Ignite Creation Date:
2024-05-05 @ 12:10 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00267826
Status:
COMPLETED
Last Update Posted:
2008-06-17
First Post:
2005-12-20
Brief Title:
Immunopharmacological Effects of Rituximab in Atopic Dermatitis
Sponsor:
University of Bern
Organization:
University of Bern
Study Overview
Official Title:
Open-Label Single Center Study to Evaluate the Immunopharmacological Effects of Rituximab in Patients With Atopic Dermatitis
Status:
COMPLETED
Status Verified Date:
2008-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Protocol Title Immunopharmacological effects of Rituximab in atopic dermatitis
Study Phase Investigator driven study
Study Design Open-label single center
Primary Study Objective To determine the efficacy safety and immunopharmacological effects of Rituximab anti-CD20 administered as a 1000mg intravenous infusion on days 1 and 15 to patients with atopic dermatitis
Secondary Study Objective To investigate key immunological parameters involved in the pathology of this common skin disease to interpret the clinical findings
Number of Patients 6
Study Population Male and female patients at least 18 years of age with atopic dermatitis active inflammation a severity score of 6-9 according to Langeland and Rajika
Treatment Group Rituximab will be administered as 1000 mg infusion intravenously at day 1 and 15 followed by a 24-week follow-up period
Visit Schedule Screening Visit within 28 days prior to Visit 1 Treatment visits Visits days 1 3 8 15 17 Follow-up Visits Visits weeks 4 8 12 16 20 24
Visit 11Early Termination Visit if applicable Visit 11 will serve as the Early Termination Visit for any patient who withdraws from the study between Visit 1 and 10
Efficacy Parameters
Clinical parameters
EASI Patient Assessment of Pruritus Pruritus score Physician Global Assessment PGA Photography
Laboratory analysis
Differential blood count Total IgE specific IgE aeroallergen panel Immunophenotyping of PBMC Lymphocyte proliferation following pan-T stimulation with PHA Cytokine release from blood T cells following pan-T stimulation with PHA
Skin tests Histopathology of skin biopsies
Safety Parameters Physical examinations vital signs selected blood chemistry including liver function tests creatinine white blood cell count WBC including total lymphocyte count platelets lymphocyte subset analysis complement immunoglobulins IgA IgM IgG IgE monitoring for infections monitoring for concomitant therapies monitoring for adverse events
Study Phase Investigator driven study
Study Design Open-label single center
Primary Study Objective To determine the efficacy safety and immunopharmacological effects of Rituximab anti-CD20 administered as a 1000mg intravenous infusion on days 1 and 15 to patients with atopic dermatitis
Secondary Study Objective To investigate key immunological parameters involved in the pathology of this common skin disease to interpret the clinical findings
Number of Patients 6
Study Population Male and female patients at least 18 years of age with atopic dermatitis active inflammation a severity score of 6-9 according to Langeland and Rajika
Treatment Group Rituximab will be administered as 1000 mg infusion intravenously at day 1 and 15 followed by a 24-week follow-up period
Visit Schedule Screening Visit within 28 days prior to Visit 1 Treatment visits Visits days 1 3 8 15 17 Follow-up Visits Visits weeks 4 8 12 16 20 24
Visit 11Early Termination Visit if applicable Visit 11 will serve as the Early Termination Visit for any patient who withdraws from the study between Visit 1 and 10
Efficacy Parameters
Clinical parameters
EASI Patient Assessment of Pruritus Pruritus score Physician Global Assessment PGA Photography
Laboratory analysis
Differential blood count Total IgE specific IgE aeroallergen panel Immunophenotyping of PBMC Lymphocyte proliferation following pan-T stimulation with PHA Cytokine release from blood T cells following pan-T stimulation with PHA
Skin tests Histopathology of skin biopsies
Safety Parameters Physical examinations vital signs selected blood chemistry including liver function tests creatinine white blood cell count WBC including total lymphocyte count platelets lymphocyte subset analysis complement immunoglobulins IgA IgM IgG IgE monitoring for infections monitoring for concomitant therapies monitoring for adverse events
Detailed Description:
Investigator driven study
Immunopharmacological Effects of Rituximab in Atopic Dermatitis
Investigators
1 Prof Dr Hans-Uwe Simon Dept of Pharmacology University of Bern Switzerland
2 Dr Dagmar Simon Prof Dr Lasse R Braathen Dept of Dermatology University of Bern Switzerland
SUMMARY
Protocol Title Immunopharmacological effects of Rituximab in atopic dermatitis
Study Phase Investigator driven study
Study Design Open-label single center
Primary Study Objective To determine the efficacy safety and immunopharmacological effects of Rituximab anti-CD20 administered as a 1000mg intravenous infusion on days 1 and 15 to patients with atopic dermatitis
Secondary Study Objective To investigate key immunological parameters involved in the pathology of this common skin disease to interpret the clinical findings
Number of Patients 6
Study Population Male and female patients at least 18 years of age with atopic dermatitis active inflammation a severity score of 6-9 according to Langeland and Rajika
Treatment Group Rituximab will be administered as 1000 mg infusion intravenously at day 1 and 15 followed by a 24-week follow-up period
Visit Schedule Screening Visit within 28 days prior to Visit 1 Treatment visits Visits days 1 3 8 15 17 Follow-up Visits Visits weeks 4 8 12 16 20 24
Visit 11Early Termination Visit if applicable Visit 11 will serve as the Early Termination Visit for any patient who withdraws from the study between Visit 1 and 10
Efficacy Parameters
Clinical parameters
EASI Patient Assessment of Pruritus Pruritus score Physician Global Assessment PGA Photography
Laboratory analysis
Differential blood count Total IgE specific IgE aeroallergen panel Immunophenotyping of PBMC Lymphocyte proliferation following pan-T stimulation Cytokine release from blood T cells following pan-T stimulation Skin tests Histopathology of skin biopsies Immunohistochemistry
Safety Parameters Physical examinations vital signs selected blood chemistry including liver function tests creatinine white blood cell count WBC including total lymphocyte count platelets lymphocyte subset analysis complement immunoglobulins IgA IgM IgG IgE monitoring for infections monitoring for concomitant therapies monitoring for adverse events
Time schedule All six patients will be recruited within 1 year following approval of the study by both Cantonal Ethics Commission Bern and Swissmedic
Aim of the study In this study we want to investigate the clinical efficacy and safety as well as the immunopharmacological effects in particular the inflammatory cells and their cytokine production in AD skin and blood under the treatment of rituximab
Primary Objective
To determine the efficacy and safety of Rituximab when administered as a 1000 mg intravenous infusion to patients with atopic dermatitis
Additional Objectives
The additional objectives of this study are
To investigate the influence of Rituximab treatment on key immunological parameters involved in immunopathology of AD
STUDY DESIGN
Study Outline
This is a open-label single center study to evaluate the efficacy and safety of Rituximab when administered as a 1000 mg intravenous infusion to patients with atopic dermatitis 6 patients should be enrolled
During the treatment course all patients will receive Rituximab administered as 1000 mg intravenous infusion at day 1 and 15 followed by a 22-week follow-up period
STUDY POPULATION
Number of Patients
Approximately 6 patients will be enrolled
Study Entry Inclusion Criteria
To be eligible for entry into this study candidates must meet the following eligibility criteria at the time of enrollment
-- --
1 Must give written informed consent
2 Must be at least 18 years of age
3 Must have been diagnosed with atopic dermatitis fulfilling the diagnostic criteria of Hanfin and Rajka and having active inflammation
4 Must have a severity score of 6-9 according to Langeland and Rajka
5 Must have a PGA of moderate severe or very severe and a pruritus score of moderate or severe at baseline
Study Entry Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of enrollment
1 Patients with other skin diseases that might interfere with the evaluation of AD
2 Patients with severe diseases of other organ systems eg cardiovascular liver kidney psychiatric neurologic that might put the patient on risk during the study or might interfere with the evaluations in the opinion of the investigator
3 Patient older than 65 years
4 Systemic treatment for atopic dermatitis e g corticosteroids cyclosporine mycophenolat- mofetil interferon-gamma UVB UVA PUVA or systemic treatment with immunosuppressiveimmunomodulating substances eg azathioprin methotrexate biologics or hyposensitization -therapy within 28 days prior to baseline
5 Local treatment for atopic dermatitis with pimecrolimustacrolimus steroids class III instable use of steroids class III emollients or local antisepticsantibiotics within 14 days prior to day 1
6 Serious local infection eg cellulitis abscess or systemic infection eg pneumonia septicemia within 3 months prior to the first dose of Rituximab
7 History of recurrent clinically significant infection
8 Congenital or acquired immunodeficiency syndrome
9 History of or a new diagnosis or treatment of an invasive malignancy within 5 years of enrollment Patients with a history of treated squamous cell andor basal cell carcinomas limited to the skin are not excluded
10 For female patients unless postmenopausal or surgically sterile unwillingness to practice effective contraception as defined by the investigator during the study The rhythm method is not to be used as the sole method of contraception Female patients considering becoming pregnant while in the study are excluded
11 Female patients who are currently pregnant or breast-feeding
12 Current enrollment in any other investigational drug study
13 Previous participation in this study or previous studies with Rituximab
Screening Log
Participating investigational site is required to document all screened candidates initially considered for inclusion in this study and to specifically state the reasons for their exclusion
STUDY MEDICATION DESCRIPTION AND ALLOCATION
Investigational Drug
Rituximab is supplied by Roche Pharma Schweiz AG Rituximab is registered for the treatment of B cell lymphoma in Switzerland Investigational site personnel should refer to the Directions for Handling and Administration DHA for specific instructions on the handling and administration of Rituximab
Enrollment Procedure
Patients are officially enrolled into the study and assigned a subject identification number after all screening evaluations have been completed and all study inclusion criteria have been met
Drug Accountability
Rituximab accountability must be maintained by the investigator The investigator must maintain accurate records demonstrating the dates and amount of Rituximab received to whom dispensed patient-by-patient accounting and accounts of any Rituximab accidentally or deliberately destroyed Unless otherwise notified all vials both used and unused will be saved
THERAPY
Once therapy that is dose number 1 has begun in order for a patient to receive a subsequent dose of Rituximab the following must occur
administration of each dose of Rituximab must be separated by an interval of at least 7 days
no clinical evidence of significant viral bacterial or fungal infection at the time of the study visit
Treatment Schedule
During the treatment course all patients will receive Rituximab administered as a 1000 mg intravenous infusion followed by a 24-week follow-up period
Dosing will be according to the schedule provided unless there is evidence of clinically significant infection as determined by the investigator or leukopenia neutropenia or thrombocytopenia
Treatment Compliance
Compliance with Rituximab dosing will be monitored and recorded by investigational site personnel
Concomitant Therapy
For patients on any prescription medication every attempt should be made to keep the patient on a stable dose of that medication for at least 14 days prior to the first dose of Rituximab in any treatment course
Any medication and any non-drug procedure or therapy including topical emollients used from study entry until the patients final study visit must be recorded in the patients CRF
Allowed Concomitant Therapy
Patients will two intravenous infusions of Rituximab either as monotherapy or in combination the following classes of treatments as described below Treatments should be kept stable through the period from 14 days before baseline until Visit 13
Topical low or medium potency corticosteroids
Topical emollients
Topical antiseptics and antibiotics
Oral Antihistamines
Disallowed Concomitant Therapy
At no time during study participation may patients receive treatment with
live vaccines or live attenuated vaccines
therapy for active tuberculosis or tuberculosis prophylaxis
UVB UVA UVA1
Psoralen plus ultraviolet A PUVA
cyclosporine methotrexate prednisone azathioprine thioguanine or other systemic immunosuppressant agents
topical pimecrolimus or tacrolimus
high potency topical corticosteroids
another investigational drug or approved therapy for investigational use
any kind of allergenspecific immunotherapy
EFFICACY ASSESSMENTS
Clinical Efficacy Assessments
All efficacy assessments are to be performed by the same investigator for each patient
PGA
EASI
Patients Pruritus Assessment
Photography
LaboratoryHistologic Efficacy Assessments
Laboratory analysis
Differential blood count platelets Total IgE specific IgE aeroallergen panel Immunophenotyping of PBMC Lymphocyte proliferation following pan-T stimulation Cytokine release from blood T cells following pan-T stimulation
Skin tests Histopathology of skin biopsies Immunohistochemistry
SAFETY ASSESSMENTS
Clinical Safety Assessments
Physical examinations including vital signs signs for infection
Monitoring for new or ongoing infections
Monitoring for concomitant therapies
Monitoring for adverse events
Laboratory Safety Assessments
Selected blood chemistry
pregnancy testing
ProductTrial-Specific Assessments
WBC Including total lymphocyte count
Platelets
Adverse Events Definition and Management
The terms relationship and severity used throughout this section are defined in the table
At the time of written informed consent the patient must be given the name and phone number of investigational site personnel who can be called in the event of an emergency or to report any medical symptom or untoward medical occurrence that is of concern to the patient
Definitions Predosing Signs and Symptoms
For the purposes of this study any sign including an abnormal laboratory result as determined by the investigator or medical diagnosis noted by medical personnel or symptom reported by the patient that occurs prior to the start of investigational drug treatment is considered to be a predosing signsymptom Any predosing signsymptom classified as serious will be reported to the IRBREBIEC
Adverse Events
For the purposes of this study any sign including an abnormal laboratory result as determined by the investigator or medical diagnosis noted by medical personnel or symptom reported by the patient regardless of relationship to investigational drug that is treatment-emergent is considered to be an adverse event Treatment-emergent is defined as follows
-- --
1 Has onset any time after the start of investigational drug treatment
OR
2 Has worsened since the event was previously reported this includes worsening of signs symptoms or diagnoses that were present prior to the first dose of investigational drug but then worsened any time after the start of investigational drug treatment
Classification of Event as Serious
As soon as a patient has given written informed consent to participate in the study any abnormal sign including an abnormal laboratory result as determined by the investigator or medical diagnosis noted by medical personnel or symptom reported by the patient regardless of whether or not the patient has received investigational drug is to be classified by the investigator as either a serious or non-serious event using the following definition
Serious Event
Events are classified as serious if they meet any of the following criteria in accordance with 21 CFR Part 31232 and the recommendations of the International Conference on Harmonization Federal Register October 7 1997 Vol 62 No 194 pp 52239-45
Any death
Any life-threatening event ie an event that places the patient in the view of the investigator at immediate risk of death from the event as it occurred does not include an event that had it occurred in a more severe form might have caused death
Any event that requires or prolongs in-patient hospitalization
Any event that results in persistent or significant disabilityincapacity
Any congenital anomalybirth defect diagnosed in a child of a patient who participated in this study
Other medically important events that in the opinion of the investigator may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above
Immediate Telephone Reporting of Serious Events
Roche Pharma Schweiz AG must immediately be made aware of events classified as SERIOUS in order to adhere to all applicable laws and regulations for reporting serious events Therefore it is the investigators responsibility to ensure the following
Any serious event that occurs any time after the patient signs the informed consent form for this study regardless of whether or not the patient has undergone any study-related procedures or received investigational drug up to the patients final study visit ie Visit 11 inclusive must be reported to Roche Pharma Schweiz AG within 24 hours following report of the event regardless of severity or relationship to investigational drug
When telephoning a serious event report to Roche Pharma Schweiz AG the investigator must provide specific information regarding the patient and the event Roche Pharma Schweiz AG must also receive written confirmation of the above information For deaths that occur following a patients enrollment into the study a Record of Death CRF as well as a copy of the autopsy report whenif available must be submitted to Roche Pharma Schweiz AG The investigator must keep a copy of all documentation related to the event in the sites study files
The investigator must also notify the local review committee ie the Institutional Review Board IRB Research Ethics Board REB as per local IRBREBIEC requirements Documentation of these reports will be kept in the sites study files
Any serious event that has onset after the patients first dose of investigational drug and that is unresolved at the time the patient permanently discontinues the study must be followed until the event resolves or until the patients clinical course has stabilized
Reporting of Serious Events to Regulatory Agencies After receipt of a serious event report Roche Pharma Schweiz AG will notify all appropriate regulatory authorities as necessary within the required time frames Written safety reports submitted to regulatory authorities will be completed by Roche Pharma Schweiz AG with the assistance of the investigator and other investigational site personnel as needed
Primary Endpoints
Primary endpoint is the change of EASI at Visit 7 and 24 compared to baseline via paired t-Test
Additional Endpoints Additional endpoints are the percentage of patients reaching a PGA of clear or almost clear andor a reduction of EASI of 50 or 75 compared to baseline at any visit after baseline
Other additional endpoints are
the percentage of patients reaching a pruritus score of none or mild Several immunological endpoints
Criteria for the Endpoints
Patients with missing PGA scores at the visit being analyzed will be considered treatment failures for that visit Patients who received disallowed therapies as listed prior to the visit of the course being analyzed will be considered treatment failures for the course in the efficacy analysis
Statistical Methods
Analysis Populations 1111 Safety
The safety population is defined as all patients who received at least 1 dose of study drug and have at least 1 post-baseline assessment of the safety parameter
1112 Efficacy
The efficacy population will be based on the intent-to-treat principle and is defined as all patients who received at least 1 dose of study drug
Demographics and statistical aspects
All appropriate background data will be summarized by presenting frequency distributions andor basic summary statistics mean standard deviation median minimum and maximum
Study question and hypothesis
Due to the pilot character of this study no formal hypotheses are issued We expect clear improvement with Rituximab The effect of Rituximab is of special interest because this may become a new therapeutic approach with reasonable costs and handling Our investigation should be a pilot trial for a following study enrolling a larger population to elucidate the clinical use for treatment of patients with atopic dermatitis
Statistical methods
Changes in the investigated variables before and after treatment will be compared using the Wilcoxons signed ranks test Subgroups will be compared using the Mann Whitney U-test Otherwise the data will be analysed and presented in a desriptive manner see above
Safety Analyses
All clinical adverse events and laboratory abnormalities will be evaluated for safety The number of patients with at least 1 dose withheld will also be evaluated
1113 White blood cell counts platelets
Lymphocyte and lymphocyte subset CD4 and CD8 counts over time will be presented
1114 Laboratory Abnormalities
Selected blood chemistry evaluations will be assessed to determine incidence of laboratory abnormalities that emerge within the course Shift tables will be used to present changes in each laboratory parameter relative to the parameters normal range
1115 Physical Examinations and Vital Signs
The incidences of abnormalities in physical examination and in vital signs respectively will be presented
Efficacy Analyses
The proportion of patients who achieve a PGA of almost clear or clear or a decrease in EASI value 50 and 75 without the use of disallowed therapy as defined in the protocol at each scheduled visit will be presented
The EASI at Visit 3-11 will be compared to EASI at baselineDay1 using a paired t-test The threshold for significant changes will be p005
APPENDIX 1 ECZEMA AREA AND SEVERITY INDEX EASI The EASI assigns proportionate body surface areas to the head and neck 10 trunk 30 upper extremities 20 and lower extremities 40 for children aged 7 and above This is roughly consistent with the rule of nine The numbers are modified when used with children under the age of 7 head and neck 20 trunk 30 upper extremities 20 and lower extremities 30 The area of involvement affected by inflammation not including dry skin of each of the four body regions is represented by a numeric coded value 0 - 6 as below the investigator is required to record the percent area on the CRF
Table 1 EASI Area of involvement Area Involvement 0 1 2 3 4 5 6 no eruption 10 10 - 29 30 - 49 50 - 69 70 - 89 90 - 100
The head trunk upper limbs and lower limbs are assessed separately for erythema E infiltrationpapulation I excoriation Ex and lichenification L The average degree of severity of each sign in each of the four body parts is assigned a score of 0-3 indicating none 0 mild 1 moderate 2 and severe 3 expression of the clinical sign Half steps are allowed
Further practical details to aid the assessment are
The lower extremities region includes the buttocks The trunk region includes the internalmedial axillae and groin The headneck region comprises the face and the anterior and posterior neck The upper extremities region includes the hands and external axillae
The definitions of the scoring signs of EASI are given below
Table 2 Scoring signs of EASI Erythema E 0 None
1 Mild Faintly detectable erythema very light pink 2 Moderate Dull red clearly distinguishable 3 Severe Deep dark red Infiltration Papulation I 0 None
1 Mild Barely perceptible elevation
2 Moderate Clearly perceptible elevation but not extensive
3 Severe Marked and extensive elevation Excoriations Ex
0 None
1 Mild Scant evidence of excoriations with no signs of deeper skin damage erosion crust 2 Moderate Several linear marks of skin with some showing evidence of deeper skin injury erosion crust 3 Severe Many erosive or crusty lesions Lichenification L 0 None
1 Mild Slight thickening of the skin discernible only by touch and with skin markings minimally exaggerated
2 Moderate Definite thickening of the skin with skin markings exaggerated so that they form a visible criss-cross pattern
3 Severe Thickened indurated skin with skin markings visibly portraying an exaggerated criss-cross pattern
The EASI will then be calculated according to the following formula
Table 3 EASI Calculation of score for ages 7 years and above HeadNeck E I Ex L x Area1 x 01 Trunk E I Ex L x Area1 x 03 Upper limbs E I Ex L x Area1 x 02 Lower limbs E I Ex L x Area1 x 04 EASI sum of the above four body areas
1 Where Area is defined on a Seven Point Ordinal Scale as shown in the table 3-3
Dermatologists Signature _______________________________ date ddMMMyyyy _____________
APPENDIX 2 PHYSICIAN GLOBAL ASSESSMENT OF EFFICACY
Please mark the box based on the patients condition at the time of this visit
Clear Almost Clear Mild Moderate Severe Very Severe
1 0 2 0 3 0 4 0 50 6 0
Very Severe severe erythema and severe papulation infiltration with oozingcrusting
Severe severe erythema and severe papulation infiltration
Moderate moderate erythema and moderate papulation infiltration
Mild mild erythema and mild papulation infiltration
Almost Clear just perceptible erythema and just perceptible papulation infiltration
Clear No inflammatory signs of AD
APPENDIX 3 PRURITUS SEVERITY SCORE IN AVERAGE ABOUT THE LAST WEEK
Severe Moderate Mild Absent
1 0 2 0 3 0 4 0
Severe Intense itching with severe sleep disturbance Moderate Moderate itching with some sleep disturbance Mild mild itching without sleep disturbance Absent no itching
Immunopharmacological Effects of Rituximab in Atopic Dermatitis
Investigators
1 Prof Dr Hans-Uwe Simon Dept of Pharmacology University of Bern Switzerland
2 Dr Dagmar Simon Prof Dr Lasse R Braathen Dept of Dermatology University of Bern Switzerland
SUMMARY
Protocol Title Immunopharmacological effects of Rituximab in atopic dermatitis
Study Phase Investigator driven study
Study Design Open-label single center
Primary Study Objective To determine the efficacy safety and immunopharmacological effects of Rituximab anti-CD20 administered as a 1000mg intravenous infusion on days 1 and 15 to patients with atopic dermatitis
Secondary Study Objective To investigate key immunological parameters involved in the pathology of this common skin disease to interpret the clinical findings
Number of Patients 6
Study Population Male and female patients at least 18 years of age with atopic dermatitis active inflammation a severity score of 6-9 according to Langeland and Rajika
Treatment Group Rituximab will be administered as 1000 mg infusion intravenously at day 1 and 15 followed by a 24-week follow-up period
Visit Schedule Screening Visit within 28 days prior to Visit 1 Treatment visits Visits days 1 3 8 15 17 Follow-up Visits Visits weeks 4 8 12 16 20 24
Visit 11Early Termination Visit if applicable Visit 11 will serve as the Early Termination Visit for any patient who withdraws from the study between Visit 1 and 10
Efficacy Parameters
Clinical parameters
EASI Patient Assessment of Pruritus Pruritus score Physician Global Assessment PGA Photography
Laboratory analysis
Differential blood count Total IgE specific IgE aeroallergen panel Immunophenotyping of PBMC Lymphocyte proliferation following pan-T stimulation Cytokine release from blood T cells following pan-T stimulation Skin tests Histopathology of skin biopsies Immunohistochemistry
Safety Parameters Physical examinations vital signs selected blood chemistry including liver function tests creatinine white blood cell count WBC including total lymphocyte count platelets lymphocyte subset analysis complement immunoglobulins IgA IgM IgG IgE monitoring for infections monitoring for concomitant therapies monitoring for adverse events
Time schedule All six patients will be recruited within 1 year following approval of the study by both Cantonal Ethics Commission Bern and Swissmedic
Aim of the study In this study we want to investigate the clinical efficacy and safety as well as the immunopharmacological effects in particular the inflammatory cells and their cytokine production in AD skin and blood under the treatment of rituximab
Primary Objective
To determine the efficacy and safety of Rituximab when administered as a 1000 mg intravenous infusion to patients with atopic dermatitis
Additional Objectives
The additional objectives of this study are
To investigate the influence of Rituximab treatment on key immunological parameters involved in immunopathology of AD
STUDY DESIGN
Study Outline
This is a open-label single center study to evaluate the efficacy and safety of Rituximab when administered as a 1000 mg intravenous infusion to patients with atopic dermatitis 6 patients should be enrolled
During the treatment course all patients will receive Rituximab administered as 1000 mg intravenous infusion at day 1 and 15 followed by a 22-week follow-up period
STUDY POPULATION
Number of Patients
Approximately 6 patients will be enrolled
Study Entry Inclusion Criteria
To be eligible for entry into this study candidates must meet the following eligibility criteria at the time of enrollment
-- --
1 Must give written informed consent
2 Must be at least 18 years of age
3 Must have been diagnosed with atopic dermatitis fulfilling the diagnostic criteria of Hanfin and Rajka and having active inflammation
4 Must have a severity score of 6-9 according to Langeland and Rajka
5 Must have a PGA of moderate severe or very severe and a pruritus score of moderate or severe at baseline
Study Entry Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of enrollment
1 Patients with other skin diseases that might interfere with the evaluation of AD
2 Patients with severe diseases of other organ systems eg cardiovascular liver kidney psychiatric neurologic that might put the patient on risk during the study or might interfere with the evaluations in the opinion of the investigator
3 Patient older than 65 years
4 Systemic treatment for atopic dermatitis e g corticosteroids cyclosporine mycophenolat- mofetil interferon-gamma UVB UVA PUVA or systemic treatment with immunosuppressiveimmunomodulating substances eg azathioprin methotrexate biologics or hyposensitization -therapy within 28 days prior to baseline
5 Local treatment for atopic dermatitis with pimecrolimustacrolimus steroids class III instable use of steroids class III emollients or local antisepticsantibiotics within 14 days prior to day 1
6 Serious local infection eg cellulitis abscess or systemic infection eg pneumonia septicemia within 3 months prior to the first dose of Rituximab
7 History of recurrent clinically significant infection
8 Congenital or acquired immunodeficiency syndrome
9 History of or a new diagnosis or treatment of an invasive malignancy within 5 years of enrollment Patients with a history of treated squamous cell andor basal cell carcinomas limited to the skin are not excluded
10 For female patients unless postmenopausal or surgically sterile unwillingness to practice effective contraception as defined by the investigator during the study The rhythm method is not to be used as the sole method of contraception Female patients considering becoming pregnant while in the study are excluded
11 Female patients who are currently pregnant or breast-feeding
12 Current enrollment in any other investigational drug study
13 Previous participation in this study or previous studies with Rituximab
Screening Log
Participating investigational site is required to document all screened candidates initially considered for inclusion in this study and to specifically state the reasons for their exclusion
STUDY MEDICATION DESCRIPTION AND ALLOCATION
Investigational Drug
Rituximab is supplied by Roche Pharma Schweiz AG Rituximab is registered for the treatment of B cell lymphoma in Switzerland Investigational site personnel should refer to the Directions for Handling and Administration DHA for specific instructions on the handling and administration of Rituximab
Enrollment Procedure
Patients are officially enrolled into the study and assigned a subject identification number after all screening evaluations have been completed and all study inclusion criteria have been met
Drug Accountability
Rituximab accountability must be maintained by the investigator The investigator must maintain accurate records demonstrating the dates and amount of Rituximab received to whom dispensed patient-by-patient accounting and accounts of any Rituximab accidentally or deliberately destroyed Unless otherwise notified all vials both used and unused will be saved
THERAPY
Once therapy that is dose number 1 has begun in order for a patient to receive a subsequent dose of Rituximab the following must occur
administration of each dose of Rituximab must be separated by an interval of at least 7 days
no clinical evidence of significant viral bacterial or fungal infection at the time of the study visit
Treatment Schedule
During the treatment course all patients will receive Rituximab administered as a 1000 mg intravenous infusion followed by a 24-week follow-up period
Dosing will be according to the schedule provided unless there is evidence of clinically significant infection as determined by the investigator or leukopenia neutropenia or thrombocytopenia
Treatment Compliance
Compliance with Rituximab dosing will be monitored and recorded by investigational site personnel
Concomitant Therapy
For patients on any prescription medication every attempt should be made to keep the patient on a stable dose of that medication for at least 14 days prior to the first dose of Rituximab in any treatment course
Any medication and any non-drug procedure or therapy including topical emollients used from study entry until the patients final study visit must be recorded in the patients CRF
Allowed Concomitant Therapy
Patients will two intravenous infusions of Rituximab either as monotherapy or in combination the following classes of treatments as described below Treatments should be kept stable through the period from 14 days before baseline until Visit 13
Topical low or medium potency corticosteroids
Topical emollients
Topical antiseptics and antibiotics
Oral Antihistamines
Disallowed Concomitant Therapy
At no time during study participation may patients receive treatment with
live vaccines or live attenuated vaccines
therapy for active tuberculosis or tuberculosis prophylaxis
UVB UVA UVA1
Psoralen plus ultraviolet A PUVA
cyclosporine methotrexate prednisone azathioprine thioguanine or other systemic immunosuppressant agents
topical pimecrolimus or tacrolimus
high potency topical corticosteroids
another investigational drug or approved therapy for investigational use
any kind of allergenspecific immunotherapy
EFFICACY ASSESSMENTS
Clinical Efficacy Assessments
All efficacy assessments are to be performed by the same investigator for each patient
PGA
EASI
Patients Pruritus Assessment
Photography
LaboratoryHistologic Efficacy Assessments
Laboratory analysis
Differential blood count platelets Total IgE specific IgE aeroallergen panel Immunophenotyping of PBMC Lymphocyte proliferation following pan-T stimulation Cytokine release from blood T cells following pan-T stimulation
Skin tests Histopathology of skin biopsies Immunohistochemistry
SAFETY ASSESSMENTS
Clinical Safety Assessments
Physical examinations including vital signs signs for infection
Monitoring for new or ongoing infections
Monitoring for concomitant therapies
Monitoring for adverse events
Laboratory Safety Assessments
Selected blood chemistry
pregnancy testing
ProductTrial-Specific Assessments
WBC Including total lymphocyte count
Platelets
Adverse Events Definition and Management
The terms relationship and severity used throughout this section are defined in the table
At the time of written informed consent the patient must be given the name and phone number of investigational site personnel who can be called in the event of an emergency or to report any medical symptom or untoward medical occurrence that is of concern to the patient
Definitions Predosing Signs and Symptoms
For the purposes of this study any sign including an abnormal laboratory result as determined by the investigator or medical diagnosis noted by medical personnel or symptom reported by the patient that occurs prior to the start of investigational drug treatment is considered to be a predosing signsymptom Any predosing signsymptom classified as serious will be reported to the IRBREBIEC
Adverse Events
For the purposes of this study any sign including an abnormal laboratory result as determined by the investigator or medical diagnosis noted by medical personnel or symptom reported by the patient regardless of relationship to investigational drug that is treatment-emergent is considered to be an adverse event Treatment-emergent is defined as follows
-- --
1 Has onset any time after the start of investigational drug treatment
OR
2 Has worsened since the event was previously reported this includes worsening of signs symptoms or diagnoses that were present prior to the first dose of investigational drug but then worsened any time after the start of investigational drug treatment
Classification of Event as Serious
As soon as a patient has given written informed consent to participate in the study any abnormal sign including an abnormal laboratory result as determined by the investigator or medical diagnosis noted by medical personnel or symptom reported by the patient regardless of whether or not the patient has received investigational drug is to be classified by the investigator as either a serious or non-serious event using the following definition
Serious Event
Events are classified as serious if they meet any of the following criteria in accordance with 21 CFR Part 31232 and the recommendations of the International Conference on Harmonization Federal Register October 7 1997 Vol 62 No 194 pp 52239-45
Any death
Any life-threatening event ie an event that places the patient in the view of the investigator at immediate risk of death from the event as it occurred does not include an event that had it occurred in a more severe form might have caused death
Any event that requires or prolongs in-patient hospitalization
Any event that results in persistent or significant disabilityincapacity
Any congenital anomalybirth defect diagnosed in a child of a patient who participated in this study
Other medically important events that in the opinion of the investigator may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above
Immediate Telephone Reporting of Serious Events
Roche Pharma Schweiz AG must immediately be made aware of events classified as SERIOUS in order to adhere to all applicable laws and regulations for reporting serious events Therefore it is the investigators responsibility to ensure the following
Any serious event that occurs any time after the patient signs the informed consent form for this study regardless of whether or not the patient has undergone any study-related procedures or received investigational drug up to the patients final study visit ie Visit 11 inclusive must be reported to Roche Pharma Schweiz AG within 24 hours following report of the event regardless of severity or relationship to investigational drug
When telephoning a serious event report to Roche Pharma Schweiz AG the investigator must provide specific information regarding the patient and the event Roche Pharma Schweiz AG must also receive written confirmation of the above information For deaths that occur following a patients enrollment into the study a Record of Death CRF as well as a copy of the autopsy report whenif available must be submitted to Roche Pharma Schweiz AG The investigator must keep a copy of all documentation related to the event in the sites study files
The investigator must also notify the local review committee ie the Institutional Review Board IRB Research Ethics Board REB as per local IRBREBIEC requirements Documentation of these reports will be kept in the sites study files
Any serious event that has onset after the patients first dose of investigational drug and that is unresolved at the time the patient permanently discontinues the study must be followed until the event resolves or until the patients clinical course has stabilized
Reporting of Serious Events to Regulatory Agencies After receipt of a serious event report Roche Pharma Schweiz AG will notify all appropriate regulatory authorities as necessary within the required time frames Written safety reports submitted to regulatory authorities will be completed by Roche Pharma Schweiz AG with the assistance of the investigator and other investigational site personnel as needed
Primary Endpoints
Primary endpoint is the change of EASI at Visit 7 and 24 compared to baseline via paired t-Test
Additional Endpoints Additional endpoints are the percentage of patients reaching a PGA of clear or almost clear andor a reduction of EASI of 50 or 75 compared to baseline at any visit after baseline
Other additional endpoints are
the percentage of patients reaching a pruritus score of none or mild Several immunological endpoints
Criteria for the Endpoints
Patients with missing PGA scores at the visit being analyzed will be considered treatment failures for that visit Patients who received disallowed therapies as listed prior to the visit of the course being analyzed will be considered treatment failures for the course in the efficacy analysis
Statistical Methods
Analysis Populations 1111 Safety
The safety population is defined as all patients who received at least 1 dose of study drug and have at least 1 post-baseline assessment of the safety parameter
1112 Efficacy
The efficacy population will be based on the intent-to-treat principle and is defined as all patients who received at least 1 dose of study drug
Demographics and statistical aspects
All appropriate background data will be summarized by presenting frequency distributions andor basic summary statistics mean standard deviation median minimum and maximum
Study question and hypothesis
Due to the pilot character of this study no formal hypotheses are issued We expect clear improvement with Rituximab The effect of Rituximab is of special interest because this may become a new therapeutic approach with reasonable costs and handling Our investigation should be a pilot trial for a following study enrolling a larger population to elucidate the clinical use for treatment of patients with atopic dermatitis
Statistical methods
Changes in the investigated variables before and after treatment will be compared using the Wilcoxons signed ranks test Subgroups will be compared using the Mann Whitney U-test Otherwise the data will be analysed and presented in a desriptive manner see above
Safety Analyses
All clinical adverse events and laboratory abnormalities will be evaluated for safety The number of patients with at least 1 dose withheld will also be evaluated
1113 White blood cell counts platelets
Lymphocyte and lymphocyte subset CD4 and CD8 counts over time will be presented
1114 Laboratory Abnormalities
Selected blood chemistry evaluations will be assessed to determine incidence of laboratory abnormalities that emerge within the course Shift tables will be used to present changes in each laboratory parameter relative to the parameters normal range
1115 Physical Examinations and Vital Signs
The incidences of abnormalities in physical examination and in vital signs respectively will be presented
Efficacy Analyses
The proportion of patients who achieve a PGA of almost clear or clear or a decrease in EASI value 50 and 75 without the use of disallowed therapy as defined in the protocol at each scheduled visit will be presented
The EASI at Visit 3-11 will be compared to EASI at baselineDay1 using a paired t-test The threshold for significant changes will be p005
APPENDIX 1 ECZEMA AREA AND SEVERITY INDEX EASI The EASI assigns proportionate body surface areas to the head and neck 10 trunk 30 upper extremities 20 and lower extremities 40 for children aged 7 and above This is roughly consistent with the rule of nine The numbers are modified when used with children under the age of 7 head and neck 20 trunk 30 upper extremities 20 and lower extremities 30 The area of involvement affected by inflammation not including dry skin of each of the four body regions is represented by a numeric coded value 0 - 6 as below the investigator is required to record the percent area on the CRF
Table 1 EASI Area of involvement Area Involvement 0 1 2 3 4 5 6 no eruption 10 10 - 29 30 - 49 50 - 69 70 - 89 90 - 100
The head trunk upper limbs and lower limbs are assessed separately for erythema E infiltrationpapulation I excoriation Ex and lichenification L The average degree of severity of each sign in each of the four body parts is assigned a score of 0-3 indicating none 0 mild 1 moderate 2 and severe 3 expression of the clinical sign Half steps are allowed
Further practical details to aid the assessment are
The lower extremities region includes the buttocks The trunk region includes the internalmedial axillae and groin The headneck region comprises the face and the anterior and posterior neck The upper extremities region includes the hands and external axillae
The definitions of the scoring signs of EASI are given below
Table 2 Scoring signs of EASI Erythema E 0 None
1 Mild Faintly detectable erythema very light pink 2 Moderate Dull red clearly distinguishable 3 Severe Deep dark red Infiltration Papulation I 0 None
1 Mild Barely perceptible elevation
2 Moderate Clearly perceptible elevation but not extensive
3 Severe Marked and extensive elevation Excoriations Ex
0 None
1 Mild Scant evidence of excoriations with no signs of deeper skin damage erosion crust 2 Moderate Several linear marks of skin with some showing evidence of deeper skin injury erosion crust 3 Severe Many erosive or crusty lesions Lichenification L 0 None
1 Mild Slight thickening of the skin discernible only by touch and with skin markings minimally exaggerated
2 Moderate Definite thickening of the skin with skin markings exaggerated so that they form a visible criss-cross pattern
3 Severe Thickened indurated skin with skin markings visibly portraying an exaggerated criss-cross pattern
The EASI will then be calculated according to the following formula
Table 3 EASI Calculation of score for ages 7 years and above HeadNeck E I Ex L x Area1 x 01 Trunk E I Ex L x Area1 x 03 Upper limbs E I Ex L x Area1 x 02 Lower limbs E I Ex L x Area1 x 04 EASI sum of the above four body areas
1 Where Area is defined on a Seven Point Ordinal Scale as shown in the table 3-3
Dermatologists Signature _______________________________ date ddMMMyyyy _____________
APPENDIX 2 PHYSICIAN GLOBAL ASSESSMENT OF EFFICACY
Please mark the box based on the patients condition at the time of this visit
Clear Almost Clear Mild Moderate Severe Very Severe
1 0 2 0 3 0 4 0 50 6 0
Very Severe severe erythema and severe papulation infiltration with oozingcrusting
Severe severe erythema and severe papulation infiltration
Moderate moderate erythema and moderate papulation infiltration
Mild mild erythema and mild papulation infiltration
Almost Clear just perceptible erythema and just perceptible papulation infiltration
Clear No inflammatory signs of AD
APPENDIX 3 PRURITUS SEVERITY SCORE IN AVERAGE ABOUT THE LAST WEEK
Severe Moderate Mild Absent
1 0 2 0 3 0 4 0
Severe Intense itching with severe sleep disturbance Moderate Moderate itching with some sleep disturbance Mild mild itching without sleep disturbance Absent no itching
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| Roche Pharma AG Switzerland | None | None | None |