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    Clinical Trial Results:
    Controlled clinical trial to evaluate the safety and efficacy of stereotactical photodynamic therapy with 5-aminolevulinic acid (Gliolan®) in recurrent glioblastoma

    Summary
    EudraCT number
    		 2015-002727-25
    Trial protocol
    		 DE  
    Global end of trial date
    30 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2026
    First version publication date
    14 Feb 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UKM12_0017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04469699
    WHO universal trial number (UTN)
    		 U1111-1182-8541
    Other trial identifiers
    		 EUDAMED number: CIV-17-03-018624
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Münster
    Sponsor organisation address
    Albert-Schweitzer-Campus 1, Münster, Germany, 48149
    Public contact
    Klinik für Neurochirurgie, Universitätsklinikum Münster, +49 1733802878, juliane.schroeteler@ukmuenster.de
    Scientific contact
    Klinik für Neurochirurgie, Universitätsklinikum Münster, +49 1733802878, juliane.schroeteler@ukmuenster.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
    27 Nov 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2025
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The study was initiated to compare the following treatment concepts of recurrent glioblastoma with respect to efficacy, safety and quality of life: • iPDT (interstitial photodynamic therapy) with 5-Aminolevulinic hydrochloric acid (5-ALA) and consecutive therapy at the investigator’s discretion • Therapy at the investigator’s discretion without iPDT and 5-ALA.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines in Good Clinical Practice. The study was not started before the competent ethics committee had given a favorable opinion. Written informed consent was obtained from all patients and the study was only conducted as approved by the Ethics committee and the competent authority. Amendments were only implemented after approval.
    Background therapy
    		 Patients were randomized with 1:1 allocation ratio in two arms, either to receive a biopsy followed by iPDT with 5-ALA (treatment arm) or only a biopsy (control arm). All patients received best possible care at the investigator’s discretion. Treatment was started as soon as adequate after stereotactic intervention. The only treatment not allowed in this study was the administration of antiangiogenic drugs.
    Evidence for comparator
    		 Due to the matter of fact, that there is no standard therapy in the recurrent situation of glioblastoma available, all patients received best possible therapy. Patients were not be disadvantaged in their treatment by participation in the study regarding standard treatment. The best possible conservative treatment was allowed.
    Actual start date of recruitment
    01 Mar 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    21
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From April 12, 2021, through October 16, 2024, a total of 30 patients were included in the study.

    Pre-assignment
    Screening details
    		 Each patient's eligibility was verified during a screening visit. Informed consent was obtained prior to any clinical procedures that are performed solely for study-related purposes. After obtaining informed consent, patients were randomized to either the treatment or control arm.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5-ALA iPDT - randomization
    Arm description
    		 Patients randomized to receive iPDT with 5-ALA (treatment arm / including screening failures).
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-ALA
    Investigational medicinal product code
    Other name
    5-aminolevulinic acid (Gliolan®)
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Four hours (range: 3.5 to 4.5 hours) prior to anaesthesia for stereotactic surgery, patients receiving iPDT took 20 mg freshly dissolved 5-ALA HCL per kg body weight orally and under supervision.

    Arm title
    		 Control - randomization
    Arm description
    		 Patients randomized to the contol arm (including screening failures)
    Arm type
    		 Therapy at investigator's discretion without iPDT

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		5-ALA iPDT - randomization Control - randomization
    Started
    15
    15
    Completed
    10
    12
    Not completed
    5
    3
         During surgery, biopsy did not verify glioblastoma
    3
    2
         Terminated trial before getting the procedure
    2
    1
    Period 2
    Period 2 title
    Modified intention-to-treat set
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5-ALA iPDT
    Arm description
    		 Patient who were randomized to iPDT with 5-ALA and who had biopsy-confirmed glioblastoma (without screening failures).
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-ALA
    Investigational medicinal product code
    Other name
    5-aminolevulinic acid (Gliolan®)
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Four hours (range: 3.5 to 4.5 hours) prior to anaesthesia for stereotactic surgery, patients receiving iPDT took 20 mg freshly dissolved 5-ALA HCL per kg body weight orally and under supervision.

    Arm title
    		 Control
    Arm description
    		 Patient who were randomized to the control arm and who had biopsy-confirmed glioblastoma (without screening failures).
    Arm type
    		 Therapy at investigator's discretion without iPDT

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: 22 patients were included in the modified intention-to-treat set (mITT). All 22 patients received treatment as planned. Because, there were no major protocol violations, the per protocol set is identical to the per protocol collective and to the safety set. 10 patients were analyzed in the 5-ALA iPDT arm and 12 patients in the control group.
    Number of subjects in period 2 [2]
    		5-ALA iPDT Control
    Started
    10
    12
    Completed
    10
    12
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 30 Patients were randomized to the treatment group 5-ALA iPDT and control group. During surgery, the biopsy did not verify a glioblastoma for n=5 patients. 3 additional patients were excluded, because an exclusion criterion was met before starting with the treatment or the tumor recurrence was too big. These 8 patients were excluded as screening failures. They did not receive the assigned treatment and discontinued the trial immediately. No further follow-up data were collected.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    5-ALA iPDT
    Reporting group description
    		 Patient who were randomized to iPDT with 5-ALA and who had biopsy-confirmed glioblastoma (without screening failures).

    Reporting group title
    Control
    Reporting group description
    		 Patient who were randomized to the control arm and who had biopsy-confirmed glioblastoma (without screening failures).

    Reporting group values
    		 5-ALA iPDT Control Total
    Number of subjects
    		 10 12 22
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 9 6 15
        From 65-84 years
    		 1 6 7
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.4 ( 13.31 ) 59.8 ( 12.50 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 7 9
        Male
    		 8 5 13
    NIHSS total score (baseline)
    Units: Subjects
        Score = 0
    		 6 5 11
        Score = 1
    		 2 4 6
        Score = 2
    		 2 0 2
        Score = 3
    		 0 1 1
        Score = 4
    		 0 2 2
    Karnofsky Performance Score (baseline)
    Units: Subjects
        unable to carry on normal activity
    		 1 0 1
        some signs or symptoms of disease
    		 1 2 3
        minor signs or symptoms of disease
    		 6 6 12
        no complaints; no evidence of disease
    		 2 4 6
    Karnofsky Performance Score (baseline)
    Units: Karnofsky Performance Score
        median (inter-quartile range (Q1-Q3))
    		 90.0 (90.0 to 90.0) 90.0 (90.0 to 100.0) -
    Mini-Mental state examination score (baseline)
    Units: Mini-Mental state examination score
        median (inter-quartile range (Q1-Q3))
    		 26.0 (24.0 to 30.0) 28.0 (25.0 to 30.0) -
    QLQ-C30 Summary Score (baseline)
    Units: QLQ-C30 Summary Score
        median (inter-quartile range (Q1-Q3))
    		 81.6 (78.0 to 90.2) 77.8 (70.4 to 93.3) -

    End points

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    End points reporting groups
    Reporting group title
    5-ALA iPDT - randomization
    Reporting group description
    		 Patients randomized to receive iPDT with 5-ALA (treatment arm / including screening failures).

    Reporting group title
    Control - randomization
    Reporting group description
    		 Patients randomized to the contol arm (including screening failures)
    Reporting group title
    5-ALA iPDT
    Reporting group description
    		 Patient who were randomized to iPDT with 5-ALA and who had biopsy-confirmed glioblastoma (without screening failures).

    Reporting group title
    Control
    Reporting group description
    		 Patient who were randomized to the control arm and who had biopsy-confirmed glioblastoma (without screening failures).

    Subject analysis set title
    modified ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized. Not included in the modified ITT (mITT) population are patients who were randomized but do not have histological confirmation of glioblastoma during surgery, or patients who were incorrectly randomized although an inclusion criterion was not met or an exclusion criterion was met and those who terminated study participation before the start of surgery. These patient were excluded as screening failures.

    Primary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    The primary endpoint was progression-free survival (PFS) defined as number of days from randomization until diagnosis of progressive disease as determined by MRI according to RANO criteria or death from any cause. For a patient with none of these events before the end of follow-up, observation of PFS was censored at the date of last follow-up.
    End point type
    Primary
    End point timeframe
    From randomization until diagnosis of progressive disease or death or last follow-up.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    12
    Units: Patients (progression or death)
    8
    7
    Attachments
    		 Kaplan-Meier plot of progression-free survival
    Statistical analysis title
    		 Adaptive analysis (two-sided)
    Statistical analysis description
    Two adaptive one-sided two-stage designs using an Pocock-type alpha-spending function and the inverse normal combination method were applied. Since the study ended before any interim analysis was performed, the one-sided alpha spending functions in the two-stage adaptive design were set to 2.5%. Consequently, the initial adaptive design now corresponds to a two-sided log-rank test with a 5% significance level. Analysis was performed in the in the modified ITT set.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.346
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.602
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.207
         upper limit
    		 1.749
    Notes
    [1] - It could not be demonstrated that the 5-ALA iPDT group differed significantly from the control group in terms of PFS. The observed PFS curves were in favor of 5-ALA iPDT with a hazard ratio of 0.602 (95% CI 0.207, 1.749).
    Statistical analysis title
    		 Adapt. 2-stage design f. superiority of 5-ALA iPDT
    Statistical analysis description
    An adaptive one-sided two-stage design for the superiority hypothesis using an Pocock-type alpha-spending function and the inverse normal combination method were applied. Since the study ended before any interim analysis was performed, the one-sided alpha spending function in the two-stage adaptive design was set to 2.5%. Analysis was performed in the in the modified ITT set.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1732
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Adapt. 2-stage design f. inferiority of 5-ALA iPDT
    Statistical analysis description
    An adaptive one-sided two-stage design for the inferiority hypothesis using an Pocock-type alpha-spending function and the inverse normal combination method were applied. Since the study ended before any interim analysis was performed, the one-sided alpha spending function in the two-stage adaptive design was set to 2.5%. Analysis was performed in the in the modified ITT set.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8268
    Method
    		 Logrank
    Confidence interval

    Secondary: 6-month rate of progression free survival (PFS)

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    End point title
    		 6-month rate of progression free survival (PFS)
    End point description
    PFS until 6 months is defined as number of days from randomization until diagnosis of progressive disease as determined by MRI according to RANO criteria or death from any cause until 6 months. All observations and events beyond 6 months were censored at 6 months. Event-free rates will be reported as Kaplan-Meier estimates with 95% confidence interval (complementary log-log-transformed).
    End point type
    Secondary
    End point timeframe
    From randomization until diagnosis of progressive disease or death or last follow-up.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    12
    Units: Percent
        number (confidence interval 95%)
    78.8 (38.1 to 94.3)
    40.9 (10.0 to 70.7)
    Statistical analysis title
    		 Two-sided logrank test
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.105
    Method
    		 Two-sided log-rank test
    Confidence interval

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS started at randomization and ended at the day of death. Patients alive were censored at the date of their last follow-up.
    End point type
    Secondary
    End point timeframe
    From the day of randomization until death or last follow-up.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    12
    Units: Deceased patients
    5
    4
    Attachments
    		 Kaplan-Meier plot of overall survival
    Statistical analysis title
    		 Two-sided logrank test
    Statistical analysis description
    OS after randomization was compared between the treatment groups in the modified ITT set using a two-sided log-rank test.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.413
    Method
    		 Two-sided log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 2.22
    Notes
    [2] - Median OS was 24 months (95% CI 5.6 - NE) and 7.9 (5.1 - NE) months.

    Secondary: 12-month overall survival (OS) rate

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    End point title
    		 12-month overall survival (OS) rate
    End point description
    Alive patients were censored at the time of their last follow-up, but at the latest after 12 months. All events beyond 12 months were censored at 12 months. Overall survival time began at randomization and ended on the day of death if this occurred earlier than 12 months after randomization. Event-free rates at 12 months are reported as Kaplan-Meier estimates with 95% confidence interval (complementary log-log-transformed).
    End point type
    Secondary
    End point timeframe
    From randomization until 12 months after randomization.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    12
    Units: Percent
        number (confidence interval 95%)
    77.8 (36.5 to 93.9)
    43.8 (10.1 to 74.2)
    Statistical analysis title
    		 Two-sided logrank test
    Statistical analysis description
    OS until 12 months after randomization was compared between the treatment groups in the modified ITT set using a two-sided log-rank test. Therefore, all observations and events beyond 12 months were censored at 12 months. The analysis was performed using all available patients in the modified ITT set.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.147
    Method
    		 Two-sided log-rank test
    Confidence interval

    Secondary: Occurrence of brain edema

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    End point title
    		 Occurrence of brain edema
    End point description
    Occurrence of brain edema as assessed by MRI (yes/no) in the first 48 hours after iPDT.
    End point type
    Secondary
    End point timeframe
    Within 26-48 hours after iPDT / biopsy.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    11
    Units: Patients with brain edema
    2
    1
    Statistical analysis title
    		 Occurrence of brain edema in the first 48h
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.586
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response rate 26-48h after treatment

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    End point title
    		 Response rate 26-48h after treatment
    End point description
    26-48h response rate on MRI according to RANO (CR/PR/SD/PD) after treatment with iPDT or after biopsy.
    End point type
    Secondary
    End point timeframe
    26-48h after treatment with iPDT or after biopsy.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    11
    Units: Patients affected
        CR (Complete Response)
    0
    2
        PR (Partial Response)
    1
    3
        SD (Stable Disease)
    7
    5
        PD (Progressive Disease)
    1
    0
        Not assessable
    1
    1
    Statistical analysis title
    		 Fisher's exakt test
    Statistical analysis description
    The categorical endpoint is compared between the treatment groups in the mITT set using Fisher's exact test. Only patients with available response measurements are included. Patients who are deceased or had no response evaluation at this timepoint are not considered.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.4925
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - Response evaluation on MRI 26-48h after surgery, revealed that 5 of 11 available control patient reached at least a PR (PR: n=3, CR: n=2), where only one 5-ALA iPDT patient reached a PR.

    Secondary: Response rate one month after randomisation

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    End point title
    		 Response rate one month after randomisation
    End point description
    One month response rate on MRI according to RANO (CR/PR/SD/PD) after randomisation.
    End point type
    Secondary
    End point timeframe
    One month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    5
    Units: Patients affected
        CR (Complete Response)
    1
    0
        PR (Partial Response)
    1
    0
        SD (Stable Disease)
    7
    2
        PD (Progressive Disease)
    0
    3
        Not assessable
    1
    0
    Statistical analysis title
    		 Fisher's exakt test
    Statistical analysis description
    The categorical endpoint is compared between the treatment groups in the mITT set using Fisher's exact test. Only patients with available response measurements are included. Patients who are deceased or had no response evaluation at this timepoint are not considered.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0709
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - One month after treatment, none of the 5 control patients with MRI measurement has reached a PR, where one 5-ALA iPDT patient reached a CR and one a PR.

    Secondary: Change in contrast medium volume uptake 26-48h after treatment

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    End point title
    		 Change in contrast medium volume uptake 26-48h after treatment
    End point description
    Change in contrast medium volume uptake between baseline and the MRI performed 26-48 hours after treatment as categorical variable T1-Gd+ (no change, ≥50% decrease, <50% decrease but <25% increase, ≥25% increase).
    End point type
    Secondary
    End point timeframe
    26-48 hours after treatment.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    11
    Units: Patients affected
        No change
    1
    3
        >= 50% decrease
    1
    2
        <50% decrease but <25% increase
    8
    5
        >=25% increase
    0
    1
    Statistical analysis title
    		 Fisher's exact test
    Statistical analysis description
    The categorical endpoint is compared between the treatment groups in the mITT set using Fisher's exact test. Only patients with available measurements are included. Patients who are deceased or missing values at this timepoint are not considered.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4381
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Change in contrast medium volume uptake 1 month after randomisation

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    End point title
    		 Change in contrast medium volume uptake 1 month after randomisation
    End point description
    Change in contrast medium volume uptake between baseline and the MRI performed one month after randomisation as categorical variable T1-Gd+ (no change, ≥50% decrease, <50% decrease but <25% increase, ≥25% increase).
    End point type
    Secondary
    End point timeframe
    One month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    5
    Units: Patients affected
        No change
    2
    1
        >= 50% decrease
    1
    0
        <50% decrease but <25% increase
    7
    3
        >=25% increase
    0
    1
    Statistical analysis title
    		 Fisher's exact test
    Statistical analysis description
    The categorical endpoint is compared between the treatment groups in the mITT set using Fisher's exact test. Only patients with available measurements are included. Patients who are deceased or missing values at this timepoint are not considered.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7902
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Difference EORTC QLQ-C30 Summary Score - baseline to discharge / d7

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    End point title
    		 Difference EORTC QLQ-C30 Summary Score - baseline to discharge / d7
    End point description
    The difference in the EORTC QLQ-C30 Summary Score from baseline to discharge / d7.
    End point type
    Secondary
    End point timeframe
    From baseline to discharge / d7.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    8
    9
    Units: QLQ-C30 Summary Score
        median (inter-quartile range (Q1-Q3))
    -4.10 (-13.57 to 1.71)
    -6.97 (-11.24 to 0.13)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9829
    Method
    		 exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference EORTC QLQ-C30 Summary Score - baseline to 1 month after randomisation

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    End point title
    		 Difference EORTC QLQ-C30 Summary Score - baseline to 1 month after randomisation
    End point description
    The difference in the EORTC QLQ-C30 Summary Score from baseline to 1 month after randomisation.
    End point type
    Secondary
    End point timeframe
    From baseline to 1 month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    7
    Units: QLQ-C30 Summary Score
        median (inter-quartile range (Q1-Q3))
    -1.45 (-4.57 to 7.26)
    -9.53 (-18.46 to -3.21)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1932
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference EORTC QLQ-BN20 Summary Score - baseline to discharge / d7

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    End point title
    		 Difference EORTC QLQ-BN20 Summary Score - baseline to discharge / d7
    End point description
    The difference in the EORTC QLQ-BN20 Summary Score from baseline to discharge / d7.
    End point type
    Secondary
    End point timeframe
    From baseline to discharge / d7.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    8
    9
    Units: EORTC QLQ-BN20 Summary Score
        median (inter-quartile range (Q1-Q3))
    4.17 (-4.67 to 8.71)
    3.03 (-11.87 to 8.08)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6058
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference EORTC QLQ-BN20 Summary Score - baseline to 1 month after randomisation

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    End point title
    		 Difference EORTC QLQ-BN20 Summary Score - baseline to 1 month after randomisation
    End point description
    The difference in the EORTC QLQ-BN20 Summary Score from baseline to 1 month after randomisation.
    End point type
    Secondary
    End point timeframe
    From baseline to 1 month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    9
    7
    Units: EORTC QLQ-BN20 Summary Score
        median (inter-quartile range (Q1-Q3))
    5.05 (3.28 to 5.81)
    -12.37 (-18.18 to 4.55)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0907
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference Karnofsky Performance Score - baseline to 26-48h after treatment

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    End point title
    		 Difference Karnofsky Performance Score - baseline to 26-48h after treatment
    End point description
    The difference in the Karnofsky Performance Score from baseline to 26-48h after treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to 26-48h after treatment.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    9
    Units: Karnofsky Performance Score
        median (inter-quartile range (Q1-Q3))
    0.00 (-10.00 to 0.00)
    -10.00 (-20.00 to 0.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1905
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference Karnofsky Performance Score - baseline to discharge / d7

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    End point title
    		 Difference Karnofsky Performance Score - baseline to discharge / d7
    End point description
    The difference in the Karnofsky Performance Score from baseline to discharge / d7.
    End point type
    Secondary
    End point timeframe
    From baseline to discharge / d7.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    9
    11
    Units: Karnofsky Performance Score
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    -10.00 (-10.00 to 0.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0903
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference Karnofsky Performance Score - baseline to 1 month after randomisation

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    End point title
    		 Difference Karnofsky Performance Score - baseline to 1 month after randomisation
    End point description
    The difference in the Karnofsky Performance Score from baseline to 1 month after randomisation.
    End point type
    Secondary
    End point timeframe
    From baseline to 1 month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    6
    Units: Karnofsky Performance Score
        median (inter-quartile range (Q1-Q3))
    -10.00 (-10.00 to 0.00)
    -5.00 (-10.00 to 0.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.764
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference Mini-Mental state examination score - baseline to 26-48h after treatment

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    End point title
    		 Difference Mini-Mental state examination score - baseline to 26-48h after treatment
    End point description
    The difference in the Mini-Mental state examination score from baseline to 26-48h after treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to 26-48h after treatment.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    9
    Units: Mini-Mental state examination score
        median (inter-quartile range (Q1-Q3))
    0.00 (-1.00 to 0.00)
    0.00 (-1.00 to 1.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8941
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference Mini-Mental state examination score - baseline to discharge / d7

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    End point title
    		 Difference Mini-Mental state examination score - baseline to discharge / d7
    End point description
    The difference in the Mini-Mental state examination score from baseline to discharge / d7.
    End point type
    Secondary
    End point timeframe
    From baseline to discharge / d7.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    9
    10
    Units: Mini-Mental state examination score
        median (inter-quartile range (Q1-Q3))
    0.00 (-1.00 to 0.00)
    0.00 (-1.00 to 3.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5187
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference Mini-Mental state examination score - baseline to 1 month after randomisation

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    End point title
    		 Difference Mini-Mental state examination score - baseline to 1 month after randomisation
    End point description
    The difference in the Mini-Mental state examination score from baseline to 1 month after randomisation.
    End point type
    Secondary
    End point timeframe
    From baseline to 1 month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    6
    Units: Mini-Mental state examination score
        median (inter-quartile range (Q1-Q3))
    0.00 (-2.00 to 2.00)
    -1.00 (-2.00 to -1.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5748
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference NIHSS total score - baseline to 26-48h after treatment

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    End point title
    		 Difference NIHSS total score - baseline to 26-48h after treatment
    End point description
    The difference in the NIHSS total score from baseline to 26-48h after treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to 26-48h after treatment.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    9
    Units: NIHSS total score
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 1.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8042
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference NIHSS total score - baseline to discharge / d7

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    End point title
    		 Difference NIHSS total score - baseline to discharge / d7
    End point description
    The difference in the NIHSS total score from baseline to discharge / d7.
    End point type
    Secondary
    End point timeframe
    From baseline to discharge / d7.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    9
    11
    Units: NIHSS total score
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 1.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8672
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Secondary: Difference NIHSS total score - baseline to 1 month after randomisation

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    End point title
    		 Difference NIHSS total score - baseline to 1 month after randomisation
    End point description
    The difference in the NIHSS total score from baseline to 1 month after randomisation.
    End point type
    Secondary
    End point timeframe
    From baseline to 1 month after randomisation.
    End point values
    		 5-ALA iPDT Control
    Number of subjects analysed
    10
    6
    Units: NIHSS total score
        median (inter-quartile range (Q1-Q3))
    1.00 (0.00 to 2.00)
    1.00 (0.00 to 2.00)
    Statistical analysis title
    		 Exact Mann-Whitney U test
    Statistical analysis description
    The change is compared between the treatment groups in the mITT set using an exact Mann-Whitney U test. Only patients with available measurements at baseline and this follow-up time were included.
    Comparison groups
    5-ALA iPDT v Control
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8689
    Method
    		 Exact Mann-Whitney U test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were documented from the time the informed consent was signed until 3 months after surgery. All serious AEs (SAEs) were documented until end of individual trial participation or until disease progression whichever occured earlier.
    Adverse event reporting additional description
    AEs occurred in 12 patients (5-ALA iPDT n=6, control n=6), and SAEs occurred in 9 patients (5-ALA iPDT n=5, control n=4). There were 14 MedDRA codes reported in the 5-ALA iPDT group and 10 in the group. 15 of them were SAEs (5-ALA iPDT n=9, control n=6). In addition to MedDRA version 26.0, versions 26.1, 27.0 and 28.1 were also used.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    5-ALA iPDT (Safety set)
    Reporting group description
    		 Patients receiving iPDT with 5-ALA (treatment arm), identical to the modified ITT treatment arm.

    Reporting group title
    Control (Safety set)
    Reporting group description
    		 Patients receiving therapy at the investigator’s discretion without iPDT (control arm), identical to the modified ITT control arm.

    Serious adverse events
    		 5-ALA iPDT (Safety set) Control (Safety set)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    5
    4
         number of deaths resulting from adverse events
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Personality disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Brain abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 5-ALA iPDT (Safety set) Control (Safety set)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 12 (25.00%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Hemianopia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Monoparesis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Partial seizures
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Quadrantanopia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Aug 2021
    The study was initiated with study protocol version 5.2 dated October 31, 2019. During the course of the study, the protocol was amended once to version 5.3 dated July 29, 2021. The chapter “Assessment of safety” has been adapted to the new medical device legislation. There have also been changes to the accompanying research project. Immunophenotyping has been removed. Instead, additional blood plasma tests will be conducted. It is clarified that the translational studies are optional and will only be performed on patients who have given their separate consent. In addition, due to the delayed start of the study, the schedule was adjusted and the change of address of the project manager was included.

    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.
    Due to the prematurely termination of the study and small sample size, the generalizability of the study results is severely limited. Furthermore, relevant differences between the treatment arms cannot be demonstrated with the small number of cases.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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