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Pilot Efficacy and Safety Study of Oral DF2156A in Patients With Active Bullous Pemphigoid

Primary Purpose

Bullous Pemphigoid

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
DF2156A
Sponsored by
Dompé Farmaceutici S.p.A
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bullous Pemphigoid focused on measuring Autoimmune inflammatory blistering disorder

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male and female patients aged >50 years.
  • Patients with newly diagnosed or relapsing bullous pemphigoid based on clinical diagnosis to be confirmed by direct immunofluorescence and indirect immunofluorescence on salt-spit skin (or BP180 and/or BP230 ELISA). Confirmation by laboratory tests will be obtained ideally before or anyway within one week after enrolment.

For the purpose of this study, clinical relapses are defined as re-appearance of clinical symptoms after the patient had attained remission lasting for more than 3 months without immunosuppressive treatment. In patients with relapsing BP, clinical diagnosis will be confirmed by indirect immunofluorescence or BP180 and/or BP230 ELISA only.

  • Patients with mild to moderate active blistering disease (total number of blisters between 1 and 30) whether associated or not with urticarial/eczematous lesions.
  • Patients with modified ABSIS score ≤50
  • Patients free from any systemic treatments that may affect the course of the disease with the following off-period prior to enrolment:

    1. 3 weeks: steroids, dapsone, tetracyclines, nicotinamide,
    2. 3 months: azathioprine, mycofenolate mofetil, cyclophosphamide, methotrexate, intravenous immunoglobulins, immunoadsorption, TNF antagonists
    3. 12 months: rituximab, leflunomide
  • Patients free from any topical treatments other than topical antibiotics and antiseptics in the 4 days prior to enrolment.
  • Patients able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
  • Patients able to provide informed consent.

Exclusion Criteria:

  • Patients with a Karnofsky rating score <40%.
  • Patients with mucosal involvement.
  • Patients with moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 50 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault , 1976).
  • Patients with hepatic dysfunction defined by increased ALT/AST > 3 x upper limit of normal (ULN) and increased total bilirubin > 3 mg/dL [>51.3 μmol/L].
  • Patients with hypoalbuminemia defined as serum albumin < 3 g/dL.
  • Patients with a baseline (day 0/1, pre-dose) QTcF > 470 msec.
  • Patients who had a myocardial infarction in the 6 months prior to enrolment.
  • Patients on treatment with phenytoin, warfarin, sulphonylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 mg/day).
  • Patients with known hypersensitivity to non-steroidal antiinflammatory drugs.
  • Patients using any investigational agent within 12 months prior to enrolment.
  • Pregnant or breast feeding women. Unwillingness to use effective contraceptive measures up to 2 months after the end of study drug administration (females and males).

Additional Exclusion Criteria for Germany only:

  • Patients with hypokalemia defined as serum potassium < 3.5 mmol/L.
  • Patients with clinically relevant bradycardia (heart rate < 50 beats/min)
  • Patients with a complete left bundle branch block.
  • Patients with a history of uncontrolled or labile hypertension
  • Patients with a history of congestive heart failure.
  • Patients with a history of cardiomyopathy.
  • Patients with unstable angina pectoris.
  • Patients with a personal or family history of congenital or documented acquired QT interval prolongation.
  • Patients with a significant atrial or ventricular arrhythmia or symptomatic arrhythmia in the past.

Sites / Locations

  • Department of Dermatology - Universitäts-Hautklinik; Hauptstraße 7
  • Klinik für Dermatologie, Allergologie und Venerologie - Universitätsklinikum Schleswig-Holstein, Campus Lübeck; Ratzeburger Allee 160
  • Klinik für Dermatologie und Allergologie - Philips Universität; 35037
  • I Divisione di Dermatologia, Istituto Dermopatico dell'Immacolata, IRCCS;

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

DF2156A 150 mg

Arm Description

150 mg capsule twice a day (every 12 h) for a maximum of 14 days

Outcomes

Primary Outcome Measures

Total number of blisters from baseline
Total number of blisters from baseline
Modified ABSIS score change from baseline
ABSIS score will be measured according to the pemphigus scoring sheet [Rosenbach, 2009] adjusted to the clinical manifestation in BP patients, as per specifications in protocol.
Physician Global Assessment (PGA) score measured on a 0-10 scale [Rosenbach, 2009]. Percent change from baseline
PGA score will be measured according to the following scale: 0 1 2 3 4 5 6 7 8 9 10 Perfect Worst health skin condition imaginable The following guidelines will help standardize PGA: 0: no lesions 2: almost cleared, no functional impairment 4: few lesions / low functional impairment 6: moderate 8: severe / extensive 10: life-threatening
Pruritus measured on a 10 cm visual analogue scale. Absolute value change from baseline
Pruritus will be measured according to the following scale: 0 10 No pruritus Worst pruritus I can imagine
Eosinophil blood count. Percent change from baseline
Eosinophil blood count. Percent change from baseline
Percentage of patients with treatment failure (drug discontinuation due to disease worsening)
treatment failure (drug discontinuation due to disease worsening)
Percentage of patients completely free from blisters
Percentage of patients completely free from blisters
Number of patients who are still free from blisters without requiring any systemic or topical rescue treatment - Optional
Number of patients who are still free from blisters without requiring any systemic or topical rescue treatment - Optional
QTcF. Change from baseline
QTcF. Change from baseline
Incidence of Adverse Events and Serious Adverse Events
Incidence of Adverse Events and Serious Adverse Events
Blisters percent change from baseline
Blisters percent change from baseline
Modified ABSIS score percent change from baseline
ABSIS score will be measured according to the pemphigus scoring sheet [Rosenbach, 2009] adjusted to the clinical manifestation in BP patients, as per specifications in protocol.
Physician Global Assessment (PGA) score measured on a 0-10 scale [Rosenbach, 2009]. Absolute value change from baseline
PGA score will be measured according to the following scale: 0 1 2 3 4 5 6 7 8 9 10 Perfect Worst health skin condition imaginable The following guidelines will help standardize PGA: 0: no lesions 2: almost cleared, no functional impairment 4: few lesions / low functional impairment 6: moderate 8: severe / extensive 10: life-threatening
Pruritus measured on a 10 cm visual analogue scale. Percent change from baseline
Pruritus will be measured according to the following scale: 0 10 No pruritus Worst pruritus I can imagine
Eosinophil blood count. Absolute number change from baseline
Eosinophil blood count. Absolute number change from baseline
Number of patients with treatment failure (drug discontinuation due to disease worsening)
Number of patients with treatment failure (drug discontinuation due to diseas
Number of patients completely free from blisters
Number of patients completely free from blisters
QTcF. Absolute value
QTcF. Absolute value

Secondary Outcome Measures

Plasma levels of DF2156A and its major metabolites (DF2227 and DF2108) at steady state conditions
Plasma levels of DF2156A and its major metabolites (DF2227 and DF2108) at steady state conditions

Full Information

First Posted
April 4, 2012
Last Updated
September 26, 2022
Sponsor
Dompé Farmaceutici S.p.A
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1. Study Identification

Unique Protocol Identification Number
NCT01571895
Brief Title
Pilot Efficacy and Safety Study of Oral DF2156A in Patients With Active Bullous Pemphigoid
Official Title
A Phase 2, Multicentre, Single Arm, Pilot Study to Assess the Efficacy and the Safety of 150 mg Twice a Day Oral DF2156A in Patients With Active Bullous Pemphigoid.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Terminated
Why Stopped
Lack of efficacy observed at 1/3 of the enrollment at investigated dosage. No results available.
Study Start Date
February 20, 2012 (Actual)
Primary Completion Date
July 5, 2012 (Actual)
Study Completion Date
July 5, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dompé Farmaceutici S.p.A

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The objective of this clinical trial was to evaluate whether DF2156A has a potential in improving the clinical outcome in patients with active blistering bullous pemphigoid (BP) to warrant its further development. The safety of DF2156A in the specific clinical setting was also evaluated.
Detailed Description
The study was a phase 2, multicentre, single arm, pilot study. It has been designed to determine if DF2156A has sufficient activity to warrant its further development. A total of twelve (12) BP patients were planned to be involved. They were planned to receive DF2156A orally at the dose of 150 mg twice a day for a maximum of 14 days. Recruitment was intended to be competitive among the study sites, until the planned number of patients is enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and to account for any unexpected occurrence at a site that negatively impact enrolment rate. The single arm design has been chosen as an appropriate tool for this pilot phase 2 study, considering that BP is a rare disease where a placebo control is not acceptable. Moreover, as there is no spontaneous acute recovery from the active blistering condition, any improvement in patient outcome can be attributed to a positive effect of the Investigational Product. Each patient was intended to be involved in the study for a screening period, for 14 days of treatment, for all required measurements up to hospital discharge (planned on day 8+1 of treatment) and for one assessment occasion on day 15+1, either during hospital stay or after hospital discharge (out-patient visit). An optional post-treatment visit might be scheduled at day 30+3. Due to the lack of efficacy observed at 1/3 of the enrollment at the investigated dosage, the patients' enrollment was interrupted and trial, hence, was early terminated. More precisely, only 1 of the 4 enrolled patients completed the study's 14-day treatment period. The remaining 3 patients were discontinued from the study early (1 patient due to treatment failure and 2 patients who were discontinued and admitted to rescue therapy). While DF2156A appeared to be safe and was generally well-tolerated with only mild AEs reported in 3 patients (and no deaths, SAEs, or discontinuations from the study due to AEs), the limited sample size of the safety population prevents any overall conclusions of safety regarding the investigational product. For this reason no results other than listings are available. See the MEX0111 synopsis on the EU Clinical Trial Register: https://www.clinicaltrialsregister.eu/ctr-search/rest/download/result/attachment/2011-000756-42/1/27931

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bullous Pemphigoid
Keywords
Autoimmune inflammatory blistering disorder

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
DF2156A 150 mg
Arm Type
Experimental
Arm Description
150 mg capsule twice a day (every 12 h) for a maximum of 14 days
Intervention Type
Drug
Intervention Name(s)
DF2156A
Intervention Description
DF2156A is a novel small molecule that inhibits the biological activity of the CXC ligand 8 [CXCL8; formerly interleukin (IL)-8] through inhibition of the activation of CXCL8 receptors: CXCR1 and CXCR2. This specific inhibitor stems from a program of drug design of molecules intended to modulate chemokine action.
Primary Outcome Measure Information:
Title
Total number of blisters from baseline
Description
Total number of blisters from baseline
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Modified ABSIS score change from baseline
Description
ABSIS score will be measured according to the pemphigus scoring sheet [Rosenbach, 2009] adjusted to the clinical manifestation in BP patients, as per specifications in protocol.
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Physician Global Assessment (PGA) score measured on a 0-10 scale [Rosenbach, 2009]. Percent change from baseline
Description
PGA score will be measured according to the following scale: 0 1 2 3 4 5 6 7 8 9 10 Perfect Worst health skin condition imaginable The following guidelines will help standardize PGA: 0: no lesions 2: almost cleared, no functional impairment 4: few lesions / low functional impairment 6: moderate 8: severe / extensive 10: life-threatening
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Pruritus measured on a 10 cm visual analogue scale. Absolute value change from baseline
Description
Pruritus will be measured according to the following scale: 0 10 No pruritus Worst pruritus I can imagine
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Eosinophil blood count. Percent change from baseline
Description
Eosinophil blood count. Percent change from baseline
Time Frame
screening and day 15
Title
Percentage of patients with treatment failure (drug discontinuation due to disease worsening)
Description
treatment failure (drug discontinuation due to disease worsening)
Time Frame
day 8
Title
Percentage of patients completely free from blisters
Description
Percentage of patients completely free from blisters
Time Frame
day 15
Title
Number of patients who are still free from blisters without requiring any systemic or topical rescue treatment - Optional
Description
Number of patients who are still free from blisters without requiring any systemic or topical rescue treatment - Optional
Time Frame
Day 30
Title
QTcF. Change from baseline
Description
QTcF. Change from baseline
Time Frame
Italy: day 0/1 (pre-dose), day 1, 5, 8 and 15___Ger:day 0/1 (pre-dose), day 1, 3, 5, 8 and 15
Title
Incidence of Adverse Events and Serious Adverse Events
Description
Incidence of Adverse Events and Serious Adverse Events
Time Frame
throughout the study up to day 15 or 30
Title
Blisters percent change from baseline
Description
Blisters percent change from baseline
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Modified ABSIS score percent change from baseline
Description
ABSIS score will be measured according to the pemphigus scoring sheet [Rosenbach, 2009] adjusted to the clinical manifestation in BP patients, as per specifications in protocol.
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Physician Global Assessment (PGA) score measured on a 0-10 scale [Rosenbach, 2009]. Absolute value change from baseline
Description
PGA score will be measured according to the following scale: 0 1 2 3 4 5 6 7 8 9 10 Perfect Worst health skin condition imaginable The following guidelines will help standardize PGA: 0: no lesions 2: almost cleared, no functional impairment 4: few lesions / low functional impairment 6: moderate 8: severe / extensive 10: life-threatening
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Pruritus measured on a 10 cm visual analogue scale. Percent change from baseline
Description
Pruritus will be measured according to the following scale: 0 10 No pruritus Worst pruritus I can imagine
Time Frame
day 0/1 (pre-dose), 8 and 15
Title
Eosinophil blood count. Absolute number change from baseline
Description
Eosinophil blood count. Absolute number change from baseline
Time Frame
screening and day 15
Title
Number of patients with treatment failure (drug discontinuation due to disease worsening)
Description
Number of patients with treatment failure (drug discontinuation due to diseas
Time Frame
day 8
Title
Number of patients completely free from blisters
Description
Number of patients completely free from blisters
Time Frame
day 15
Title
QTcF. Absolute value
Description
QTcF. Absolute value
Time Frame
Italy: day 0/1 (pre-dose), day 1, 5, 8 and 15___Ger:day 0/1 (pre-dose), day 1, 3, 5, 8 and 15
Secondary Outcome Measure Information:
Title
Plasma levels of DF2156A and its major metabolites (DF2227 and DF2108) at steady state conditions
Description
Plasma levels of DF2156A and its major metabolites (DF2227 and DF2108) at steady state conditions
Time Frame
day 5 and 8

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female patients aged >50 years. Patients with newly diagnosed or relapsing bullous pemphigoid based on clinical diagnosis to be confirmed by direct immunofluorescence and indirect immunofluorescence on salt-spit skin (or BP180 and/or BP230 ELISA). Confirmation by laboratory tests will be obtained ideally before or anyway within one week after enrolment. For the purpose of this study, clinical relapses are defined as re-appearance of clinical symptoms after the patient had attained remission lasting for more than 3 months without immunosuppressive treatment. In patients with relapsing BP, clinical diagnosis will be confirmed by indirect immunofluorescence or BP180 and/or BP230 ELISA only. Patients with mild to moderate active blistering disease (total number of blisters between 1 and 30) whether associated or not with urticarial/eczematous lesions. Patients with modified ABSIS score ≤50 Patients free from any systemic treatments that may affect the course of the disease with the following off-period prior to enrolment: 3 weeks: steroids, dapsone, tetracyclines, nicotinamide, 3 months: azathioprine, mycofenolate mofetil, cyclophosphamide, methotrexate, intravenous immunoglobulins, immunoadsorption, TNF antagonists 12 months: rituximab, leflunomide Patients free from any topical treatments other than topical antibiotics and antiseptics in the 4 days prior to enrolment. Patients able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations. Patients able to provide informed consent. Exclusion Criteria: Patients with a Karnofsky rating score <40%. Patients with mucosal involvement. Patients with moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 50 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault , 1976). Patients with hepatic dysfunction defined by increased ALT/AST > 3 x upper limit of normal (ULN) and increased total bilirubin > 3 mg/dL [>51.3 μmol/L]. Patients with hypoalbuminemia defined as serum albumin < 3 g/dL. Patients with a baseline (day 0/1, pre-dose) QTcF > 470 msec. Patients who had a myocardial infarction in the 6 months prior to enrolment. Patients on treatment with phenytoin, warfarin, sulphonylurea hypoglycemics (e.g. tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 mg/day). Patients with known hypersensitivity to non-steroidal antiinflammatory drugs. Patients using any investigational agent within 12 months prior to enrolment. Pregnant or breast feeding women. Unwillingness to use effective contraceptive measures up to 2 months after the end of study drug administration (females and males). Additional Exclusion Criteria for Germany only: Patients with hypokalemia defined as serum potassium < 3.5 mmol/L. Patients with clinically relevant bradycardia (heart rate < 50 beats/min) Patients with a complete left bundle branch block. Patients with a history of uncontrolled or labile hypertension Patients with a history of congestive heart failure. Patients with a history of cardiomyopathy. Patients with unstable angina pectoris. Patients with a personal or family history of congenital or documented acquired QT interval prolongation. Patients with a significant atrial or ventricular arrhythmia or symptomatic arrhythmia in the past.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Biagio Didona, MD
Organizational Affiliation
I Divisione di Dermatologia, Istituto Dermopatico dell'Immacolata, IRCCS; 00167 Roma, Italy
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Detlef Zillikens, MD
Organizational Affiliation
Klinik für Dermatologie, Allergologie und Venerologie - Univ. Schleswig-Holstein; Lübeck, Germany
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Andrea Kneisel, MD
Organizational Affiliation
Klinik für Dermatologie und Allergologie - Philips Universität; 35037 Marburg, Germany
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Johannes Kern, MD
Organizational Affiliation
Department of Dermatology - Universitäts-Hautklinik; 79104 Freiburg, Germany
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pier Adelchi Ruffini, MD
Organizational Affiliation
Development Director Dompé s.p.a., 20122 Milan, Italy
Official's Role
Study Director
Facility Information:
Facility Name
Department of Dermatology - Universitäts-Hautklinik; Hauptstraße 7
City
Freiburg
ZIP/Postal Code
79104
Country
Germany
Facility Name
Klinik für Dermatologie, Allergologie und Venerologie - Universitätsklinikum Schleswig-Holstein, Campus Lübeck; Ratzeburger Allee 160
City
Lübeck
ZIP/Postal Code
23538
Country
Germany
Facility Name
Klinik für Dermatologie und Allergologie - Philips Universität; 35037
City
Marburg
ZIP/Postal Code
35037
Country
Germany
Facility Name
I Divisione di Dermatologia, Istituto Dermopatico dell'Immacolata, IRCCS;
City
Roma
ZIP/Postal Code
00167
Country
Italy

12. IPD Sharing Statement

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Pilot Efficacy and Safety Study of Oral DF2156A in Patients With Active Bullous Pemphigoid

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