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

• ClinicalTrials.gov Identifier: NCT03073967
• Recruitment Status: Active, not recruiting
• First Posted: March 8, 2017
• Last Update Posted: December 14, 2020
• Sponsor: AiCuris Anti-infective Cures GmbH
• Collaborator: Medpace, Inc.
• Information provided by (Responsible Party): AiCuris Anti-infective Cures GmbH

Tracking Information

• First Submitted Date: March 3, 2017
• First Posted Date: March 8, 2017
• Last Update Posted Date: December 14, 2020
• Actual Study Start Date: May 8, 2017
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Current 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 4, 2018)

• Efficacy measured by time to lesion healing [ Time Frame: up to the last visit ]
  Time to lesion healing defined as complete epithelization of the mucocutaneous HSV lesion(s) up to the last visit, as assessed by lesion photography and no appearance of new lesions.
• 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 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 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 swabs 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

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 Adults
• 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 Adults (PRIOH-1)
• Brief Summary: Randomized, open-label, multi-center, comparative trial to assess the efficacy and safety in immunocompromised subjects with acyclovir resistant mucocutaneous HSV infection, treated with pritelivir 100 mg qd (following a loading dose of 400 mg as first dose to rapidly reach steady-state plasma concentration) or foscarnet 40 mg/kg iv tid/60mg/kg iv bid.

Detailed Description

The Trial comprises 2 Parts, Part A and Part B.

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).

Pritelivir trial medication, in both Part A and Part B, will be given orally as single daily doses of 100 mg (following a loading dose of 400 mg as first dose) until 7 days after the mucocutaneous HSV lesions are healed or up to a maximum of 28 days, whichever is earlier.

Foscarnet, in Part A, 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 7 days after the mucocutaneous HSV lesions are healed or up to a maximum of 28 days, whichever is earlier.

• Study Type: Interventional
• Study Phase: Phase 2
• 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 A, Pritelivir
  Oral tablets, 100mg/day (400mg loading dose on day 1) over 4 weeks
  Intervention: Drug: Pritelivir
• Active Comparator: Part A, Foscarnet
  iv solution, 40 mg/kg tid or 60mg/kg bid.
  Intervention: Drug: Foscarnet
• Experimental: Part B, Pritelivir
  Oral tablets, 100mg/day (400mg loading dose on day 1) over 4 weeks
  Intervention: Drug: Pritelivir

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 3, 2017): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2021
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Part A, Inclusion Criteria:

1. 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. Acyclovir resistant mucocutaneous HSV infection based on clinical failure (no improvement after at least 5 days with FDA approved high doses with acyclovir, valacyclovir or famciclovir) requiring switch to foscarnet Treatment or positive genotypic/phenotypic resistance testing for current lesion.
3. Lesion accessible for size measurement and photography.
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. Willing to use non-hormonal birth control: Male subjects who are surgically sterile (eg, after vasectomy) or who must agree to use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final dose of trial medication. Female subjects who are surgically sterile (eg, 2-sided tubal ligation, resection or ovariectomy, hysterectomy) or post-menopausal (defined as at least 50 years of age and who have a history of no menses for at least 24 months) or female subjects of childbearing potential with no male partner, or use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final dose of trial medication. An adequate method of contraception is defined as one of the following acceptable birth control methods:

   • the use of the copper-releasing intrauterine device (to have been in place for at least 2 months prior to screening)
   • the use of one of the following: diaphragm, Lea's shield, FemCap, sponge, and
   • monogamous relationship with vasectomized partner
   • the use of a male condom during each act of sexual intercourse.
6. Subject must be willing and able (in the opinion of the investigator) to understand the informed consent form
7. Negative serum β -HCG (beta human chorionic gonadotropin) test for female of child bearing potential at screening and a negative urine pregnancy test at Day 1.
8. Subject must give written informed consent.

Part B, Inclusion criteria

All inclusion criteria as for Part A, except for inclusion criterion 2 which is replaced by:

2. ACV-resistant and foscarnet-resistant/intolerant mucocutaneous HSV infection based on clinical failure (no improvement after at least 5 days of foscarnet therapy or intolerance to foscarnet requiring cessation of foscarnet treatment) or result from genotypic/phenotypic testing.

Manifestations of foscarnet intolerance may include, renal function impairment, seizures, genital irritation and/or ulcerations, extremity paraesthesia, nausea, granulocytopenia, anemia, leukopenia, thrombopenia, hypokalemia, hypocalcemia, hypomagnesemia, diabetes insipidus, injection site reactions, psychotic disorders, including but not limited to anxiety and aggression.

Subjects entering Part B after cessation of foscarnet treatment in Part A will require a washout period of at least 3 days prior to starting pritelivir.

Part A, Exclusion criteria:

1. Known intolerance to pritelivir and/or foscarnet or any of the excipients.
2. Need to use drugs that have a narrow therapeutic index and are substrates for CYP2B6, CYP2C8, CYP2C9, CYP2C19, OATP1B1, OATP1B3, and OCT1 (organic cation transporter 1), ie warfarin, digoxin, phenytoin, paclitaxel, S-mephenytoin
3. Baseline safety laboratory abnormalities: ANC (absolute neutrophil Count) < 1000 cells/mm3, platelet count < 25,000 cells/mm3, hemoglobin < 8.0 g/dL, AST (aspartate transaminase) or ALT (alanine transaminase) > 5 x ULN (upper Limit of normal), bilirubin > 2.5 x ULN
4. History or current evidence of gastrointestinal malabsorption which, in the opinion of the investigator, may affect the extent of absorption of pritelivir.
5. Severe renal insufficiency (GFR ≤ 29).
6. History or current evidence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other diseases, which, in the opinion of the investigator, may affect the subject's safety or interfere with the trial.
7. Abnormalities in hematological, clinical chemical or any other laboratory variables at Screening measured by the central or local laboratory regarded as clinically relevant by the investigator unless they are due to underlying disease or condition.
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 local condition including bacterial superinfection which in the opinion of the investigator would interfere with the efficacy evaluation.
11. Pregnant and/or breastfeeding women.
12. Having received an investigational drug in an investigational drug trial within the last 30 days before randomization for this clinical trial. Participation in a clinical trial without receiving other investigational drugs (e.g. follow-up phase of a trial, observational study) is permitted.

Part B, Exclusion criteria:

All exclusion criteria as for Part A, except for inclusion criteria 1 and 12 which are replaced by:

1. Known intolerance to pritelivir or any of the excipients and 12. Having received an investigational drug in an investigational drug trial within the last 30 days before Day 1 for this clinical trial (except for subjects entering Part B who have previously received foscarnet treatment in Part A of this trial). Participation in a clinical trial without receiving other investigational drugs (e.g. follow-up phase of a trial, observational study) is permitted.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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

• Responsible Party: AiCuris Anti-infective Cures GmbH
• Study Sponsor: AiCuris Anti-infective Cures GmbH
• Collaborators: Medpace, Inc.
• Investigators: Not Provided
• PRS Account: AiCuris Anti-infective Cures GmbH
• Verification Date: August 2020