Clinical Trials Register

Summary
EudraCT Number:	2018-001724-19
Sponsor's Protocol Code Number:	CLI-06467AA1-01
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-08-08
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

Bulgarian Drug Agency

A.2

EudraCT number

2018-001724-19

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled study to investigate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of CHF6467 after single and repeated ascending doses in subjects with diabetic neuropathic foot ulcers (DFU).

A.3.1

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

A study of CHF6467 after administration of single and repeated ascending doses in participants with diabetic neuropathic foot ulcers (DFU)

A.4.1

Sponsor's protocol code number

CLI-06467AA1-01

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	Chiesi Farmaceutici S.p.A.
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	Chiesi Farmaceutici S.p.A.
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	Chiesi Farmaceutici S.p.A.
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Via Palermo 26/A
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43122
B.5.3.4	Country	Italy
B.5.4	Telephone number	+3905211689 215
B.5.6	E-mail	clinicaltrials_info@chiesi.com

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.3.2	Product code	CHF6467
D.3.4	Pharmaceutical form	Cutaneous solution
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	Recombinant human mutant nerve growth factor painless ( hNGFp)
D.3.9.2	Current sponsor code	CHF6467
D.3.9.3	Other descriptive name	Recombinant human mutant nerve growth factor painless (hNGFp)
D.3.9.4	EV Substance Code	SUB193423
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	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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 solution
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

Diabetic Neuropathic Foot Ulcers (DFU) Texas Scale Grade 1A and 2A

E.1.1.1

Medical condition in easily understood language

Diabetic Foot Ulcer is a major complication of diabetes mellitus, a non-healing or poorly healing full-thickness wound, through the dermis, below the ankle in an individual with diabetes

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10012664
E.1.2	Term	Diabetic foot ulcer
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

• To assess the safety and tolerability of single and multiple days’ topical dosing with CHF6467 in subjects with DFU.

E.2.2

Secondary objectives of the trial

• To assess the pharmacokinetic profile of systemically available drug following single and multiple days’ topical dosing with CHF6467 in subjects with DFU;

• To assess the pharmacodynamic effects of multiple days’ topical dosing with CHF6467 on the healing of DFU over a 12-week period.

• To assess the potential for immunogenicity through the evaluation of the presence of CHF6467 Antidrug Antibodies (ADA).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part 1 SD and Part 2 MD:
Subjects must meet all the following criteria in order to be eligible for enrolment into the study:
1. Subject’s written informed consent obtained prior to any study-related procedure;
2. Male or female subject aged 18 – 80 years (extremes inclusive), diagnosed with Type I or Type II diabetes mellitus, with glycosylated haemoglobin (HbA1c) ≤ 10%.
3. Female subjects of non-childbearing potential (WONCBP):
- they must report surgical sterilization (performed at least 6 months prior to screening), or
- menopause (must have had no regular menstrual bleeding for at least one year
prior to screening, age ≥ 45 years and FSH at screening ≥ 40 mIU/ml).
4. Female subject with childbearing potential (WOCBP): they must be using one or more of the following reliable methods of contraception during the study period and at least within 90 days after the last study drug administration:
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS).
b) Hormonal contraception (implantable, patch, oral).
c) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository.
d) Male Partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
5. Male subjects; they must be using two effective methods of contraception during the entire study period and not donate sperm within 90 days after the last study drug administration.
6. Presence of at least one diabetic foot ulcer meeting the following criteria:
a) Diagnosed as a full-thickness, neuropathic DFU, located at or distal to the malleolus (excluding ulcers between the toes but including those of the heel)
b) SD: Present for 6 weeks to 12 months, and of 3 – 5 cm 2 in area following sharp debridement, confirmed at screening.
MD: Present for 6 weeks to 12 months, and of 3 – 6 cm2 in area following sharp debridement confirmed at screening, and of 2-5 cm2 after the 2 weeks run-in period with an area reduction compared to screening <50%.
c) A minimum 1 cm margin between the qualifying study ulcer and any other ulcers on the specified foot.
d) SD: Ulcer must have a depth ≥ 5 mm at some point in its area and be graded 1A according to “The University of Texas Staging System for Diabetic Foot Ulcers”, with no capsule, tendon or bone exposed and no tunnelling, undermining, or sinus tracts, after the initial sharp debridement, confirmed at screening.
MD: Ulcer must have a depth ≥ 5 mm at some point in its area and be graded 1A or 2A according to “The University of Texas Staging System for Diabetic Foot Ulcers”, after the initial sharp debridement, confirmed at screening.
7. Subject must be able to hold the target ulcer in such a position and orientation that the study medication can be applied without significant loss of substance through run-off, until the dressing has been applied.
8. Adequate vascular perfusion of the affected limb demonstrated within 30 days prior to screening, as defined by at least one of the following:
a) Ankle-Brachial Index (ABI) ≥ 0.9 and ≤ 1.2, confirmed by transcutaneous oxygen partial pressure (TcPO2) >50 mmHg
b) Toe pressure (plethysmography) >50 mmHg
c) Doppler ultrasound (biphasic or triphasic waveforms) on at least two vessels at the ankle consistent with adequate blood flow to the affected extremity, as determined by SoC.

E.4

Principal exclusion criteria

Part 1 SD and Part 2 MD:
Subjects must meet none of the following criteria in order to be eligible for enrolment into the study:
1. For females only: pregnant or lactating female subject, confirmed by a positive serum pregnancy test at screening and a urine test performed on Day -1.
2. Subject with:
a) Ulcer(s) accompanied by infected cellulitis, osteomyelitis, or clinical signs or symptoms of infection confirmed by a cultural exam made on the material taken off from the ulcer according to the technique described in the guidelines for diagnosis and management of diabetic foot infections of the Infectious Diseases Society of the Americas (IDSA).
b) Gangrene or necrosis on any part of the affected limb.
c) Active or chronic Charcot's foot on the study limb.
d) Planned vascular surgery, angioplasty or thrombolysis or previous revascularization procedure performed within 1 month prior to enrolment.
e) SD only: Ulcers involving exposure of tendon, bone, or joint capsule (It is acceptable to have ulcers extending through the dermis and into subcutaneous tissue with presence of granulation tissue).
f) Ulcer(s) of non-diabetic aetiology.
g) Previous Lisfranc or Chopart's amputations on the same target foot.
h) Actual or recent (3 weeks) antibiotic therapy for any reason.
i) Bedridden subjects or subjects with a life expectancy less than one year.
3. Use of any growth factor therapy in the 3 months prior to screening.
4. History of malignancy in the 5 years prior to screening or those with a strong family history of cancer (e.g. familial cancer disorders), with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated.
5. Clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurological, psychiatric, immunological, gastrointestinal, haematological or metabolic disease that is, in the opinion of the Investigator, not stabilised or may otherwise impact subject safety or study results (in cases of doubt, the Sponsor’s Clinical Research Physician and CRO Medical Monitor should be consulted).
6. Subject undergoing haemodialysis or peritoneal dialysis or with chronic renal insufficiency (plasma creatinine > 2 mg/dl).
7. Subject with significantly abnormal key laboratory parameters interfering with the safety of the subject according to the PI judgement.

E.5 End points

E.5.1

Primary end point(s)

Part 1 SD:
Safety:
Аssessed throughout the trial (Screening, Treatment Period and Follow-up):
• Adverse Events (AEs) and Adverse Drug Reactions (ADRs)
• Vital signs: Systolic (SBP) and Diastolic (DBP) Blood Pressure
• Triplicate 12-lead ECG
• 12-lead ECG parameters extracted from Holter (HR, PR, QRS, QTcF, QT)
• Clinical laboratory evaluations (chemistry, haematology and urinalysis).

Part 2 MD:
Safety:
Аssessed throughout the trial (Screening, Treatment Period and Follow-up):
• AEs and ADRs;
• Vital signs: SBP, DBP; temperature;
• Triplicate 12-lead ECG;
(Should any ECG/cardiovascular findings emerge from Part 1 of the study, the SAC may also implement Holter monitoring for part, or all, of Part 2, as indicated);
• 12-lead ECG parameters extracted from Holter (HR, PR, QRS, QTcF, QT);
• 24h Holter ECG abnormal findings (total pauses >2.5 secs, atrial fibrillation and atrial flutter, ventricular runs, premature atrial contractions (PAC) burden, premature ventricular contractions (PVC) burden, aberrant morphologies); 0-24h heart rate (from 24h Holter ECG) and hourly average HR;
• Clinical laboratory evaluations (chemistry, haematology and urinalysis).

E.5.1.1

Timepoint(s) of evaluation of this end point

Indicated above.

E.5.2

Secondary end point(s)

Part 1 SD:
Pharmacokinetic variables:
The following PK parameters will be derived from CHF6467 serum concentrations:
On Day 1, 2, 3 and 4:
• AUC0-12h, AUC00-24h, AUC0-t, AUC0-∞, Cmax, tmax, t½, CL/F, Vd/F;
• AUC0-12h DN, AUC00-24h DN, AUC0-t DN, AUC0-∞ DN, Cmax DN.

Immunogenicity variables:
• Antidrug antibody (ADA) serum concentrations will be evaluated on Day 1 and during the first visit of Week 4 (Day 24)
• ADA presence/absence and titer

Part 2 MD:
Pharmacokinetic variables:
The following PK parameters will be derived from CHF6467 serum concentrations:
• On Day 1: AUC0-12h, Cmax, and tmax,;
• From Day 2 to Day 13: Ctrough
• On the last day of drug administration (Day 14): AUC0-12h, AUC0-t, AUC0-∞, Ctrough, Cmax, Cmin, tmax, tmin, Cav, and Rac, t½, CL/F, and Vd/F.

Immunogenicity variables:
• Antidrug antibody (ADA) serum concentrations will be evaluated on Day 1 prior to the first dose application, on Day 15 prior to discharge, on Day 24 (Week 4), Day 52 (Week 8) and on Day 80 (Week 12).
• ADA presence/absence and titer

Pharmacodynamic/ Efficacy variables:
• Mean reduction in target ulcer area and volume from Baseline to D14, D21, D28, D56 and D84;
• Time to healing of the target ulcer area and volume. Healing will be defined as “complete recovery”. Different “healing” definitions will also be applied (Partial reduction: 50%, 66%, 75%).

E.5.2.1

Timepoint(s) of evaluation of this end point

Indicated above.

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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

Part 1 SD - single ascending dose; Part 2 MD - multiple ascending dose;

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

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:

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.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)

Standard of Care

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

2018-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-01-07

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