Clinical Trials Register

Summary
EudraCT Number:	2015-003627-54
Sponsor's Protocol Code Number:	150601
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:	2016-02-19
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

2015-003627-54

A.3

Full title of the trial

Randomized, multicenter, placebo-controlled, double blind study to assess the efficacy and tolerability of 2% diltiazem hydrochloride in the treatment of chronic anal fissure and a 24 week follow-up period

Randomizovaná, multicentrická, placebem kontrolovaná, dvojitě zaslepená studie pro vyhodnocení účinnosti a snášenlivosti 2% diltiazem hydrochloridu při léčbě chronické anální fisury a 24týdenní následné sledování

A.3.1

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

Clinical Trial to assess the efficacy and tolerability of 2% diltiazem hydrochloride versus placebo in the treatment of chronic anal fissure with a follow up period of 24 weeks

A.3.2

Name or abbreviated title of the trial where available

EFAC II

A.4.1

Sponsor's protocol code number

150601

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	R. da Tapada Grande, nº 2, 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	+351 210 414 100
B.5.5	Fax number	+351 210 414 105
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.3.4	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.3.9.3	Other descriptive name	DILTIAZEM HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB13602MIG
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.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	Cutaneous paste
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.

E.1.1.1

Medical condition in easily understood language

Chronic anal fissure

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10071195
E.1.2	Term	Chronic anal fissure
E.1.2	System Organ Class	100000016260

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 (cure of chronic anal fissure) of the DTZ 2% cutaneous paste compared to placebo, in the treatment of chronic anal fissure (CAF), for up to 12 weeks (cure defined as complete closing evaluated through physical examination and re-epithelialization of the anal fissure observed in the anoscopy).

E.2.2

Secondary objectives of the trial

Secondary objectives include the comparison between the two treatment arms of:
a) cure rate within 8 weeks of treatment;
b) cure rate within 4 weeks of treatment;
c) improvement of symptoms triggered by defecation*) at 4, 8 and 12 weeks of treatment;
d) tolerability within 12 weeks of treatment;
e) assessment of CAF relapse rate during a 24-week follow-up period (for cured patients).
* Pain triggered by defecation is considered the pain felt during and after defecation.

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

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 New York Heart Association (NYHA) class III and IV heart failure, atrial fibrillation or atrial flutter caused by Wolff-Parkinson-White or Lown-Ganong-Levine syndromes, second and third degree atrioventricular block or sinoatrial node disease (except in the presence of a functioning artificial ventricular pacemaker), myocardial infarction with an ejection fraction below 0.40, ventricular tachycardia, severe bradycardia (lower than or equal to 40 beats per minute) or severe aortic stenosis.;
8. Patients with orthostatic (postural) hypotension or severe hypotension (systolic blood pressure below 90 mmHg);
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 human immunodeficiency virus (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.
15. Patients with any changes in the previous 12 weeks to oral, sublingual, intravenous or intra-muscular therapy with vasodilators (beta blockers, nitrates, calcium antagonists, phosphodiesterase 4 inhibitors) or muscle relaxants (for example infusion of dantrolene);
16. Use of glyceryl trinitrate (GTN) ointment for 7 days (continuous or not) in the 4 weeks prior to signing the informed consent form (ICF).
17. Previous treatment with diltiazem hydrochloride cutaneous formulations or any other topical calcium channel blockers in the 8 weeks before randomization.
18. Patients who used an analgesic, anesthetic, cicatrizant, other 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.
19. History of hypersensitivity or intolerance to any of the investigational medicinal products, or to their active substances or excipients, or to similar drugs;
20. Patients with clotting disorders, unless the patients are taking anticoagulants drugs and the investigator considers that the International Normalized Ratio (INR) is adequate and stable;
21. Any known abnormal clinical or laboratory change that, as per the investigator, might interfere with the safety or efficacy assessment or any study procedure;
22. Patients who have participated in another clinical trial less than one month prior to enrolment or who are still involved in another trial.

E.5 End points

E.5.1

Primary end point(s)

For the treatment part of the trial:
- Proportion of patients for which CAF cure (defined as complete closing (anal fissure extension and depth equal to zero (0) mm) evaluated through physical examination and complete re-epithelialization of anal fissure observed in the anoscopy) was observed during the 12 week treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

For the double blind part of the trial: 12 weeks of treatment (V2, V3, and V4)

E.5.2

Secondary end point(s)

1. Proportion of patients for which cure of the CAF was observed until the 8th week of treatment (cured on visit 2 or 3 - V2 or V3);
2. Proportion of patients for which cure of the CAF was observed until the 4th week of treatment (cured on visit 2 - V2 );
3. Symptomatic improvement of pain triggered by defecation vs. baseline assessed as variation in millimeters, using a visual analogue scale (VAS) for pain applied on the 12th week of treatment (visit 4 – V4);
4. Symptomatic improvement of pain triggered by defecation assessed as variation in millimeters, using a visual analogue scale (VAS) for pain applied on the 8th week of treatment (visit 3 – V3);
5. Symptomatic improvement of pain triggered by defecation assessed as variation in millimeters, using a visual analogue scale (VAS) for pain applied on the 4th week of treatment (visit 2 – V2);

For the follow-up period:
-For patients who complete the 24 week follow up phase, proportion of
patients with fissure relapse during a 24-week follow up period after
treatment withdrawal (final visit VF).

Secondary safety endpoints:
No. of adverse events (AE) reported for each treatment arm during the treatment phase;
No. of serious and/or unexpected adverse reactions reported for each treatment arm during the treatment phase.

E.5.2.1

Timepoint(s) of evaluation of this end point

1 - Visit 2 and 3 - 8th week of treatment.
2- V2 - 4th week of treatment
3 - V4 - 12th week of treatment
4- V3 - 8th week of treatment
5- V2 - 4th week of treatment

For follow-up period endpoint - Final visit

Safety endpoints: total duration of the 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)

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

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

LVLS

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

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:

180

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Signed and dated informed consent form by the patient representative/witness (as per applicable law)

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

220

F.4.2.2

In the whole clinical trial

220

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)

None

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

2016-05-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-05-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-07-21

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