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Clinical Trial Results:
Evaluation of phage therapy for the treatment of Pseudomonas aeruginosa wound infections in burned patients (Phase I-II clinical trial)

Summary
EudraCT number	2014-000714-65
Trial protocol	BE
Global end of trial date	16 Jan 2017

Results information
Results version number	v1(current)
This version publication date	11 Jan 2022
First version publication date	11 Jan 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

PHAGOBURN

ISRCTN number

US NCT number

NCT02116010

WHO universal trial number (UTN)

Other trial identifiers

Pherecydes Pharma: PP

Sponsor organisation name

Pherecydes Pharma

Sponsor organisation address

Campus Biocitech, ROMAINVILLE, France, 93230

Public contact

Guy-Charles Fanneau de La Horie, Pherecydes Pharma, +33 184861613, gc.delahorie@pherecydes-pharma.com

Scientific contact

Guy-Charles Fanneau de La Horie, Pherecydes Pharma, +33 184861613, gc.delahorie@pherecydes-pharma.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

27 Jun 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Jan 2017

Global end of trial reached?

Yes

Global end of trial date

16 Jan 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of PHAGOBURN study is to assess the efficacy and safety of topical applications of PP1131 bacteriophage cocktail, targeting P. aeruginosa infected third degree wounds in hospitalized patients, in comparison to silver sulfadiazine treatment.

Protection of trial subjects

use of antibiotics

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Jul 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

France: 20

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

Screening details

No specific screening visit is planned since swabs are routinely performed for each hospitalized burned patients in the participating centers.

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

PP1131

Arm description

anti P aeruginosa PP1131 cocktail

Arm type

Experimental

Investigational medicinal product name

PP1131 anti P aeruginosa Phage cocktail

Investigational medicinal product code

PP1131

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Topical use

Dosage and administration details

An Algosteril® plaque of 200 cm² is saturated with 20 ml of 106 PFU/ml phage cocktail solution.

Investigational medicinal product name

PP1131 anti P aeruginosa Phage cocktail

Investigational medicinal product code

PP1131

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Topical

Dosage and administration details

An Algosteril® plaque of 200 cm² is saturated with 20 ml of 106 PFU/ml phage cocktail solution. The phage saturated Algosteril® plaques are directly placed on the treatment area. A hydrophobic dressing as Jelonet ® type covers the treatment area. Sterile gauze covers the primary dressing. A band like Velpeau ® closes the dressing.

Silver Sulfadiazine

Arm description

Arm type

Active comparator

Investigational medicinal product name

Silver sulfadiazine

Investigational medicinal product code

Other name

Pharmaceutical forms

Cream

Routes of administration

Topical

Dosage and administration details

Silver Sulfadiazine® is directly placed on the treatment area. The layer must be thick (several millimeters) covered by a gauze saturated with Silver sulfadiazine ® cream. A band like Velpeau ® closes the dressing.

Number of subjects in period 1	PP1131	Silver Sulfadiazine
Started	13	13
Completed	10	9
Not completed	3	4
Consent withdrawn by subject	1	-
Drug supplies	1	-
Adverse event, non-fatal	-	1
transfer to re-habilitation center	1	-
Transfer to rehabilitation center	-	1
transfer to a conventionnal care unit	-	1
fully cured	-	1

Baseline characteristics

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Reporting group title

PP1131

Reporting group description

anti P aeruginosa PP1131 cocktail

Reporting group title

Silver Sulfadiazine

Reporting group description

Reporting group values	PP1131	Silver Sulfadiazine	Total
Number of subjects	13	13	26
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
adults	13	13	26
Age continuous
Units: years
arithmetic mean (standard deviation)	57.0 ± 21.1	45.8 ± 20.6	-
Gender categorical
Units: Subjects
Female	5	6	11
Male	8	7	15

End points

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Reporting group title

PP1131

Reporting group description

anti P aeruginosa PP1131 cocktail

Reporting group title

Silver Sulfadiazine

Reporting group description

Primary: time necessary for a persistent reduction of bacterial burden

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End point title

time necessary for a persistent reduction of bacterial burden

End point description

The primary endpoint is the time necessary for a persistent reduction of bacterial burden (for Pseudomonas aeruginosa as appropriate) of at least two quadrants (semi-quantitative technique of the four quadrants) or persistent bacteria eradication relative to D0.

End point type

Primary

End point timeframe

Time from D0 until 7 days.

End point values	PP1131	Silver Sulfadiazine
Number of subjects analysed	12	13
Units: time in hours and days	12	13

Statistical analysis Primary Endpoint

Statistical analysis description

The primary endpoint was the time required for a persistent reduction in a semi-quantitative bacterial burden (Pseudomonas aeruginosa) of two quadrants or more or persistent bacteria eradication relative to D0. In case of multiple mono-bacterial infected wounds, the semi-quantitative bacterial burden used to evaluate the primary endpoint was defined as the highest semi-quantitative bacterial burden of all samples collected at the same visit.

Comparison groups

PP1131 v Silver Sulfadiazine

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.018

Method

Regression, Cox

Parameter type

Cox proportional hazard

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.79

Variability estimate

Standard deviation

Notes
[1] - Ordinal and continuous data were presented overall and by treatment arm, in the form of descriptive statistics as the number of patients, mean, standard deviation, minimum, median and maximum. Categorical data were presented overall and by treatment arm using contingency tables with absolute and relative frequencies. Baseline was defined as the last measurement prior to first study drug administration.

Secondary: Rate of patients with bacterial burden reduction

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End point title

Rate of patients with bacterial burden reduction

End point description

End point type

Secondary

End point timeframe

The time required for a persistent reduction in semi-quantitative bacterial burden (for Pseudomonas aeruginosa) of two quadrants or more or persistent bacteria eradication relative to D0.

End point values	PP1131	Silver Sulfadiazine
Number of subjects analysed	12	13
Units: patients number
number (not applicable)	12	13

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

D0 to D21

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

PP1131

Reporting group description

Reporting group title

Silver Sulfadiazine

Reporting group description

Serious adverse events	PP1131	Silver Sulfadiazine
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 13 (7.69%)	4 / 13 (30.77%)
number of deaths (all causes)	1	1
number of deaths resulting from adverse events	1	1
Respiratory, thoracic and mediastinal disorders
Pneumonia
subjects affected / exposed	0 / 13 (0.00%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bacteriama fatal
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary Superinfection
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Septic shock
subjects affected / exposed	0 / 13 (0.00%)	3 / 13 (23.08%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
pseudomonas infection
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.05%

Non-serious adverse events	PP1131	Silver Sulfadiazine
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 13 (15.38%)	7 / 13 (53.85%)
Investigations
oxygene saturation decrease
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
post procedural haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Vascular disorders
chock haemorrhagic
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
General disorders and administration site conditions
Hyperthermia
subjects affected / exposed	1 / 13 (7.69%)	1 / 13 (7.69%)
occurrences all number	1	2
Impaired healing
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Blood and lymphatic system disorders
pancythopenia
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Haemorrhage urinary tract
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Infections and infestations
urinary tract infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Pseudomonal sepsis
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
Ear infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 13 (0.00%)
occurrences all number	1	0
bacteremia
subjects affected / exposed	1 / 13 (7.69%)	1 / 13 (7.69%)
occurrences all number	1	1
Skin graft infection
subjects affected / exposed	0 / 13 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	2
facial infection
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1
Bronchitis
subjects affected / exposed	0 / 13 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

22 Dec 2015

The first one submitted on December 22nd 2015, recommended including day 14 after treatment as a day for wound microbiological swabbing, in addition to the seven other days of infected burn wound swabbing already mentioned in the genuine protocol (D0 to D6).

31 May 2016

In the second amendment of May 31st, 2016, in view of the difficult recruitment of patients with E. coli infections, the sponsor and the coordinator decided to drop the clinical evaluation of PP0121 and both corresponding arms were closed. Furthermore, the possibility to recruit patients with a basal colonization level of bacteria belonging to other species than P. aeruginosa was authorized (basal level was set up at at maximum of 101 CFU/ml or one quadrant). Finally, in agreement with a recommendation of the DSMB (meeting of March 2016), it was decided to practice a SOFA evaluation before including patients in the remaining two arms (P. aeruginosa infections) , with the purpose to reduce the risk to recruit patients in severe condition.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Jan 2017	Decision of DSMB following insufficient efficacy	-

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/30292481

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Clinical trials

Clinical Trial Results:
Evaluation of phage therapy for the treatment of Pseudomonas aeruginosa wound infections in burned patients (Phase I-II clinical trial)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: time necessary for a persistent reduction of bacterial burden

Primary: time necessary for a persistent reduction of bacterial burden

Secondary: Rate of patients with bacterial burden reduction

Secondary: Rate of patients with bacterial burden reduction

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Evaluation of phage therapy for the treatment of Pseudomonas aeruginosa wound infections in burned patients (Phase I-II clinical trial)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: time necessary for a persistent reduction of bacterial burden

Primary: time necessary for a persistent reduction of bacterial burden

Secondary: Rate of patients with bacterial burden reduction

Secondary: Rate of patients with bacterial burden reduction

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Evaluation of phage therapy for the treatment of Pseudomonas aeruginosa wound infections in burned patients (Phase I-II clinical trial)