Clinical Trials Register

Summary
EudraCT Number:	2016-002772-27
Sponsor's Protocol Code Number:	039(B)PO16143
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-02-20
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2016-002772-27

A.3

Full title of the trial

Efficacy and safety of low doses of trazodone in patients affected by painful diabetic neuropathy: randomized, controlled, pilot study.

A.3.1

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

A study of the effectiveness and safety of low doses od trazodone in patients affected by painful diabetic neuropathy: randomized, controlled, pilot study.

A.3.2

Name or abbreviated title of the trial where available

Trazodone in PDN

A.4.1

Sponsor's protocol code number

039(B)PO16143

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	A.C.R.A.F. SpA (Angelini SpA)
B.1.3.4	Country	Italy
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	Angelini SpA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	A.C.R.A.F. SpA (Angelini SpA)
B.5.2	Functional name of contact point	Study Manager
B.5.3	Address:
B.5.3.1	Street Address	Piazzale della Stazione
B.5.3.2	Town/ city	S. Palomba - Pomezia (Rome)
B.5.3.3	Post code	00071
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390691045349
B.5.5	Fax number	0039069109729
B.5.6	E-mail	p.lipone@angelini.it

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	Trittico® 60 mg/ml oral drops, solution
D.2.1.1.2	Name of the Marketing Authorisation holder	A.C.R.A.F. S.p.A
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Trazodone
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Trazodone hydrochloride
D.3.9.1	CAS number	25332-39-2
D.3.9.2	Current sponsor code	039(B)
D.3.9.4	EV Substance Code	SUB15596MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
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	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Painful diabetic neuropathy

E.1.1.1

Medical condition in easily understood language

Painful diabetic neuropathy

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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	10012683
E.1.2	Term	Diabetic peripheral neuropathy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10012680
E.1.2	Term	Diabetic neuropathy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10014698
E.1.2	Term	Endocrine disorders
E.1.2	System Organ Class	10014698 - Endocrine disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To collect preliminary information on the effect of low doses of trazodone on pain intensity in patients with painful diabetic neuropathy after 8-week treatment period.

E.2.2

Secondary objectives of the trial

To evaluate the neuropathic pain symptoms, anxiety, sleep, quality of life, safety and tolerability.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female patient of any ethnic origin between 18 and 75 years of age (limits included).
2. Patient with painful diabetic symmetric polyneuropathy manifesting with distally distributed neuropathic pain.
3. Stable glycemic control with a value of HbA1c ≤ 10% at Screening Visit.
4. Pain persisting for at least 3 months.
5. Neuropathic pain confirmed by DN4 score ≥ 4 at Screening Visit.
6. BPI-SF 24-hour average pain score (item 5) ≥ 4 at Screening Visit and Baseline Visit
7. Patient who is currently not receiving treatment for diabetic neuropathic pain or patient who is receiving treatment, with drug/s other than gabapentin, and have completed the required washout.
8. Women of childbearing potential must have a negative pregnancy test at Screening Visit and have to agree not to start a pregnancy from the signature of the informed consent up to thirty days after the last administration of the investigational product, using an appropriate birth control method, such as combined estrogen and progestogen containing hormonal contraception (e.g. oral, intravaginal, transdermal), progestogen-only hormonal contraception (e.g. oral, injectable, implantable), intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) in combination with male condom, bilateral tubal occlusion, vasectomised partner, sexual abstinence.
9. Legally capable to give their consent to participate in the study and available to sign and date the written informed consent.

E.4

Principal exclusion criteria

1. Known hypersensitivity to trazodone or gabapentin or their excipients.
2. Other forms of neuropathic pain or non-neuropathic pain (included but not limited to peripheral arterial disease, radiculopathy, mononeuropathy, proximal motor neuropathy, post-operative pain, etc).
3. Concomitant treatment with other medications for pain management.
4. Concomitant treatment with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, indinavir) or drugs known to prolong QT interval.
5. Use of trazodone or gabapentin in the previous 3 months.
6. Clinically significant abnormalities on physical examination, vital signs, ECG, laboratory tests at Screening Visit that in the opinion of Investigator would compromise patient’s participation in the study.
7. Active foot ulcer or previous major limb amputation.
8. Myocardial infarction or angioplasty or by-pass graft procedures within the past 6 months.
9. Patient with increased risk of Torsade de Pointes (e.g. family history of long QT syndrome) or QTcF value higher than 450 msec (male) and QTcF value higher than 470 msec (female) at Screening Visit.
10. Transient ischemic attack or cerebral vascular accident within the past 6 months.
11. GFR value < 60 ml/min calculated with MDRD formula.
12. Significant liver disease, defined as known active hepatitis or elevated liver enzymes over 3 fold the upper normal limit of laboratory normal ranges.
13. Patient with latent or known hereditary problems of galactose intolerance or the Lapp lactase deficiency or glucose-galactose malabsorption.
14. Positive urine drug screen for CNS active drugs (cocaine, opioids, amphetamines and cannabinoids) a Screening Visit.
15. Positive present history of glaucoma.
16. Hyperthyroidism, even if pharmacologically corrected.
17. Significant mental disorders.
18. History of seizure events other than a single childhood febrile seizure.
19. History of alcohol or psychoactive substance abuse or addiction.
20. Patients suffering from adrenal hypofunction (e.g. Addison Disease).
21. Women during pregnancy or lactation period.
22. Inability to comply with the protocol requirements, instructions or study-related restrictions (e.g. uncooperative attitude, inability to return for study-visits, improbability of completing the clinical study, etc).
23. Subject involved in the conduct of the study (e.g. Investigator or his/her deputy, first grade relatives, pharmacist, assistant or other personnel, etc).
24. Participation to an interventional clinical trial within 3 months prior to Screening Visit.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline of the BPI-SF item 5 score at Visit 8 (Day 56 ±2).

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline - Visit 8 (Day 56 ±2).

E.5.2

Secondary end point(s)

• Change from baseline of BPI-SF item 5 score at V1, V2, V3, V4, V5, V6, V7 and V9.
• Change from baseline of BPI-SF items 3, 4, 5, 6, 8 and 9 score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline of NPSI total score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline in quality of life score (SF-36 short form) at V8.
• Change from baseline of HAM-A at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline of Leeds Sleep Evaluation Questionnaire at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• PGIC score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Safety and tolerability evaluation.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

double-dummy, dose finding, multicentre, international, prospective, pilot study

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

The end of the trial will be the date of the last visit performed by the last ongoing patient.

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:

100

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

120

F.4.2.2

In the whole clinical trial

120

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)

The patients will be followed according to the Investigator's judgement and the current clinical practice.

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

2017-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-08-09

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