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    Clinical Trial Results:
    A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate the Efficacy and Safety of Oral PRV-6527 (JNJ-40346527), an Inhibitor of Colony Stimulating Factor-1 Receptor, in Subjects with Moderately to Severely Active Crohn’s Disease

    Summary
    EudraCT number
    		 2017-003017-25
    Trial protocol
    		 HU   AT   ES   PL   DE  
    Global end of trial date
    13 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2021
    First version publication date
    19 Nov 2021
    Other versions
    Summary report(s)
    		 PRV-6527-CD2a_Clinical Study Report Synopsis v1.1

    Trial information

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    Trial identification
    Sponsor protocol code
    PRV-6527-CD2a
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03854305
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Provention Bio, Inc.
    Sponsor organisation address
    55 Broad Street, 2nd Floor, Red Bank, NJ, United States, 07701
    Public contact
    Gail M. Comer, MD, Provention Bio, Inc., +1 908 698 4612, gcomer@proventionbio.com
    Scientific contact
    Gail M. Comer, MD, Provention Bio, Inc., +1 908 698 4612, gcomer@proventionbio.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
    13 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of PRV-6527 (JNJ-40346527) for 12 weeks in the treatment of moderately to severely active CD, as measured by the Crohn’s Disease Activity Index (CDAI).
    Protection of trial subjects
    This trial was designed and monitored in compliance with the ethical principles of Good Clinical Practice as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki. Each subject was required to give written consent according to local requirements after the Investigator or designee had fully explained the aims, methods, and potential benefits and risks of the study. The subject was given sufficient time to read the Informed Consent Form (ICF) and the opportunity to ask questions. The ICF(s) were signed before any study-related activity was initiated. An independent Data Monitoring Committee (DMC) was established to monitor safety and benefit/risk throughout the trial. Additionally, the DMC reviewed PK data after at least the first 9 subjects completed their Week 4 visit to assure minimum threshold exposures were achieved. The DMC monitored data on an ongoing basis based upon enrollment and the emerging safety profile to ensure the continuing safety of the subjects enrolled in this study. The committee met at least quarterly to review unblinded safety data. The DMC made the recommendation for the continuation of the study without modifications.
    Background therapy
    		 Mesalamine and low dose steroids.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    01 Feb 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Ukraine: 34
    Worldwide total number of subjects
    93
    EEA total number of subjects
    38
    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)
    90
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient enrolled on 20 March 2018; last patient completed on 13 Aug 2019. A total of 93 patients were enrolled at 54 sites in in 6 countries: Austria, Germany, Hungary, Poland, Russia, and Ukraine.

    Pre-assignment
    Screening details
    		 186 subjects were screened and 93 subjects were randomized; 93 screen failures were due to inclusion/exclusion criteria not met.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Every effort was made to retain the integrity of the blind. To maintain blinding, the study drug container had a label containing the study name, the container number, and other information. The study drugs were identical in appearance and were packaged in identical containers. The label did not identify the study drug in the container. One subject with an SAE was unblinded by the investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PRV-6527 150 mg
    Arm description
    		 Experimental therapy arm: PRV-6527 150 mg (50 mg, 3 capsules), taken orally BID for 12 weeks. Results are presented for the Intent-to-Treat (ITT) population, which included all 63 subjects who were randomized to the PRV-6527 150 mg arm. To note, the ITT, Safety, and PK populations contained the same data sets, as all randomized subjects received at least one dose of the study drug as assigned. 10 subjects in the PRV-6527 150 mg arm discontinued treatment due to: adverse event (3) or other reason (7).
    Arm type
    		 Experimental

    Investigational medicinal product name
    PRV-6527
    Investigational medicinal product code
    Other name
    JNJ-40346527
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    PRV-6527 was provided as 50 mg capsules. The dose was 150 mg (3 capsules) BID. The study drug, PRV-6527 50 mg, was provided as free-base equivalent hard gelatin, size 3, gray opaque capsules for oral administration. All subjects were instructed to self-administer 6 capsules daily, 3 in the morning and 3 in the evening at approximately the same times each day with or without food. Subjects who were taking a histamine-2 receptor antagonist (H2RA) (e.g., ranitidine, famotidine, or nizatidine) or frequent antacids were instructed to take their dose of study drug BID always with food.

    Arm title
    		 Placebo
    Arm description
    		 Placebo arm: placebo capsules taken orally BID for 12 weeks. Results are presented for the Intent-to-Treat (ITT) population, which included all 30 subjects who were randomized to the placebo arm. To note, the ITT, Safety, and PK populations contained the same data sets, as all randomized subjects received at least one dose of the study drug as assigned. 4 subjects in the placebo arm discontinued treatment due to: prohibited medication (1), adverse event (2), or other reason (1).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was provided as 50 mg capsules. The dose was 3 capsules BID. The placebo with a matching appearance consisted of lactose monohydrate in a gray-colored, hard, gelatin capsule. All subjects were instructed to self-administer 6 capsules daily, 3 in the morning and 3 in the evening at approximately the same times each day with or without food. Subjects who were taking a histamine-2 receptor antagonist (H2RA) (e.g., ranitidine, famotidine, or nizatidine) or frequent antacids were instructed to take their dose of study drug BID always with food.

    Number of subjects in period 1
    		PRV-6527 150 mg Placebo
    Started
    63
    30
    Completed
    53
    26
    Not completed
    10
    4
         Early termination
    10
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PRV-6527 150 mg
    Reporting group description
    		 Experimental therapy arm: PRV-6527 150 mg (50 mg, 3 capsules), taken orally BID for 12 weeks. Results are presented for the Intent-to-Treat (ITT) population, which included all 63 subjects who were randomized to the PRV-6527 150 mg arm. To note, the ITT, Safety, and PK populations contained the same data sets, as all randomized subjects received at least one dose of the study drug as assigned. 10 subjects in the PRV-6527 150 mg arm discontinued treatment due to: adverse event (3) or other reason (7).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm: placebo capsules taken orally BID for 12 weeks. Results are presented for the Intent-to-Treat (ITT) population, which included all 30 subjects who were randomized to the placebo arm. To note, the ITT, Safety, and PK populations contained the same data sets, as all randomized subjects received at least one dose of the study drug as assigned. 4 subjects in the placebo arm discontinued treatment due to: prohibited medication (1), adverse event (2), or other reason (1).

    Reporting group values
    		 PRV-6527 150 mg Placebo Total
    Number of subjects
    		 63 30 93
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 61 29 90
        From 65-84 years
    		 2 1 3
    Age continuous
    Overall, the mean (SD) age was 38.3 (14.61) years.
    Units: years
        arithmetic mean (standard deviation)
    		 37.0 ( 14.95 ) 41.1 ( 13.67 ) -
    Gender categorical
    Nearly half of the subjects were female (48.4%).
    Units: Subjects
        Female
    		 28 17 45
        Male
    		 35 13 48
    Ethnicity
    Nearly all subjects were not Hispanic or Latino (96.8%).
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 61 29 90
    Race
    All subjects were white.
    Units: Subjects
        White
    		 63 30 93
    Use of nicotine products
    Most subjects in both groups reported no nicotine use (77.4%).
    Units: Subjects
        Never used
    		 51 21 72
        Ex-user
    		 7 4 11
        Current user
    		 5 5 10
    Alcohol consumption
    Most subjects in both groups reported no alcohol use (95.7%).
    Units: Subjects
        Never used
    		 59 30 89
        Ex-user
    		 1 0 1
        Current user
    		 3 0 3
    Extra-intestinal manifestations
    Approximately half of the subjects had extra-intestinal manifestations (50.5%). The most common extra-intestinal manifestations were arthritis/arthralgia (44.1%).
    Units: Subjects
        Yes
    		 30 17 47
        No
    		 33 13 46
    Prior Crohn's Disease-related Surgeries
    The majority of subjects had no previous CD-related surgeries (83.9%).
    Units: Subjects
        Yes
    		 9 6 15
        No
    		 54 24 78
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 66.3 ( 11.82 ) 71.7 ( 14.70 ) -
    Weight
    Units: kg
        median (full range (min-max))
    		 65.3 (44.7 to 100.0) 73.0 (48.2 to 107.0) -
    Body Mass Index
    The mean (SD) BMI was 23.2 (4.19) kg/m2.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 22.5 ( 3.73 ) 24.8 ( 4.69 ) -
    Body Mass Index
    Units: kg/m^2
        median (full range (min-max))
    		 21.8 (15.5 to 31.9) 24.1 (18.8 to 41.4) -
    Duration of Crohn's Disease
    The mean (SD) duration of disease at baseline was 5.8 (5.98) years. The extent of the disease occurs most frequently in the ileum (65.6%) and rectum (55.9%).
    Units: years
        arithmetic mean (standard deviation)
    		 5.7 ( 6.19 ) 5.8 ( 5.62 ) -
    Duration of Crohn's Disease
    Units: years
        median (full range (min-max))
    		 3.3 (0.3 to 32.0) 3.2 (0.5 to 22.0) -

    End points

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    End points reporting groups
    Reporting group title
    PRV-6527 150 mg
    Reporting group description
    		 Experimental therapy arm: PRV-6527 150 mg (50 mg, 3 capsules), taken orally BID for 12 weeks. Results are presented for the Intent-to-Treat (ITT) population, which included all 63 subjects who were randomized to the PRV-6527 150 mg arm. To note, the ITT, Safety, and PK populations contained the same data sets, as all randomized subjects received at least one dose of the study drug as assigned. 10 subjects in the PRV-6527 150 mg arm discontinued treatment due to: adverse event (3) or other reason (7).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm: placebo capsules taken orally BID for 12 weeks. Results are presented for the Intent-to-Treat (ITT) population, which included all 30 subjects who were randomized to the placebo arm. To note, the ITT, Safety, and PK populations contained the same data sets, as all randomized subjects received at least one dose of the study drug as assigned. 4 subjects in the placebo arm discontinued treatment due to: prohibited medication (1), adverse event (2), or other reason (1).

    Primary: Change in Crohn’s Disease Activity Index (CDAI) Scores from Baseline to Week 12

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    End point title
    		 Change in Crohn’s Disease Activity Index (CDAI) Scores from Baseline to Week 12
    End point description
    The primary endpoint of the study was the change in Crohn’s Disease Activity Index (CDAI) score from baseline to Week 12, compared between the PRV-6527 and placebo groups. The CDAI was assessed by collecting information on 8 different Crohn's Disease-related variables (Best 1976): extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools (Bristol Stool Form Scale type 6 or 7 stools), abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. The last 4 variables were collected from the 7 most recent noncensored days as reported by the subject on the eDiary. Subjects were asked to complete the eDiary daily entry and bring the eDiary to each visit.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 PRV-6527 150 mg Placebo
    Number of subjects analysed
    63
    30
    Units: Change from baseline to Week 12
        arithmetic mean (standard deviation)
    -128.0 ( 113.35 )
    -166.0 ( 93.65 )
    Statistical analysis title
    		 CDAI scores
    Comparison groups
    PRV-6527 150 mg v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0841
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    38.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.34
         upper limit
    		 83.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    22.24
    Notes
    [1] - Descriptive statistics

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events and special reporting situations, whether serious or nonserious, were reported from the time a signed and dated ICF was obtained until completion of the subject's last study-related procedure, which may include follow-up of safety.
    Adverse event reporting additional description
    Treatment emergent adverse events were those that occurred after dosing of study drug through the study follow-up period. Events that occurred prior to study drug administration were considered baseline signs/symptoms.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    PRV-6527 150 mg
    Reporting group description
    		 Treatment-emergent adverse events (TEAEs) are presented for the Safety population, which includes all randomized subjects who received at least 1 dose of study drug. The Safety population includes all 63 subjects who were randomized to the PRV-6527 arm. All treatment-emergent serious adverse events (SAEs) that occurred are reported. Non-serious TEAEs that occurred in 3 or more subjects in the active treatment group are reported. No deaths occurred during the study.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment-emergent adverse events (TEAEs) are presented for the Safety population, which includes all randomized subjects who received at least 1 dose of study drug. The Safety population includes all 30 subjects who were randomized to the Placebo arm. All treatment-emergent serious adverse events (SAEs) that occurred are reported. Non-serious TEAEs that occurred in 3 or more subjects in the active treatment group are reported. No deaths occurred during the study.

    Serious adverse events
    		 PRV-6527 150 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 30 (3.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 PRV-6527 150 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 63 (38.10%)
    6 / 30 (20.00%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 63 (7.94%)
    2 / 30 (6.67%)
         occurrences all number
    5
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 30 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 30 (6.67%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2018
    - In Exclusion criterion #1, the condition of “tight stricture that prevents the passage of any colonoscope” was added to be excluded. - In Exclusion criterion #22 and in Section 9.2.1, the TB screening procedures were clarified. Only an indeterminate result was inconclusive and required repeat testing. - In Exclusion criterion #23, Hy’s Law is specified as an indicator of hepatic impairment. - In Exclusion criterion #29, the history of substance abuse is added for exclusion. - The randomization method was revised from dynamic block central randomization to list-based block central randomization, as the list-based method was considered more appropriate for this study. - DMC was unblinded to both safety and efficacy data to better monitor the benefit/risk ratio for study subjects during the study.
    19 Nov 2018
    - Prior biologic treatment remained a stratification factor but the required percentages (30% to 40% of all enrolled subjects being bio-naïve) were removed to facilitate patient recruitment. This did not affect any planned analyses. - The screening HIV test was changed from HIV antibody tests to antibody to p24 antigen (Ab-p24Ag) confirmed by HIV 1/2 Western blot as the replacement test is able to detect earlier infection.

    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.
    Despite the limitations of the study (placebo effect, single dose-level, limited duration and sample size, and geography), the totality of the data confirmed a role of CSF-1R in the pathophysiology of Crohn’s disease.
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    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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