Clinical Trials Register

Summary
EudraCT Number:	2005-005675-15
Sponsor's Protocol Code Number:	DIL-UBI-DEX-CLOII/2003/003/PT
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-09-27
Trial results	View 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

Czechia - SUKL

A.2

EudraCT number

2005-005675-15

A.3

Full title of the trial

Randomized, multicenter, placebo-controlled, single blind study to assess the efficacy and tolerability of a combination of a cream containing ubidecarenone, dexpanthenol and chlorohexidine and a paste containing 2% diltiazem hydrochloride in the treatment of chronic anal fissure.

Estudo clínico multicêntrico, controlado por placebo, com distribuição aleatória e em ocultação simples para avaliação da eficácia e da tolerabilidade da associação de um creme de ubidecarenona, dexpantenol e cloro-hexidina e de uma pasta de cloridrato de diltiazem a 2%, no tratamento da fissura anal crónica.

A.3.1

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

Clinical trial of the combination of a cream containing ubidecarenone, dexpanthenol and chlorohexidine and a paste containing 2% diltiazem in the treatment of chronic anal fissure.

Estudo clínico da associação de um creme de ubidecarenona, dexpantenol e cloro-hexidina e uma pasta de cloridrato diltiazem a 2%, no tratamento da fissura anal crónica.

A.3.2

Name or abbreviated title of the trial where available

EFAC

A.4.1

Sponsor's protocol code number

DIL-UBI-DEX-CLOII/2003/003/PT

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	Tecnimede, Sociedade Técnico-Medicinal S.A.
B.1.3.4	Country	Portugal
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	Tecnimede Sociedade Técnico-Medicinal S.A.
B.4.2	Country	Portugal
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Tecnimede Sociedade Técnico Medicinal, S.A.
B.5.2	Functional name of contact point	Medical Department
B.5.3	Address:
B.5.3.1	Street Address	Rua da Tapada Grande nº2, Abrunheira
B.5.3.2	Town/ city	Sintra
B.5.3.3	Post code	2710-089
B.5.3.4	Country	Portugal
B.5.4	Telephone number	00351210 414 100
B.5.5	Fax number	00351210 414 105
B.5.6	E-mail	dmed.ct@tecnimede.pt

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	Yes
D.2.1.1.1	Trade name	Anotrit
D.2.1.1.2	Name of the Marketing Authorisation holder	Tecnimede Sociedade Técnico Medicinal, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Portugal
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	Diltiazem 2% paste
D.3.2	Product code	0002
D.3.4	Pharmaceutical form	Cutaneous paste
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Diltiazem Hydrochloride
D.3.9.1	CAS number	33286-22-5
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	No
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	ubidecarenone 4%, Dexpanthenol 5% and chlorohexidine 0.5% cream
D.3.2	Product code	4505
D.3.4	Pharmaceutical form	Cream
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ubidecarenone
D.3.9.1	CAS number	303-98-0
D.3.9.3	Other descriptive name	Coenzyme Q10; Ubiquinone 10
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dexpanthenol
D.3.9.1	CAS number	81-13-0
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Chlorohexidine dihydrochloride
D.3.9.1	CAS number	3697-42-5
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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	No

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	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cronic Anal fissure (CAF)
The underlying pathogenesis of chronic anal fissure involves initial local trauma (generally caused by hard stools), resulting in a wound, internal anal sphincter spasm and reduced blood flow to the anal mucosa. The last two factors contribute to the appearance of an ulcer that does not heal, given that perfusion is inversely correlated with anal pressure.

Fissura anal crónica (FAC)
Na patogenia da fissura anal crónica participam um traumatismo local inicial (geralmente provocado por fezes duras) de que resulta uma ferida, espasmo do esfíncter anal interno e redução do fluxo sanguíneo da mucosa anal. Estes dois últimos factores contribuem para o aparecimento de uma úlcera que perdura, pois a taxa de perfusão está inversamente relacionada com a pressão anal.

E.1.1.1

Medical condition in easily understood language

Chronic anal fissure

Fissura Anal Crónica

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10071195
E.1.2	Term	Chronic anal fissure
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of this clinical trial is to assess the relative efficacy of the concomitant administration of an UDC cream and DTZ2% paste with the administration of DTZ2% paste alone, with a chronic anal fissure (CAF) treatment phase of 8 weeks.

O objectivo primário do estudo clínico é avaliar a eficácia relativa da administração concomitante de um creme de UDC com uma pasta de DTZ 2% e da administração isolada da pasta de DTZ 2% durante as 8 semanas de tratamento da fissura anal crónica (FAC).

E.2.2

Secondary objectives of the trial

Secondary objectives include the comparison between the two treatment arms of: a) improvement of symptoms (pain) within 8 weeks of treatment; b) improvement of symptoms (pain) within 4 weeks of treatment; c) cure rate within 4 weeks of treatment; d) tolerability within 8 weeks of treatment; e) CAF relapse rate during a 24 week follow up period.

Os objectivos secundários do estudo clínico são proceder à comparação entre os dois grupos de tratamento de: a) melhoria dos sintomas (dor) observada após 8 semanas de tratamento; b) melhoria dos sintomas (dor) observada à 4.ª semana de tratamento; c) taxa de cura até à 4ª semana de tratamento; d) tolerabilidade após 8 semanas de tratamento; e) taxas de recidiva da FAC durante as 24 semanas de seguimento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients aged 18 years old or above; 2.Diagnosis of idiopathic chronic anal fissure unresponsive to previous therapy,
3. Patient able to comply with the study protocol as per investigator criteria; 4.Signed and dated informed consent by the patient or his/her representative/witness (as per applicable law). 5. Absence of any exclusion criterion.

1.Doentes com idade igual ou superior a 18 anos; 2. Diagnóstico de fissura anal crónica idiopática sem resposta à terapêutica anteriormente instituída;3. Doentes com capacidade para cumprir o protocolo do estudo de acordo com o critério do investigador; 4.Consentimento informado datado e assinado pelo doente ou pelo seu representante/testemunha nas situações especiais previstas na lei; 5.Ausência de critérios de exclusão.

E.4

Principal exclusion criteria

1.Patient presenting with any of the clinical conditions mentioned below. a.Anal fissure lacking features for chronicity;b.Cured anal fissure;c.Infected chronic anal fissure;d.Multiple fissures;e.Fissure with irregular margins; f. Fissure at locations other than the midline; g. Fissure unassociated to sphincter spasm;2. Patients with fecal incontinence, rectocele, rectal prolapse or fibrotic anal stenosis;3. Patients with prior anal surgery; 4. Patients treated with botulinum toxin less than 6 months prior to enrolment;5.Patients with chronic anal fissure secondary to other disorders such as chronic inflammatory bowel disease, intestinal tuberculosis, anal or peri-anal cancer, anal fistula, sexually transmitted diseases, anal or peri-anal sepsis;6. Patients with malignant diseases and a life expectancy of less than 1 year or patients undergoing chemo- or radiotherapy less than 6 months prior to enrolment; 7.Patients with clinically significant cardiovascular disorder, namely NYHA class III and IV heart failure, atrial fibrillation, atrioventricular block, or clinically significant bradycardia; 8. Patients with orthostatic (postural) hypotension;9.Patients with respiratory insufficiency and need for long term oxygen therapy or home ventilation;10.Patients with clinically significant renal failure;11. Patients with known HIV infection; 12. Patients with known neuromuscular disease;13. Pregnant or lactating patients; 14. Women of childbearing potential who are sexually active and who do not use an effective contraceptive method. The following are considered to be effective contraceptive methods: intra-uterine device (IUD), oral contraceptives, injected contraceptives, contraceptive implants, surgical sterilization of partner (vasectomy with negative sperm count and in a monogamous relationship). In case barrier methods are used, double protection methods (condoms, spermicidal, diaphragm and similar) are deemed effective;15.Patients with any changes in the previous 12 weeks to oral, sublingual or intra-muscular therapy with vasodilators (beta blockers, nitrates, calcium antagonists, phosphodiesterase 4 inhibitors) or muscle relaxants;16.Patients who used an analgesic, anesthetic, cicatrizant, topical vasodilators, corticosteroid, vitamins A or E, or any other active substances that might be active in anal mucosa regeneration, less than 3 days before.17.History of hypersensitivity or intolerance to any of the investigational medicinal products, or to their active substances or excipients, or to similar drugs;18.Patients with clotting disorders;19.Any known abnormal clinical or laboratory change that, as per the investigator, might interfere with the safety or efficacy assessment or any study procedure;20.Patients who have participated in another clinical trial less than one month prior to enrolment or who are still involved in another trial.

1.Doente portador de qualquer uma das condições clínicas abaixo indicadas: a.fissura anal que não cumpre os critérios de cronicidade;b.fissura anal curada;c. fissura anal crónica infectada;d.fissuras múltiplas;e.fissura com bordos irregulares;f.fissura não localizada na linha média; g.fissura não associada a espasmo do esfíncter;2.Doentes com incontinência fecal, rectocelo, prolapso rectal ou estenose anal fibrótica;3.Doentes que tenham efectuado uma cirurgia anal prévia; 4.Doentes que tenham efectuado terapêutica com toxina botulínica há menos de 6 meses;5.Doentes com fissura anal secundária a outras doenças tais como doença inflamatória intestinal crónica, tuberculose intestinal, cancro anal ou peri-anal, fístula anal, doenças venéreas, sepsis anal ou peri-anal;6.Doentes portadores de doenças malignas com esperança de vida inferior a 1 ano ou submetidos a quimioterapia e/ou radioterapia há menos de 6 meses;7.Doentes com doença cardiovascular clinicamente significativa, designadamente insuficiência cardíaca das classes III e IV do NYHA, fibrilhação auricular, bloqueio auriculo-ventricular ou bradicardia clinicamente significativa;8. Doentes com hipotensão ortostática;9. Doentes com insuficiência respiratória e necessidade de oxigenoterapia de longa duração ou ventilação domiciliária;10. Doentes com insuficiência renal clinicamente significativa;11.Doentes com infecção conhecida pelo VIH; 12.Doentes com doença neuromuscular conhecida;13.Grávidas ou em período de aleitamento; 14.Mulheres férteis e com vida sexual activa que não utilizem um método anticoncepcional considerado eficaz. Consideram-se métodos contraceptivos eficazes: dispositivo intra-uterino (D.I.U.); anticoncepcionais orais; anticoncepcionais injectáveis; implantes anticoncepcionais; esterilização cirúrgica do parceiro (vasectomia com contagem de espermatozóides negativa e numa relação monogâmica). No caso de serem utilizados métodos de barreira considera-se eficaz a dupla protecção (preservativos, espermicidas, diafragmas e semelhantes); 15.Doentes com qualquer alteração, ocorrida nas últimas 12 semanas, do tratamento oral, sub-lingual ou intra-muscular com vasodilatadores (β-bloqueantes, nitratos, antagonistas dos canais do cálcio, inibidores das fosfodiesterases de tipo 4) ou miorrelaxantes;16.Doentes que administraram medicamentos contendo analgésicos, anestésicos, vasodilatadores tópicos, cicatrizantes, corticosteróides, vitaminas A ou E ou quaisquer outras substâncias activas com actividade regeneradora da mucosa, há menos de 3 dias;17. História de hipersensibilidade ou intolerância a algum dos medicamentos experimentais, ou às substâncias activas ou excipientes que os constituem, ou a fármacos análogos;18.Doentes com distúrbios da coagulação;19.Qualquer alteração clínica ou laboratorial conhecida que no critério do investigador possa interferir na avaliação da segurança, da eficácia ou em qualquer procedimento do estudo;20.Doentes que terminaram a participação num estudo clínico há menos de um mês ou se encontrem a participar noutro estudo clínico.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients for which CAF cure (defined as total closing of anal fissure observed in the physical examination) was observed during the 8 week treatment period.

Proporção de doentes em que foi observada a cura da FAC (encerramento completo da fissura anal no exame objectivo) durante as 8 semanas de tratamento

E.5.1.1

Timepoint(s) of evaluation of this end point

During the 8 week treatment period.

Durante as 8 semanas de tratamento

E.5.2

Secondary end point(s)

1.Symptomatic improvement assessed as variation in millimeters, using a visual analogue scale (VAS) for pain applied on the 8th week of treatment (visit 4 – V4);
2.Symptomatic improvement assessed as variation in millimeters, using a visual analogue scale (VAS) for pain applied on the 4th week of treatment (visit 3 – V3);
3.Proportion of patients for which cure of the CAF was observed until the 4th week of treatment (visit 2 and 3 - V2 and V3);
4.Proportion of patients with relapsing disease during a 24-week follow up period after treatment withdrawal (final visit VF).
5.No. of adverse events (AE) reported for each treatment arm during the total duration of the study;
6.No. of serious and/or unexpected adverse reactions reported for each treatment arm during the total duration of the study.

1.Melhoria dos sintomas avaliada pela variação em milímetros medida numa EVA de dor aplicada na 8.ª semana de tratamento (visita 4 - V4);
2.Melhoria dos sintomas avaliada pela variação em milímetros, medida numa EVA para a dor aplicada na 4ª semana de tratamento (visita 3 – V3);
3.Proporção de doentes em que foi observada a cura da FAC até à 4.ª semana de tratamento (visitas 2 e 3 – V2 e V3);
4.Proporção de doentes em que foi observada a recidiva da doença durante as 24 semanas de seguimento após interrupção do tratamento (visita final – VF).
5.N.º de acontecimentos adversos (AA) reportados em cada um dos grupos do estudo, durante o período do estudo;
6. N.º de reacções adversas graves e/ou inesperadas reportadas em cada um dos grupos do estudo, durante o período do estudo.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Visit 4 - the 8th week of treatment
2. Visit 3 - the 4th week of treatment
3. Visit 2 and 3 - Until the 4th week of treatment.
4. During a 24-week follow up period after treatment withdrawal - Final Visit
5.Total duration of the study
6. Total duration of the study

1. Na visita 4 - 8.ª semana de tratamento
2. Na visita 3 - 4.ª semana de tratamento
3. Visitas 2 e 3 - até à 4.ª semana de tratamento.
4. Durante as 24 semanas de seguimento após interrupção do tratamento - Visita Final.
5.Durante o período do estudo.
6.Durante o período do estudo.

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

Yes

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)

Yes

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

Yes

E.8.1.4

Double blind

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

Last visit of the last subject

Última visita do último sujeito.

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.1.1.1

In Utero