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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AiCuris Anti-infective Cures AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

15 Mar 2022 → 11 Nov 2025

Decision date (initial)

2024-06-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AiCuris Anti-infective Cures AG

External identifiers

EU CT number

2023-510088-37-00

EudraCT number

2020-004940-27

WHO UTN

U1111-1304-5320

ClinicalTrials.gov

NCT03073967

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Efficacy, Safety

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 "Investigator's Choice treatment" for a max treatment duration of 28 days

Part D (complete): investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-R and foscarnetR/intolerant mucocutaneous HSV infections for a treatment period of 28 days as a maximum

Part E: to investigate the safety and tolerability 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.

Part F (complete): investigate the safety and tolerability 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 after
completion of enrollment in Part D.

Secondary objectives 4

1. Part C: 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 "Investigator's Choice" treatment for a maximum treatment duration of 42 days
2. Part D (complete): to investigate the efficacy of oral pritelivir 100 mg once a day in immunocompromised subjects with ACV-R and foscarnetR/intolerant mucocutaneous HSV infections for a treatment period of 42 days as a maximum.
3. Part E: 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.
4. Part F (complete): 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; 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

Conditions and MedDRA coding

Acyclovir-resistant mucocutaneous HSV infections in immunocompromised subjects

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-002180-PIP02-19

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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.
2. 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.
3. Part C: 3. Lesions accessible for visual inspection to allow assessment of lesion healing including visualization by endoscopy.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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).
9. 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 15

1. Part C: Known resistance/intolerance to pritelivir or any of the excipients.
2. Part C: Previous treatment in PRIOH-1
3. 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
4. Part C: History or current evidence of gastrointestinal malabsorption which, in the opinion of the Investigator, may affect the extent of absorption of pritelivir.
5. Part C: Hemodialysis for any indication and ESRD (eGFR <15 mL/min; stage 5 CKD).
6. 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.
7. 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.
8. Part C: Not able to communicate meaningfully with the Investigator and site staff.
9. Part C: Any other condition which in the opinion of the Investigator would interfere with successful completion of this clinical trial.
10. Part C: Any other local condition including bacterial superinfection which in the opinion of the Investigator would interfere with the efficacy evaluation.
11. Part C: Pregnant and/or breastfeeding women.
12. 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.
13. 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.
14. 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
15. Part F (complete) All exclusion criteria of Part D, and 13. Part D open for enrollment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 10

1. (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.
2. (Part C) 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.
3. (Part C) Recurrence rate at 1, 2, and 3 months following PoTV, defined as number of subjects with a recurrence as assessed by the Investigator following 1/2/3 months after PoTV relative to the total number of subjects assessed for recurrence
4. (Part C) Pain rate: number of days with pain at lesion site relative to the total number of days with analyzable pain data through daily subject selfreporting.
5. (Part C) 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).
6. (Part C) 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.
7. (Part C) Clinical shedding rate (number of HSV positive HSV PCR swabs per subject relative to the total number of swabs collected per subject) from HSV PCR swabs taken from HSV lesion(s) until healing.
8. (Part C) Time to cessation of shedding.
9. (Part C) Mean log number of HSV DNA copies on HSV DNA positive HSV PCR swabs from lesion(s) as detected by quantitative real-time polymerase chain reaction (PCR).
10. (Part C) Resistance to trial medication for lesions not healed within the treatment period or newly appeared lesions under treatment before or at the PoTV. Only applicable for trial medication comprising pritelivir, foscarnet, or cidofovir.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AiCuris Anti-infective Cures AG

Sponsor organisation

AiCuris Anti-infective Cures AG

Address

Friedrich-Ebert-Strasse 475, Elberfeld West Elberfeld West

City

Wuppertal

Postcode

42117

Country

Germany

Scientific contact point

Organisation

AiCuris Anti-infective Cures AG

Contact name

Regulatory Affairs

Public contact point

Organisation

AiCuris Anti-infective Cures AG

Contact name

Regulatory Affairs

Third parties 2

Locations

5 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 184 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications