Efficacy and Safety Evaluation of Pritelivir in Immunocompromised Patients with Acyclovir-Resistant Mucocutaneous Herpes Simplex Virus Infections
- Trial ID
- 2023-510088-37-00
- Protocol
- AIC316-03-II-01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of oral pritelivir 100 mg administered once daily in **immunocompromised** subjects with **acyclovir-resistant** (ACV-R) mucocutaneous **herpes simplex virus** (HSV) infections. This evaluation is conducted over a maximum treatment period of 28 days, compared to the "Investigator's Choice" treatment, which is clinically relevant as it addresses the challenge of managing HSV infections resistant to standard antiviral therapies in a vulnerable patient population.
Secondary objectives include:
- Part C: Investigating the efficacy of pritelivir in immunocompromised subjects with ACV-R mucocutaneous HSV infections for up to 42 days, compared to "Investigator's Choice" treatment.
- Part D: Assessing the efficacy of pritelivir in subjects with ACV-R and foscarnet-resistant/intolerant mucocutaneous HSV infections for a maximum of 42 days.
- Part E: Evaluating the efficacy of pritelivir in subjects with acyclovir-sensitive (ACV-S) mucocutaneous HSV infections for treatment periods of 28 and 42 days.
- Part F: Investigating the efficacy of pritelivir in subjects with ACV-R and foscarnet-resistant/intolerant mucocutaneous HSV infections for treatment periods of 28 and 42 days.
Participants
The clinical trial involves a total of **98 participants** who are immunocompromised individuals suffering from **acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections**. The study population includes both male and female subjects, with an age range starting from 16 years and above, depending on the country of participation. Participants were selected based on their immunocompromised status, which may be due to conditions such as HIV infection, hematopoietic cell or solid organ transplantation, or chronic use of immunosuppressive treatment. The trial population is characterized by a vulnerable group, given their compromised immune systems. Lifestyle considerations such as diet and physical activity are not specified, but participants are required to adhere to specific contraceptive measures during the study. The selection criteria ensure that participants have lesions accessible for visual inspection, and they must provide informed consent or have a legally authorized representative do so on their behalf. The trial does not specify additional lifestyle factors or habits that may influence participation.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **pritelivir** for the treatment of acyclovir-resistant mucocutaneous **HSV** infections in immunocompromised subjects. This is a randomized, open-label, multi-center, comparative trial. The study involves a maximum treatment period of 28 days, with the overall trial duration estimated to conclude by November 30, 2025. Participants will be randomly assigned to receive either pritelivir or an investigator's choice treatment. The trial will assess primary endpoints such as the cure rate, defined as the number of subjects with all lesions healed during the treatment period. Secondary endpoints include time to lesion healing, recurrence rate, and pain rate, among others.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will determine participant eligibility based on criteria such as immunocompromised status and confirmed acyclovir-resistant HSV infection. Follow-up visits will occur throughout the treatment period to assess lesion healing, monitor adverse events, and ensure compliance with the study protocol. The end-of-study visit will evaluate the final outcomes and collect data on any long-term effects or recurrence of infection.
Participant involvement is expected to last up to 42 days, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events that compromise participant safety. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Foscavir 24 mg/ml Solution for Infusion** is utilized as a comparator treatment. It contains the active substance **foscarnet sodium hexahydrate** and is provided in the form of a solution for infusion. The administration route is intravenous, with a maximum daily dose of 120 mg/kg and a total maximum dose of 5040 mg/kg over a treatment period of up to 42 days. This medication is produced by Clinigen Healthcare Ltd and is classified under the ATC code J05AD01.
**Pritelivir mesylate monohydrate** serves as the experimental treatment in this trial. It is administered orally in the form of a film-coated tablet. The active substance is **pritelivir**, and the maximum daily dose is 400 mg, with a total maximum dose of 4500 mg over a 42-day treatment period. This medication is developed by AiCuris Anti-Infective Cures GmbH and is identified by the sponsor product code AIC090016.
Another comparator treatment used in the study is **IMIQUIMOD**, which is applied topically in the form of a cream. The active substance is **imiquimod**, with a maximum daily dose of 12.5 mg and a total maximum dose of 225 mg over a 42-day treatment period. This treatment is utilized to provide a comparative analysis against the experimental medication.
Additionally, **ANHYDROUS CIDOFOVIR** is included as a comparator treatment. It is administered intravenously as a solution for infusion. The active substance is **anhydrous cidofovir**, with a maximum daily dose of 5 mg/kg and a total maximum dose of 30 mg/kg over a 42-day treatment period. This treatment is used to further evaluate the efficacy and safety of the experimental medication.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to assess the efficacy and safety of the experimental treatment in comparison to the standard-of-care therapies provided by the comparator treatments.
Efficacy
The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **cure rate**, defined as the number of subjects whose lesions are completely 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. Secondary endpoints include the cure rate over a treatment period of up to 42 days, time to lesion healing, recurrence rate at 1, 2, and 3 months following the point of treatment verification (PoTV), and pain-related measures such as the number of days with pain at the lesion site, time to pain cessation, and average pain score using a Numeric Rating Scale (NRS). Additional secondary endpoints involve clinical shedding rate, time to cessation of shedding, mean log number of HSV DNA copies from HSV PCR swabs, and resistance to trial medication for lesions not healed within the treatment period or newly appeared lesions under treatment before or at the PoTV.
These efficacy parameters will be measured and collected through various methods, including investigator assessments and daily subject self-reporting. The timepoints for these assessments include the treatment period of up to 28 or 42 days, as well as follow-up periods at 1, 2, and 3 months post-treatment. The Numeric Rating Scale (NRS) will be used for assessing pain intensity, and quantitative real-time polymerase chain reaction (PCR) will be employed for detecting HSV DNA copies. The analysis of these parameters will provide comprehensive insights into the efficacy of the treatment regimen in the study population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part C: 1. 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 ≥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.
- Part C: 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 doses of acyclovir, valacyclovir or Famciclovir.
- Part C: 3. Lesions accessible for visual inspection to allow assessment of lesion healing including visualization by endoscopy.
- Part C: 4. Willing to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods (defined below): The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. Male subjects must remain abstinent,be surgically sterile (eg, documented vasectomy) or must agree to use an adequate method of contraception during sexual intercourse with women of childbearing potential for at least 6 months after the final dose of trial medication. Male subjects must refrain from sperm donation during the same period. Female subjects of non-childbearing potential must be either surgically sterile (documented hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy or postmenopausal (defined as amenorrhea for at least 12 months without an alternative medical cause) at start of treatment). Female subjects of childbearing potential must remain abstinent, have a sole vasectomized partner, or must agree to use an adequate method of contraception. Female subjects must refrain from donating eggs during the same period. An adequate method of contraception is defined as a highly effective method of contraception (failure rate of <1% per year) plus use of a condom during participation in this trial and for at least 6,5 complete months after the final dose of foscarnet and 1 complete month after the last dose of pritelivir. A highly effective method of contraception is defined as: o copper intrauterine device, o the levonorgestrel-releasing intrauterine system, o the progestogen implant, o combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) associated with inhibition of ovulation, o progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation.
- Part C: 5. Subject, and/or their legally authorized representative, must be willing and able (in the opinion of the Investigator) to understand the Informed Consent Form.
- Part C: 6. Negative serum β-HCG (beta-human chorionic gonadotropin) test for women of childbearing potential at Screening and a negative urine pregnancy test at Day 1.
- Part C: 7. Subject must give written informed consent. For subjects, who are unable to provide informed consent for whatever reason, written consent must be obtained from the legal representative.
- Parts D (complete) and F (complete): Inclusion criteria in Part D are identical to those in Part C, except for inclusion criteria 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 foscarnet requiring cessation of foscarnet treatment or precluding foscarnet treatment. Clinical failure of ACV treatment 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 doses of acyclovir, valacyclovir, or famciclovir. Clinical failure of foscarnet treatment is defined as no improvement after at least 7 days offoscarnet iv therapy. For subjects coming from Part C due to clinical failure of foscarnet, clinical failure is defined as discontinuation and/or replacement of foscarnet after at least 7 days of treatment due to worsening of lesion(s) and/or appearance of new lesion(s). Manifestations of foscarnet intolerance may include, impairment of renal function, seizures, genital irritation and/or ulcerations, extremity paresthesia, nausea, granulocytopenia, anemia, leukopenia, thrombopenia, hypokalemia, hypocalcemia, hypomagnesemia, diabetes insipidus, injection site reactions, psychiatric disorders, including but not limitedto anxiety and aggression. Subjects entering Part D or Part F (both complete) after cessation of foscarnet treatment in Part C will require a washout period of at least 3 days prior to starting pritelivir. New subjects may be enrolled into Part F (complete) only after closure of enrollment in Part D (complete).
- Part E (not being conducted in Germany) Inclusion criteria in Part E are identical to those in Part C, except for inclusion criterion 2 which is replaced by: 2. Recurrent mucocutaneous HSV infection considered ACV-S.
Exclusion Criteria
- Part C: Known resistance/intolerance to pritelivir or any of the excipients.
- Part C: Previous treatment in PRIOH-1
- Part C: Baseline safety laboratory abnormalities: o ANC <1000 cells/mm3 o platelet count <25,000 cells/mm3 o hemoglobin <8.0 g/dL o AST or ALT >5 x ULN o total bilirubin >2.5 x ULN
- Part C: History or current evidence of gastrointestinal malabsorption which, in the opinion of the Investigator, may affect the extent of absorption of pritelivir.
- Part C: Hemodialysis for any indication and ESRD (eGFR <15 mL/min; stage 5 CKD).
- Part C: 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 orinterfere with the trial.
- Part C: 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.
- Part C: Not able to communicate meaningfully with the Investigator and site staff.
- Part C: Any other condition which in the opinion of the Investigator would interfere with successful completion of this clinical trial.
- Part C: Any other local condition including bacterial superinfection which in the opinion of the Investigator would interfere with the efficacy evaluation.
- Part C: Pregnant and/or breastfeeding women.
- Part C: Having received an investigational drug in an investigational drug trial within 7 half-lives after the last administration of this drug before initiating trial medication. Current participation in a clinical trial without receiving other investigational drugs (eg, follow-upphase of a trial, observational study) is permitted. Other investigational drugs are also not permitted during participation in this trial.
- Part D (complete) All exclusion criteria in Part D are identical to those in Part C, except for exclusion criteria 1 and 12 which are replaced by: All exclusion criteria as for Part C, except for exclusion criteria 1 and 12 which are replaced by: All exclusion criteria as for Part C, except for exclusion 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 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 (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 (complete) All exclusion criteria of Part D, and 13. Part D open for enrollment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Jun 2021 | 13 |
 France | Not Recruiting | 18 Jun 2021 | 15 |
 Germany | Not Recruiting | 18 Jun 2021 | 12 |
 Greece | Not Recruiting | 18 Jun 2021 | 4 |
 Italy | Not Recruiting | 18 Jun 2021 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ANHYDROUS CIDOFOVIR | Comparator | — | INTRAVENOUS USE | 5 | 42 | SUB25415 |
Foscavir 24 mg/ml Solution for Infusion | Comparator | SOLUTION FOR INFUSION | INTRAVENOUS USE | 120 | 42 | PRD346376 |
Pritelivir mesylate monohydrate | Test | FILM-COATED TABLET | ORAL USE | 400 | 42 | PRD8738401 |
IMIQUIMOD | Comparator | — | TOPICAL | 12.5 | 42 | SUB12453MIG |