Double-blind, Randomised, Placebo-controlled Trial Investigating BIRT 2584 XX in Patients With Moderate/Severe Psoriasis

A 12 Week Double-blind, Randomised, Placebo-controlled, Modified Dose-escalation Trial to Investigate Safety, Efficacy, and Pharmacokinetics of BIRT 2584XX Tablets at Doses of 100, 300 and 500 mg Administered Once Daily in Patients With Moderate to Severe Psoriasis With a 12 Week Treatment Extension

The purpose of this clinical study is to determine the effectiveness, pharmacokinetics and safety of several doses of BIRT 2584 XX (100mg, 300mg and 500mg) taken once daily in the treatment of moderate to severe plaque-type psoriasis. This new medicine will be compared to a so-called placebo medicine over 12 weeks with a 12 weeks treatment extension possible.

Study Overview

• Status: Completed
• Conditions: Psoriasis
• Intervention / Treatment: Drug: Placebo; Drug: BIRT 2584 XX

Detailed Description

The proposed study is a phase 2a/b international multicentre clinical trial. The general aim of this study is to investigate the safety and efficacy (clinical proof of concept) of three different doses (100 mg, 300 mg, or 500 mg) of BIRT 2584 XX tablets administered orally once daily compared to placebo tablets for the treatment of patients with moderate to severe plaque-type psoriasis patients who are candidates for systemic treatment or phototherapy. This study may also provide dose-finding information for future pivotal studies.

The response to treatment will be measured for all patients in the study after 12 weeks of treatment using the PASI as the primary endpoint, and also the sPGA. Both instruments evaluate the clinical severity of plaque-type psoriatic lesions. Training on PASI and sPGA assessment will be provided in order to decrease inter-observer variability. The sPGA is thus to be validated for future phase 3 trials.

After 12 weeks of treatment, only those patients with a response equivalent or better than PASI50 and with a satisfactory safety experience will enter a 12 week extension of the treatment period. The total time of exposure to study drug in this subgroup of patients will be 24 weeks. All other study patients will terminate treatment with study drug after 12 weeks.

In addition, the durability of remission/response, and the occurrence of any relapse or rebound during the treatment with study drug and after the end of treatment will be assessed in an 8 weeks follow-up period. The follow-up period is applicable to all study participants who have taken at least one dose of study drug. It initiates after the last dose of study medication has been taken, irrespective of the duration of the patients actual treatment period.

The trial will use a modified dose-escalation scheme. The randomisation to the 500 mg treatment arm will initiate only after a Data Safety Monitoring Board (DSMB) decision on the safety of the other treatment arms. An IVRS will be used for randomisation in this trial.

Ninety (90) patients are required per dose group. With four groups and an overall 1:1:1:1 randomisation scheme, a total of 360 eligible patients are planned to be randomised to treatment.

Study Hypothesis:

Psoriasis is a chronic inflammatory disease that leads to skin sores. These skin sores are dependent on the rate of growth of the skin which is driven by an underlying corresponding degree of local inflammation. The skin inflammation is caused by different cell types that move from the blood vessels into the skin. This cell movement is a result of interaction of different proteins. One of these proteins is called LFA-1 (Lymphocyte Function Associated Antigen 1). LFA-1 is then a promising target for psoriasis therapy. BIRT 2584 XX will block the passage of these inflammatory cells from the blood to the skin by blocking LFA-1, and thus indirectly block the inflammatory process. BIRT 2584 XX can also block the activation of local inflammatory cells, which altogether may reduce the signs and symptoms of psoriasis.

A dose-dependent effect of BIRT 2584 XX was observed on a set of markers in the blood that are believed to correlate with the severity of the inflammatory process leading to psoriasis.

Comparison(s):

In this clinical study, BIRT 2584 XX in a dose of 100 mg, 300 mg or 500 mg, or placebo will be given once daily. Patients will receive the same treatment throughout the study.

Patients will have a 1 in 4 chance (25%) of being allocated to placebo treatment. The placebo is identical in appearance compared to any one of the three dose groups with BIRT 2584 XX, but does not contain any active ingredient. The purpose of a comparison with placebo is to ensure a more reliable assessment of the therapeutic effect and of the side effects of BIRT 2584 XX.

• Study Type: Interventional
• Enrollment (Actual): 360
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2018
    • Dermatologie Kliniek
  • Bruxelles, Belgium, 1070
    • Hopital Erasme
  • Edegem, Belgium, 2650
    • UZ Antwerpen
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2S 3B3
      • Boehringer Ingelheim Investigational Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E8
      • Boehringer Ingelheim Investigational Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1Z4
      • Eastern Canada Cutaneous Research Associates Ltd.
  • Ontario
    • London, Ontario, Canada, N6A 3H7
      • Boehringer Ingelheim Investigational Site
    • Markham, Ontario, Canada, L3P 7N8
      • Boehringer Ingelheim Investigational Site
    • Waterloo, Ontario, Canada, N2J 1C4
      • Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H2K 4L5
      • Innovaderm Research Inc.
    • Montreal, Quebec, Canada, H3G 1C6
      • Dr. Wayne Carey
    • Montreal, Quebec, Canada, H3H 1V4
      • Boehringer Ingelheim Investigational Site
    • Sainte-Foy, Quebec, Canada, G1V 4X7
      • Boehringer Ingelheim Investigational Site
• Denmark
  • Aarhus C, Denmark, DK-8000
    • Marselisborg Centret
  • Hellerup, Denmark, DK-2900
    • Amtssygehuset i Gentofte
  • Odense C, Denmark, 5000
    • Odense Universitetshospital
• Finland
  • Lahti, Finland, FI-15850
    • Päijät-Hämeen keskussairaala
• France
  • Besançon cedex, France, 25030
    • Hôpital Saint Jacques
  • Limoges cedex 1, France, 87042
    • Hôpital Dupuytren
  • Nice, France, 06202
    • Hopital de l'Archet
  • Paris cedex 10, France, 75475
    • Hopital Saint Louis
  • Saint Priest en Jarez cedex, France, 42277
    • Hopital Nord
  • St Priest en Jarez cedex, France, 42277
    • CHU - Hôpital Nord
• Germany
  • Berlin, Germany, 10117
    • Charité, Campus Virchow-Klinikum
  • Bochum, Germany, 44791
    • St. Josef-Hospital
  • Dresden, Germany, 01307
    • Universitätsklinikum an der TU Dresden
  • Erlangen, Germany, 91052
    • Universitatsklinikum Erlangen
  • Freiburg, Germany, 79104
    • Universitäts-Hautklinik
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein
  • Magdeburg, Germany, 39120
    • Otto-von-Guericke-Universität Magdeburg
  • Mahlow, Germany, 15831
    • Boehringer Ingelheim Investigational Site
  • Mainz, Germany, 55101
    • Johannes Gutenberg-Universität Mainz
  • Münster, Germany, 48149
    • Universitätsklinikum Münster
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Centre
  • Nijmegen, Netherlands, 6525 GL
    • University Medical Centre Nijmegen St. Radboud West
• Spain
  • Barcelona, Spain, 08025
    • Boehringer Ingelheim Investigational Site
  • Madrid, Spain, 28006
    • Servicio de Dermatología
  • Madrid, Spain, 28041
    • Servicio de Dermatología
• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset Solna
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Aberdeen Royal Infirmary, Department of Dermatology
  • Cardiff, United Kingdom, CF14 4XN
    • Cardiff University, Dermatology Department
  • Glasgow, United Kingdom, G11 6NT
    • Western Infirmary, Department of Dermatology
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital, Dermatology Department,
  • London, United Kingdom, SE1 7EH
    • Skin Therapy Research Unit, St John's Inst of Dermatolology
  • Nuneaton,, United Kingdom, CV10 7DJ
    • George Eliot Hospital, Dermatology Department
  • Salford, United Kingdom, M6 8HD
    • Hope Hospital, The Dermatology Centre,
  • Southampton, United Kingdom, SO14 0YG
    • Royal South Hants Hospital, Dept of Dermatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion_Criteria:

1. Age 18 to 75, males or females
2. Patients with stable moderate to severe plaque-type psoriasis involving ?10% body surface area, with minimum disease severity PASI ?10 and with static PGA of at least moderate (score of at least 3) at screening visit
3. Psoriasis disease duration of at least 6 months prior to screening
4. Patients must be candidates for systemic psoriasis treatment or phototherapy
5. Patient must give informed consent and sign an approved consent form prior to any study procedures, including wash out of prohibited medications (Patients participating in the PK sub-study will sign an additional consent form. Refusal to participate in the sub-study will not exclude from participation in the main trial)

Exclusion_Criteria:

1. Patients with primary guttatae, erythrodermic, or pustular psoriasis
2. Patients who have previously discontinued efalizumab treatment due to lack of efficacy
3. Patients using treatments that could interfere with the primary endpoint of the study (cf. protocol section 4.2.2.1)
4. Patients on treatment with warfarin, paracetamol (acetaminophen), some NSAIDs, some antidepressants, medications known to induce or inhibit CYP3A4, or any other concomitant medication where potential drug-drug interactions with BIRT 2584 XX could either result in decreased efficacy or an unacceptable benefit-risk assessment, and where replacement of that concomitant medication with a safe equivalent drug is not possible (cf. protocol section 4.2.2.2 and the Investigator Site File).
5. Patients with active liver disease or history of any significant liver disease.
6. Any clinically significant illness or unstable disease which according to investigator judgement may either put the patient at risk because of participation in the study or may influence the results of the study or the patients ability to participate.

7. Patient with serum creatinine and/or white blood cell count >1.5 x ULN at screening.

   (Repeat laboratory is allowed once between screening and randomisation prior to excluding the patient)

8. Patients with ALT, AST and/or total bilirubin > 1.5xULN at screening (Repeat laboratory is allowed once between screening and randomisation prior to excluding the patient)
9. Abnormal values of other laboratory parameters at screening that would define a clinically significant disease as described in # 6 above (Repeat laboratory is allowed once between screening and randomisation prior to excluding the patient)
10. Positive testing at screening, or history of HIV or hepatitis B or hepatitis C, or any serious infection (requiring hospitalisation or parenteral antibiotic therapy) in the past 3 months prior to screening
11. History of malignancy in the past 5 years or suspicion of active malignant disease except treated cutaneous squamous cell or basal cell carcinoma

12. Patients with the following findings at the screening visit that could interfere with cardiac repolarisation:

    • marked baseline prolongation of QT/QTc interval as measured on ECG (e.g. QTc interval >450ms);
    • history of additional risk factors for Torsade de pointe (e.g. heart failure, - hypokalemia, family history of long QT syndrome);
    • use of concomitant medications that prolong the QT/QTc interval
13. History of drug or alcohol abuse within the past two years

14. Pre-menopausal (last menstruation ≤ 1 year prior to screening) sexually active woman who:

    • is pregnant or nursing
    • is of child bearing potential and not practicing acceptable methods of birth control, or does not plan to continue practising an acceptable method throughout the study (acceptable methods of birth control include surgical sterilisation, intrauterine devices, double barrier, male partner sterilisation, but not hormonal contraceptives**) [A negative serum pregnancy test at screening (Visit 1) and a negative urine test prior to randomisation (Visit 2) are required]
15. Patient not willing to avoid excess sun exposure during the trial duration
16. Patients who have taken an investigational drug, within the last 4 weeks or 5 half lives (which ever is greater) prior to randomisation [Patients who have been treated with any investigational antibody or fusion protein within the past 12 weeks before randomisation are excluded]
17. Known allergy to BIRT 2584 XX or to the excipients used for tablet formulation
18. Body mass index > 34 kg/m2 at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo
EXPERIMENTAL: BIRT 2584 XX high dose	Drug: BIRT 2584 XX
EXPERIMENTAL: BIRT 2584 XX medium dose	Drug: BIRT 2584 XX
EXPERIMENTAL: BIRT 2584 XX low dose	Drug: BIRT 2584 XX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Achievement of > 75% reduction from baseline in Psoriasis Area and Severity Index (PASI) score (PASI75 ) at 12 weeks	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Other PASI assessments, NPF Psoriasis Score Static Psoriasis Global Assessment (sPGA), Discontinuations of therapy due to lack of efficacy, Relapse and rebound, Dermatology Life Quality Index, Pain Visual Analog Scale for psoriatic arthritis	12 and 24 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (ACTUAL): June 1, 2008

Study Registration Dates

• First Submitted: June 2, 2006
• First Submitted That Met QC Criteria: June 2, 2006
• First Posted (ESTIMATE): June 5, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): June 19, 2014
• Last Update Submitted That Met QC Criteria: June 13, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Skin Diseases, Papulosquamous; Psoriasis
• Other Study ID Numbers: 1206.5