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    Clinical Trial Results:
    A Randomized, Double-Blind, Double-Dummy Phase II Study of Single Dose HDIT101 versus Standard of Care Valaciclovir in Patients with Chronic Recurrent Anogenital HSV-2 Infection

    Summary
    EudraCT number
    		 2019-000880-26
    Trial protocol
    		 DE  
    Global end of trial date
    25 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Sep 2022
    First version publication date
    10 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HTX101-02G
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04165122
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Heldelberg ImmunoTherapeutics GmbH
    Sponsor organisation address
    Max-Jarecki-Str. 21, Heidelberg, Germany,
    Public contact
    Stefan Schöffel, Heidelberg ImmunoTherapeutics GmbH, +49 6221391938, stefan.schoeffel@hditx.de
    Scientific contact
    Prof. Dr. Jürgen Krauss, Heidelberg ImmunoTherapeutics GmbH, +49 622139190, juergen.krauss@hditx.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of single dose of HDIT101 versus episodic standard of care treatment with Valaciclovir in patients with chronic recurrent anogenital HSV-2 infection as measured by the percentage of days with lesion(s) during the study (calculated as number of days with lesion, except the lesion episode at randomization, divided by the number of days in the study after IMP infusion).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Patients were allowed to be treated symptomatically with 1 gram paracetamol taken orally for flu-like symptoms that might occur due to the mode of action of HDIT101
    Background therapy
    		 There were restrictions on the use of concomitant medications/therapies during the trial. The following medications/therapies were not permitted: immunosuppressive or immunomodulatory therapy (topical, oral, parenteral and/or inhaling steroids), hepatotoxic drugs, any herpes simplex virus therapy different than the investigational medicinal product, nephrotoxic medicinal products, and medicinal products that compete with or inhibit active tubular secretion due to their potential influence on the outcome measures of the study.
    Evidence for comparator
    		 Valaciclovir 500 mg tablets twice daily for 3 days was used as standard of care therapy of HSV-2 lesions occurrence during the trial. Treatment with Valaciclovir is one of the available options for treatment of HSV-2 mediated anogenital infections that has shown efficacy in reducing clinical symptoms in patients with chronic recurrent anogenital HSV-2 infection. Valaciclovir-placebo was used in patients receiving the test drug (HDIT101 group) to ensure treatment blinding and reduce potential bias during data collection.
    Actual start date of recruitment
    18 Nov 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 122
    Worldwide total number of subjects
    122
    EEA total number of subjects
    122
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    111
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 261 patients (≥ 18 years of age) were screened for eligibility in 8 trial sites in Germany. Of these, 122 patients were randomized: 81 to HDIT101 and Valaciclovir-placebo; 41 to Valaciclovir and HDIT101-placebo. The remaining 139 patients were screening failures.

    Pre-assignment
    Screening details
    		 261 patients with history of chronic recurrent anogenital HSV-2 infection ≥4 outbreaks in the last year (≥2 lesions under standard suppressive antiviral therapy), and no active lesion at enrolment were screened. Screening failures (139) including patients who did not develop lesion within 4 months after enrolment were withdrawn.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Study treatments were blinded and the allocation to treatment groups was not known to the investigator or other persons involved in the conduct of the study until completion of the study, except the site pharmacies personnel and in cases of emergency. To ensure that the double-blind design of the study was maintained, HDIT101 and Valaciclovir were identical in appearance with the respective placebos matching the intravenous (IV) infusion and oral treatments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HDIT101
    Arm description
    		 Patients receiving single intravenous infusion of HDIT101 on Day 1 and episodic standard of care treatment with Valaciclovir-placebo starting at Day 1 and in case of recurrences during the trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HDIT101
    Investigational medicinal product code
    HDIT101
    Other name
    Humanized IgG1 monoclonal antibody
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 1: Single intravenous infusion of HDI101 2 grams flat over 1 hour and Valaciclovir-placebo (1 capsule twice daily for 3 days). Starting at Day 1 and until end of study: episodic treatment with Valaciclovir-placebo, 1 capsule twice daily for 3 days, in case of new recurrences during the trial.

    Arm title
    		 Valaciclovir
    Arm description
    		 Patients receiving single IV infusion of HDIT101-placebo on Day 1 and episodic standard of care treatment with Valaciclovir starting at Day1 and in case of recurrences during the trial.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Valaciclovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Day 1: Single intravenous infusion of HDI101-placebo flat over 1 hour and Valaciclovir 500 mg (1 capsule twice daily for 3 days). Starting at Day 1 and until end of study: episodic treatment with Valaciclovir 500 mg, 1 capsule twice daily for 3 days, in case of new recurrences during the trial.

    Number of subjects in period 1
    		HDIT101 Valaciclovir
    Started
    81
    41
    Completed
    61
    35
    Not completed
    20
    6
         Physician decision
    4
    -
         Consent withdrawn by subject
    11
    5
         Other
    1
    1
         Lost to follow-up
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HDIT101
    Reporting group description
    		 Patients receiving single intravenous infusion of HDIT101 on Day 1 and episodic standard of care treatment with Valaciclovir-placebo starting at Day 1 and in case of recurrences during the trial.

    Reporting group title
    Valaciclovir
    Reporting group description
    		 Patients receiving single IV infusion of HDIT101-placebo on Day 1 and episodic standard of care treatment with Valaciclovir starting at Day1 and in case of recurrences during the trial.

    Reporting group values
    		 HDIT101 Valaciclovir Total
    Number of subjects
    		 81 41 122
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 73 38 111
        From 65-84 years
    		 8 3 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.4 ± 13.66 43.3 ± 13.42 -
    Gender categorical
    Units: Subjects
        Female
    		 42 22 64
        Male
    		 39 19 58
    HSV-1 seropositivity test
    Herpes simplex virus-1 seropositivity test
    Units: Subjects
        Positive
    		 42 22 64
        Negative
    		 39 19 58
    Episodes of anogenital herpes
    Number of episodes of anogenital herpes in the last year
    Units: Subjects
        3 episodes
    		 1 1 2
        4 episodes
    		 12 6 18
        5 episodes
    		 9 3 12
        more than 5 episodes
    		 59 31 90
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not-Hispanic or Latino
    		 79 40 119
    Smoking habits
    Units: Subjects
        Current smoker
    		 22 11 33
        Ex-smoker
    		 22 10 32
        Non-smoker
    		 37 20 57
    Post hoc: Subgroups based on number of episodes of anogenital herpes in the last year
    Subgroups were defined for a post hoc analysis of time to first recurrence.
    Units: Subjects
        3-4
    		 13 7 20
        5-9
    		 40 21 61
        10-14
    		 23 10 33
        15 or more
    		 5 3 8
    Time since first diagnosis
    Time since first diagnosis/symptoms of genital herpes
    Units: years
        median (full range (min-max))
    		 4.731 (0.74 to 45.77) 4.709 (0.29 to 39.95) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 72.9 ± 12.95 72.7 ± 15.35 -
    Body mass index
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 24.016 ± 3.2904 23.938 ± 3.5120 -

    End points

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    End points reporting groups
    Reporting group title
    HDIT101
    Reporting group description
    		 Patients receiving single intravenous infusion of HDIT101 on Day 1 and episodic standard of care treatment with Valaciclovir-placebo starting at Day 1 and in case of recurrences during the trial.

    Reporting group title
    Valaciclovir
    Reporting group description
    		 Patients receiving single IV infusion of HDIT101-placebo on Day 1 and episodic standard of care treatment with Valaciclovir starting at Day1 and in case of recurrences during the trial.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in the FAS who received at least one dose of IMP (i.e., “treated population”) and had at least one post-baseline safety assessment (where the statement that a patient had no AE on the AE eCRF constitutes a safety assessment). The assignment of patients to the treatment groups was as actually treated.

    Subject analysis set title
    Pharmacokinetic set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received a single dose of HDIT101 and had at least one post-dose PK assessment. Of note, one patient with a positive HDIT101 concentration pre-dose was excluded from the PK analysis as it could not be ruled out that the PK samples of this patient were mixed up

    Subject analysis set title
    Immunogenicity set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received a single dose of HDIT101 and had at least one post-dose immunogenicity assessment

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients; following the intent-to-treat principle, patients were analyzed as randomized.

    Primary: Percentage of days with lesion(s)

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    End point title
    		 Percentage of days with lesion(s)
    End point description
    End point type
    Primary
    End point timeframe
    Number of days with lesion (except the lesion episode at randomization) divided by the number of study days after the investigational medicinal product infusion.
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    80
    41
    Units: Percentage
        median (full range (min-max))
    11.926 (0 to 77.78)
    12.000 (0 to 33.51)
    Statistical analysis title
    		 Treatment contrast
    Statistical analysis description
    The primary alternative hypothesis (H1) was that the percentage of days with lesions relative to the days in the study after initial treatment was lower with HDIT101 treatment than with Valaciclovir treatment. H1 was tested against the null hypothesis (H0, one-sided) that the percentage of days with lesions in the HDIT101 arm was equal or larger than in the valaciclovir arm.
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5772
    Method
    		 Wald statistics
    Parameter type
    		 event rate ratio
    Point estimate
    1.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.718
         upper limit
    		 1.498

    Secondary: Key Secondary: 1_Time to first recurrence

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    End point title
    		 Key Secondary: 1_Time to first recurrence
    End point description
    Time to first recurrence of lesion was defined as time from HDIT101/HDIT101-placebo infusion to the day with presence of a new recurrence with HSV score 2-7
    End point type
    Secondary
    End point timeframe
    Time from initial IMP infusion until the first day of a new recurrence with HSV score 2-7 as reported by the patient and verified by the investigator.
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    80
    41
    Units: days
        arithmetic mean (standard deviation)
    57.5 ± 53.61
    44.3 ± 44.00
    No statistical analyses for this end point

    Secondary: Key secondary: 2_Recurrence rate

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    End point title
    		 Key secondary: 2_Recurrence rate
    End point description
    A right censoring was made after study day 187 (upper limit of visit 7 window). Recurrence rates were calculated for each subject and standardised to a period of 180 days by 180* (number of recurrences / days in the study after start of initial IMP infusion
    End point type
    Secondary
    End point timeframe
    Number of recurrences divided by the total number of study days after IMP infusion
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    77
    41
    Units: percent
        arithmetic mean (standard deviation)
    3.173 ± 2.7719
    3.764 ± 2.5850
    Statistical analysis title
    		 Treatment contrast
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0658
    Method
    		 van Elteren test
    Confidence interval

    Secondary: Key secondary: 3_Duration of recurrent lesion

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    End point title
    		 Key secondary: 3_Duration of recurrent lesion
    End point description
    Total number of consecutive days with lesions of HSV score 2-7 divided by the number of recurrences
    End point type
    Secondary
    End point timeframe
    Recurrence duration was defined as the accumulated duration of all recurrences after clearance from symptoms after initial treatment as reported by patient divided by the number of recurrences.
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    77
    41
    Units: day
        arithmetic mean (standard deviation)
    8.5 ± 5.25
    6.1 ± 3.86
    Statistical analysis title
    		 Treatment contrast
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9943
    Method
    		 van Elteren test
    Confidence interval

    Secondary: Key secondary: 4_Disease-specific symptoms

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    End point title
    		 Key secondary: 4_Disease-specific symptoms
    End point description
    Average Herpes Symptom Checklist (HSC) total score as measure of the disease-specific symptoms severity assessed by the patient and documented in the patient's diary on daily basis.
    End point type
    Secondary
    End point timeframe
    Daily basis from the first to the last day of disease-specific symptoms during the study
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    80
    40
    Units: Average total score
        arithmetic mean (standard deviation)
    6.827 ± 4.4939
    6.958 ± 5.3335
    Statistical analysis title
    		 Treatment contrast
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6902
    Method
    		 van Elteren test
    Confidence interval

    Secondary: Key secondary: 5_Herpes outbreak impact

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    End point title
    		 Key secondary: 5_Herpes outbreak impact
    End point description
    Average Herpes Outbreak Impact Questionnaire (HOIQ) total score as measure of the daily impact specific to herpes outbreaks on patient's emotional, self-care, social, sexual, and work-related functioning
    End point type
    Secondary
    End point timeframe
    Daily basis from the first to the last day of symptoms per lesion episode during the study
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    80
    40
    Units: Total score
        arithmetic mean (standard deviation)
    10.390 ± 7.4588
    10.246 ± 6.7861
    Statistical analysis title
    		 Treatment contrast
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5005
    Method
    		 van Elteren test
    Confidence interval

    Secondary: Key secondary: 6_Changes in patients' quality of life

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    End point title
    		 Key secondary: 6_Changes in patients' quality of life
    End point description
    Change in Recurrent Genital Herpes Quality of Life (RGHQoL) total score from baseline to end of the study
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1, Visit 1) to end of study (Visit 7)
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    14
    9
    Units: Total score
        arithmetic mean (standard deviation)
    5.3 ± 8.16
    6.1 ± 12.19
    Statistical analysis title
    		 Treatment contrast
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5854
    Method
    		 van Elteren test
    Confidence interval

    Secondary: Immunogenicity: Number of patients with positive ADA

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    End point title
    		 Immunogenicity: Number of patients with positive ADA
    End point description
    Serum titers of ADA against HDIT101
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1, Visit 1) to end of study (Visit 7)
    End point values
    		 Immunogenicity set
    Number of subjects analysed
    49
    Units: Number of patients
        Visit 1 (Baseline)
    5
        Visit 2
    0
        Visit 4
    0
        Visit 6
    5
        Visit 7
    6
        Overall post baseline
    8
    No statistical analyses for this end point

    Other pre-specified: Secondary: Number of lesion episodes

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    End point title
    		 Secondary: Number of lesion episodes
    End point description
    Number of lesion episodes (i.e. lesion with HSV score 2-7 after initial treatment) using right censored data after Day 187
    End point type
    Other pre-specified
    End point timeframe
    Lesion episodes after initial treatment to Day 187
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    80
    41
    Units: Number
        arithmetic mean (standard deviation)
    2.4 ± 1.96
    3.4 ± 2.43
    No statistical analyses for this end point

    Other pre-specified: Secondary: Mean log number of HSV-2 DNA Copies in positive samples

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    End point title
    		 Secondary: Mean log number of HSV-2 DNA Copies in positive samples
    End point description
    Mean log number of HSV-2 DNA copies in HSV-2 positive swabs collected during Screening, Visit 1 and Visit 6 periods
    End point type
    Other pre-specified
    End point timeframe
    The number of HSV-2 DNA copies was determined in all HSV-2 positive swabs of the swabbing periods, i.e., collected during a 28-day swabbing period after IMP infusion (Visit 1 [Day 1]) and during a 28-day swabbing period after Visit 6 (Day 150).
    End point values
    		 HDIT101 Valaciclovir
    Number of subjects analysed
    80
    41
    Units: Log number
    arithmetic mean (standard deviation)
        Screening
    4.889 ± 1.2459
    5.305 ± 1.0146
        Visit 1
    4.954 ± 0.9168
    4.854 ± 0.7783
        Visit 6
    4.759 ± 0.9988
    4.236 ± 1.1298
    Statistical analysis title
    		 Treatment contrast
    Comparison groups
    HDIT101 v Valaciclovir
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6438
    Method
    		 Wald statistics
    Confidence interval

    Other pre-specified: PK: AUC0-inf

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    End point title
    		 PK: AUC0-inf
    End point description
    Total exposure - area under the serum concentration-time curve from administration until infinity
    End point type
    Other pre-specified
    End point timeframe
    Scheduled sampling time point (Pre-dose, End of infusion, Visit 2 (Day 15), Visit 4 (Day 60), Visit 6 (Day 150) and Visit 7 (Day 180)
    End point values
    		 Pharmacokinetic set
    Number of subjects analysed
    44
    Units: day*ng/mL
        geometric mean (geometric coefficient of variation)
    10447685.2 ± 21.72
    No statistical analyses for this end point

    Other pre-specified: PK: Cmax

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    End point title
    		 PK: Cmax
    End point description
    Concentration maximum until the end of the 180 days pharmacokinetics period
    End point type
    Other pre-specified
    End point timeframe
    Scheduled sampling time point (Pre-dose, End of infusion, Visit 2 (Day 15), Visit 4 (Day 60), Visit 6 (Day 150) and Visit 7 (Day 180)
    End point values
    		 Pharmacokinetic set
    Number of subjects analysed
    45
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    590771.74 ± 16.526
    No statistical analyses for this end point

    Other pre-specified: PK: Tmax

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    End point title
    		 PK: Tmax
    End point description
    Time when concentration maximum is observed
    End point type
    Other pre-specified
    End point timeframe
    Scheduled sampling time point (Pre-dose, End of infusion, Visit 2 (Day 15), Visit 4 (Day 60), Visit 6 (Day 150) and Visit 7 (Day 180)
    End point values
    		 Pharmacokinetic set
    Number of subjects analysed
    45
    Units: day
        geometric mean (geometric coefficient of variation)
    0.00745 ± 47.130644
    No statistical analyses for this end point

    Other pre-specified: PK: T1/2

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    End point title
    		 PK: T1/2
    End point description
    Apparent elimination half-life
    End point type
    Other pre-specified
    End point timeframe
    Scheduled sampling time point (Pre-dose, End of infusion, Visit 2 (Day 15), Visit 4 (Day 60), Visit 6 (Day 150) and Visit 7 (Day 180)
    End point values
    		 Pharmacokinetic set
    Number of subjects analysed
    44
    Units: day
        geometric mean (geometric coefficient of variation)
    20.64 ± 21.135
    No statistical analyses for this end point

    Other pre-specified: PK: Clearance

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    End point title
    		 PK: Clearance
    End point description
    Pharmacokinetic measurement of the volume of plasma from which study treatment was completely removed per unit time (mL/day)
    End point type
    Other pre-specified
    End point timeframe
    Scheduled sampling time point (Pre-dose, End of infusion, Visit 2 (Day 15), Visit 4 (Day 60), Visit 6 (Day 150) and Visit 7 (Day 180)
    End point values
    		 Pharmacokinetic set
    Number of subjects analysed
    44
    Units: mL/day
        geometric mean (geometric coefficient of variation)
    189.93 ± 21.794
    No statistical analyses for this end point

    Other pre-specified: PK: Volume of distribution

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    End point title
    		 PK: Volume of distribution
    End point description
    Individual drug's propensity to either remain in the plasma or redistribute to other tissue compartments.
    End point type
    Other pre-specified
    End point timeframe
    Scheduled sampling time point (Pre-dose, End of infusion, Visit 2 (Day 15), Visit 4 (Day 60), Visit 6 (Day 150) and Visit 7 (Day 180)
    End point values
    		 Pharmacokinetic set
    Number of subjects analysed
    44
    Units: millilitre(s)
        geometric mean (geometric coefficient of variation)
    5655.27 ± 21.859
    No statistical analyses for this end point

    Other pre-specified: Immunogenicity: ADA titer

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    End point title
    		 Immunogenicity: ADA titer
    End point description
    Serum titers of ADA against HDIT101
    End point type
    Other pre-specified
    End point timeframe
    Blood sampling for ADA titer assessments was performed at all on-site visits except screening as well as at all unscheduled visits (UV) except an UV prior to Day 15
    End point values
    		 Immunogenicity set
    Number of subjects analysed
    49
    Units: serum titer
    arithmetic mean (standard deviation)
        Visit 1 (Baseline)
    2.2 ± 1.1
        Visit 2
    0 ± 0
        Visit 4
    0 ± 0
        Visit 6
    9.0 ± 13.15
        Visit 7
    8.5 ± 14.07
        Overall post baseline
    0 ± 0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to end of the study (Day 180)
    Adverse event reporting additional description
    Patients were expected to volunteer information about adverse events that they experienced. In addition, the investigator or designee questioned the patient at each visit about adverse events and recorded these as well as other adverse events at the visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    HDIT101
    Reporting group description
    		 -

    Reporting group title
    Valaciclovir
    Reporting group description
    		 -

    Serious adverse events
    		 HDIT101 Valaciclovir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 41 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 HDIT101 Valaciclovir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 80 (56.25%)
    19 / 41 (46.34%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 80 (10.00%)
    6 / 41 (14.63%)
         occurrences all number
    10
    8
    Migraine
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 41 (4.88%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 80 (8.75%)
    0 / 41 (0.00%)
         occurrences all number
    8
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    4 / 80 (5.00%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 41 (7.32%)
         occurrences all number
    2
    4
    Arthralgia
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    Pain in extremity
         subjects affected / exposed
    3 / 80 (3.75%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    8 / 80 (10.00%)
    5 / 41 (12.20%)
         occurrences all number
    12
    6
    Nasopharyngitis
         subjects affected / exposed
    7 / 80 (8.75%)
    1 / 41 (2.44%)
         occurrences all number
    8
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2020
    Main changes included in protocol v3.0 were adaptations with regard to adaptations for the COVID-19 pandemic, further clarifications, and minor changes. Note: The study was approved with protocol v2.0 - therefore no changes are listed for protocol v1.0 to v2.0

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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