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    Clinical Trial Results:
    A double-blind, multi-center, two-part, randomized, placebo-controlled study of the safety, tolerability, and efficacy of 4 weeks of treatment with AP1189 in early rheumatoid arthritis (RA) patients with active joint disease

    Summary
    EudraCT number
    		 2019-001185-15
    Trial protocol
    		 DK   SE   NO   BG  
    Global end of trial date
    16 Nov 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SynAct-CS002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04004429
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SynAct Pharma ApS
    Sponsor organisation address
    Dronninggårds allé 136, Holte, Denmark, 2840
    Public contact
    CSO, SynAct Pharma ApS, 45 4015 6669, tj@synactpharma.com
    Scientific contact
    CSO, SynAct Pharma ApS, 45 4015 6669, tj@synactpharma.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
    16 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary efficacy Objective: •Effect of AP1189 vs. placebo in subjects with severe active RA (CDAI > 22), undergoing up-titration with MTX, by showing a change in CDAI from severe (CDAI > 22) to moderate (CDAI ≤ 22) after 4 weeks treatment compared to baseline.
    Protection of trial subjects
    Based on available non-clinical data, AP1189 appears to be well tolerated at dose levels that induce exposure well above the expected therapeutic level for this trial. Furthermore, AP1189 presents an excellent safety profile allowing administration of 50 mg and 100 mg doses for 4 weeks. An interim analysis was performed, evaluation the first 29 patients in order to access the safety and efficacy, before proceeding. The outcome of the interim analysis was that it was safe to continue with the same doses. The study was approved by both EC and CA prior to any screening activities. Furthermore, the Danish Medicines Agency (DMA) was consulted on the study design. Occurrence of AE was monitored throughout the study at all visits. During and following a patient's participation in the trial, the investigator was ensuring adequate medical care to patients for any adverse events, including clinically significant laboratory values, related to the trial.
    Background therapy
    		 The treatment with AP1189 was an add on to patients starting up on Methotrexate treatment for Rheumatoid Arthritis.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 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
    Norway: 3
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Bulgaria: 31
    Country: Number of subjects enrolled
    Denmark: 43
    Country: Number of subjects enrolled
    Moldova, Republic of: 21
    Worldwide total number of subjects
    105
    EEA total number of subjects
    84
    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)
    76
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population consisted of newly diagnosed patients with severe active RA with a CDAI > 22 and who were to start up-titration with MTX. Newly diagnosed patients were admitted to the hospital/clinic and evaluated for the study. If a patient was potential eligible, the patient was asked if he/she was interested to participate in the study.

    Pre-assignment
    Screening details
    		 Each potential patient signed and dated an informed consent document before any study-specified procedures were performed. Then the screening visit was performed to evaluate to the inclusion and exclusion criteria for the trial.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    All IMPs were supplied in identical appearing boxes containing bottles with screw caps, where each bottle represented one daily dosis. Each patient package contained 4 inner boxes with 8 bottles each, added up to 32 bottles per patient for a total treatment of 4 weeks, Each bottle, inner box and outer box were carrying an investigational label, indicating that the content was intended for investigational use only. The labeling was complying with local regulatory requirement.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AP1189, 50 mg
    Arm description
    		 AP1189, 50 mg, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly
    Arm type
    		 Experimental

    Investigational medicinal product name
    AP1189, 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The subject had to add 50 ml of tap water to the powder in the bottle, shake well for about 1 minute, allow all powder to dissolve, and immediately drink the solution and rinse the bottle twice with 50 ml water to ensure ingesting all the content in the bottle. Between each rinse, the content of the bottle was drunk.

    Arm title
    		 AP1189, 100 mg
    Arm description
    		 AP1189, 100 mg, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly
    Arm type
    		 Experimental

    Investigational medicinal product name
    AP1189, 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The subject had to add 50 ml of tap water to the powder in the bottle, shake well for about 1 minute, allow all powder to dissolve, and immediately drink the solution and rinse the bottle twice with 50 ml water to ensure ingesting all the content in the bottle. Between each rinse, the content of the bottle was drunk.

    Arm title
    		 Placebo
    Arm description
    		 Placebo, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The subject had to add 50 ml of tap water to the powder in the bottle, shake well for about 1 minute, allow all powder to dissolve, and immediately drink the solution and rinse the bottle twice with 50 ml water to ensure ingesting all the content in the bottle. Between each rinse, the content of the bottle was drunk.

    Number of subjects in period 1
    		AP1189, 50 mg AP1189, 100 mg Placebo
    Started
    35
    36
    34
    Completed
    33
    34
    32
    Not completed
    2
    2
    2
         Consent withdrawn by subject
    1
    1
    1
         Physician decision
    -
    1
    1
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AP1189, 50 mg
    Reporting group description
    		 AP1189, 50 mg, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly

    Reporting group title
    AP1189, 100 mg
    Reporting group description
    		 AP1189, 100 mg, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly

    Reporting group values
    		 AP1189, 50 mg AP1189, 100 mg Placebo Total
    Number of subjects
    		 35 36 34 105
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 26 25 76
        From 65-84 years
    		 10 10 9 29
    Gender categorical
    Units: Subjects
        Female
    		 27 28 27 82
        Male
    		 8 8 7 23

    End points

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    End points reporting groups
    Reporting group title
    AP1189, 50 mg
    Reporting group description
    		 AP1189, 50 mg, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly

    Reporting group title
    AP1189, 100 mg
    Reporting group description
    		 AP1189, 100 mg, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, once daily for 4 weeks (28 days) plus MTX (10 25 mg) weekly

    Primary: Change in CDAI

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    End point title
    		 Change in CDAI
    End point description
    End point type
    Primary
    End point timeframe
    The change in CDAI from severe (CDAI > 22) to moderate (CDAI <= 22) after 4 weeks treatment compared to baseline.
    End point values
    		 AP1189, 50 mg AP1189, 100 mg Placebo
    Number of subjects analysed
    29
    33
    30
    Units: Number of participants
    18
    17
    12
    Statistical analysis title
    		 Change in CDAI
    Comparison groups
    AP1189, 100 mg v AP1189, 50 mg v Placebo
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.039 [2]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.05
         upper limit
    		 -0.31
    Notes
    [1] - Superiority of interest but evaluated with descriptive statistics.
    [2] - Post-hoc analysis

    Secondary: ACR (American College of Rheumatology) Response

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    End point title
    		 ACR (American College of Rheumatology) Response
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of subjects achieving a response assessed by ACR20 after 4 weeks treatment compared to baseline.
    End point values
    		 AP1189, 50 mg AP1189, 100 mg Placebo
    Number of subjects analysed
    29
    33
    30
    Units: Count of Participants
    11
    20
    10
    No statistical analyses for this end point

    Secondary: ACR (American College of Rheumatology) Response

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    End point title
    		 ACR (American College of Rheumatology) Response
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of subjects achieving a response assessed by ACR50 after 4 weeks treatment compared to baseline.
    End point values
    		 AP1189, 50 mg AP1189, 100 mg Placebo
    Number of subjects analysed
    29
    33
    30
    Units: Count of Participants
    2
    8
    4
    No statistical analyses for this end point

    Secondary: ACR (American College of Rheumatology) Response

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    End point title
    		 ACR (American College of Rheumatology) Response
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of subjects achieving a response assessed by ACR70 after 4 weeks treatment compared to baseline.
    End point values
    		 AP1189, 50 mg AP1189, 100 mg Placebo
    Number of subjects analysed
    29
    33
    30
    Units: Count of Participants
    0
    4
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected starting from the time of signed informed consent and until the final visit (End of Study/Early Termination Visit) had occurred. Any AE that was ongoing at the final visit was followed until resolution or until four weeks after the
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    AP1189, 50 mg
    Reporting group description
    		 -

    Reporting group title
    AP1189, 100 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 AP1189, 50 mg AP1189, 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 36 (0.00%)
    0 / 34 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AP1189, 50 mg AP1189, 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 35 (40.00%)
    20 / 36 (55.56%)
    12 / 34 (35.29%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 35 (17.14%)
    0 / 36 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    6
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 35 (5.71%)
    5 / 36 (13.89%)
    0 / 34 (0.00%)
         occurrences all number
    2
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 36 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    1
    Nausea
         subjects affected / exposed
    5 / 35 (14.29%)
    7 / 36 (19.44%)
    7 / 34 (20.59%)
         occurrences all number
    5
    8
    7
    Obstipation
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthritis rheumatoid aggravated
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 36 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    4
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2019
    Submission to the Medical Products Agency (MPA) in Sweden. MPA's objections were addressed, and relevant changes and updates were incorporated into version 3.0 of the protocol, version 6.0 of the IB and version 6.0, Volume 2, Nonclinical and Clinical data of the IMPD (the IMPD_AP1189, Volume 1 - Pharmaceutical dossier, V5.0 dated 17MAR2019 is unchanged).
    28 Jan 2020
    Application to the Norwegian Medicines Agency (NOMA) on 5. November 2019 (protocol version 4.0 where the only addition, compared to version 3.0, was "Norway". Protocol versions 5 and 6 addressed NMA's objections and recommendations.
    30 Apr 2020
    Amendment 3 concerned a permission to continue dosing with AP1189, 100 mg dose after 12 completed subjects on AP1189, 50 mg, and to reduce the sample size in the (100 mg) group of Part 1 from 18 down to a minimum of 12 subjects (protocol version 7.0).
    22 Sep 2020
    Amendment 4 concerned the determination of melanocortin receptor type 1 (MC1r) variants in subjects randomized to treatment by analyzing a tissue sample using RT-PCR (Reverse transcription-polymerase chain reaction (RT-PCR can be used, for example, to enable molecular cloning, sequencing, or simple detection of RNA)) (protocol version 8.0).
    27 Jan 2021
    Amendment 4 concerned adding a sub-study in Bulgaria and Moldova to the clinical study protocol. The purpose of the sub-study was to investigate if the effect of AP1189 in newly diagnosed subjects with severe rheumatoid arthritis who were to start up-titration with methotrexate was comparable in these two countries compared to the main study (protocol version 9.0)

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

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