Clinical Trials Register

Summary
EudraCT Number:	2010-022439-12
Sponsor's Protocol Code Number:	ATH008-CLN02
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-04-26
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2010-022439-12

A.3

Full title of the trial

A Phase II Placebo Controlled, Multicenter Study to Investigate the Safety and Efficacy of ATH008 cream in Patients with Palmar-Plantar Erythrodysesthesia Syndrome (PPES) secondary to capecitabine therapy.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study to investigate the safety and efficacy of ATH008 cream in the treatment of the hand-foot syndrome (Palmar-Plantar Erythrodysesthesia – PPES) caused by chemotherapy with capecitabine.

A.3.2

Name or abbreviated title of the trial where available

not applicable

A.4.1

Sponsor's protocol code number

ATH008-CLN02

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Advancell Advanced In Vitro Cell Technologies, S.A
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Advancell Advanced In Vitro Cell Technologies, S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Advancell Advanced In Vitro Cell Technologies, S.A
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Via Augusta, 59, 3rd floor
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	0806
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34930130 561
B.5.5	Fax number	+34932380 766
B.5.6	E-mail	advancell@advancell.net

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ATH008 cream 3%
D.3.2	Product code	ATH008 cream
D.3.4	Pharmaceutical form	Cream
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Allopurinol
D.3.9.1	CAS number	315-30-0
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	hypoxanthine analogon
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ATH008 cream 8%
D.3.2	Product code	ATH008 cream
D.3.4	Pharmaceutical form	Cream
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Allopurinol
D.3.9.1	CAS number	315-30-0
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	hypoxanthine analogon

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Cream
D.8.4	Route of administration of the placebo	Topical use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Palmar-Plantar Erythrodysesthesia Syndrome (PPES)

E.1.1.1

Medical condition in easily understood language

Hand-foot syndrome; a relatively common reaction of the skin in palms and soles, caused by a variety of chemotherapeutic agents.

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10054524
E.1.2	Term	Palmar-plantar erythrodysesthesia syndrome
E.1.2	System Organ Class	100000004858

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part II – Safety and Primary Efficacy evaluation
• To demonstrate the safety of ATH008 cream in patients presenting PPES secondary to capecitabine therapy.
• To demonstrate the efficacy of ATH008 cream in reducing the number of subjects presenting PPES grade 2/3 secondary to capecitabine therapy.

E.2.2

Secondary objectives of the trial

Part II – Secondary Efficacy evaluation
• To determine the plasmatic levels of the active ingredient, allopurinol, and its metabolite, oxypurinol, when given topically.
• To demonstrate the efficacy of ATH008 cream in improving the quality of life of patients presenting PPES.
• To demonstrate the efficacy of ATH008 cream in improving the signs and symptoms of PPES.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Have signed Informed Consent.
• Are under capecitabine therapy for treatment of colon or breast cancer at a regimen of 2 weeks on and 1 week off (14+7) and a daily doses between 2000 and 2500 mg/m2.
• Diagnosis of PPES grade 1 in any hand or foot according to the NCI CTCAE v4.03 definition.
• Are able to apply topical medication or provide for another person to apply it.
• Have a life expectancy longer than 3 months.
• In Part II, subjects still have to undergo at least 2 planned cycles with capecitabine therapy

E.4

Principal exclusion criteria

• Are younger than 18 years.
• Diagnosis of PPES grade 1in any hand or foot according to the NCI CTCAE v4.03 definition for more than 2 cycles previously to inclusion in this clinical study.
• Use of other chemotherapies for the treatment of cancer except trastuzumab (Herceptin®) or bevacizumab (Avastin®).
• Haematological limits indicating that capecitabine (Xeloda®) cannot be administered due to safety reasons, based on the PI review before each cycle of chemotherapy.
• Total bilirubin > 3 upper normal value.
• Serum creatinine level > 2 upper normal value.
• Have neurologic symptoms greater than grade 1, which under the criteria of the clinician could interfere with PPES diagnosis or study treatment (e.g. hands or feet neuropathy).
• Have any dermatologic condition that in the opinion of the investigator may affect hands or feet or may complicate evaluation during study treatment (e.g. neurodermatitis, psoriasis, etc).
• Have onycholysis with a non-stable grade 1 or onycholysis greater than grade 1 (nail loss, NCI CTCAE v4.03 criteria) which in the assessment of the clinician could interfere with PPES diagnosis or study treatment.
• Need to use other emollient creams or other topical treatments in hands and/or feet during the study.
• Are receiving radiotherapy.
• Are actively treated with systemic allopurinol (oral or parenteral) for the treatment of gout, or any other indication.
• Have developed a severe reaction to allopurinol in the past (e.g. Lyell syndrome).
• Known allergy to allopurinol or any of the excipients of the product.
• Previous contraindication to treatment with capecitabine.
• Have received topical corticosteroids in hands and/ or feet 7 days prior to planned inclusion in the study.
• Are participating in any other investigational studies for the treatment of PPES.
• Have participated in any other investigational studies for the treatment of PPES, or received an experimental therapeutic procedure, considered to potentially interfere with the study in the 4 weeks preceding Day 1.
• Have a serious medical or psychiatric condition that could, in the investigator’s opinion, potentially interfere with their study treatment or participation in the study.
• Pregnant women, women in child bearing age not using contraceptives or men not using contraceptives. Methods of contraception which have a failure rate (Pearl index) of less than 1% per year are regarded as highly effective.
• Are participating in other clinical trials.

E.5 End points

E.5.1

Primary end point(s)

Safety variables
Part II
Adverse events and serious adverse events (incidence, causality, and severity) related to treatment with ATH008 cream.

Pharmacokinetic variables
Part II
• Plasmatic allopurinol levels
• Plasmatic oxypurinol levels
Primary efficacy variable
Part II
Percentage of subjects that develop PPES grade 2 or 3 according to the NCI CTCAE v4.03 criteria

E.5.1.1

Timepoint(s) of evaluation of this end point

PPES evaluation is performed at each study visit until end of treatment.

E.5.2

Secondary end point(s)

Secondary efficacy variable
Part II
Proportion of subjects that present no PPES signs or symptoms.
Quality of life compared to baseline.
Time to progression of PPES grade 1 to PPES grade 2 or 3 (days).
Time to improvement of PPES grade 1 to absence of all PPES signs or symptoms (days).
Proportion of subjects whose capecitabine therapy was stopped or reduced due any reason related to PPES.
Time to capecitabine dose reduction or capecitabine therapy interruption due to any reason related to PPES (days).
Erythema (graded 1 to 10).
Desquamation (graded 1 to 10).
Existence of blisters (yes / no)
Existence of fissures (yes / no)
Existence of ulcers (yes / no).
Percentage of the palms and soles affected by PPES.
Pain (graded 1 to 10) compared to baseline.
Capecitabine dose intensity (mg/m²/week) accumulated from the starting of capecitabine treatment.
Capecitabine dose intensity (mg/m²/week) accumulated from the starting of ATH008 cream treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

continously from baseline to end of study.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

This is provided in the protocol

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

114

F.4.2.2

In the whole clinical trial

114

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subject will be allowed to continue with the ATH008 cream treatment and will be followed up separately until the end of capecitabine therapy or evolution of PPES to grade 2 or 3, or until delivery of statistical results at the end of the study, whichever comes first.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-08-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-08-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-08-14

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