| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe chronic plaque psoriasis patients |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | M15 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050576 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Overall safety and tolerability of multiple dose twice daily oral administration of AEB071. |
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| E.2.2 | Secondary objectives of the trial |
Pharmacodynamics of oral AEB071versus AEB071 matching placebo:
Skin: Change in histological score as assessed by number of T cells (dermal and epidermal), activation status of T cells, epidermal thickening, Ki67 and K16 expression in keratinocytes.
Clinical assessment: Evaluated using PASI score and digital photography.
•Pharmacokinetics of AEB071 in:
•Blood & skin to determine the levels of AEB071 and AEE800.
•Pharmacogenomics
•To conduct exploratory genomic studies to identify gene expression patterns of blood and tissue that are associated with treatment response to AEB071, or that possibly correlate with the severity or progression of psoriasis
•Exploratory Biomarker Assessments
•The effect of AEB071 on:
1. Monitor Macrophage migration inhibitory factor (MIF) in serum, as a function of time.
2. sIL-2R and TNF-α expression in serum will be assayed (if there is sufficient level of expression).
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male or female patients from 18-65 years of age and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
2. Female patients must be postmenopausal (i.e. must have had no regular menstrual bleeding for at least 2 years prior to inclusion) or must have been surgically sterilized (bilateral oophorectomy) or hysterectomized at least 6 months prior to screening. Menopause will be confirmed by a plasma 17β-estradiol concentration of <20 pg/mL and a plasma FSH level of >40 IU/L. Surgical sterilization procedures or hysterectomy must be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF
3. Body weight must be between 50 and 100kg (inclusive).
4. Moderate/severe chronic plaque psoriasis.
5. Able to provide written informed consent prior to study participation.
Subject information and consent forms generated by the investigator must be approved by the sponsor prior to submission to the Ethics Committee (EC)/Institutional Review Board (IRB). A copy of the subject information and consent forms approved by the EC/IRB must be forwarded to the sponsor prior to study initiation.
6. Able to communicate well with the investigator and comply with the requirements of the study.
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| E.4 | Principal exclusion criteria |
1. Use of any prescription drug or over-the-counter (OTC) medication (including herbal remedies) within 2 weeks prior to dosing. Paracetamol is acceptable, but must be documented in the Concomitant medications / Significant non-drug therapies page of the eCRF
Concomitant medication/ other therapies or medication for psoriasis:
• Topical therapy for psoriasis (eg, tar, corticosteroids, anthralin (dithranol), vitamin D analogues, retinoids) within 2 weeks prior to first administration of study medication with the exception of indifferent topical substances (eg, Vaseline), topical formulations containing salicylic acid (not more than 10%) or tar shampoos.
• Immunosuppressive agents, radiation therapy, chemotherapy or any specific systemic therapy for psoriasis (eg, methotrexate, cyclosporine, tacrolimus, steroids, retinoids, fumaric acid, biologicals) within 4 weeks (8 weeks for biologicals with a half-life longer than 2 days) prior to first administration of study drug OR the anticipated use of these therapies at any time during the study.
• Who are currently receiving or have received photochemotherapy/phototherapy (eg, PUVA, UVB, etc.) within 4 weeks prior to first administration of study drug.
2. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation.
3. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
4. Significant illness within the two weeks prior to dosing.
5. 5. A past medical history or family history of a prolonged QT-interval syndrome; clinically significant ECG findings including QTcB > 450 for males and > 470 for females, PR > 220, QRS > 110; hypokalemia or hypomagnesemia; history of heart failure or known left ventricular dysfunction (EF < 45%); history of clinically significant atrial arrhythmias eg atrial fibrillation, atrial flutter, supraventricular tachycardia) or ventricular arrhythmias; history of clinically significant atherosclerotic cardiovascular disease (eg, angina, coronary artery disease, history of MI or CVA).
6. History of autonomic dysfunction.
7. History of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
8. History of clinically significant drug allergy; history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug.
9. History of malignancies including skin cancer or lymphoproliferative disorders
10. Who have hypertension (systolic BP >150 mmHg or diastolic BP >95 mmHg after 5 minutes in sitting or supine position) and who have other cardiovascular diseases requiring medical intervention. Subjects with drug-controlled hypertension are also excluded.
11. Other forms of psoriasis:
• Guttate, generalized erythrodermic, local or generalized pustular, or drug-associated (eg, beta-blockers, lithium) psoriasis.
• Psoriasis is limited to palmar/plantar areas.
12. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the subject in case of participation in the study. The investigator should be guided by evidence of any of the following:
• history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding;
• history of major gastrointestinal tract surgery such as gastrectomy, gastroentero-stomy, or bowel resection;
• history or clinical evidence of pancreatic injury or pancreatitis;
• clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as SGOT, SGPT, GGT, alkaline phosphatase, or serum bilirubin.
• history or presence of impaired renal function as indicated by abnormal creatinine or BUN values or abnormal urinary constituents (e.g., albuminuria);
• evidence of urinary obstruction or difficulty in voiding at screening;
• polymorphonuclears <1500/µL or platelets <109/L at inclusion.
13. History of immunocompromise, including a positive HIV (ELISA and Western blot) test result.
14. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
15. A positive Pregnancy test result at screening or baseline.
16. History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| no specified primary end point; the study is focussed on the safety and tolerability of AEB1071 as monotherapy in psoriasis patients exposed to 2 weeks of treatment. The exploratory aspects of the study also allow the evaluation of efficacy and patient biomarkers in psoriatic patients. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| double-blind, sequential cohort , randomised, multiple ascending dose, placebo controlled design |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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