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    Clinical Trial Results:
    Phase 1/2 study to assess the safety and pharmacokinetics of subcutaneous injection of OCTA101 in previously treated adult patients with severe hemophilia A

    Summary
    EudraCT number
    		 2018-002776-40
    Trial protocol
    		 BG  
    Global end of trial date
    18 Feb 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SubQ8-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04046848
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstrasse 2, Lachen, Switzerland, 8853
    Public contact
    Sigurd Knaub, Octapharma AG, sigurd.knaub@octapharma.com
    Scientific contact
    Sigurd Knaub, Octapharma AG, sigurd.knaub@octapharma.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
    12 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the safety of various doses of OCTA101 after subcutaneous (sc) injection.
    Protection of trial subjects
    This trial was conducted in accordance to the principles of ICH- GCP E6 (R2), ensuring that the rights, safety and well-being of patients are protected and in consistency with the Declaration of Helsinki and with applicable regulatory requirements. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and risk factors associated with the investigational medicinal product. For each subject safety was assessed throughout the study duration, such as monitoring of AEs, SAEs and recording of concomitant medication. Safety data and study progress were reviewed quite frequently by an Independent Data Monitoring Committee. The decision of going to the next higher dose was to taken after each cohort by an external independent DMC after review of safety and tolerability data, FVIII:C plasma levels, and PK characteristics of FVIII:C and von Willebrand Factor fragment dimer. Any safety-relevant signals were also forwarded to the DMC for their review as they occurred.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jul 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
    Bulgaria: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    35
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male patients aged ≥18 years with severe haemophilia A (<1% FVIII:C) as documented in medical records and having had ≥150 exposure days (EDs) with a FVIII product were screened according to predefined in- and exclusion criteria.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: OCTA101 50 IU/kg sc
    Arm description
    		 Single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing (abdomen or thigh) Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months. Patients received prophylactic Nuwiq for home treatment until the IDMC had confirmed that OCTA101 could be used as daily prophylaxis. At the end of the 3-month daily prophylactic period PK assessment was performed with 50 IU/kg OCTA101 (abdomen).
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCTA101 (human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of OCTA101 50 IU/kg sc was administered by sc injection into the abdomen or thigh. Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months.

    Arm title
    		 Cohort 2 : OCTA101 100 IU/kg sc
    Arm description
    		 Single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing (abdomen or thigh) followed by a daily prophylactic dosing (40-60 IU/kg) for 3 months. At the end of the 3-month daily prophylactic period PK assessment was to be performed with 50 IU/kg OCTA101 (abdomen). 4 patients completed the initial PK assessment, but only 2 completed the 3-month daily sc treatment period. Only 1 patient completed the repeat PK assessment. The two inhibitor patients as well as one patient whose FVIII levels were very low did not do the repeat PK assessment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCTA101 (human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of OCTA101 100 IU/kg sc was administered by sc injection into the abdomen or thigh. Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months.

    Arm title
    		 Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc
    Arm description
    		 Two-period investigation of a single iv dose of 50 IU/kg Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 administered into the abdomen profiled up to 72 hours. Treatments were to be administered in fixed sequence, with Nuwiq first. Following completion of the PK assessments in Cohort 3 and 1-month into OCTA101 daily prophylaxis in this cohort, the study was put on hold due to inhibitor development in a second patient (in Cohort 2). 8 patients completed the PK assessment but 0 completed the 3-month daily sc treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCTA101 (human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of OCTA101 50 IU/kg sc was administered by sc injection into the abdomen.

    Investigational medicinal product name
    Nuwiq
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nuwiq was to be injected iv once for PK evaluation at a dose of 50 IU/kg.

    Arm title
    		 Cohort 5: OCTA101 20, 40 and 60 IU/kg sc
    Arm description
    		 Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing, respectively. Treatments were to be administered in fixed dose-ascending sequence (each in the abdomen).
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCTA101 (human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each patient first received a single dose of 20 IU/kg sc (with 72 hours of observation), followed by a single dose of 40 IU/kg sc (with 72 hours of observation), followed by a single dose of 60 IU/kg sc (with 72 hours of observation) in the abdomen.

    Arm title
    		 Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Arm description
    		 Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily, then 25 IU/kg OCTA101 sc, and then depending on the overall data of the first 2 dose levels, 40 IU/kg OCTA101 sc could be considered (exact dosing depends on vial strength). Site of administration (abdomen or thigh) to be chosen by the patient. The study was stopped prematurely during the 12.5 IU/kg OCTA101 sc daily. 16 patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nuwiq
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nuwiq administered for prophylaxis in a 4 to 6-week run-in period.

    Investigational medicinal product name
    OCTA101 (human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Planned as 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily, then 25 IU/kg OCTA101 sc, and then depending on the overall data of the first 2 dose levels, 40 IU/kg OCTA101 sc could be considered (exact dosing depends on vial strength). Site of administration (abdomen or thigh) to be chosen by the patient. The study was stopped prematurely during the 12.5 IU/kg.

    Number of subjects in period 1
    		Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Started
    4
    4
    8
    4
    16
    Completed
    4
    2
    0
    4
    0
    Not completed
    0
    2
    8
    0
    16
         Adverse event, non-fatal
    -
    -
    -
    -
    2
         Sponsor decision
    -
    2
    8
    -
    13
         Consent withdrawn by subject
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: OCTA101 50 IU/kg sc
    Reporting group description
    		 Single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing (abdomen or thigh) Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months. Patients received prophylactic Nuwiq for home treatment until the IDMC had confirmed that OCTA101 could be used as daily prophylaxis. At the end of the 3-month daily prophylactic period PK assessment was performed with 50 IU/kg OCTA101 (abdomen).

    Reporting group title
    Cohort 2 : OCTA101 100 IU/kg sc
    Reporting group description
    		 Single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing (abdomen or thigh) followed by a daily prophylactic dosing (40-60 IU/kg) for 3 months. At the end of the 3-month daily prophylactic period PK assessment was to be performed with 50 IU/kg OCTA101 (abdomen). 4 patients completed the initial PK assessment, but only 2 completed the 3-month daily sc treatment period. Only 1 patient completed the repeat PK assessment. The two inhibitor patients as well as one patient whose FVIII levels were very low did not do the repeat PK assessment.

    Reporting group title
    Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc
    Reporting group description
    		 Two-period investigation of a single iv dose of 50 IU/kg Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 administered into the abdomen profiled up to 72 hours. Treatments were to be administered in fixed sequence, with Nuwiq first. Following completion of the PK assessments in Cohort 3 and 1-month into OCTA101 daily prophylaxis in this cohort, the study was put on hold due to inhibitor development in a second patient (in Cohort 2). 8 patients completed the PK assessment but 0 completed the 3-month daily sc treatment period.

    Reporting group title
    Cohort 5: OCTA101 20, 40 and 60 IU/kg sc
    Reporting group description
    		 Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing, respectively. Treatments were to be administered in fixed dose-ascending sequence (each in the abdomen).

    Reporting group title
    Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Reporting group description
    		 Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily, then 25 IU/kg OCTA101 sc, and then depending on the overall data of the first 2 dose levels, 40 IU/kg OCTA101 sc could be considered (exact dosing depends on vial strength). Site of administration (abdomen or thigh) to be chosen by the patient. The study was stopped prematurely during the 12.5 IU/kg OCTA101 sc daily. 16 patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed.

    Reporting group values
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily Total
    Number of subjects
    		 4 4 8 4 16 36
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.0 ± 7.35 40.5 ± 11.82 43.5 ± 12.78 29.5 ± 5.51 41.9 ± 12.37 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0
        Male
    		 4 4 8 4 16 36

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: OCTA101 50 IU/kg sc
    Reporting group description
    		 Single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing (abdomen or thigh) Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months. Patients received prophylactic Nuwiq for home treatment until the IDMC had confirmed that OCTA101 could be used as daily prophylaxis. At the end of the 3-month daily prophylactic period PK assessment was performed with 50 IU/kg OCTA101 (abdomen).

    Reporting group title
    Cohort 2 : OCTA101 100 IU/kg sc
    Reporting group description
    		 Single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing (abdomen or thigh) followed by a daily prophylactic dosing (40-60 IU/kg) for 3 months. At the end of the 3-month daily prophylactic period PK assessment was to be performed with 50 IU/kg OCTA101 (abdomen). 4 patients completed the initial PK assessment, but only 2 completed the 3-month daily sc treatment period. Only 1 patient completed the repeat PK assessment. The two inhibitor patients as well as one patient whose FVIII levels were very low did not do the repeat PK assessment.

    Reporting group title
    Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc
    Reporting group description
    		 Two-period investigation of a single iv dose of 50 IU/kg Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 administered into the abdomen profiled up to 72 hours. Treatments were to be administered in fixed sequence, with Nuwiq first. Following completion of the PK assessments in Cohort 3 and 1-month into OCTA101 daily prophylaxis in this cohort, the study was put on hold due to inhibitor development in a second patient (in Cohort 2). 8 patients completed the PK assessment but 0 completed the 3-month daily sc treatment period.

    Reporting group title
    Cohort 5: OCTA101 20, 40 and 60 IU/kg sc
    Reporting group description
    		 Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing, respectively. Treatments were to be administered in fixed dose-ascending sequence (each in the abdomen).

    Reporting group title
    Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Reporting group description
    		 Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily, then 25 IU/kg OCTA101 sc, and then depending on the overall data of the first 2 dose levels, 40 IU/kg OCTA101 sc could be considered (exact dosing depends on vial strength). Site of administration (abdomen or thigh) to be chosen by the patient. The study was stopped prematurely during the 12.5 IU/kg OCTA101 sc daily. 16 patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed.

    Subject analysis set title
    Safety Analysis (SAF) Cohort 1,2,3,5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients of Cohorts 1,2,3 and 5 who received at least one dose of IMP.

    Subject analysis set title
    Safety Analysis (SAF) Cohort 6
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients of Cohort 6 who received at least one dose of IMP.

    Primary: Adverse Events

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    End point title
    		 Adverse Events [1]
    End point description
    End point type
    Primary
    End point timeframe
    Entire study period after 1st IMP administration
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis, data are provided as tables and listings.
    End point values
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Number of subjects analysed
    4
    4
    8
    4
    10
    Units: participants
    0
    2
    1
    0
    3
    No statistical analyses for this end point

    Primary: Dose-limiting Toxicities (DLTs)

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    End point title
    		 Dose-limiting Toxicities (DLTs) [2]
    End point description
    Pre-defined DLTs for this study were: 1. Severe allergic reactions at least possibly related to study drug. 2. Severe vital organ toxicity at least possibly related to study drug that does not resolve to at least mild severity within 48 to 72 hours. 3. Any treatment-emergent severe toxicity at least possibly related to study drug other than the toxicities referenced in 2) that does not decrease to mild or resolve within 7 days.
    End point type
    Primary
    End point timeframe
    Entire study period after 1st IMP administration
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis, data are provided as tables and listings.
    End point values
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Number of subjects analysed
    4
    4
    8
    4
    10
    Units: participants
        number (not applicable)
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Thromboembolic Events

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    End point title
    		 Thromboembolic Events [3]
    End point description
    The definition of the cluster thromboembolic events was based on the standardised MedDRA query (SMQ) “Embolic and thrombotic events”: Definition: Thrombotic disorders are diseases characterized by formation of a thrombus that obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow downstream. Embolism is the sudden blocking of a vessel by a clot or foreign material which has been brought to its site of lodgment by the blood current. (Thrombo-)phlebitis is an inflammation of a vein (phlebitis) associated with thrombus formation (thrombosis). This SMQ includes 3 sub-SMQ: • Embolic and thrombotic events, venous (SMQ) • Embolic and thrombotic events, arterial (SMQ) • Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous (SMQ)
    End point type
    Primary
    End point timeframe
    throughout the study
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis, data are provided as tables and listings.
    End point values
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Number of subjects analysed
    4
    4
    8
    4
    10
    Units: participants
        number (not applicable)
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Local Injection Site Reactions

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    End point title
    		 Local Injection Site Reactions [4]
    End point description
    Investigator (and patient in case of home treatment) did assess local injection reactivity directly after injection and at 15 ± 5 min post-injection as described in ISO10999-10 standard: • 0=no skin reactivity; • 1=mild (subject is aware of the signs/symptoms, but finds it easily tolerated) • 2=moderate (discomfort enough to cause interference with usual activities) • 3=severe (subject is incapacitated and unable to work or participate in many or all usual activities).
    End point type
    Primary
    End point timeframe
    throughout the period where OCTA-101 was injected subcutaneously (sc).
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis, data are provided as tables and listings.
    End point values
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Number of subjects analysed
    4
    4
    8
    4
    10
    Units: participants
        number (not applicable)
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Inhibitor Formation to FVIII

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    End point title
    		 Inhibitor Formation to FVIII [5]
    End point description
    Inhibitor formation to FVIII was considered if at least one result of neutralizing antibody was equal or greater than 0.6 BU/mL as determined by the central lab.
    End point type
    Primary
    End point timeframe
    From first injection to 4 months after start of of daily injection (cohorts 1, 2 and 3), 4 weeks after last PK injection (cohort 5), monthly during the daily sc treatment period (cohort 6)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis, data are provided as tables and listings.
    End point values
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20, 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Number of subjects analysed
    4
    4
    8
    4
    10
    Units: participants
        number (not applicable)
    0
    2
    1
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire study period after 1st IMP administration
    Adverse event reporting additional description
    Data from repeat dosing were analysed separately from data related to the first doses.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Cohort 1: OCTA101 50 IU/kg sc
    Reporting group description
    		 Single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing (abdomen or thigh) Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months. At the end of the 3-month daily prophylactic period PK assessment was to be performed with 50 IU/kg OCTA101 (abdomen).

    Reporting group title
    Cohort 2 : OCTA101 100 IU/kg sc
    Reporting group description
    		 Single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing. (abdomrn of tigh) Following review of safety and tolerability data by Data Monitoring Committee a daily prophylactic dosing (40-60 IU/kg) for 3 months. At the end of the 3-month daily prophylactic period PK assessment was to be performed with 50 IU/kg OCTA101 (abdomen). 4 patients completed the PK assessment, but only 2 completed the 3-month daily sc treatment period as the DMC recommended cessation of all current and planned dosing of OCTA101 for any reason

    Reporting group title
    Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc
    Reporting group description
    		 Two-period investigation of a single iv dose of 50 IU/kg Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 administered into the abdomen profiled up to 72 hours. Treatments were to be administered in fixed sequence, with Nuwiq first. Following review of safety and tolerability data by Data Monitoring Committee daily prophylactic dosing (40-60 IU/kg) for 3 months 8 patients completed the PK assessment but 0 completed the 3-month daily sc treatment period as the DMC recommended cessation of all current and planned dosing of OCTA101 for any reason

    Reporting group title
    Cohort 5: OCTA101 20 , 40 and 60 IU/kg sc
    Reporting group description
    		 Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing, respectively. Treatments were to be administered in fixed dose-ascending sequence (each in the abdomen). 4 patients completed the PK assessment, but were not assigned to treatment as the DMC recommended cessation of all current and planned dosing of OCTA101 for any reason.

    Reporting group title
    Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Reporting group description
    		 Planned as 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily, then 25 IU/kg OCTA101 sc, and then depending on the overall data of the first 2 dose levels, 40 IU/kg OCTA101 sc could be considered (exact dosing depends on vial strength). Site of administration (abdomen or thigh) to be chosen by the patient. The study was stopped prematurely during the 12.5 IU/kg OCTA101 sc daily 16 patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed.

    Serious adverse events
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20 , 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    2 / 16 (12.50%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Spontaneous haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hemoperitoneum
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1: OCTA101 50 IU/kg sc Cohort 2 : OCTA101 100 IU/kg sc Cohort 3: Nuwiq 50 IU/kg iv followed by OCTA101 50 IU/kg sc Cohort 5: OCTA101 20 , 40 and 60 IU/kg sc Cohort 6: Nuwiq iv prophylaxis, OCTA101 sc daily
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    Investigations
    Roseolovirus test positive
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Sep 2019
    Amendment 1 • The study timelines were updated. • It was clarified that only 1 study centre will be required. • It was clarified that the molar ratio of 1:6 FVIII to OCTA12 is with regards to the binding sites in OCTA12. • An additional PK assessment was added in all patients from Cohorts 1 and 2 who completed their 3-month daily injection period further characterizing the PK of FVIII:C and OCTA12. • Clarification of the use of vials to achieve targeted doses. • Clarification that haemophilia joint health score (HJHS) was to be assessed at screening. • Final physical examination in Cohorts 1 and 2 moved to end of additional PK assessment. • Time windows for additional PK assessment in Cohorts 1 and 2 added. • Change of address for central laboratory assessing anti-OCTA12.
    19 Nov 2019
    Amendment 2 • Based on the results from Cohorts 1 and 2, the sponsor and DMC decided that escalation to higher doses should not take place and that further characterization of the 50 IU/kg dose was instead warranted. The study design was modified accordingly. Cohort 4 was cancelled. • The benefit-risk statement was updated to reflect the observation of an inhibitor in Cohort 2 and the revised study design. The stopping rules were also revised. • It was clarified that the full content of vials does not have to be injected.
    28 Apr 2020
    Amendment 3 • The study design was adapted based on the observation of inhibitor formation in Cohort 2, with the introduction of another cohort, Cohort 6. In Cohort 6, 12.5 IU/kg OCTA101, then 25 IU/kg OCTA101, and then 40 IU/kg OCTA101 daily prophylaxis will be investigated in a cohort of 16 patients following a run-in period with Nuwiq iv prophylaxis. • The protocol was updated to reflect the status of the study at the time of amendment 3 and a summary of findings from Cohorts 1, 2, 3 and 5 was added. • The benefit-risk statement was updated to reflect the observation of an inhibitor in Cohort 2 and the revised study design. The stopping rules were also revised. • A new exclusion criterion was added: “For Cohort 6, patients with a positive LumiTope test at screening will be excluded.” • Home visits by a study nurse were planned for Cohort 6. • Given the revised study design, the estimated date for the clinical end of the study was updated.
    06 Jul 2020
    Amendment 4 • At the request of the Bulgarian Drug Agency, there will be no home visits by a study nurse in Cohort 6. • The IND for this product was withdrawn so the IND number was removed from the protocol. • The test base for inhibitor determination was clarified. • The method for determining positive/negative LumiTope assay results was added.
    03 Mar 2021
    Amended Protocol version 08 Cohort 6 revised to: around 18 – 20 patients (to compensate for possible early drop-outs) will have an initial 4 to 6-week run-in treatment period with Nuwiq iv prophylaxis followed by 12.5 IU/kg OCTA101 sc daily prophylaxis for >3 up to 6-7 months. With DMC agreement, the patients will then proceed to 25 IU/kg OCTA101 sc daily prophylaxis for 6-7 months. Based on the results of both dosing phases, a 40 IU/kg OCTA101 will be considered.
    30 Jul 2021
    Amended Protocol version 09 It was decided to stop all further treatment with OCTA101, but to offer all enrolled patients access to Nuwiq prophylactic treatment until they were integrated into the National Health Insurance program for haemophilia A patients, again, but no longer than until the end of September 2021 + 2 week time window.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Dec 2019
    The DMC put the study on hold on 02-Dec-2019 as two patients of cohort 2 had developed an inhibitor to FVIII. As a consequence, patients of cohort 3 terminated the IMP treatment prematurely while patients of cohorts 1, 2 and 5 had already completed IMP study treatment at this time (there were no cohort 4 patients). Later on, the study continued with a revised protocol with a new cohort (cohort 6).
    07 Oct 2020

    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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