| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acyclovir-resistant mucocutaneous HSV infections in immunocompromised subjects |
|
| E.1.1.1 | Medical condition in easily understood language |
| Herpes Simplex Virus infections on the skin and mucous membranes which is resistant to acyclovir in subjects with weakened immune system. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Part C: to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with acyclovir (ACV)-resistant (ACV-R) mucocutaneous herpes simplex virus (HSV) infections for a treatment period of 28 days as a maximum in comparison to foscarnet given as intermittent intravenous (iv) infusions at a dose of 40 mg/kg every 8 hours or 60 mg/kg every 12 hours for a minimum of one hour duration
for a maximum treatment duration of 28 days
• Part D: to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-R and foscarnet-R/intolerant mucocutaneous HSV infections for a treatment period of 28 days as a maximum
• Part E: to investigate the safety of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-susceptible (ACV-S) mucocutaneous HSV infections for a treatment period of 28 days as a maximum |
|
| E.2.2 | Secondary objectives of the trial |
• to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-R mucocutaneous HSV infections for a treatment period of 42 days as a maximum in comparison to foscarnet given as intermittent iv infusions at a dose of 40 mg/kg every 8 hours or 60 mg/kg every 12 hours for a minimum of one hour duration for a maximum treatment duration of 42 days
• to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-R and foscarnet-R/intolerant mucocutaneous HSV infections for a treatment period of 42 days as a maximum
• to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-S mucocutaneous HSV infections for a treatment period of 28 days as a maximum
• to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-S mucocutaneous HSV infections for a treatment period of 42 days as a maximum |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part C 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 >16 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 at least 7 days with local agency approved high doses with acyclovir, valacyclovir or famciclovir.
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. Willing to use highly effective birth control:
Male subjects must be surgically sterile (eg, vasectomy at least for the 26 weeks before starting treatment) or must agree to use an adequate method of contraception during sexual intercourse with women of childbearing potential to make sure the fathering of a child will be ruled out during treatment and for at least 1 complete month after the final dose of trial medication. Female subjects of non-childbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before starting treatment) or postmenopausal (defined as spontaneous amenorrhea for at least 2 years, with follicle-stimulating hormone (FSH) in the postmenopausal range at start of treatment based on the laboratory’s ranges). Female subjects of childbearing potential must use an adequate method of contraception.
An adequate method of contraception is defined as a highly effective method of contraception plus use of a condom during participation in this trial and for at least 1 complete month after the final dose of trial medication. 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.
6. Subject, and/or their legally authorized representative, 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 women of childbearing potential at Screening and a negative urine pregnancy test at Day 1.
8. 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.
Part D 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 foscarnet requiring cessation of foscarnet treatment or precluding foscarnet
treatment. Clinical failure of ACV treatment is defined as no improvement after at least 7 days with local agency approved high doses with acyclovir, valacyclovir or famciclovir. Clinical failure of foscarnet treatment is defined as no improvement after at least 7 days of
foscarnet 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, renal function impairment, 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 limited
to anxiety and aggression. Subjects entering Part D after cessation of foscarnet treatment in Part C will require a washout period of at least 3 days prior to starting pritelivir.
Part E inclusion criteria
All inclusion criteria as for Part C, except for inclusion criterion 2 which is replaced by:
2. Recurrent mucocutaneous HSV infection considered ACV-S. |
|
| E.4 | Principal exclusion criteria |
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 warfarin, phenytoin, paclitaxel.
4. 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 bilirubin >2.5 x ULN
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).
7. 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.
8. 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.
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 local condition including bacterial superinfection which in the opinion of the Investigator would interfere with the efficacy evaluation.
12. Pregnant and/or breastfeeding women.
13. 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-up
phase of a trial, observational study) is permitted.
Part D exclusion criteria
All exclusion criteria as for Part C, except for exclusion criteria 1 and 13 which are replaced by:
1. Known intolerance to pritelivir or any of the excipients
and
13. 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 exclusion criteria
All exclusion criteria as for Part C, except for exclusion criteria 1 and 14 which are replaced by:
1. Known intolerance to pritelivir or any of the excipients
and
14. Having used (val)acyclovir within 3 days prior to starting pritelivir. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints will be evaluated separately in Part C, Part D and Part E.
Efficacy
Primary endpoint
• 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.
o Failure is defined as meeting at least one of the following criteria at the end of treatment within the treatment period of up to 28 days:
a) not all lesions have healed,
b) discontinuation and/or replacement of trial medication after at least 7 days of treatment due to worsening of lesion(s) and/or appearance of new lesion(s),
c) discontinuation of trial medication due to trial medication related adverse event or intolerance to trial medication before lesion healing, or
d) discontinuation due to resistance to trial medication.
o Indeterminate: Circumstances preclude where it is not possible to attribute either cure or failure, for example due to:
a) lost during treatment period,
b) subject treated with trial medication needed concomitant CMV treatment or treatment for other infection with medications that were also active against HSV,
c) subject refuses endoscopy or pharyngoscopy for esophageal lesion at the end of treatment when the Investigator considers the lesions have healed in the absence of any clinical signs and symptoms. Indeterminate responses will be considered as failures in the Full Analysis Set
(FAS) and the modified FAS (mFAS) and will be excluded from the denominator (major protocol violation) for the calculation of cure rates in PP1 and PP2 sets. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints (Part C)
• 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.
• 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.
• Recurrence rate at 2 and 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.
• 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.
• 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).
• Average pain score 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.
• 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) until healing.
• Time to cessation of shedding.
• Mean log number of HSV DNA copies on HSV DNA positive swabs from lesion(s) as detected by quantitative real-time polymerase chain reaction (PCR).
• Resistance to trial medication for lesions not healed within the treatment period or newly appeared lesions under treatment before or at the PoTV. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Georgia |
| Mexico |
| Argentina |
| Belgium |
| Canada |
| China |
| Germany |
| Greece |
| Israel |
| Italy |
| Russian Federation |
| Switzerland |
| Ukraine |
| United Kingdom |
| United States |
| France |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial is defined as the last subject’s last visit/call. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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