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Clinical Trial Results:
An International, Multicenter, Randomized, Double-Blind, Parallel-Group Phase 2 Study Evaluating the Safety and Efficacy of Diacerein 1% Ointment Topical Formulation in Subjects with Epidermolysis Bullosa Simplex (EBS) [DELIVERS Study]

Summary
EudraCT number	2016-004427-24
Trial protocol	DE AT NL GB FR
Global end of trial date	31 Oct 2018

Results information
Results version number	v1(current)
This version publication date	30 Oct 2019
First version publication date	30 Oct 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CCP-020-301

ISRCTN number

-

US NCT number

NCT03154333

WHO universal trial number (UTN)

-

Other trial identifiers

IND: 131 384

Sponsor organisation name

Castle Creek Pharmaceuticals, LLC

Sponsor organisation address

6 Century Drive , Parsippany, NJ , United States, NJ 07054

Public contact

Dr. Mary Spellman, Castle Creek Pharmaceuticals, LLC , 001 8622860400, mspellman@castlecreekpharma.com

Scientific contact

Dr. Mary Spellman, Castle Creek Pharmaceuticals, LLC , 001 8622860400, mspellman@castlecreekpharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

17 Jan 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Oct 2018

Global end of trial reached?

Yes

Global end of trial date

31 Oct 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of this study was to compare the efficacy of diacerein 1% ointment to control ointment when applied once daily for 8 weeks in subjects with epidermolysis bullosa simplex (EBS).

Protection of trial subjects

The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonization (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

01 Jun 2017

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

Israel: 5

Country: Number of subjects enrolled

United States: 23

Worldwide total number of subjects

54

EEA total number of subjects

24

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

37

Adolescents (12-17 years)

5

Adults (18-64 years)

12

From 65 to 84 years

0

85 years and over

0

Subject disposition

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Recruitment details

-

Screening details

Subjects were screened for inclusion and exclusion criteria at Visit 1 (Week -6). Subjects must have had a genotypic confirmation of an EBS protocol-defined mutation through prior genetic testing or via a blood or saliva genetic assessment as part of the study.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

This study used a double-blind design. The study drugs were indistinguishable in appearance, packaging, and labeling.

Are arms mutually exclusive

Yes

Diacerein 1%

Arm description

At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive diacerein 1% ointment to all EBS lesions in the Assessment Area.

Arm type

Experimental

Investigational medicinal product name

Diacerein

Investigational medicinal product code

CCP-020

Other name

Pharmaceutical forms

Ointment

Routes of administration

Topical use

Dosage and administration details

During the 8-week Treatment Period, Diacerein was administered from Visit 2 (Week 0) to Visit 6 (Week 8) once daily in the evening to EBS lesions in the Assessment Area (regardless of lesion resolution) and Treatment Area (until lesion(s) resolution). The subject/caregiver applied sufficient quantity of Diacerein to cover all EBS lesions and to approximately ¾ inch (2 cm) of uninvolved skin surrounding each lesion with a thin layer and gently rubbed it in.

Control

Arm description

At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive control ointment to all EBS lesions in the Assessment Area.

Arm type

Placebo

Investigational medicinal product name

Control

Investigational medicinal product code

Other name

Vehicle

Pharmaceutical forms

Ointment

Routes of administration

Topical use

Dosage and administration details

During the 8-week Treatment Period, the control ointment was administered from Visit 2 (Week 0) to Visit 6 (Week 8) once daily in the evening to EBS lesions in the Assessment Area (regardless of lesion resolution) and Treatment Area (until lesion(s) resolution). The subject/caregiver applied sufficient quantity of the control ointment to cover all EBS lesions and to approximately ¾ inch (2 cm) of uninvolved skin surrounding each lesion with a thin layer and gently rubbed it in.

Number of subjects in period 1	Diacerein 1%	Control
Started	28	26
Completed	21	21
Not completed	7	5
Study terminated by Sponsor	6	5
Lost to follow-up	1	-

Baseline characteristics

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Reporting group title

Diacerein 1%

Reporting group description

At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive diacerein 1% ointment to all EBS lesions in the Assessment Area.

Reporting group title

Control

Reporting group description

At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive control ointment to all EBS lesions in the Assessment Area.

Reporting group values	Diacerein 1%	Control	Total
Number of subjects	28	26	54
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	19	18	37
Adolescents (12-17 years)	1	4	5
Adults (18-64 years)	8	4	12
From 65-84 years	0	0	0
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	14	16	30
Male	14	10	24

End points

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Reporting group title

Diacerein 1%

Reporting group description

At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive diacerein 1% ointment to all EBS lesions in the Assessment Area.

Reporting group title

Control

Reporting group description

At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive control ointment to all EBS lesions in the Assessment Area.

Primary: Achievement ≥60% reduction in BSA of EBS in the assessment area

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End point title

Achievement ≥60% reduction in BSA of EBS in the assessment area

End point description

The primary efficacy endpoint of this study was the proportion of subjects who achieved ≥60% reduction in body surface area (BSA) of Epidermolysis Bullosa Simplex (EBS) lesions within the Assessment Area from Baseline to Week 8.

End point type

Primary

End point timeframe

The primary efficacy endpoint was examined from Baseline/Visit 2 (Week 0) to Visit 6 (Week 8).

End point values	Diacerein 1%	Control
Number of subjects analysed	28	26
Units: Subjects	16	14

Comparison in ≥60% reduction in BSA of EBS

Comparison groups

Diacerein 1% v Control

Number of subjects included in analysis

54

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.9666

Method

Cochran-Mantel-Haenszel

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

1.62

Notes
[1] - Subjects who achieved ≥60% reduction in BSA of EBS lesions within the Assessment Area from Baseline to Week 8 for the diacerein 1% group compared to the control group for the ITT Population.

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from Week 0 Day 1 through the study until the end.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Diacerein 1%

Reporting group description

-

Reporting group title

Control

Reporting group description

-

Serious adverse events	Diacerein 1%	Control
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 28 (0.00%)	2 / 26 (7.69%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 28 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Meniere's disease
subjects affected / exposed	0 / 28 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Diacerein 1%	Control
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 28 (78.57%)	21 / 26 (80.77%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 28 (0.00%)	3 / 26 (11.54%)
occurrences all number	0	4
Skin abrasion
subjects affected / exposed	0 / 28 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Nervous system disorders
Headache
subjects affected / exposed	1 / 28 (3.57%)	3 / 26 (11.54%)
occurrences all number	1	3
General disorders and administration site conditions
Application site pruritus
subjects affected / exposed	0 / 28 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Fatigue
subjects affected / exposed	2 / 28 (7.14%)	0 / 26 (0.00%)
occurrences all number	2	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	2 / 28 (7.14%)	1 / 26 (3.85%)
occurrences all number	2	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 28 (10.71%)	0 / 26 (0.00%)
occurrences all number	4	0
Nausea
subjects affected / exposed	2 / 28 (7.14%)	0 / 26 (0.00%)
occurrences all number	2	0
Vomiting
subjects affected / exposed	4 / 28 (14.29%)	1 / 26 (3.85%)
occurrences all number	5	1
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	2 / 28 (7.14%)	0 / 26 (0.00%)
occurrences all number	2	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 28 (14.29%)	1 / 26 (3.85%)
occurrences all number	4	1
Nasal congestion
subjects affected / exposed	2 / 28 (7.14%)	1 / 26 (3.85%)
occurrences all number	2	1
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	1 / 28 (3.57%)	2 / 26 (7.69%)
occurrences all number	1	2
Pruritus
subjects affected / exposed	3 / 28 (10.71%)	1 / 26 (3.85%)
occurrences all number	3	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 28 (14.29%)	2 / 26 (7.69%)
occurrences all number	4	2
Skin infection
subjects affected / exposed	3 / 28 (10.71%)	3 / 26 (11.54%)
occurrences all number	4	4
Upper respiratory tract infection
subjects affected / exposed	1 / 28 (3.57%)	2 / 26 (7.69%)
occurrences all number	1	3
Viral upper respiratory tract infection
subjects affected / exposed	2 / 28 (7.14%)	2 / 26 (7.69%)
occurrences all number	2	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

17 Mar 2017

Global Protocol Amendment 1, dated 17 March 2017. The key changes to the primary endpoint were as follows: - Removal of the LSA and addition of the IGA at Visit 8 (Week 16). - Inclusion Criterion 1 was updated to reflect an increase in the subject’s minimum age from 6 months to 4 years. - Inclusion Criterion 5 was revised to the minimum IGA score of 3. - PK sampling was removed from the protocol. - Genotyping criteria were expanded. - Sample size was recalculated.

08 Jun 2017

Global Protocol Amendment 2. The key changes were as follows: - Clarification of BSA of an EBS lesion and LSA Area. - Inclusion Criterion 2, clarification of eligibility criteria. - Inclusion Criterion 3, clarification of eligibility criteria. - Treatment Area clarified (not to exceed 30% BSA). - Inclusion Criterion 5 and 6,clarification of eligibility criteria. - An IDMC added to conduct interim analysis. - Exclusion Criterion 11 clarification of eligibility criteria. - Exclusion Criterion 12 clarification of eligibility criteria. - PK was added to protocol . - Subject withdrawals clarified. - Clarified study procedures and safety reporting, where necessary.

02 Jan 2018

Global Protocol Amendment 3a. - Clarification dose and treatment rationale. - Clarification risk and/or benefits to subjects. - Primary objective updated to include reduction in BSA of EBS lesions. - Secondary objective updated to include changes in IGA scores. - Primary endpoint updated. - Key secondary endpoint was added and other secondary endpoints were updated. - PK endpoints clarified. - eDiary instructions clarified and updated. - Number of sites were updated. - The list of permitted topical products and therapies was further updated. - Siblings of those enrolled were not allowed in the study, was removed. - Clarification on exclusion of subjects with controlled diabetes and HbA1c<6.5% . - Describing prohibited therapies was removed. - Instructions for treatment of EBS were clarified. - Laboratory tests updated. - Use of body charts to record the location of EBS lesion revised. - Definitions of occluded lesions clarified. - Pruritus and pain scales updated. - SAEs and AESI clarified. - Contraception methods clarified. - Safety methods updated to include ECG.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
30 Oct 2018	Following the interim analysis on 40 randomized subjects, the IDMC made the recommendation to the Sponsor to terminate the study on the basis that the primary BSA endpoint was unlikely to achieve statistical significance. Per this recommendation, Castle Creek terminated the study but allowed patients to roll over into a separate open-label extension study.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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