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Clinical Trial Results:
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).

Summary
EudraCT number	2018-001724-19
Trial protocol	BG
Global end of trial date	06 Jan 2021

Results information
Results version number	v1(current)
This version publication date	04 Feb 2022
First version publication date	04 Feb 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLI-06467AA1-01

ISRCTN number

US NCT number

NCT04077671

WHO universal trial number (UTN)

Sponsor organisation name

Chiesi Farmaceutici S.p.A.

Sponsor organisation address

Via Palermo 26/A, Parma, Italy, 43122

Public contact

Clinical Trial Trasparency, Chiesi Farmaceutici S.p.A., clinicaltrials_info@chiesi.com

Scientific contact

Clinical Trial Trasparency, Chiesi Farmaceutici S.p.A., clinicaltrials_info@chiesi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

19 Nov 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Jan 2021

Was the trial ended prematurely?

Main objective of the trial

To assess: - the safety and tolerability of single and multiple days topical dosing with CHF6467 in patients with diabetic foot ulcers (DFU); - the pharmacokinetic (PK) profile of systemically available drug following single and multiple days topical dosing with CHF6467 in patients with DFU; - the pharmacodynamic (PD) effects of multiple days topical dosing with CHF6467 on the healing of DFU over a 12-week period; - the potential for immunogenicity through the evaluation of the presence of CHF6467 anti-drug antibodies (ADA).

Protection of trial subjects

This clinical study was performed in accordance with the principles that have their origin in the declaration of Helsinki, and with local regulations. The study was carried out in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP) (ICH/CPMP/135/95). Before the start of the study, all patients gave their written informed consent to participate in the study after having been informed of the nature and implications of the study. The study consisted of two parts: - Part 1 was a randomised, double-blind, placebo-controlled, single ascending dose, serial Cohort design in patients with neuropathic DFUs. - Part 2 was a randomised, double-blind, placebo-controlled, multiple ascending dose, off-set parallel group design in patients with neuropathic DFUs.

Background therapy

CHF6467, human NGF (hNGF) P61S R100E, is a recombinant and “painless” form of hNGF. The mutation on arginine R100 in mature NGF is linked to the rare human genetic disease hereditary sensory autonomic neuropathy type V (HSAN V). In HSAN V subjects, a mutation in the NGFβ gene (exon 3, nucleotide C661T), changing arginine R100 to a tryptophan, determines the complete loss of pain perception without affecting most neurological functions. In addition to the pain-related R100E mutation, CHF6467 harbours a second “tagging” P61S mutation, which replaces the proline residue at position 61 of hNGF with the serine residue present in murine NGF (mNGF). In vitro and in vivo data have confirmed that CHF6467 maintains neurotrophic and neuroprotective properties identical to NGF in a variety of cell assays, while displaying a significantly reduced pain-inducing activity in vivo. CHF6467 has shown promising efficacy in accelerating the healing of wounds in diabetic mice, without any indication of the induction of pain or hyperalgesia.

Evidence for comparator

Actual start date of recruitment

16 Oct 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 94

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In Part1, a total of 38 subjects were screened: 33 were randomised and divided into 4 Cohorts (A, B, C, D) of 8 subjects each (except for Cohort B which included 9 patients) and 5 failed screening. In Part 2, a total of 82 subjects were screened: 61 were randomised into one of 2 Cohorts (E, F) with 30 patients in Cohort E and 31 in Cohort F.

Screening details

The screening was performed from 3 to 21 days prior to randomisation (Part 1) and prior to run-in period (Part 2). The eligibility (inclusion/exclusion criteria) was assessed, medical history, concomitant medications were recorded, and clinical serology, haematology, chemistry, urinalysis, vital sign, ECG, ulcer size measurement were performed.

Period 1 title

Treatment Period Part 1 and Part 2 (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Part 1: Cohort A (SD1) CHF6467

Arm description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort A consisted of 6 subjects that received the active drug CHF6467 at a dose of 0.3 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Arm type

Experimental

Investigational medicinal product name

CHF6467

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

CHF6467 was a colourless aqueous solution for topical administration as single doses given in the morning through 1 mL topical graduated syringe using the necessary dilution steps to reach the final concentration which for Cohort A corresponds to: 0.3 μg/mm² (two steps of dilution, final concentration of 0.03 mg/mL). Doses have been standardised in terms of volume/mm² of ulcer size by serial dilution of CHF6467 at the initial concentration of 1 mg/mL with the corresponding amount of diluent.

Part 1: Cohort B (SD2) CHF6467

Arm description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort B consisted of 6 subjects that received the active drug CHF6467 at a dose of 1.0 μg/mm² ulcer area, and 3 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Arm type

Experimental

Investigational medicinal product name

CHF6467

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

CHF6467 was a colourless aqueous solution for topical administration as single doses given in the morning through 1 mL topical graduated syringe using the necessary dilution steps to reach the final concentration which for Cohort B corresponds to: 1.0 μg/mm² (one steps of dilution, final concentration of 0.1 mg/mL). Doses have been standardised in terms of volume/mm² of ulcer size by serial dilution of CHF6467 at the initial concentration of 1 mg/mL with the corresponding amount of diluent.

Part 1: Cohort C (SD3) CHF6467

Arm description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort C consisted of 6 subjects that received the active drug CHF6467 at a dose of 3 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Arm type

Experimental

Investigational medicinal product name

CHF6467

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

CHF6467 was a colorless aqueous solution for topical administration as single doses given in the morning through 1 mL topical graduated syringe using the necessary dilution steps to reach the final concentration which for Cohort C corresponds to: 3 μg/mm² (one step of dilution, final concentration of 0.3 mg/mL). Doses have been standardised in terms of volume/mm² of ulcer size by serial dilution of CHF6467 at the initial concentration of 1 mg/mL with the corresponding amount of diluent.

Part 1: Cohort D (SD4) CHF6467

Arm description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort D consisted of 6 subjects that received the active drug CHF6467 at a dose of 6 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Arm type

Experimental

Investigational medicinal product name

CHF6467

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

CHF6467 was a colourless aqueous solution for topical administration as single doses given in the morning through 1 mL topical graduated syringe using the necessary dilution steps to reach the final concentration which for Cohort D corresponds to: 6 μg/mm² (one steps of dilution, final concentration of 0.6 mg/mL). Doses have been standardised in terms of volume/mm² of ulcer size by serial dilution of CHF6467 at the initial concentration of 1 mg/mL with the corresponding amount of diluent.

Part 1: Placebo

Arm description

Part 1_Includes subjects from Cohorts A, B, C, D who received placebo and are respectively: Cohort A_2 subjects Cohort B_3 subjects Cohort C_2 subjects Cohort D_2 subjects

Arm type

Placebo

Investigational medicinal product name

CHF6467 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

Placebo was a colourless aqueous solution for topical administration as single doses given in the morning through 1 mL topical graduated syringe.

Part 2: Cohort E (MD1) CHF6467

Arm description

Part 2: Multiple ascending doses in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, multiple ascending doses, parallel group design in 2 Cohorts (E, F). During Part 2, two total dose levels of CHF6467 were administered topically applied as a once daily (q.d.) regimen, for 14 consecutive days according to an escalation scheme. Cohort E consisted of 17 subjects that received the active drug CHF6467 at a dose of 1 μg/mm²/day for 14 consecutive days q.d., and 10 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Arm type

Experimental

Investigational medicinal product name

CHF6467

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

Multiple doses of CHF6467 - total daily dose 1 μg/mm²/day given q.d. plus SoC. Topical administration of Active Drug was given under a q.d. dosing regimen in order to achieve a total daily dose of 1 μg/mm² through graduated topical syringe. Dose was standardised in terms of volume/mm² of ulcer size (10 μL/mm²) by serial dilution (if required) of CHF6467 at the initial concentration of 1 mg/mL with the corresponding amount of vehicle.

Part 2: Cohort F (MD2) CHF6467

Arm description

Part 2: Multiple ascending doses in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, multiple ascending doses, parallel group design in 2 Cohorts (E, F). During Part 2, two total dose levels of CHF6467 were administered topically applied as a once daily (q.d.) regimen, for 14 consecutive days according to an escalation scheme. Cohort F consisted of 18 subjects that received the active drug CHF6467 at a dose of 3 μg/mm²/day for 14 consecutive days q.d., and 10 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Arm type

Experimental

Investigational medicinal product name

CHF6467

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

Multiple doses of CHF6467 - total daily dose 3 μg/mm²/day given q.d. plus SoC. Topical administration of Active Drug was given under a q.d. dosing regimen in order to achieve a total daily dose of 3 μg/mm² through graduated topical syringe. Dose was standardised in terms of volume/mm² of ulcer size (10 μL/mm²) by serial dilution (if required) of CHF6467 at the initial concentration of 1 mg/mL with the corresponding amount of vehicle.

Part 2: Placebo

Arm description

Part 2_Includes subjects from Cohorts E, F who received placebo and are respectively: Cohort E_10 subjects Cohort F_10 subjects

Arm type

Placebo

Investigational medicinal product name

CHF6467 - Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Cutaneous solution

Routes of administration

Topical use

Dosage and administration details

Placebo was a colourless aqueous solution, topically administered, multiple ascending doses given under a q.d. dosing regimen through a graduated topical 1 mL syringe.

Number of subjects in period 1	Part 1: Cohort A (SD1) CHF6467	Part 1: Cohort B (SD2) CHF6467	Part 1: Cohort C (SD3) CHF6467	Part 1: Cohort D (SD4) CHF6467	Part 1: Placebo	Part 2: Cohort E (MD1) CHF6467	Part 2: Cohort F (MD2) CHF6467	Part 2: Placebo
Started	6	6	6	6	9	20	21	20
Completed	6	6	6	6	8	17	18	17
Not completed	0	0	0	0	1	3	3	3
Consent withdrawn by subject	-	-	-	-	1	3	3	2
Adverse event, non-fatal	-	-	-	-	-	-	-	1

Baseline characteristics

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Reporting group title

Part 1: Cohort A (SD1) CHF6467

Reporting group description

Reporting group title

Part 1: Cohort B (SD2) CHF6467

Reporting group description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort B consisted of 6 subjects that received the active drug CHF6467 at a dose of 1.0 μg/mm² ulcer area, and 3 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 1: Cohort C (SD3) CHF6467

Reporting group description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort C consisted of 6 subjects that received the active drug CHF6467 at a dose of 3 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 1: Cohort D (SD4) CHF6467

Reporting group description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort D consisted of 6 subjects that received the active drug CHF6467 at a dose of 6 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 1: Placebo

Reporting group description

Part 1_Includes subjects from Cohorts A, B, C, D who received placebo and are respectively: Cohort A_2 subjects Cohort B_3 subjects Cohort C_2 subjects Cohort D_2 subjects

Reporting group title

Part 2: Cohort E (MD1) CHF6467

Reporting group description

Reporting group title

Part 2: Cohort F (MD2) CHF6467

Reporting group description

Part 2: Multiple ascending doses in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, multiple ascending doses, parallel group design in 2 Cohorts (E, F). During Part 2, two total dose levels of CHF6467 were administered topically applied as a once daily (q.d.) regimen, for 14 consecutive days according to an escalation scheme. Cohort F consisted of 18 subjects that received the active drug CHF6467 at a dose of 3 μg/mm²/day for 14 consecutive days q.d., and 10 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 2: Placebo

Reporting group description

Part 2_Includes subjects from Cohorts E, F who received placebo and are respectively: Cohort E_10 subjects Cohort F_10 subjects

Reporting group values	Part 1: Cohort A (SD1) CHF6467	Part 1: Cohort B (SD2) CHF6467	Part 1: Cohort C (SD3) CHF6467	Part 1: Cohort D (SD4) CHF6467	Part 1: Placebo	Part 2: Cohort E (MD1) CHF6467	Part 2: Cohort F (MD2) CHF6467	Part 2: Placebo	Total
Number of subjects	6	6	6	6	9	20	21	20	94
Age categorical
Units: Subjects
Adults (18-64 years)	4	4	4	3	7	15	18	12	67
From 65-84 years	2	2	2	3	2	5	3	8	27
Age continuous
Units: years
arithmetic mean (standard deviation)	58.2 ± 11.8	60.2 ± 11.5	62.3 ± 10.3	62.5 ± 9.2	57.8 ± 8.9	58.0 ± 9.1	56.7 ± 8.6	60.8 ± 8.4	-
Gender categorical
Units: Subjects
Female	1	1	1	1	2	3	3	2	14
Male	5	5	5	5	7	17	18	18	80
Race
Units: Subjects
White	6	6	6	6	9	20	21	20	94
Body Mass Index (BMI)
Units: kg/m2
arithmetic mean (standard deviation)	32.39 ± 3.25	30.51 ± 5.52	28.93 ± 2.74	31.20 ± 4.26	31.23 ± 3.57	29.957 ± 5.319	29.338 ± 5.116	29.342 ± 3.067	-

End points

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Reporting group title

Part 1: Cohort A (SD1) CHF6467

Reporting group description

Reporting group title

Part 1: Cohort B (SD2) CHF6467

Reporting group description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort B consisted of 6 subjects that received the active drug CHF6467 at a dose of 1.0 μg/mm² ulcer area, and 3 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 1: Cohort C (SD3) CHF6467

Reporting group description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort C consisted of 6 subjects that received the active drug CHF6467 at a dose of 3 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 1: Cohort D (SD4) CHF6467

Reporting group description

Part 1: Single ascending dose in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, single ascending dose, parallel group design in 4 Cohorts (A, B, C, D). During Part 1, four single dose levels of CHF6467 were administered topically according to an escalating dose regimen. Cohort D consisted of 6 subjects that received the active drug CHF6467 at a dose of 6 μg/mm² ulcer area, and 2 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 1: Placebo

Reporting group description

Part 1_Includes subjects from Cohorts A, B, C, D who received placebo and are respectively: Cohort A_2 subjects Cohort B_3 subjects Cohort C_2 subjects Cohort D_2 subjects

Reporting group title

Part 2: Cohort E (MD1) CHF6467

Reporting group description

Reporting group title

Part 2: Cohort F (MD2) CHF6467

Reporting group description

Part 2: Multiple ascending doses in subjects with neuropathic DFUs. Randomised, double-blind, placebo-controlled, multiple ascending doses, parallel group design in 2 Cohorts (E, F). During Part 2, two total dose levels of CHF6467 were administered topically applied as a once daily (q.d.) regimen, for 14 consecutive days according to an escalation scheme. Cohort F consisted of 18 subjects that received the active drug CHF6467 at a dose of 3 μg/mm²/day for 14 consecutive days q.d., and 10 subjects dosed with matching placebo. The doses to be administered were adapted based on the actual ulcer area.

Reporting group title

Part 2: Placebo

Reporting group description

Part 2_Includes subjects from Cohorts E, F who received placebo and are respectively: Cohort E_10 subjects Cohort F_10 subjects

Subject analysis set title

Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 1: Placebo - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 2: Placebo - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population included all randomised subjects who received at least one dose of study treatment.

Subject analysis set title

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PD population included all subjects from Safety set, also having evaluable PD data (ulcer tissue measurements) in at least one timepoint after the first administration of the study drug and without any major protocol deviation affecting PD evaluation.

Subject analysis set title

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Part 2: Placebo - PD set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - PK set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviations affecting PK evaluations.

Subject analysis set title

Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - PK set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviations affecting PK evaluations.

Subject analysis set title

Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - PK set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviations affecting PK evaluations.

Subject analysis set title

Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - PK set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviations affecting PK evaluations.

Subject analysis set title

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviations affecting PK evaluations.

Subject analysis set title

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviations affecting PK evaluations.

Primary: 1_Part 1 - Abnormal SBP and DBP Change from baseline - Any post-baseline timepoint

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End point title

1_Part 1 - Abnormal SBP and DBP Change from baseline - Any post-baseline timepoint ^[1]

End point description

Systolic and diastolic blood pressure was measured after at least 5 min rest in supine position. Vital signs could be repeated at the discretion of the Investigator for the purposes of safety or to confirm eligibility. Baseline is defined as pre-dose value on Day 1 of each treatment for Cohorts A, B, C and D. The number of subjects contributing to the data is indicated (Cohort A, B, C and D). Then, presented values are representative results of all post-dose time points. The following change from baseline abnormality categories was defined: • > 20mmHg for systolic blood pressure; • > 10mmHg for diastolic blood pressure.

End point type

Primary

End point timeframe

At any timepoint: On Day 1 at pre-dose, 15, 30 min, 1, 2, 4, 8, 12 h post-dose, on Day 2 at 24 h post-dose, on Day 3 at 48 h post-dose, on Day 4 at 72 h post-dose, and at follow-up.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - Safety	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - Safety	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - Safety	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - Safety	Part 1: Placebo - Safety
Number of subjects analysed	6	6	6	6	9
Units: subjects
SBP > 20 mmHg	0	1	0	0	0
DBP > 10 mmHg	2	0	1	2	1

No statistical analyses for this end point

Primary: 2_Part 1 - Abnormal QTcF Change from baseline - Any timepoint

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End point title

2_Part 1 - Abnormal QTcF Change from baseline - Any timepoint ^[2]

End point description

QtcF is QT corrected for the heart rate with the Fridericia formula and derived from triplicate 12-lead ECG parameters extracted from Holter.

End point type

Primary

End point timeframe

On Day 1 at 15, 30, 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 14 h post-dose. On Day 2 at 24 h post-dose. On screening using the time-matched points from Day 1.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - Safety	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - Safety	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - Safety	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - Safety	Part 1: Placebo - Safety
Number of subjects analysed	6	6	6	6	9
Units: subjects
QTcF <= 30 msec	5	6	6	5	9
30 <= QTcF change from Baseline <= 60 msec	1	0	0	1	0
QTcF change from baseline > 60 msec	0	0	0	0	0

No statistical analyses for this end point

Primary: 3_Part 1 - Heart rate (0-24 h) - Change from Baseline

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End point title

3_Part 1 - Heart rate (0-24 h) - Change from Baseline

End point description

Data were derived from measurements using 12-lead ECG, extracted from 24 h Holter monitoring. For 12-lead ECG parameter extracted from Holter (HR) the baseline value is defined at each time point as the time-matched triplicate (mean values) at screening. For HR0-24 extracted from Holter the baseline value is the HR0-24 value at screening. Data are presented as mean and standard deviation.

End point type

Primary

End point timeframe

24 h 12-lead digital Holter ECG recording: at screening visit, on Day 1 from at least 90 min prior to dosing up to at least 24 h post-dose, on Day 2, and at follow-up.

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - Safety	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - Safety	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - Safety	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - Safety	Part 1: Placebo - Safety
Number of subjects analysed	6	6	6	6	9
Units: bpm
arithmetic mean (standard deviation)	-7.8 ± 6.2	-8.7 ± 7.8	-8.2 ± 5.1	-3.7 ± 4.2	-8.4 ± 6.0

1_CHF6467 SD1 VS Placebo

Statistical analysis description

HR0-24 extracted from Holter: Mean difference vs. placebo in change from baseline was calculated for HR0-24 for each dose level and 90% CI derived using ANCOVA models with treatment as fixed effect and baseline as covariate.

Comparison groups

Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - Safety v Part 1: Placebo - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.954

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-5.2

upper limit

4.8

Notes
[3] - Adjusted mean difference

2_CHF6467 SD2 VS Placebo

Statistical analysis description

Comparison groups

Part 1: Placebo - Safety v Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.736

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1

Confidence interval

level

90%

sides

2-sided

lower limit

-6

upper limit

Notes
[4] - Adjusted mean difference

3_CHF6467 SD3 VS Placebo

Statistical analysis description

Comparison groups

Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - Safety v Part 1: Placebo - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.802

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.7

Confidence interval

level

90%

sides

2-sided

lower limit

-5.8

upper limit

4.3

Notes
[5] - Adjusted mean difference

4_CHF6467 SD4 VS Placebo

Statistical analysis description

Comparison groups

Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - Safety v Part 1: Placebo - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.163

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

4.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.8

upper limit

9.2

Notes
[6] - Adjusted mean difference

Primary: 4_Part 2 - Abnormal SBP and DBP - Any post-baseline timepoint

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End point title

4_Part 2 - Abnormal SBP and DBP - Any post-baseline timepoint ^[7]

End point description

End point type

Primary

End point timeframe

On Day 1 and on the day of last administration (Day 14) at pre-dose and 15, 30 min, 1, 2, 4, 8, 12 h post-dose, from Day 2 to Day 13 at pre-dose in the morning, and on Day 15 (24 h post-dose after Day 14 administration), at follow-up.

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety	Part 2: Placebo - Safety
Number of subjects analysed	20	21	20
Units: subjects
SBP > 20 mmHg	4	2	1
DBP > 10 mmHg	10	2	4

No statistical analyses for this end point

Primary: 5_Part 2 - Abnormal QTcF Change from baseline - Any post-dose timepoint

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End point title

5_Part 2 - Abnormal QTcF Change from baseline - Any post-dose timepoint ^[8]

End point description

QTcF is QT corrected for the heart rate with the Fridericia formula and derived from triplicate 12-lead ECG parameters extracted from Holter.

End point type

Primary

End point timeframe

On Day 1 at 15, 30, 45 min, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 h post-dose and at 24 h post-on Day 1 dose (Day 2), on the last administration day (Day 14) at 15, 30, 45 min, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 h post-dose.

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety	Part 2: Placebo - Safety
Number of subjects analysed	20	21	20
Units: subjects
QTcF <=30 msec	17	20	19
30 <= QTcF change from Baseline <= 60 msec	3	1	1
QTcF change from Baseline > 60 msec	0	0	0

No statistical analyses for this end point

Primary: 6_Part 2 - Abnormal QTcF Change from baseline - Day 1 Any timepoint

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End point title

6_Part 2 - Abnormal QTcF Change from baseline - Day 1 Any timepoint ^[9]

End point description

QTcF is QT corrected for the heart rate with the Fridericia formula and derived from triplicate 12-lead ECG parameters extracted from Holter.

End point type

Primary

End point timeframe

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety	Part 2: Placebo - Safety
Number of subjects analysed	20	21	20
Units: subjects
QTcF <=30 msec	18	20	19
30 <= QTcF change from Baseline <= 60 msec	2	1	1
QTcF change from baseline > 60 msec	0	0	0

No statistical analyses for this end point

Primary: 7_Part 2 - Abnormal QTcF Change from Baseline - Day 14 Any timepoint

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End point title

7_Part 2 - Abnormal QTcF Change from Baseline - Day 14 Any timepoint ^[10]

End point description

QTcF is QT corrected for the heart rate with the Fridericia formula and derived from triplicate 12-lead ECG parameters extracted from Holter.

End point type

Primary

End point timeframe

On Day 1 at 15, 30, 45 min, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 h, post-dose and at 24 h post-on Day 1 dose (Day 2), on the last administration day (Day 14) at 15, 30, 45 min, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 h post-dose.

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical evaluation was performed. The focus of the primary end points was safety. Evaluation of the safety data was done descriptively.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety	Part 2: Placebo - Safety
Number of subjects analysed	19	20	20
Units: subjects
QTcF <=30 msec	17	20	20
30 <= QTcF change from Baseline <= 60 msec	2	0	0
QTcF change from baseline > 60 msec	0	0	0

No statistical analyses for this end point

Primary: 8_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 1

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End point title

8_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 1

End point description

ECG Mean Heart Rate (beats/min) Change from Baseline to Treatment Day 1, 24 h. Data are presented as mean and Standard Deviation.

End point type

Primary

End point timeframe

24 h 12-lead digital Holter ECG recording: at screening visit, on Day 1 and last administration day (Day 14) from at least 90 min prior to dosing up to at least 24 h post-dose. At Day 28 follow-up.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety	Part 2: Placebo - Safety
Number of subjects analysed	16	16	18
Units: bpm
arithmetic mean (standard deviation)	-4.1 ± 6.7	-7.4 ± 9.2	-3.7 ± 5.9

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Placebo - Safety v Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.669

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.9

Confidence interval

level

90%

sides

2-sided

lower limit

-2.6

upper limit

4.4

Notes
[11] - Adjusted mean difference

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety v Part 2: Placebo - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.308

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.1

Confidence interval

level

90%

sides

2-sided

lower limit

-5.6

upper limit

1.3

Notes
[12] - Adjusted mean difference

Primary: 9_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 14

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End point title

9_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 14

End point description

ECG Mean Heart Rate (beats/min) Change from Baseline to Treatment Day 14, 24 h. Data are presented as mean and Standard Deviation.

End point type

Primary

End point timeframe

24 h 12-lead digital Holter ECG recording: at screening visit, on Day 1 and last administration day (Day 14) from at least 90 min prior to dosing up to at least 24 h post-dose. At Day 28 follow-up.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety	Part 2: Placebo - Safety
Number of subjects analysed	17	17	17
Units: bpm
arithmetic mean (standard deviation)	-6.1 ± 9.1	-8.6 ± 8.1	-4.8 ± 5.0

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - Safety v Part 2: Placebo - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.722

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.8

Confidence interval

level

90%

sides

2-sided

lower limit

-2.8

upper limit

4.3

Notes
[13] - Adjusted mean difference

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Placebo - Safety v Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - Safety

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.197

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-6.2

upper limit

0.8

Notes
[14] - Adjusted mean difference

Secondary: 10_Part 1 - Cmax - PK

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End point title

10_Part 1 - Cmax - PK

End point description

Cmax is the value of the maximum plasma concentration of CHF6467. Dose proportionality (assessed considering the absolute individual dose) of CHF6467 for Cmax was evaluated using the power model, including the log-transformed PK parameters as dependent variables and the log-transformed CHF6467 dose as fixed effect. The slope for log-transformed dose (ß) was estimated with its 90% CI to examine dose proportionality. Data are presented as mean and standard deviation. Statistical analysis was not reported but was performed. The results are described below: The 90% CI of the slope of Cmax did not include 1, indicating that CHF6467 Cmax did not increase dose-proportionally but less than dose-proportionally between 1 µg/mm2 and 6 µg/mm2.

End point type

Secondary

End point timeframe

The Cmax of CHF6467 was studied in serum up to 72 h post-dose after four single ascending topical doses (CHF6467 SD1 0.3 μg/mm2; CHF6467 SD2 1 μg/mm2; CHF6467 SD3 3 μg/mm2; CHF6467 SD4 6 μg/mm2) in subjects with DFU.

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - PK set	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - PK set	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - PK set	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - PK set
Number of subjects analysed	2 ^[15]	4 ^[16]	5 ^[17]	5 ^[18]
Units: pg/mL
arithmetic mean (standard deviation)	1.27 ± 0.948	8.58 ± 5.46	4.58 ± 3.61	9.67 ± 9.22

Notes
[15] - PK population
[16] - PK population
[17] - PK population
[18] - PK population

No statistical analyses for this end point

Secondary: 11_Part 1 - AUC 0-t - PK

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End point title

11_Part 1 - AUC 0-t - PK

End point description

AUC 0-t is the area under the plasma concentration-time curve from 0 to the last quantifiable concentration, computed using the linear trapezoidal rule. Dose proportionality (assessed considering the absolute individual dose) of CHF6467 for AUC 0-t was evaluated using the power model, including the log-transformed pharmacokinetic parameters as dependent variables and the log transformed CHF6467 dose as fixed effect. The slope for log-transformed dose (ß) was estimated with its 90% CI to examine dose proportionality. Data are presented as mean and standard deviation. Statistical analysis was not reported but was performed. The results are described below: The 90% CI of the slope of AUC 0-t included 1, suggesting that CHF6467 AUC 0-t increased dose proportionally. However, it can be noted that the point estimate (PE) was not close to 1 and that the mean AUC 0-t values were comparable for both 1 µg/mm² and 6 µg/mm² doses and the inter‑subject variability was high.

End point type

Secondary

End point timeframe

The AUC 0-t of CHF6467 was studied in serum up to 72 h post-dose after four single ascending topical doses (CHF6467 SD1 0.3 μg/mm²; CHF6467 SD2 1 μg/mm²; CHF6467 SD3 3 μg/mm²; CHF6467 SD4 6 μg/mm²) in subjects with DFU.

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - PK set	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - PK set	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - PK set	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - PK set
Number of subjects analysed	1 ^[19]	4 ^[20]	4 ^[21]	5 ^[22]
Units: pg.h/mL
arithmetic mean (standard deviation)	6.25 ± 0	43.4 ± 28.5	53.8 ± 74.7	43.1 ± 36.9

Notes
[19] - PK population CHF6467 SD1 SD= Not Calculated
[20] - PK population
[21] - PK population
[22] - PK population

No statistical analyses for this end point

Secondary: 12_Part 1 - Tmax - PK

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End point title

12_Part 1 - Tmax - PK

End point description

Tmax is the time of the maximum plasma concentration of CHF6467, obtained directly from the experimental data without interpolation. Data are presented as median (minimum-maximum).

End point type

Secondary

End point timeframe

The Tmax of CHF6467 was studied in serum up to 72 h post-dose after four single ascending topical doses (CHF6467 SD1 0.3 μg/mm2; CHF6467 SD2 1 μg/mm2; CHF6467 SD3 3 μg/mm2; CHF6467 SD4 6 μg/mm2) in subjects with DFU.

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - PK set	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - PK set	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - PK set	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - PK set
Number of subjects analysed	2 ^[23]	4 ^[24]	5 ^[25]	5 ^[26]
Units: hours
median (full range (min-max))	3.40 (0.75 to 6.05)	2.50 (2.0 to 3.0)	2.0 (0.75 to 6.0)	2.0 (0.50 to 2.0)

Notes
[23] - PK population
[24] - PK population
[25] - PK population
[26] - PK population

No statistical analyses for this end point

Secondary: 13_Part 2 - Cmax - Day 1 - PK

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End point title

13_Part 2 - Cmax - Day 1 - PK

End point description

Cmax is the value of the maximum plasma concentration of CHF6467. The dose proportionality (assessed as absolute individual dose) of CHF6467 for Cmax was evaluated using the power model, including the log-transformed PK parameters as dependent variables and the log-transformed dose as fixed effect. The analysis was performed separately on Day 1 and on the last administration day. The slope for log-transformed dose (ß) was estimated with its 90% CI to examine dose proportionality. Data are presented as mean and standard deviation.

End point type

Secondary

End point timeframe

After repeated q.d. CHF6467 topical doses for 14 days in subjects with DFU, the Cmax of CHF6467 was studied in serum up to 24 h post-dose after the first dose and 336 h post-dose (i.e., 14 days after the last CHF6467 application) after the last dose.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	14 ^[27]	10 ^[28]
Units: pg/mL
arithmetic mean (standard deviation)	2.37 ± 1.54	3.77 ± 3.64

Notes
[27] - PK population
[28] - PK population

No statistical analyses for this end point

Secondary: 14_Part 2 - Cmax - Day 14 - PK

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End point title

14_Part 2 - Cmax - Day 14 - PK

End point description

End point type

Secondary

End point timeframe

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	10 ^[29]	9 ^[30]
Units: pg/mL
arithmetic mean (standard deviation)	1.93 ± 1.24	5.90 ± 7.39

Notes
[29] - PK population
[30] - PK population

No statistical analyses for this end point

Secondary: 15_Part 2 - AUC 0-t - Day 1 - PK

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End point title

15_Part 2 - AUC 0-t - Day 1 - PK

End point description

AUC 0-t is the area under the plasma concentration-time curve from 0 to the last quantifiable concentration, computed using the linear trapezoidal rule. Data are presented as mean and standard deviation.

End point type

Secondary

End point timeframe

After repeated q.d. CHF6467 topical doses for 14 days in subjects with DFU, the AUC 0-t of CHF6467 was studied in serum up to 24 h post-dose after the first dose and 336 h post-dose (i.e., 14 days after the last CHF6467 application) after the last dose.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	14 ^[31]	10 ^[32]
Units: pg.h/mL
arithmetic mean (standard deviation)	7.77 ± 8.31	27.7 ± 48.9

Notes
[31] - PK population
[32] - PK population

No statistical analyses for this end point

Secondary: 16_Part 2 - AUC 0-t - Day 14 - PK

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End point title

16_Part 2 - AUC 0-t - Day 14 - PK

End point description

End point type

Secondary

End point timeframe

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	10 ^[33]	9 ^[34]
Units: pg.h/mL
arithmetic mean (standard deviation)	26.5 ± 65.6	131 ± 201

Notes
[33] - PK population
[34] - PK population

No statistical analyses for this end point

Secondary: 17_Part 2 - AUC 0-12 - Day 1 - PK

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End point title

17_Part 2 - AUC 0-12 - Day 1 - PK

End point description

AUC 0-12 is the area under the plasma concentration-time curve from 0 to 12 hours post-dose of CHF6467. Data are presented as mean and standard deviation.

End point type

Secondary

End point timeframe

After repeated q.d. CHF6467 topical doses for 14 days in subjects with DFU, the PK of CHF6467 was studied in serum up to 12 h post-dose after the first dose and 336 h post-dose (i.e., 14 days after the last CHF6467 application) after the last dose.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	2 ^[35]	2 ^[36]
Units: pg.h/mL
arithmetic mean (standard deviation)	22.4 ± 1.15	67.1 ± 44.0

Notes
[35] - PK population
[36] - PK population

No statistical analyses for this end point

Secondary: 18_Part 2 - AUC 0-12 - Day 14 - PK

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End point title

18_Part 2 - AUC 0-12 - Day 14 - PK

End point description

AUC 0-12 is the area under the plasma concentration-time curve from 0 to 12 hours post-dose of CHF6467. Data are presented as mean and standard deviation.

End point type

Secondary

End point timeframe

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	1 ^[37]	6 ^[38]
Units: pg.h/mL
arithmetic mean (standard deviation)	27.2 ± 0	54.7 ± 62.8

Notes
[37] - PK population SD=Not Calculated
[38] - PK population

No statistical analyses for this end point

Secondary: 19_Part 2 - Ulcer Area (cm²) Actual Values - Baseline - PD

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End point title

19_Part 2 - Ulcer Area (cm²) Actual Values - Baseline - PD

End point description

Ulcer tissue measurements was performed following the standard of care procedure at the time points indicated in the Timeframe. Area (in cm²), volume (in cm³), average depth (in mm), maximum depth (in mm), perimeter (in cm), tissue type 1 to 7 presence (yes/no), and tissue type 1 to 7 percentage, if present and measured. Tissue types: - Type 1: Granulating tissue/Granulation - Type 2: Hypergranulating tissue/Hypergranulation - Type 3: Epithelizing tissue/epithelial - Type 4: Healed tissue/healthy - Type 5: Scab/Eschar - Type 6: Necrotic tissue/Slough - Type 7: Other/not classified Data are presented as mean and standard deviation.

End point type

Secondary

End point timeframe

Timing of the ulcer measurements - During treatment period: daily assessments (from Day 1 to Day 15) - During the follow-up period: weekly assessments (Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 63, Day 70, Day 77, Day 84).

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	20 ^[39]	20 ^[40]	20 ^[41]
Units: cm2
arithmetic mean (standard deviation)	4.190 ± 0.770	3.620 ± 0.841	3.745 ± 0.737

Notes
[39] - PD population
[40] - PD population
[41] - PD population

1_CHF6467 MD1 VS Placebo

Statistical analysis description

The model for repeated measures (MMRM) is linear mixed model including treatment, visit, and treatment by visit interaction as fixed effects, and baseline value and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed and the Kenward-Roger adjustment was used for the degrees of freedom.

Comparison groups

Part 2: Placebo - PD set v Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

= 0.691

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.81

upper limit

0.54

Notes
[42] - MMRM model

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

= 0.761

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.55

upper limit

0.75

Notes
[43] - MMRM Model

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[44]

P-value

= 0.495

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.91

upper limit

0.45

Notes
[44] - MMRM Model

Secondary: 20_Part 2 - Ulcer Area (cm²) Change from baseline - Day 14 - PD

Top of page

End point title

20_Part 2 - Ulcer Area (cm²) Change from baseline - Day 14 - PD

End point description

End point type

Secondary

End point timeframe

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	19 ^[45]	20 ^[46]	20 ^[47]
Units: cm2
arithmetic mean (standard deviation)	-1.626 ± 0.892	-1.395 ± 0.630	-1.630 ± 0.761

Notes
[45] - PD population
[46] - PD population
[47] - PD population

1_CHF6467 MD1 VS Placebo

Statistical analysis description

P-values and estimates are based on an MMRM model on Change From Baseline including Treatment, Visit, Baseline, Treatment by Visit interaction and Treatment by Baseline interaction as effects. An unstructured covariance matrix is assumed and Kenward-Roger adjustment was used for the degrees of freedom.

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

= 0.761

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

0.56

Notes
[48] - Adjusted mean difference

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.428

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

0.89

Notes
[49] - Adjusted mean difference

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.292

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

0.31

Notes
[50] - Adjusted mean difference

Secondary: 21_Part 2 - Ulcer Area (cm²) Change from baseline - Day 84 - PD

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End point title

21_Part 2 - Ulcer Area (cm²) Change from baseline - Day 84 - PD

End point description

Ulcer tissue measurements were performed following the standard of care procedure at the time points indicated in the Timeframe. Area (in cm²), volume (in cm³), average depth (in mm), maximum depth (in mm), perimeter (in cm), tissue type 1 to 7 presence (yes/no), and tissue type 1 to 7 percentage, if present and measured. Tissue types: - Type 1: Granulating tissue/Granulation - Type 2: Hypergranulating tissue/Hypergranulation - Type 3: Epithelizing tissue/epithelial - Type 4: Healed tissue/healthy - Type 5: Scab/Eschar - Type 6: Necrotic tissue/Slough - Type 7: Other/not classified Data are presented as mean and standard deviation.

End point type

Secondary

End point timeframe

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	17	18	17
Units: cm2
arithmetic mean (standard deviation)	-3.224 ± 1.513	-2.844 ± 0.720	-2.835 ± 1.229

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

= 0.541

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-1.04

upper limit

0.55

Notes
[51] - Adjusted mean difference

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.605

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

0.57

Notes
[52] - Adjusted mean difference

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

= 0.913

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.85

upper limit

0.76

Notes
[53] - Adjusted mean difference

Secondary: 22_Part 2 - Time to Healing (days) >= 50%

Top of page

End point title

22_Part 2 - Time to Healing (days) >= 50%

End point description

Time to healing (days) is the date of healing (depending on the degree of healing as listed above). Four different degrees of healing were computed at a given day as follow: A) Healed_50 (Y/N) = ≥50% ulcer area reduction (also considered as the % of healed tissue); B) Healed_66 (Y/N) = ≥66% ulcer area reduction (also considered as the % of healed tissue); C) Healed_75 (Y/N) = ≥75% ulcer area reduction (also considered as the % of healed tissue); D) Healed_100_CH (Y/N) = 100% ulcer area reduction (no more ulcer) also considered as the 100% of healed tissue (Tissue type 4) (complete healing). The subjects who contributed to the following statistical analyses of time to healing were all subjects in the PD set (both healed and non-healed subjects).

End point type

Secondary

End point timeframe

Day 14, 21, 28, 56, and 84

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	20 ^[54]	20 ^[55]	20 ^[56]
Units: days
arithmetic mean (standard deviation)	21.2 ± 19.6	23.1 ± 20.1	16.8 ± 10.2

Notes
[54] - PD population number of patients/number of patients with data: 20/13
[55] - PD population number of patients/number of patients with data: 20/17
[56] - PD population number of patients/number of patients with data: 20/16

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison between treatments was performed using the following contrasts (P vs MD1, P vs MD2, MD1 vs MD2). Curves were compared by the two-sided Log-Rank test. Values present the Log-Rank test results for the comparison of CHF6467 MD1 vs Placebo.

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.148

Method

Logrank

Parameter type

median time to healing

Confidence interval

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.886

Method

Logrank

Parameter type

median time to healing (Days)

Confidence interval

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.205

Method

Logrank

Parameter type

median time to healing

Confidence interval

Secondary: 23_Part 2 - Time to Healing (days) >= 66%

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End point title

23_Part 2 - Time to Healing (days) >= 66%

End point description

End point type

Secondary

End point timeframe

Day 14, 21, 28, 56, and 84

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	20 ^[57]	20 ^[58]	20 ^[59]
Units: days
arithmetic mean (standard deviation)	32.2 ± 15.0	30.2 ± 16.6	29.5 ± 19.9

Notes
[57] - PD population number of patients/number of patients with data: 20/12
[58] - PD population number of patients/number of patients with data: 20/15
[59] - PD population number of patients/number of patients with data: 20/15

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.152

Method

Logrank

Parameter type

median time to healing

Confidence interval

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.797

Method

Logrank

Parameter type

median time to healing

Confidence interval

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.245

Method

Logrank

Parameter type

median time to healing

Confidence interval

Secondary: 24_Part 2 - Time to Healing (days) >= 75%

Top of page

End point title

24_Part 2 - Time to Healing (days) >= 75%

End point description

End point type

Secondary

End point timeframe

Day 14, 21, 28, 56, and 84.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	20 ^[60]	20 ^[61]	20 ^[62]
Units: days
arithmetic mean (standard deviation)	40.8 ± 18.8	42.0 ± 19.8	40.8 ± 20.1

Notes
[60] - PD population number of patients/number of patients with data: 20/12
[61] - PD population number of patients/number of patients with data: 20/13
[62] - PD population number of patients/number of patients with data: 20/13

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Placebo - PD set v Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.672

Method

Logrank

Parameter type

median time to healing

Confidence interval

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.916

Method

Logrank

Parameter type

median time to healing

Confidence interval

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.752

Method

Logrank

Parameter type

median time to healing

Confidence interval

Secondary: 25_Part 2 - Time to Healing (days) 100%

Top of page

End point title

25_Part 2 - Time to Healing (days) 100%

End point description

End point type

Secondary

End point timeframe

Day 14, 21, 28, 56, and 84.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set	Part 2: Placebo - PD set
Number of subjects analysed	20 ^[63]	20 ^[64]	20 ^[65]
Units: days
arithmetic mean (standard deviation)	43.4 ± 12.5	59.5 ± 14.8	47.4 ± 18.7

Notes
[63] - PD population number of patients/number of patients with data: 20/5
[64] - PD population number of patients/number of patients with data: 20/2
[65] - PD population number of patients/number of patients with data: 20/5

1_CHF6467 MD1 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.983

Method

Logrank

Parameter type

median time to healing

Confidence interval

2_CHF6467 MD2 VS Placebo

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Placebo - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.226

Method

Logrank

Parameter type

median time to healing

Confidence interval

3_CHF6467 MD1 VS CHF6467 MD2

Statistical analysis description

Comparison groups

Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PD set v Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PD set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.216

Method

Logrank

Parameter type

median time to healing

Confidence interval

Secondary: 26_ Part 1 - CHF6467 Anti-Drug Antibodies Presence - Day 1 and Day 24

Top of page

End point title

26_ Part 1 - CHF6467 Anti-Drug Antibodies Presence - Day 1 and Day 24

End point description

The potential for immunogenicity was determined by assessing the presence of CHF6467 Anti-Drug Antibodies (ADA). No subjects were reported with the presence of CHF6467 ADAs in Part 1.

End point type

Secondary

End point timeframe

The Blood samples were collected for the determination of CHF6467 anti-drug antibodies (ADA) presence and titer when appropriate at Day 1, pre-dose and Day 24.

End point values	Part 1: Cohort A - SD1 - CHF6467 - 0.3 μg/mm² - PK set	Part 1: Cohort B - SD2 - CHF6467 - 1 μg/mm² - PK set	Part 1: Cohort C - SD3 - CHF6467 - 3 μg/mm² - PK set	Part 1: Cohort D - SD4 - CHF6467 - 6 μg/mm² - PK set
Number of subjects analysed	6 ^[66]	6 ^[67]	6 ^[68]	6 ^[69]
Units: subjects
(Day 1) No	6	6	6	6
(Day 24) No	6	6	6	6

Notes
[66] - PK population
[67] - PK population
[68] - PK population
[69] - PK population

No statistical analyses for this end point

Secondary: 27_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 1

Top of page

End point title

27_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 1

End point description

The potential for immunogenicity was determined by assessing the presence of CHF6467 Anti-Drug Antibodies (ADA). No subjects were reported with the presence of CHF6467 ADAs in Part 2 on Day 1.

End point type

Secondary

End point timeframe

The Blood samples were collected for the determination of CHF6467 anti-drug antibodies (ADA) presence and titer when appropriate at day 1, pre-dose, Day 15, and follow-up Day 24, Day 52, and Day 80.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	20 ^[70]	21 ^[71]
Units: subjects
No	20	21
Yes	0	0

Notes
[70] - PK population
[71] - PK population

No statistical analyses for this end point

Secondary: 28_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 15

Top of page

End point title

28_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 15

End point description

The potential for immunogenicity was determined by assessing the presence of CHF6467 Anti-Drug Antibodies (ADA). One subject had a positive ADA screening test on Day 15 after application of placebo (titer of 1), which was likely a false positive result.

End point type

Secondary

End point timeframe

The Blood samples were collected for the determination of CHF6467 anti-drug antibodies (ADA) presence and titer when appropriate at Day 1, pre-dose, Day 15, and follow-up Day 24, Day 52, and Day 80.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	19 ^[72]	20 ^[73]
Units: subjects
No	19	20
Yes	0	0

Notes
[72] - PK population
[73] - PK population

No statistical analyses for this end point

Secondary: 29_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 24

Top of page

End point title

29_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 24

End point description

The potential for immunogenicity was determined by assessing the presence of CHF6467 Anti-Drug Antibodies (ADA). One subject had a positive ADA screening test on follow-up Day 24 (titer of 10) after application of CHF6467 MD2.

End point type

Secondary

End point timeframe

The Blood samples were collected for the determination of CHF6467 anti-drug antibodies (ADA) presence and titer when appropriate at Day 1, pre-dose, Day 15, and follow-up Day 24, Day 52, and Day 80.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	19 ^[74]	19 ^[75]
Units: subjects
No	19	18
Yes	0	1

Notes
[74] - PK population
[75] - PK population

No statistical analyses for this end point

Secondary: 30_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 52

Top of page

End point title

30_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 52

End point description

End point type

Secondary

End point timeframe

The Blood samples were collected for the determination of CHF6467 anti-drug antibodies (ADA) presence and titer when appropriate at Day 1, pre-dose, Day 15, and follow-up Day 24, Day 52, and Day 80.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	18 ^[76]	18 ^[77]
Units: subjects
No	18	17
Yes	0	1

Notes
[76] - PK population
[77] - PK population

No statistical analyses for this end point

Secondary: 31_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 80

Top of page

End point title

31_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 80

End point description

End point type

Secondary

End point timeframe

The Blood samples were collected for the determination of CHF6467 anti-drug antibodies (ADA) presence and titer when appropriate at Day 1, pre-dose, Day 15, and follow-up Day 24, Day 52, and Day 80.

End point values	Part 2: Cohort E - MD1 - CHF6467 - 1 μg/mm²/day - PK set	Part 2: Cohort F - MD2 - CHF6467 - 3 μg/mm²/day - PK set
Number of subjects analysed	17 ^[78]	18 ^[79]
Units: subjects
No	17	17
Yes	0	1

Notes
[78] - PK population
[79] - PK population

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events (AEs) were reported from the Informed Consent signature until the subject’s study participation ends (study completion or discontinuation).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Part 1: Cohort A (SD1) CHF6467

Reporting group description

Part 1 of the study: Subjects who received a single dose of CHF6467 (total dose 0.3 μg/mm²)

Reporting group title

Part 1: Cohort B (SD2) CHF6467

Reporting group description

Part 1 of the study: Subjects who received a single dose of CHF6467 (total dose 1 μg/mm²).

Reporting group title

Part 1: Cohort C (SD3) CHF6467

Reporting group description

Part 1 of the study: Subjects who received a single dose of CHF6467 (total dose 3 μg/mm²).

Reporting group title

Part 1: Cohort D (SD4) CHF6467

Reporting group description

Part 1 of the study: Subjects who received a single dose of CHF6467 (total dose 6 μg/mm²).

Reporting group title

Part 1: Placebo

Reporting group description

Part 1 of the study: Subjects who received a single dose of Placebo.

Reporting group title

Part 2: Cohort E (MD1) CHF6467

Reporting group description

Part 2 of the study: Subjects who received a multiple doses of CHF6467 for 14 consecutive days (total daily dose 1 μg/mm²/day).

Reporting group title

Part 2: Cohort F (MD2) CHF6467

Reporting group description

Part 2 of the study: Subjects who received a multiple doses of CHF6467 for 14 consecutive days (total daily dose 3 μg/mm²/day).

Reporting group title

Part 2: Placebo

Reporting group description

Part 2 of the study: Subjects who received a multiple doses of Placebo for 14 consecutive days.

Serious adverse events	Part 1: Cohort A (SD1) CHF6467	Part 1: Cohort B (SD2) CHF6467	Part 1: Cohort C (SD3) CHF6467	Part 1: Cohort D (SD4) CHF6467	Part 1: Placebo	Part 2: Cohort E (MD1) CHF6467	Part 2: Cohort F (MD2) CHF6467	Part 2: Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Part 1: Cohort A (SD1) CHF6467	Part 1: Cohort B (SD2) CHF6467	Part 1: Cohort C (SD3) CHF6467	Part 1: Cohort D (SD4) CHF6467	Part 1: Placebo	Part 2: Cohort E (MD1) CHF6467	Part 2: Cohort F (MD2) CHF6467	Part 2: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	0 / 6 (0.00%)	4 / 6 (66.67%)	2 / 9 (22.22%)	9 / 20 (45.00%)	8 / 21 (38.10%)	13 / 20 (65.00%)
Investigations
Blood glucose increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 20 (10.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Blood creatine increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Gastric pH decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	2	0	0	0	0	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 20 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Atrial fibrillation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0
Atrial tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Supraventricular tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Ventricular extrasystoles
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Ventricular tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	2 / 21 (9.52%)	3 / 20 (15.00%)
occurrences all number	0	0	0	3	0	1	2	4
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Hyperchlorhydria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	0	0	0	1
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1	0	1
Toothache
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 20 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	1	0	1	1
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	1 / 21 (4.76%)	3 / 20 (15.00%)
occurrences all number	0	0	0	0	0	0	1	3
Skin and subcutaneous tissue disorders
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	2 / 21 (9.52%)	4 / 20 (20.00%)
occurrences all number	0	0	0	0	0	1	2	4
Diabetic foot infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Erysipelas
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 20 (5.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Coronavirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 20 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

14 May 2019

A substantial protocol amendment (CTP version 3.0, dated 21 March 2019) was created to list and clarify all changes implemented in the protocol from version 1.0, dated 9 July 2018 to version 3.0, dated 21 March 2019. Below listed the main changes: - An additional secondary objective was added; - In the study population of Part 2, Texas grade 2A (deeper ulcers) was added to allow the recruitment of DFU subjects with ulcer located at metatarsal level where the nature of the ulcer could involve the exposure of tendon, bone, or joint capsule as per the Texas grade 2A description. Moreover, the definition of the depth (e.g., inclusion criterion 6) was clarified; - Exclusion criterion 2 (points a and g) was clarified; - Exclusion criterion 3 was rephrased; - In the study design of Part 2, the dose regimen was made flexible and the run-in period description was updated according to the changes in inclusion criterion 6; - Throughout Part 2, a new section on microbiology assessments was added; - The statistical analysis section was adapted; - The early withdrawal assessments were listed and clarified; - A new section was created to regulate the possibility of re-screening subjects at discretion of the Principal Investigator.

20 Dec 2019

A substantial protocol amendment (CTP version 4.0, dated 8 November 2019) was created to record the following changes: - Change of site location; - The time window for the study drug administration has been enlarged; - IMP dose options for the Cohort F have been clarified.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_Part 1 - Abnormal SBP and DBP Change from baseline - Any post-baseline timepoint

Primary: 1_Part 1 - Abnormal SBP and DBP Change from baseline - Any post-baseline timepoint

Primary: 2_Part 1 - Abnormal QTcF Change from baseline - Any timepoint

Primary: 2_Part 1 - Abnormal QTcF Change from baseline - Any timepoint

Primary: 3_Part 1 - Heart rate (0-24 h) - Change from Baseline

Primary: 3_Part 1 - Heart rate (0-24 h) - Change from Baseline

Primary: 4_Part 2 - Abnormal SBP and DBP - Any post-baseline timepoint

Primary: 4_Part 2 - Abnormal SBP and DBP - Any post-baseline timepoint

Primary: 5_Part 2 - Abnormal QTcF Change from baseline - Any post-dose timepoint

Primary: 5_Part 2 - Abnormal QTcF Change from baseline - Any post-dose timepoint

Primary: 6_Part 2 - Abnormal QTcF Change from baseline - Day 1 Any timepoint

Primary: 6_Part 2 - Abnormal QTcF Change from baseline - Day 1 Any timepoint

Primary: 7_Part 2 - Abnormal QTcF Change from Baseline - Day 14 Any timepoint

Primary: 7_Part 2 - Abnormal QTcF Change from Baseline - Day 14 Any timepoint

Primary: 8_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 1

Primary: 8_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 1

Primary: 9_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 14

Primary: 9_Part 2 - Abnormal Heart rate (0-24 h) Change from baseline - Day 14

Secondary: 10_Part 1 - Cmax - PK

Secondary: 10_Part 1 - Cmax - PK

Secondary: 11_Part 1 - AUC 0-t - PK

Secondary: 11_Part 1 - AUC 0-t - PK

Secondary: 12_Part 1 - Tmax - PK

Secondary: 12_Part 1 - Tmax - PK

Secondary: 13_Part 2 - Cmax - Day 1 - PK

Secondary: 13_Part 2 - Cmax - Day 1 - PK

Secondary: 14_Part 2 - Cmax - Day 14 - PK

Secondary: 14_Part 2 - Cmax - Day 14 - PK

Secondary: 15_Part 2 - AUC 0-t - Day 1 - PK

Secondary: 15_Part 2 - AUC 0-t - Day 1 - PK

Secondary: 16_Part 2 - AUC 0-t - Day 14 - PK

Secondary: 16_Part 2 - AUC 0-t - Day 14 - PK

Secondary: 17_Part 2 - AUC 0-12 - Day 1 - PK

Secondary: 17_Part 2 - AUC 0-12 - Day 1 - PK

Secondary: 18_Part 2 - AUC 0-12 - Day 14 - PK

Secondary: 18_Part 2 - AUC 0-12 - Day 14 - PK

Secondary: 19_Part 2 - Ulcer Area (cm²) Actual Values - Baseline - PD

Secondary: 19_Part 2 - Ulcer Area (cm²) Actual Values - Baseline - PD

Secondary: 20_Part 2 - Ulcer Area (cm²) Change from baseline - Day 14 - PD

Secondary: 20_Part 2 - Ulcer Area (cm²) Change from baseline - Day 14 - PD

Secondary: 21_Part 2 - Ulcer Area (cm²) Change from baseline - Day 84 - PD

Secondary: 21_Part 2 - Ulcer Area (cm²) Change from baseline - Day 84 - PD

Secondary: 22_Part 2 - Time to Healing (days) >= 50%

Secondary: 22_Part 2 - Time to Healing (days) >= 50%

Secondary: 23_Part 2 - Time to Healing (days) >= 66%

Secondary: 23_Part 2 - Time to Healing (days) >= 66%

Secondary: 24_Part 2 - Time to Healing (days) >= 75%

Secondary: 24_Part 2 - Time to Healing (days) >= 75%

Secondary: 25_Part 2 - Time to Healing (days) 100%

Secondary: 25_Part 2 - Time to Healing (days) 100%

Secondary: 26_ Part 1 - CHF6467 Anti-Drug Antibodies Presence - Day 1 and Day 24

Secondary: 26_ Part 1 - CHF6467 Anti-Drug Antibodies Presence - Day 1 and Day 24

Secondary: 27_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 1

Secondary: 27_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 1

Secondary: 28_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 15

Secondary: 28_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Treatment Day 15

Secondary: 29_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 24

Secondary: 29_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 24

Secondary: 30_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 52

Secondary: 30_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 52

Secondary: 31_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 80

Secondary: 31_Part 2 - CHF6467 Anti-Drug Antibodies Presence - Follow Up Day 80

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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).