaneous HSV episodes. Subjects with ACV-R mucocutaneous HSV infection will be randomized 1:1 to receive either oral pritelivir or Investigator's Choice. This trial part is designed to show superiority of pritelivir against Investigator's Choice in obtaining clinical cure, ie, number of subjects with all lesions healed within 28 days. - Part D is an open-label, multi-center design to assess the efficacy and safety of pritelivir in subjects with ACV-R mucocutaneous HSV episodes and who in addition either: 1. present with iv foscarnet resistance/intolerance already at Screening for inclusion, or 2. developed foscarnet resistance/intolerance during treatment in Part C (no improvement after at least 7 days of foscarnet treatment or intolerance to foscarnet requiring cessation of foscarnet treatment). Part D has been closed in June 2022. - Part E is an open-label, multi-center design to assess the safety and efficacy of pritelivir in subjects with acyclovir susceptible (ACV-S) mucocutaneous HSV episodes, (Part E is not being conducted in Germany). - Part F is an open-label, multi-center design to assess the efficacy and safety of pritelivir in subjects with ACV-R mucocutaneous HSV episodes and who in addition either: 1. present with iv foscarnet resistance/intolerance already at Screening for inclusion, or 2. developed foscarnet resistance/intolerance during treatment in Part C (no improvement after at least 7 days of foscarnet treatment or intolerance to foscarnet requiring cessation of foscarnet treatment). 3. cannot be enrolled into Part D anymore because enrollment into Part D has been completed. Dosing of trial medication: Pritelivir oral tablet as single daily doses of 100 mg (following a loading dose of 400 mg as first dose) Comparator per investigator's choice (provided the drug listed below is nationally approved): Foscarnet intermittent infusions of 40 mg/kg every 8 hours or 60 mg/kg every 12 hours (to be adjusted in case of renal impairment) for a minimum of 1 hour duration, or Cidofovir iv infusion of 5 mg/kg body weight given once weekly, or Cidofovir 1% or 3% topical treatment, applied 2 to 4 times daily, or Imiquimod 5% topical treatment, 3 times per week. Duration of treatment: Until all mucocutaneous HSV lesions are healed or up to 28 days, whichever is earlier. A prolongation up to a maximum of 42 days may be possible depending on the clinical progress.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 153
• Est. completion date: April 2025
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Part C inclusion criteria

1. Immunocompromised men and women of any ethnic group aged =16 years. In Canada, Germany, Belgium: Immunocompromised (due to conditions including but not limited to HIV infection, hematopoietic cell or solid organ transplantation, and chronic use of immunosuppressive treatment) men and women of any ethnic group aged >18 years.

2. ACV-R mucocutaneous HSV infection based on clinical failure or positive genotypic/phenotypic ACV resistance testing for current lesion. Clinical failure is defined as no improvement after oral or iv doses for at least 7 days at doses equivalent to or greater than the local agency approved high oral doses of acyclovir, valacyclovir or famciclovir.

3. Lesions accessible for visual inspection to allow assessment of lesion healing including visualization by endoscopy.

4. Willingness to use highly effective birth control.

5. Subject, and/or their legally authorized representative, (proxy consent is not permitted in Germany), must be willing and able to understand the Informed Consent Form.

6. Negative serum ß-HCG (beta-human chorionic gonadotropin) test for women of child-bearing potential at Screening and a negative urine pregnancy test at Day 1.

7. Written informed consent. For subjects, who are unable to provide informed consent for whatever reason, written consent must be obtained from the legal representative, (proxy consent is not permitted in Germany). Part D and F inclusion criteria All inclusion criteria as for Part C, except for inclusion criterion 2, which is replaced

by:

2. ACV-R and foscarnet-R mucocutaneous HSV infection based on clinical failure or positive genotypic/phenotypic resistance testing for current lesion or documented intolerance to iv foscarnet requiring cessation of foscarnet treatment or precluding foscarnet treatment. Subjects will be able to enter Part F only after closure of enrollment in Part D. Part E inclusion (Part E is not being conducted in Germany) All inclusion criteria as for Part C, except for inclusion criterion 2, which is replaced

by:

2. Recurrent mucocutaneous HSV infection considered ACV-S. Part C exclusion criteria

1. Known resistance/intolerance to pritelivir or any of the excipients.

2. Previous treatment in PRIOH-1.

3. Baseline safety laboratory abnormalities.

4. History or current evidence of gastrointestinal malabsorption which, in the opinion of the Investigator, may affect the extent of absorption of pritelivir.

5. Hemodialysis for any indication and ESRD (eGFR <15 mL/min; stage 5 CKD)

6. History or current evidence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other relevant diseases.

7. Abnormalities in hematological, clinical chemical or any other laboratory variables.

8. Not able to communicate meaningfully with the Investigator and site staff.

9. Any other condition which in the opinion of the Investigator would interfere with successful completion of this clinical trial.

10. Any other important local condition.

11. Pregnant and/or breastfeeding women.

12. Having received an investigational drug in an investigational drug trial unter certain conditions. Part D (complete) exclusion criteria

All exclusion criteria as for Part C, except criterion 12, which is replaced by:

13. Having received an investigational drug in an investigational trial within 7 half-lives after the last administration of this drug before initiating trial medication, except for subjects entering Part D, who have previously received foscarnet treatment in Part C of this trial. Participation in a clinical trial without receiving other investigational drugs (eg, follow-up phase of a trial, observational study) is permitted. Part E exclusion criteria (Part E is not being conducted in Germany)

All exclusion criteria in Part E are identical to those in Part C with the addition of:

13. Having used acyclovir, valacyclovir, or famciclovir within 3 days prior to starting pritelivir. Part F exclusion criteria All exclusion criteria for Part D plus 13. Part D open for enrollment

Related Conditions & MeSH terms

• Communicable Diseases
• Herpes Simplex
• HSV Infection
• Infections

Intervention

Drug:
• Pritelivir
100 mg oral tablets
• Investigator's choice
Foscarnet iv, 40 mg/kg BW tid or 60mg/kg bid or Cidofovir iv, 5 mg/kg BW given once weekly or Cidofovir 1% or 3%, topically applied 2 to 4 times daily or Imiquimod 5%, Solution for iv infusion or topical application

Locations

Country	Name	City	State
Argentina	Hospital Rawson	Córdoba
Argentina	Sanatorio Mayo Privado S.A.	Córdoba
Argentina	Instituto FIDES	La Plata
Australia	Melbourne Health - Royal Melbourne Hospital	Parkville
Australia	Westmead Hospital, Centre for Infectious Disease and Microbiology	Westmead
Belgium	Centre Hospitalier Universitaire Saint Pierre	Brussels
Belgium	AZ Delta	Roeselare
Canada	Alberta Health Services Cross Cancer Institute at the University of Alberta	Edmonton	Alberta
France	CHU Limoges - Centre national de reference des Herpes virus	Limoges
France	CHU de Nantes	Nantes
France	AP-HP Hopital Bichat - Claude Bernard	Paris
France	AP-HP Hopital Necker-Enfants Malades	Paris
France	Hôpital Saint Louis - AP-HP	Paris
Georgia	LLC Diakor	Tbilisi
Georgia	Multiprofile Clinic Consilium Medulla LTD	Tbilisi
Germany	Universitätsklinikum Köln	Köln
Greece	General Hospital of Athens - Laiko	Athens
Greece	Regional University General Hospital of Heraklion	Heraklion
Israel	Chaim Sheba Medical Center	Tel-Hashomer
Italy	Grande Ospedale Metropolitano "Bianchi Melacrino Morelli"	Calabria
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano	Milano
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Mexico	Unidad de Investigacion CIMA SC	Chihuahua
Mexico	Centro de Investigacion Clinica GRAMEL S.C.	Distrito Federal
Mexico	Instituto de Investigaciones Aplicadas a la Neurociencia A.C	Durango
Mexico	Centro de Investigacion Farmaceutica Especializado de Occidente S.C.	Guadalajara
Mexico	Arke SMO S.A. de C.V.	Veracruz
Switzerland	Hopitaux universitaires de Geneve	Genève
Switzerland	Universitaetsspital Zuerich	Zuerich
United Kingdom	Research Department of Haematology, UCL Cancer Institute	London
United Kingdom	Freeman Hospital	Newcastle Upon Tyne
United States	Emory Hospital Midtown Infectious Disease Clinic	Atlanta	Georgia
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	LSU Health Baton Rouge Pulmonary Clinic	Baton Rouge	Louisiana
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Department of Medicine J. H. Stroger Hospital of Cook County	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Midland Florida Clinical Research Center, LLC	DeLand	Florida
United States	City of Hope	Duarte	California
United States	Midway Immunology and Research Center (MIRC)	Fort Pierce	Florida
United States	University of Florida (UF) - Division of Infectious Disease	Gainesville	Florida
United States	MD Anderson Cancer Center	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Links Clinical Trials	Miami	Florida
United States	Rutgers Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Tulane University - School of Medicine	New Orleans	Louisiana
United States	David H. Koch Center at Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	University of California, Division of Infectious Diseases	Sacramento	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	University Arizona - Department of Medicine Arizona Health Sciences Center	Tucson	Arizona
United States	Atrium Health Wake Forest Baptist	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
AiCuris Anti-infective Cures AG	Medpace, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  France,  Georgia,  Germany,  Greece,  Israel,  Italy,  Mexico,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy measured by cure rate	Number of subjects cured (all lesions healed as assessed by the Investigator) during the treatment period of up to 28 days relative to the total number of subjects treated with trial medication in the respective treatment group.	Up to a maximum of 28 days
Secondary	Efficacy measured by cure rate	Number of subjects cured (all lesions healed as assessed by the Investigator) during the treatment period of up to 42 days relative to the total number of subjects treated with trial medication in the respective treatment group.	Up to a maximum of 42 days
Secondary	Efficacy measured by time to lesion healing	Time to lesion healing, defined as complete epithelization of the mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, as assessed by the Investigator.	Up to a maximum of 42 days
Secondary	Efficacy measured by recurrence rate	Recurrence rate at 2 months following PoTV assessed by telephone, defined as number of subjects with a recurrence as assessed by the Investigator following 2/3 months after PoTV relative to the total number of subjects assessed for recurrence at the respective telephone call per treatment.	At 2 months following post treatment visit, from randomization up to a maximum of 108 days
Secondary	Efficacy measured by recurrence rate	Recurrence rate at 3 months following PoTV assessed by telephone, defined as number of subjects with a recurrence as assessed by the Investigator following 2/3 months after PoTV relative to the total number of subjects assessed for recurrence at the respective telephone call per treatment.	At 3 months following post treatment visit, from randomization up to a maximum of 139 days
Secondary	Efficacy measured by pain rate	Number of days with pain at lesion site relative to the total number of days with analyzable pain data through daily subject self-reporting	Up to a maximum of 42 days
Secondary	Efficacy measured by time to pain cessation at site of lesion	Starting at first dose of trial medication until pain is no longer reported by the subject (date and time)	Up to a maximum of 42 days
Secondary	Efficacy measured by average pain score	Using a single-dimensional scale assessing pain intensity through daily subject self-reporting	Up to a maximum of 42 days
Secondary	Efficacy measured by clinical shedding rate	Number of HSV positive swabs per subject relative to the total number of swabs collected per subject from lesion swabs taken from HSV lesion(s)	From date of randomization until the date of first documented healing, assessed up to a maximum of 42 days
Secondary	Efficacy measured by time to cessation of shedding	Number of days until swabs taken are negative	Up to a maximum of 42 days
Secondary	Efficacy measured by mean log number of HSV DNA copies	Mean log number of HSV DNA copies on HSV DNA positive swabs from lesion(s) as detected by quantitative real-time PCR (polymerase chain reaction).	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Efficacy measured by resistance to trial medication	Resistance to trial medication for lesions not healed within the treatment period or newly appeared lesions under treatment before or at the PoTV.	From date of randomization until the date of post treatment visit, assessed up to a maximum of 73 days
Secondary	Safety measured by number of subjects developing chronic kidney disease	Chronic kidney disease	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by percentage of subjects developing chronic kidney disease	Chronic kidney disease	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by percentage of subjects developing acute Kidney Injury	Acute Kidney Injury (AKI) stage >1 of KDIGO (Kidney Disease: Improving Global Outcome) criteria (increase in serum creatinine by 2.0 to 2.9 times compared to baseline or urine output <0.5 mL/kg/h for >12 hours)	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by percentage of subjects developing renal impairment	Renal impairment	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by percentage of subjects developing electrolyte abnormality	All abnormal values	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by percentage of subjects developing seizures	All seizures	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by percentage of subjects developing anemia	Haemoglobin measurement	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by adverse events	Incidence of Adverse Events	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by haematology	Incidence of abnormal hematologic laboratory test results	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by lymphadenopathy	Incidence of lymphadenopathy measured by physical examination	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by CRP (C reactive protein )	Incidence of CRP increase	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by cutaneous adverse events	Incidence of cutaneous adverse events by physical examination	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by (a)PTT (partial thromboplastin time)	Incidence of (a)PTT increase	From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
Secondary	Safety measured by discontinuation rate	Number of subjects discontinuing pritelivir or 'Inverstigator's Choice' due to AE(s) or intolerance relative to the total number of subjects treated with pritelivir or foscarnet, respectively	Up to a maximum of 42 days