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    Clinical Trial Results:
    A single center, open-label, two-period, non-randomized, paired-design study to compare steady-state plasma levels following switch from a 10 mg/ml treprostinil formulation to a 20 mg/ml treprostinil formulation in patients with pulmonary arterial hypertension (PAH)

    Summary
    EudraCT number
    		 2021-004002-21
    Trial protocol
    		 AT  
    Global end of trial date
    21 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2023
    First version publication date
    03 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Bio-Eq-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AOP Orphan Pharmaceuticals GmbH
    Sponsor organisation address
    Leopold-Ungar-Platz 2, Vienna, Austria, 1190
    Public contact
    Clinical Project Manager, AOP Orphan Pharmaceuticals GmbH, bio-eq-20@aoporphan.com
    Scientific contact
    Clinical Project Manager, AOP Orphan Pharmaceuticals GmbH, bio-eq-20@aoporphan.com
    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
    07 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the interchangeability of 20 mg/ml treprostinil compared to a 10 mg/ml treprostinil formulation by using pharmacokinetic (PK) endpoints.
    Protection of trial subjects
    The Investigator obtained a freely given signed ICF, with name and date and time noted by the patient before the patient was exposed to any study-related procedure. The study was carried out in compliance with the principles of Good Clinical Practice (GCP), data protection and confidentiality were handled in compliance with local laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    9
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients aged 18 years at screening or above with confirmed PAH diagnosis and who met all inclusion and exclusion criteria, were invited to participate in the study.

    Pre-assignment
    Screening details
    		 Patients who fulfill inclusion and exclusion criteria were enrolled into the study after giving their informed consent. A total of 12 patients was screened and were enrolled into the study.

    Period 1
    Period 1 title
    Non-IMP - 10 mg/ml treprostinil
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Non-IMP - 10 mg/ml treprostinil
    Arm description
    		 -
    Arm type
    		 Non-IMP - 10 mg/ml treprostinil

    Investigational medicinal product name
    Non-IMP - 10 mg/ml treprostinil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients who were already receiving 10 mg/ml treprostinil as continuous SC infusion via an ambulatory infusion pump as standard treatment for their PAH disease and on a stable dose of at least 15 ng/kg/min since at least 2 weeks.

    Number of subjects in period 1
    		Non-IMP - 10 mg/ml treprostinil
    Started
    12
    Completed
    12
    Period 2
    Period 2 title
    IMP - 20 mg/ml treprostinil
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMP - 20 mg/ml treprostinil
    Arm description
    		 The patients started with period 2 in the morning at 09:00 hours clock time after non-IMP was switched to the 20 mg/ml treprostinil formulation.
    Arm type
    		 20 mg/ml treprostinil

    Investigational medicinal product name
    20 mg/ml treprostinil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as continuous subcutaneous infusion via an ambulatory infusion pump. Dosage and regimen: Each patient was administered 20 mg/ml treprostinil formulation for 24 hours maintaining the same dose used for at least 2 weeks prior to study start.

    Number of subjects in period 2
    		IMP - 20 mg/ml treprostinil
    Started
    12
    Completed
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Non-IMP - 10 mg/ml treprostinil
    Reporting group description
    		 Number of subjects at baseline: 12

    Reporting group values
    		 Non-IMP - 10 mg/ml treprostinil Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        aged 18 years or above
    		 12 12
    Gender categorical
    Units: Subjects
        male
    		 7 7
        female
    		 5 5
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all patients who have signed the informed consent (i.e., including screening failures plus subject enrolled). The FAS is the primary set used for patient disposition and baseline characteristics, analyses of the secondary endpoint and safety data.

    Subject analysis sets values
    		 FAS
    Number of subjects
    12
    Age categorical
    Units: Subjects
        aged 18 years or above
    12
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        male
    7
        female
    5

    End points

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    End points reporting groups
    Reporting group title
    Non-IMP - 10 mg/ml treprostinil
    Reporting group description
    		 -
    Reporting group title
    IMP - 20 mg/ml treprostinil
    Reporting group description
    		 The patients started with period 2 in the morning at 09:00 hours clock time after non-IMP was switched to the 20 mg/ml treprostinil formulation.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all patients who have signed the informed consent (i.e., including screening failures plus subject enrolled). The FAS is the primary set used for patient disposition and baseline characteristics, analyses of the secondary endpoint and safety data.

    Primary: Average concentration of treprostinil at steady-state (Cavg.ss)

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    End point title
    		 Average concentration of treprostinil at steady-state (Cavg.ss)
    End point description
    To evaluate the primary endpoint a two-way ANOVA model was fitted using the ln-transformed Cavg,ss as output variable including Patient N° and period as categorical covariates. The point estimate, geometric mean ratio was obtained by back transformation from the ln-scale of the estimated treatment covariate coefficient (i.e., difference of ln(Cavg,ss) between periods). The two-sided 90% confidence interval of the point estimate was obtained by back transformation from the ln-scale of the two-sided 90% confidence interval of the estimated treatment covariate coefficient. Bioequivalence was to be concluded if the 2-sided 90% CI is contained within the closed interval [0.8, 1.25].
    End point type
    Primary
    End point timeframe
    Two 24h periods - one 24h period on non-IMP (10 mg/ml TRE) followed by 24h period on IMP (20 mg/ml TRE)
    End point values
    		 Non-IMP - 10 mg/ml treprostinil IMP - 20 mg/ml treprostinil
    Number of subjects analysed
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    10.3850 ( 5.89362 )
    9.2863 ( 6.11273 )
    Statistical analysis title
    		 Primary Endpoint Analysis
    Statistical analysis description
    The point estimate of the ratio of the geometric mean of IMP to the geometric mean of the non-IMP for Cavg,ss was obtained from the ANOVA model by back transformation from the ln-scale of the estimated treatment covariate coefficient (i.e., difference of ln(Cavg,ss) between periods). The corresponding two-sided CI90% of the point estimate was obtained from the ANOVA model by back transformation from the ln-scale of the two-sided CI90% of the estimated treatment covariate coefficient.
    Comparison groups
    Non-IMP - 10 mg/ml treprostinil v IMP - 20 mg/ml treprostinil
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    		 ANOVA
    Parameter type
    		 GMR
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 0.97
    Notes
    [1] - In total, 12 subjects were analyzed in period 1 and period 2, which are automatically calculated and displayed as "Number of subjects included in analysis: *24"

    Secondary: Average pain scale score

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    End point title
    		 Average pain scale score
    End point description
    The pain scale was designed as a 5-scale intensity score (ranging from 1 no pain to 5 extreme pain) (score 1 = no pain; score 2 = slight pain; score 3 = moderate pain; score 4 = severe pain; score 5 = extreme pain). The secondary endpoint analysis was performed using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    The local infusion site tolerability was assessed per patient by a non-validated pain scale at screening in period 1 (4 h, 24h) and in period 2 (28h, 48h).
    End point values
    		 FAS
    Number of subjects analysed
    Units: NA
    arithmetic mean (standard deviation)
        Screening
    1.4 ( 0.51 )
        Period P1-4h
    1.6 ( 0.51 )
        Period P1-24h
    1.3 ( 0.49 )
        Period P2-28h
    1.4 ( 0.51 )
        Period P2-48
    1.2 ( 0.39 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded throughout the study from screening until the subject completed the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 -

    Reporting group title
    Period 2
    Reporting group description
    		 -

    Reporting group title
    Overall
    Reporting group description
    		 -

    Reporting group title
    AE over both Periods
    Reporting group description
    		 AEs reported as overlapping from Period 1 to Period 2

    Serious adverse events
    		 Period 1 Period 2 Overall AE over both Periods
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Period 1 Period 2 Overall AE over both Periods
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    7 / 12 (58.33%)
    9 / 12 (75.00%)
    2 / 12 (16.67%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    General disorders and administration site conditions
    Infusion Site Pain
         subjects affected / exposed
    7 / 12 (58.33%)
    6 / 12 (50.00%)
    8 / 12 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    7
    6
    8
    2
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2021
    Following inclusion and exclusion criteria were adjusted to ensure fast enrolment of the patients: • Inclusion of patients aged 18 years and older • Patients on a stable dose of at least 15 ng/kg/min instead of 30 ng/kg/min • No limitations regarding the BMI • Infusion site pain not > 3 (5-scale intensity score) at the time of screening.

    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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