Clinical trial NCT03073967: Trial on Efficacy and Safety of Pritelivir Tablets for Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: HSV Infection
Lead sponsor: AiCuris Anti-infective Cures AG
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
First posted: 2017-03-08
Enrollment: 153
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility criteria: 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 β-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

Primary outcomes:
measure: Efficacy measured by cure rate
timeFrame: Up to a maximum of 28 days
Secondary outcomes:
measure: Efficacy measured by cure rate
timeFrame: Up to a maximum of 42 days
measure: Efficacy measured by time to lesion healing
timeFrame: Up to a maximum of 42 days
measure: Efficacy measured by recurrence rate
timeFrame: At 2 months following post treatment visit, from randomization up to a maximum of 108 days
measure: Efficacy measured by recurrence rate
timeFrame: At 3 months following post treatment visit, from randomization up to a maximum of 139 days
measure: Efficacy measured by pain rate
timeFrame: Up to a maximum of 42 days
measure: Efficacy measured by time to pain cessation at site of lesion
timeFrame: Up to a maximum of 42 days
measure: Efficacy measured by average pain score
timeFrame: Up to a maximum of 42 days
measure: Efficacy measured by clinical shedding rate
timeFrame: From date of randomization until the date of first documented healing, assessed up to a maximum of 42 days
measure: Efficacy measured by time to cessation of shedding
timeFrame: Up to a maximum of 42 days
measure: Efficacy measured by mean log number of HSV DNA copies
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Efficacy measured by resistance to trial medication
timeFrame: From date of randomization until the date of post treatment visit, assessed up to a maximum of 73 days
measure: Safety measured by number of subjects developing chronic kidney disease
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by percentage of subjects developing chronic kidney disease
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by percentage of subjects developing acute Kidney Injury
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by percentage of subjects developing renal impairment
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by percentage of subjects developing electrolyte abnormality
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by percentage of subjects developing seizures
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by percentage of subjects developing anemia
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by adverse events
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by haematology
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by lymphadenopathy
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by CRP (C reactive protein )
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by cutaneous adverse events
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by (a)PTT (partial thromboplastin time)
timeFrame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days
measure: Safety measured by discontinuation rate
timeFrame: Up to a maximum of 42 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Tucson
country: United States
facility: University Arizona - Department of Medicine Arizona Health Sciences Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Division of Infectious Diseases
state: California
city: DeLand
country: United States
facility: Midland Florida Clinical Research Center, LLC
state: Florida
city: Fort Pierce
country: United States
facility: Midway Immunology and Research Center (MIRC)
state: Florida
city: Gainesville
country: United States
facility: University of Florida (UF) - Division of Infectious Disease
state: Florida
city: Miami
country: United States
facility: Links Clinical Trials
state: Florida
city: Atlanta
country: United States
facility: Emory Hospital Midtown Infectious Disease Clinic
state: Georgia
city: Chicago
country: United States
facility: Department of Medicine J. H. Stroger Hospital of Cook County
state: Illinois
city: Baton Rouge
country: United States
facility: LSU Health Baton Rouge Pulmonary Clinic
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University - School of Medicine
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New Brunswick
country: United States
facility: Rutgers Robert Wood Johnson Medical School
state: New Jersey
city: Brooklyn
country: United States
facility: Kings Country Hospital Center
state: New York
city: New York
country: United States
facility: David H. Koch Center at Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center - Division of Infectious Diseases
state: North Carolina
city: Winston-Salem
country: United States
facility: Atrium Health Wake Forest Baptist
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Córdoba
country: Argentina
facility: Hospital Rawson
city: Córdoba
country: Argentina
facility: Sanatorio Mayo Privado S.A.
city: La Plata
country: Argentina
facility: Instituto FIDES
city: Parkville
country: Australia
facility: Melbourne Health - Royal Melbourne Hospital
city: Westmead
country: Australia
facility: Westmead Hospital, Centre for Infectious Disease and Microbiology
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge
city: Brussels
country: Belgium
facility: Centre Hospitalier Universitaire Saint Pierre
city: Roeselare
country: Belgium
facility: AZ Delta
city: Edmonton
country: Canada
facility: Alberta Health Services Cross Cancer Institute at the University of Alberta
state: Alberta
city: Limoges
country: France
facility: CHU Limoges - Centre national de reference des Herpes virus
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital Saint Louis - AP-HP
city: Paris
country: France
facility: AP-HP Hopital Necker-Enfants Malades
city: Paris
country: France
facility: AP-HP Hopital Bichat - Claude Bernard
city: Tbilisi
country: Georgia
facility: LLC Diakor
city: Tbilisi
country: Georgia
facility: Multiprofile Clinic Consilium Medulla LTD
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Athens
country: Greece
facility: General Hospital of Athens - Laiko
city: Heraklion
country: Greece
facility: Regional University General Hospital of Heraklion
city: Tel-Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Calabria
country: Italy
facility: Grande Ospedale Metropolitano "Bianchi Melacrino Morelli"
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Chihuahua
country: Mexico
facility: Unidad de Investigacion CIMA SC
city: Distrito Federal
country: Mexico
facility: Centro de Investigacion Clinica GRAMEL S.C.
city: Durango
country: Mexico
facility: Instituto de Investigaciones Aplicadas a la Neurociencia A.C
city: Guadalajara
country: Mexico
facility: Centro de Investigacion Farmaceutica Especializado de Occidente S.C.
city: Veracruz
country: Mexico
facility: Arke SMO S.A. de C.V.
city: Basel
country: Switzerland
facility: Universitaetsspital Basel
city: Genève
country: Switzerland
facility: Hopitaux universitaires de Geneve
city: Zuerich
country: Switzerland
facility: Universitaetsspital Zuerich
city: Edinburgh
country: United Kingdom
facility: Nhs Lothian
city: London
country: United Kingdom
facility: Research Department of Haematology, UCL Cancer Institute
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
Study officials:
References: