| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037153 |
| E.1.2 | Term | Psoriasis |
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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 |
• Investigate the safety and tolerability of single and multiple doses of BFH772 in two different formulations in healthy and psoriatic subjects
• Assess the efficacy of topically applied BFH772 to treat psoriasis as assessed by plaque PASI scoring at week 4.
The main objective of this first-in-man study with BFH772 topical formulation, planned to demonstrate the safety and tolerability and proof of mechanism of BFH772 followed by the proof of concept of BFH772 in psoriasis patients. Two parts will be considered sequentially:
Safety cohorts and Part 1: study the safety and tolerability of BFH772 after single dose in two different formulations, a cream and an ointment with two strengths of each. In addition, the proof of mechanism (PoM) of BFH772 will be assessed. The local safety and tolerability of BFH772 will be used as a decision making endpoint to progress to the Part 2 of the study.
Part 2: This will be a proof of concept study (PoC) in psoriasis patients. |
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| E.2.2 | Secondary objectives of the trial |
• Determine the cellular changes in healthy skin after UV-B irradiation
• Determine systemic and skin exposure of topically applied BFH772 after multiple dosing
• Determine the pharmacodynamic effects of BFH772 (psoriasis and angiogenesis related cellular changes) in psoriatic and adjacent undiseased skin by immunohistology.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Common inclusion criteria:
- able to communicate well with the investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent.
Safety cohorts and Part 1 (healthy volunteers)
- Caucasian male and female (of non-childbearing potential) subjects age 18 to 45 years of age included, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
- At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the supine position after the subject has rested for at least 3 minutes, and again when required after 3 minutes in the standing position. Vital signs should be within the following ranges:
Auricular oral body temperature between 35.0-37.5 °C
systolic blood pressure, 90-140 mm Hg
diastolic blood pressure, 50-90 mm Hg
pulse rate, 40 - 90 bpm
- Postmenopausal females must have had no regular menstrual bleeding for at least 1 year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of >26.72 IU/L at screening.
Female subjects who report surgical sterilization must have had the procedure at least 6 months prior to initial dosing.
- Male subjects must be using highly effective methods of contraception , (e.g., spermicidal gel plus condom) for the entire duration of the study, up to the Study Completion visit, and refrain from fathering a child 1 month following the last study drug administration.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- Subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 to 29 kg/m2.
Part 2 (psoriasis patients)
- Male and female (of non-childbearing potential) patients age 18 to 75 years of age included at the time of the screening visit, having passed screening examinations
- Diagnosis of stable mild to moderate plaque psoriasis; diagnosed or history of psoriasis for at least 6 months prior to screening
- Postmenopausal females must have had no regular menstrual bleeding for at least 1 year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of >40 IU/L at screening.
Female subjects who report surgical sterilization must have had the procedure at least 6 months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF.
- Male subjects must be using highly effective methods of contraception , (e.g., spermicidal gel plus condom) for the entire duration of the study, up to the Study Completion visit, and refrain from fathering a child 1 month following the last study drug administration.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the supine position after the subject has rested for at least 3 minutes, and again when required after 3 minutes in the standing position. Vital signs should be within the following ranges:
Auricular oral body temperature between 35.0-37.5 °C
systolic blood pressure, 90-160 mm Hg
diastolic blood pressure, 50-100 mm Hg
pulse rate, 40 - 90 bpm
If vital signs are out-of-range, the Investigator should obtain two additional readings, so that a total of up to 3 consecutive assessments are made, each after at least 5 minutes and with the subject lying quietly during the 5 minutes preceding the assessment. At least the last reading must be within the ranges provided above in order for the subject to qualify.
When blood pressure and pulse will be taken again after 3 minutes standing, there shall be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure and increase in heart rate (>20 bpm) associated with clinical manifestation of postural hypotension.
All blood pressure measurements at other time-points should be assessed with the subject lying, unless stated otherwise in the protocol design, and utilizing the same arm for each determination.
- Absence of clinically relevant abnormalities for screening laboratory test results of hematological (hemoglobin, white blood cells, neutrophils, platelets) renal (serum creatinine) and hepatic (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, bilirubin) parameters.
- Psoriatic plaques accessible for skin biopsies convenient for the patients and sufficient number and size to meet the requirements of the study. |
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| E.4 | Principal exclusion criteria |
Safety cohorts and Part 1 (healthy volunteers)
- Use of any prescription drugs, herbal supplements, within 4 weeks prior to initial dosing, and/or OTC medication, dietary supplements (vitamins included) within 2 weeks prior to initial dosing. If needed, (i.e. an incidental and limited need) paracetamol is acceptable, but must be documented in the Concomitant medications / Significant non-drug therapies page of the CRF.
- Participation in any clinical investigation within 4 weeks prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.
- Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing, or longer if required by local regulation.
- Significant illness within 2 weeks prior to initial dosing.
- A past medical history of clinically significant ECG abnormalities.
- Recent (within the last 3 years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc).
- History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug.
- Total WBC count which falls outside the range of 4500–11,000/µL (or that of the local laboratory 4400-11300/µL), or platelets <100,000/µL at screening.
- History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result or a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
- 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 and at baseline.
- History of abnormal skin reactivity to UV light. Unusual exposure to UV light in the previous 3 weeks to study start (screening), including tanning, sunbeds etc.
Part 2 (psoriasis patients)
- Currently have any of the nonplaque forms of psoriasis: erythrodermic, guttate, or pustular.
- Currently have drug-induced psoriasis (new onset or exacerbation of psoriasis from beta blockers, calcium channel blockers, or lithium).
- Used any investigational drug within the previous 4 weeks.
- Currently use beta blockers
- Recent previous treatment with anti-TNF therapy (or other biological therapy), immunosuppressive agents such as cyclosporine, mycophenolate, pimecrolimus or tacrolimus. The following washout period will be required for such patients to be eligible to participate in the trial:
2 months washout prior to screening for etanercept, adalimumab, efalizumab, infliximab or any other biologic therapy or UVB / PUVA therapy.
1 month washout prior to screening for cyclosporine, mycophenolate, tacrolimus and any systemic immunosuppressants including, but not limited to, methotrexate and azathioprine
- Within 1 month of randomization, received any systemic medications/treatments that could affect psoriasis or PASI evaluation including, but not limited to, oral or injectable corticosteroids, retinoids, vitamin D analogs, psoralins, sulfsalazine, fumaric acid derivatives, or phototherapy.
- Within 1 month of randomization, used topical medications/treatments at the skin sites to be chosen for topical treatment with BFH772 that could affect psoriasis of PASI evaluation including, but not limited to corticosteroids, anthralin, calcipotriene, topical vitamin D derivatives , retinoids, tazarotene, methoxsalen, pimecrolimus, tacrolimus and trimethylpsoralens.
- History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result, or a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
- Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, psychiatric, or other disease which would make the patient unsuitable for the trial.
- Patients with congestive heart failure (NYHA > III), QT interval >450 msec or poorly controlled diabetes mellitus.
- Presence of major chronic inflammatory autoimmune diseases like rheumatoid arthritis, spondyloarthropathy, inflammatory bowel disease or SLE.
- A history of serious allergic reaction, collagen disease, neurological disease (including demyelating disease).
- History of malignancy (other than non-melanoma skin cancer or adequately treated carcinoma-in-situ of the cervix).
- Unable or unwilling to undergo multiple venapuntures because of poor tolerability or lack of access to veins.
- 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 and at baseline
- Subjects who have been committed to an institution by way of official or judicial order will be excluded from participitation to the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety cohorts and Part 1 (healthy volunteers)
• investigate the safety and tolerability of single and multiple doses of BFH772 in 2 different formulations in healthy and psoriatic subjects
The local safety and tolerability of BFH772 will be used as a decision making endpoint to progress to the Part 2 of the study.
Progression from cohort 1 to 2 and from cohort 2 to part 1 will be made unless there is a grade 4 local reaction occurring.
Furthermore, in case of a grade 4 local reaction on any location in healthy skin, no further healthy volunteers are to be treated with this formulation.
In the case of a single suspected serious adverse reaction (SAR) in a healthy volunteer the study is to be terminated.
Criteria for Transition from Part 1 to Part 2
The local tolerability of the non-irradiated applications areas will be used as a decision making endpoint to progress to the Part 2 of the study. Provided that there are no subjects with a maximum local tolerability score of 3 or greater on the matching placebo, then any active dose with no more than 4 out of 6 subjects with a maximum local tolerability score of 3 or greater can be taken forward to Part 2 of the study. If, however, there are any subjects with a maximum local tolerability scores of 3 or greater on placebo then this formulation will not be taken forward into Part 2 of the study. If this occurs in both of the placebo groups, then the study will not be moved forward to Part 2.
Furthermore, in case of a grade 4 local reaction on any location in healthy skin, no further healthy volunteers are to be treated with this formulation.
In the case of a single suspected serious adverse reaction (SAR) in a healthy volunteer the study is to be terminated.
Local tolerability will be assessed by the investigator using a validated score for each treatment area:
0 = no visible reaction,
1 = faint, minimal erythema,
2 = erythema,
3 = erythema with induration or vesicles,
4 = severe erythema with induration, vesicles or bullae or pustules and/or erosion/ulceration.
Part 2 (PoC study)
• assess the efficacy of topically applied BFH772 to treat psoriasis as assessed by plaque PASI scoring at week 4. |
|
| 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 | Yes |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 |
| Persons will apply study drugs and placebos as well as the comparator in Part 2 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
| |
| 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 | 15 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
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