Trial on Efficacy and Safety of Pritelivir Tablets for Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects (PRIOH-1)

• ClinicalTrials.gov Identifier: NCT03073967
• Recruitment Status: Recruiting
• First Posted: March 8, 2017
• Last Update Posted: March 24, 2023
• Sponsor: AiCuris Anti-infective Cures AG
• Collaborator: Medpace, Inc.
• Information provided by (Responsible Party): AiCuris Anti-infective Cures AG

Tracking Information

• First Submitted Date: March 3, 2017
• First Posted Date: March 8, 2017
• Last Update Posted Date: March 24, 2023
• Actual Study Start Date: May 8, 2017
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 23, 2021)

Efficacy measured by cure rate [ Time Frame: Up to a maximum of 28 days ]

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.

Original Primary Outcome Measures (submitted: March 3, 2017)

Efficacy measured by time to lesion healing [ Time Frame: Up to a maximum of 28 days ]

Complete epithelization of the mucocutaneous HSV lesion(s) assessed by lesion photography and no appearance of new lesions

Current Secondary Outcome Measures (submitted: February 23, 2021)

• Efficacy measured by cure rate [ Time Frame: Up to a maximum of 42 days ]
  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.
• Efficacy measured by time to lesion healing [ Time Frame: Up to a maximum of 42 days ]
  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.
• Efficacy measured by recurrence rate [ Time Frame: At 2 months following post treatment visit, from randomization up to a maximum of 108 days ]
  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.
• Efficacy measured by recurrence rate [ Time Frame: At 3 months following post treatment visit, from randomization up to a maximum of 139 days ]
  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.
• Efficacy measured by pain rate [ Time Frame: Up to a maximum of 42 days ]
  Number of days with pain at lesion site relative to the total number of days with analyzable pain data through daily subject self-reporting
• Efficacy measured by time to pain cessation at site of lesion [ Time Frame: Up to a maximum of 42 days ]
  Starting at first dose of trial medication until pain is no longer reported by the subject (date and time)
• Efficacy measured by average pain score [ Time Frame: Up to a maximum of 42 days ]
  Using a single-dimensional scale assessing pain intensity through daily subject self-reporting
• Efficacy measured by clinical shedding rate [ Time Frame: From date of randomization until the date of first documented healing, assessed up to a maximum of 42 days ]
  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)
• Efficacy measured by time to cessation of shedding [ Time Frame: Up to a maximum of 42 days ]
  Number of days until swabs taken are negative
• Efficacy measured by mean log number of HSV DNA copies [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  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).
• Efficacy measured by resistance to trial medication [ Time Frame: From date of randomization until the date of post treatment visit, assessed up to a maximum of 73 days ]
  Resistance to trial medication for lesions not healed within the treatment period or newly appeared lesions under treatment before or at the PoTV.
• Safety measured by number of subjects developing chronic kidney disease [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Chronic kidney disease
• Safety measured by percentage of subjects developing chronic kidney disease [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Chronic kidney disease
• Safety measured by number of subjects developing acute Kidney Injury [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  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)
• Safety measured by number of subjects developing renal impairment [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Renal impairment
• Safety measured by percentage of subjects developing renal impairment [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Renal impairment
• Safety measured by number of subjects developing electrolyte abnormality [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  All abnormal values
• Safety measured by number of subjects developing seizures [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  All seizures
• Safety measured by number of subjects developing anemia [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Haemoglobin measurement
• Safety measured by adverse events [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Incidence of Adverse Events
• Safety measured by haematology [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Incidence of abnormal hematologic laboratory test results
• Safety measured by lymphadenopathy [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Incidence of lymphadenopathy measured by physical examination
• Safety measured by CRP (C reactive protein ) [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Incidence of CRP increase
• Safety measured by cutaneous adverse events [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Incidence of cutaneous adverse events by physical examination
• Safety measured by (a)PTT (partial thromboplastin time) [ Time Frame: From date of randomization until the date of safety follow-up visit, assessed up to a maximum of 73 days ]
  Incidence of (a)PTT increase
• Safety measured by discontinuation rate [ Time Frame: Up to a maximum of 42 days ]
  Number of subjects discontinuing pritelivir or foscarnet due to AE(s) or intolerance relative to the total number of subjects treated with pritelivir or foscarnet, respectively

Original Secondary Outcome Measures (submitted: March 3, 2017)

• Efficacy measured by pain rate [ Time Frame: Up to a maximum of 28 days ]
  Number of days with pain at lesion site relative to the total number of days with analyzable pain data through daily subject self-reporting
• Efficacy measured by time to pain cessation at site of lesion [ Time Frame: Up to a maximum of 28 days ]
  Starting at first dose of trial medication until pain is no longer reported by the subject (date and time)
• Efficacy measured by average pain score [ Time Frame: Over 28 days ]
  Using a single-dimensional scale assessing pain intensity (NUMERIC RATING SCALE (NRS), 11 intensities: no pain to worst pain imaginable) through daily subject self-reporting
• Efficacy measured by clinical shedding rate [ Time Frame: Until healing or up to a maximum of 28 days, whichever occurs first ]
  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)
• Efficacy measured by time to cessation of shedding [ Time Frame: Up to a maximum of 28 days ]
  Number of days until swaps taken are negative
• Efficacy measured by mean log number of HSV DNA copies [ Time Frame: 28 days ]
  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).
• Efficacy measured by cure rate [ Time Frame: 28 days ]
  Number of subjects cured (lesion healed) at Day28 relative to the total number of subjects treated with pritelivir or foscarnet
• Efficacy measured by therapeutic failure rate [ Time Frame: 28 days ]
  Number of subjects with therapeutic failure under pritelivir or foscarnet treatment relative to the total number of subjects treated with pritelivir or foscarnet, respectively. Therapeutic failure is defined as: a) discontinuation and or replacement of trial medication due to failure of lesion healing and/or appearance of new lesion(s) post-healing within 28 days from the start of treatment or b) discontinuation of trial medication due to adverse event or intolerance to Trial medication before lesion healing or c) no lesion healing at 28 days from the start of treatment
• Efficacy measured by resistance to trial medication [ Time Frame: 28 days ]
  Genotypic and phenotypic resistance testing if lesion has not healed by Day 28, an additional swab will be taken.
• Efficacy measured by time to next recurrence [ Time Frame: Within 28 days after stop of trial medication ]
  In subjects with healed lesion(s).
• Safety measured by number of subjects developing acute Kidney Injury [ Time Frame: 28 days ]
  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)
• Safety measured by number of subjects developing electrolyte abnormality [ Time Frame: 28 days ]
  All abnormal values
• Safety measured by number of subjects developing seizures [ Time Frame: 28 days ]
  All seizures
• Safety measured by number of subjects developing anemia [ Time Frame: 28 days ]
  Haemoglobin measurement
• Safety measured by adverse events [ Time Frame: 28 days ]
  Nature, frequency, duration, severity of and discontinuation due to adverse Events (AEs), seriousness, causality and outcome
• Safety measured by haematology [ Time Frame: 28 days ]
  Changes in all hematologic parameters
• Safety measured by lymphadenopathy [ Time Frame: 28 days ]
  Physical examination
• Safety measured by CRP (C reactive protein ) [ Time Frame: 28 days ]
  Increase
• Safety measured by cutaneous adverse events [ Time Frame: 28 days ]
  Physical examination
• Safety measured by (a)PTT (partial thromboplastin time) [ Time Frame: 28 days ]
  Increase
• Safety measured by discontinuation rate [ Time Frame: 28 days ]
  Number of subjects discontinuing pritelivir or foscarnet due to AE(s) or intolerance relative to the total number of subjects treated with pritelivir or foscarnet, respectively

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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 Versus Foscarnet for the Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects (PRIOH-1)
• 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 foscarnet 40 mg/kg every 8 hours or 60 mg/kg every 12 hours.

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 iv foscarnet. The trial is designed to show superiority of pritelivir against foscarnet in obtaining clinical cure, ie, number of subjects with all lesions healed within 28 days.

• Part D is an open-label, multi-center (performed in the same trial sites as Part C) 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 (performed in the same trial sites as Part C) design to assess the safety and efficacy of pritelivir in subjects with acyclovir susceptible (ACV-S) mucocutaneous HSV episodes, (Part E is not beeing conducted in Germany).

• Part F is an open-label, multi-center (performed in the same trial sites as Part C) 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.

Pritelivir trial medication will be given orally as single daily doses of 100 mg (following a loading dose of 400 mg as first dose) 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.

Foscarnet will be given as intermittent infusions at a dose 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 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HSV Infection

Intervention

• Drug: Pritelivir
  100 mg tablets
• Drug: Foscarnet
  Solution for iv infusion

Study Arms

• Experimental: Part C, Pritelivir
  Oral tablets, 100mg/day (400mg loading dose on day 1) for up to 28 days and potential prolongation for up to additional 14 days
  Intervention: Drug: Pritelivir
• Active Comparator: Part C, Foscarnet
  iv solution, 40 mg/kg tid or 60mg/kg bid for up to 28 days and potential prolongation for up to additional 14 days.
  Intervention: Drug: Foscarnet
• Experimental: Part D, Pritelivir
  Oral tablets, 100mg/day (400mg loading dose on day 1) for up to 28 days and potential prolongation for up to additional 14 days
  Intervention: Drug: Pritelivir
• Experimental: Part E, Pritelivir
  Oral tablets, 100mg/day (400mg loading dose on day 1) for up to 28 days and potential prolongation for up to additional 14 days
  Intervention: Drug: Pritelivir
• Experimental: Part F, Pritelivir
  Oral tablets, 100mg/day (400mg loading dose on day 1) for up to 28 days and potential prolongation for up to additional 14 days
  Intervention: Drug: Pritelivir

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 27, 2022): 153
• Original Estimated Enrollment (submitted: March 3, 2017): 30
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

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 HIV infection, hematopoietic cell or solid organ transplantation, and chronic glucocorticoid use) men and women of any ethnic group aged >18 years.

2. ACV-R mucocutaneous HSV infection based on clinical failure, requiring switch to foscarnet treatment 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 withat doses equivalent to or greater than the local agency approved high oral doses withof acyclovir, (800 mg TID) or valacyclovir or famciclovir.(1 g TID).
3. Lesions accessible for visual inspection to allow assessment of lesion healing including visualization by endoscopy or pharyngoscopy.
4. Willingness to abstain from the application of lotions and/or creams to the area with HSV lesions. Wet/dry saline dressings or bandages at lesion site are allowed.
5. Willingness to use highly effective birth control.
6. 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.
7. 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.
8. 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 and/or foscarnet or any of the excipients.
2. Previous treatment in PRIOH-1.
3. Need to use paclitaxel.
4. Baseline safety laboratory abnormalities.
5. History or current evidence of gastrointestinal malabsorption which, in the opinion of the Investigator, may affect the extent of absorption of pritelivir.
6. Severe renal insufficiency (eGFR ≤29 mL/min/1.73 m2).
7. History or current evidence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other relevant diseases.
8. Abnormalities in hematological, clinical chemical or any other laboratory variables.
9. Not able to communicate meaningfully with the Investigator and site staff.
10. Any other condition which in the opinion of the Investigator would interfere with successful completion of this clinical trial.
11. Any other important local condition.
12. Pregnant and/or breastfeeding women.
13. Having received an investigational drug in an investigational drug trial unter certain conditions.

Part D exclusion criteria

All exclusion criteria as for Part C, except for exclusion criterion 1, which is replaced by: 1. Known intolerance to pritelivir or any of the excipients and except criterion 13, which is replaced by: 13. Having received an investigational drug in an investigational drug 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 as for Part C, except for exclusion criteria 1, which is replaced by

1. known intolerance to pritelivir or any of the excipients and addition of 14. Having used (val)acyclovir within 3 days prior to starting pritelivir.

Part F exclusion criteria All exclusion criteria for Part D plus 14. Part D open for enrollment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Argentina, Australia, Belgium, China, France, Georgia, Germany, Greece, Italy, Mexico, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03073967
• Other Study ID Numbers: AIC316-03-II-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AiCuris Anti-infective Cures AG
• Original Responsible Party: Same as current
• Current Study Sponsor: AiCuris Anti-infective Cures AG
• Original Study Sponsor: Same as current
• Collaborators: Medpace, Inc.
• Investigators: Not Provided
• PRS Account: AiCuris Anti-infective Cures AG
• Verification Date: March 2023