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    Clinical Trial Results:
    A Randomised, Double-Blind Phase II Trial of Topical HDIT101 versus Placebo in Patients with Chronic Recurrent HSV-1 Infection and Orolabial Lesion

    Summary
    EudraCT number
    		 2020-000926-24
    Trial protocol
    		 DE   AT  
    Global end of trial date
    31 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2024
    First version publication date
    13 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HTX101-03L
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04539483
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Heidelberg ImmunoTherapeutics
    Sponsor organisation address
    Max-Jarecki-Str. 21, Heidelberg, Germany, 69115
    Public contact
    Dr. Michaela Arndt, Heidelberg ImmunoTherapeutics, michaela.arndt@hditx.de
    Scientific contact
    Dr. Michaela Arndt, Heidelberg ImmunoTherapeutics, michaela.arndt@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
    24 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the clinical efficacy of topical HDIT101 in patients with chronic recurrent orolabial HSV-1 infection and at least 6 lesion outbreaks/year by comparing the number of recurrences of orolabial lesions for 12 months after topical administration of HDIT101/placebo. Following the treatment phase of the first 55 patients, an interim analysis was conducted per protocol by an unblinded expert panel. This analysis, carried out on March 9, 2023, recommended premature termination of the study due to futility in achieving the primary endpoint. A thorough analysis excluded any possible systemic error, therefore, on April 27, 2023, the decision was made to prematurely terminate MATCH-1, stop IMP allocation and end all ongoing patients until May 31, 2023.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. The subjects were allowed to use topical aciclovir for all recurrences except the two recurrences treated with HDIT101/placebo.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2020
    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: 158
    Worldwide total number of subjects
    158
    EEA total number of subjects
    158
    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)
    157
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with a history of at least 12 months of chronic recurrent orolabial HSV-1 infection with ≥ 6 outbreaks in the last year were eligible for enrolment in this study.

    Pre-assignment
    Screening details
    		 Eligible patients entered observation/screening phase of max 9 months. Patients must have had 3 recurrences within the observation phase, Randomisation / treatment took place upon occurrence of the third lesion. Patients who did not develop 3 recurrences in 9 months (or first recurrence 150 days after enrollment) were considered screening failures.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HDIT101
    Arm description
    		 Topical application of HDIT101
    Arm type
    		 Experimental

    Investigational medicinal product name
    HDIT101
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous liquid
    Routes of administration
    Topical use
    Dosage and administration details
    A humanised monoclonal antibody (mAb) against herpes simplex virus (HSV) type 1 and 2 surface glycoprotein B (gB) locally administered two times daily for two consecutive days (4x one vial containing 500 μl, each 5 mg/mL) upon ≥ 3 (and ≤ 4) grade lesion outbreak. A maximum of 2 outbreaks were treated (i.e. max. 8 applications per patient).

    Arm title
    		 Placebo
    Arm description
    		 Topical application of Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous liquid
    Routes of administration
    Topical use
    Dosage and administration details
    Placebo consisted of the formulation buffer of HDIT101 and was identical in appearance to verum. Placebo was also locally administered two times daily for two consecutive days upon ≥ 3 grade lesion outbreak. A maximum of 2 outbreaks were treated (i.e. max. 8 applications per patient)

    Number of subjects in period 1
    		HDIT101 Placebo
    Started
    104
    54
    Completed
    58
    31
    Not completed
    46
    23
         Consent withdrawn by subject
    4
    1
         Lost to follow-up
    1
    1
         Premature termination of trial
    41
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HDIT101
    Reporting group description
    		 Topical application of HDIT101

    Reporting group title
    Placebo
    Reporting group description
    		 Topical application of Placebo

    Reporting group values
    		 HDIT101 Placebo Total
    Number of subjects
    		 104 54 158
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.3 ( 11.6 ) 34.7 ( 11.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 83 41 124
        Male
    		 21 13 34
    BMI
    Body mass index (mean)
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 24.85 ( 4.23 ) 23.31 ( 2.96 ) -
    Time from onset of orolabial herpes
    Units: years
        arithmetic mean (standard deviation)
    		 24.11 ( 11.85 ) 22.77 ( 12.11 ) -
    Number of episodes in the last 12 months
    Units: recurrence
        arithmetic mean (standard deviation)
    		 8.86 ( 3.86 ) 8.37 ( 2.37 ) -

    End points

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    End points reporting groups
    Reporting group title
    HDIT101
    Reporting group description
    		 Topical application of HDIT101

    Reporting group title
    Placebo
    Reporting group description
    		 Topical application of Placebo

    Primary: Primary: Recurrence of lesions

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    End point title
    		 Primary: Recurrence of lesions
    End point description
    Number of recurrences after topical HDIT101 versus placebo after 12 months. A lesion was considered as such, if rated 3-7 according the HSV lesion score (grade 2 was rated as “aborted lesion”). The recurrence rate was defined as number of recurrences in the 12 months treatment phase divided by the total number of study days (in the 12 months treatment phase) after IMP treatment for lesion 3.
    End point type
    Primary
    End point timeframe
    12 months from start of treatment
    End point values
    		 HDIT101 Placebo
    Number of subjects analysed
    104
    54
    Units: Number of Recurrences
        arithmetic mean (standard deviation)
    3.1 ( 2.4 )
    2.3 ( 1.8 )
    Statistical analysis title
    		 Treatment contrast
    Statistical analysis description
    The contrast between both treatment groups estimating the rate ratio as ratio of number of recurrences rHDIT101 / rplacebo adjusted for total days in study, with lower values in favour of HDIT101 -Wald z-statistic, one-sided p-value and the associated Wald CI was analyzed. The significance level set to 2.5% (one-sided, ), the corresponding level of one-sided (upper) CI was 97.5%
    Comparison groups
    HDIT101 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9934
    Method
    		 Wald z-statistic
    Parameter type
    		 event rate ratio
    Point estimate
    1.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.93

    Secondary: Key Secondary 1 - Percentage of days with a lesion

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    End point title
    		 Key Secondary 1 - Percentage of days with a lesion
    End point description
    Percentage of days with a lesion in the 12 months treatment period.
    End point type
    Secondary
    End point timeframe
    12 months after start of treatment
    End point values
    		 HDIT101 Placebo
    Number of subjects analysed
    104
    54
    Units: percent
        arithmetic mean (standard deviation)
    13.9 ( 9.2 )
    11.7 ( 8.8 )
    No statistical analyses for this end point

    Secondary: Key Secondary 2 - Recurrence Duration

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    End point title
    		 Key Secondary 2 - Recurrence Duration
    End point description
    Mean duration of recurrent lesions (calculated as consecutive days with lesions of HSV score ≥ 3-7).
    End point type
    Secondary
    End point timeframe
    12 month after start of treatment
    End point values
    		 HDIT101 Placebo
    Number of subjects analysed
    104
    54
    Units: Days
        arithmetic mean (standard deviation)
    8.23 ( 5.99 )
    7.54 ( 5.48 )
    No statistical analyses for this end point

    Secondary: Key Secondary 3: Time to first recurrence

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    End point title
    		 Key Secondary 3: Time to first recurrence
    End point description
    Time to first recurrence of lesion (= lesion no. 4; HSV lesion score must be 3-7) reported by the patient and verified by the investigator.
    End point type
    Secondary
    End point timeframe
    12 months after start of treatment
    End point values
    		 HDIT101 Placebo
    Number of subjects analysed
    104
    54
    Units: Days
        median (inter-quartile range (Q1-Q3))
    67.0 (36.5 to 129.0)
    101.0 (38.0 to 204.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were recorded throughout the study from FPI - Early termination of the study (01-Oct-2020 - 31-May-2023)
    Adverse event reporting additional description
    The analysis of AEs focused on TEAEs (defined as all AEs that started or worsened after first treatment with IMP) and were performed by primary MedDRA SOC and PT. Patients were counted only once if they had more than one TEAE within a SOC or experienced a preferred term more than once.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    HDIT101
    Reporting group description
    		 Topical application of HDIT101

    Reporting group title
    Placebo
    Reporting group description
    		 Topical application of Placebo

    Serious adverse events
    		 HDIT101 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 54 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 HDIT101 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 104 (25.00%)
    11 / 54 (20.37%)
    Cardiac disorders
    Cardiac disorder
    Additional description: All
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    surgical and medical procedures
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Nervous system disorder
    Additional description: All
         subjects affected / exposed
    5 / 104 (4.81%)
    1 / 54 (1.85%)
         occurrences all number
    6
    1
    General disorders and administration site conditions
    General Disorder
    Additional description: All
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 54 (0.00%)
         occurrences all number
    5
    0
    Immune system disorders
    Immune system disorder
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastrointestinal disorders
    Additional description: All
         subjects affected / exposed
    4 / 104 (3.85%)
    1 / 54 (1.85%)
         occurrences all number
    4
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 54 (1.85%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Renal and urinary disorders
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    infections and infestations
    Additional description: All
         subjects affected / exposed
    13 / 104 (12.50%)
    6 / 54 (11.11%)
         occurrences all number
    14
    9
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
    Additional description: All
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 54 (1.85%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2020
    Section 12.8: Criteria for Premature Termination were added as requested from the Competent Authority Change in address of Coordinating investigator Additional minor correction of typos, changes in wording or other minor clarifications/changes.
    15 Apr 2021
    Screening phase criteria were updated (1 lesion within 150 day required) Several inclusion and exclusion criteria were specified or adapted contraception methods were updated Paracetamol and ibuprofen were allowed as concomitant medication Documentation of lesion score and aborted lesion definition was specified in more detail Study timelines updated Sponsor address updated Additional minor correction of typos, changes in wording or other minor clarifications/changes.
    28 Jun 2022
    Number of sites was increased Endpoint definitions were specified Country specific text for Austria included Timelines were updated Minor changes and corrections

    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.
    The DMC recommended to terminate the study early due to futility. There were no safety concerns. Due to the early termination, not all planned analyses could be or have been performed, therefore only key outcome and safety results are reported.
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