Clinical Trials Register

Summary
EudraCT Number:	2021-004469-11
Sponsor's Protocol Code Number:	PP-SA-001
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-10-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2021-004469-11

A.3

Full title of the trial

PhagoDAIR I: A Phase I/II Multicenter, Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Phage Therapy in Patients with Hip or Knee Prosthetic Joint Infection due to Staphylococcus aureus Treated with DAIR and Antibiotic Therapy.

Etude de phase I/II, multicentrique, randomisée, en double aveugle pour évaluer l’efficacité et la tolérance des bactériophages dans le traitement des patients présentant une infection de prothèse due à Staphylococcus aureus de la hanche ou du genou, associé à un DAIR et une antibiothérapie.

A.3.2

Name or abbreviated title of the trial where available

PhagoDAIR I

A.4.1

Sponsor's protocol code number

PP-SA-001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	PHERECYDES PHARMA
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Eurofins Optimed
B.5.2	Functional name of contact point	Sophie Moulin
B.5.3	Address:
B.5.3.1	Street Address	1 rue des Essarts
B.5.3.2	Town/ city	Gières
B.5.3.3	Post code	38610
B.5.3.4	Country	France
B.5.4	Telephone number	+330438374758
B.5.6	E-mail	AecOptimed@eurofins.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Anti-Staphylococcus aureus Bacteriophages- PP1493
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Solution for injection (Noncurrent)
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Bacteriophages
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Anti-Staphylococcus aureus Bacteriophages- PP1815
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Solution for injection (Noncurrent)
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Bacteriophages

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Injection (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

knee or hip prosthetic joint infection (PJI) due to Staphylococcus aureus, with the indication of DAIR and Suppressive Antibiotics Therapy (SAT

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of two different therapeutic regimens: DAIR + curative antibiotics therapy combined with bacteriophages or solution of NaCl 0,9%; by clinical control of the infection due to Staphylococcus aureus at Week 12, in patients presenting a Prosthesis Joint Infection (PJI) later than 3 months after the arthroplasty, with the indication of DAIR + Suppressive Antibiotics Therapy (SAT).

E.2.2

Secondary objectives of the trial

1. evaluate the safety of two different therapeutic regimens (DAIR + curative antibiotics therapy combined with bacteriophages or Solution of NaCl 0,9%) during the whole study;
2. describe initial activity of phages on patients’ Staphylococcus aureus strain and the clinical outcome (infection control or relapse) of patients at Week 12;
3. describe superinfected patients (other species found in per operative sample) in terms of clinical control of the infection at Week 12;
4. describe the profile of the Staphylococcus aureus strain in case of failure before Week 12;
5. describe the Staphylococcus Aureus quantification in blood and in serum at D0, D0-T2H, D2, D4, D14, D28 and Week 12; and in case of rescue treatment
6. describe the immunological response in serum at D0, D14, D28 and Week 12, and in joint fluid at D0 and D14 only for patients with a Total Knee Arthroplasty (TKA); and in case of rescue treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female ≥ 18 years
2.Staphylococcus aureus monomicrobial knee or hip PJI ˃3 months after prosthesis implantation with clinical signs of infection and with indication of DAIR with direct closure and Suppressive Antibiotics Therapy (SAT)
3.Staphylococcus aureus in joint fluid during the pre-inclusion period or in case of relapse of under antibiotics therapy in the first 6 months after a DAIR
4.Without preoperative diagnosis of superinfection due to another pathogen
5.Phagogram displaying the susceptibility of the strain to at least one of the phages.
6.Patient with a life expectancy of 2 years and more as determined by the principal investigator
7.Females of childbearing potential/Sexually active males with partner of childbearing potential: commitment to consistently and correctly use an acceptable method of birth control (oral, transdermal, systemic or implant contraception birth control, intrauterine devices, diaphragm or condoms) for 1 month after the last study drug administration
8.Females of non-childbearing potential: either surgically sterilized or at least 1 year postmenopausal (amenorrhea duration at least 12 months)
9.Negative pregnancy test for women with childbearing potential
10.Signing a written informed consent before any study related procedyres including phagogramprior to the phagogram
11.Affiliated to a national social security system and / or private health insuranceCovered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.

E.4

Principal exclusion criteria

1. Early Staphylococcus aureus Prosthesis Joint infection (˂3months after the prosthesis implantation)
2. Other germ found in culture of joint fluid sample
3. No active anti Staphylococcus aureus bacteriophages in phagogram
4. Patients with ASA score ≥ 4
5. Severe sepsis or Septic shock or hemodynamic instability
6. Immunosuppressed patients
7. Any known phage allergy
8. Medical history which in the opinion of the investigator would mean that the patient is unsuitable for participation in the study
9. Patient who, in the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development
10. Currently in exclusion period from a previous study
11. Concomitant participation to another interventional clinical trial.
12. Patients who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the treatment period and 1 month after the last administration of study drug
13. Women/Men refusing to use an effective contraception during 1 month after the last administration of study drug
14. No possibility of contact in case of emergency
15. Minors, persons deprived of liberty by judicial or administrative decision, persons receiving psychiatric care and persons admitted to a health or social institution, to adult patient under legal protection or unable to express consent.

E.5 End points

E.5.1

Primary end point(s)

Clinical control of infection at Week 12±2 will be defined by:
- no clinical signs of active infection (no fever, no recurrent or worsening local post-surgical painful or swelling joint, no abnormal discharge or fistula, no abnormal aspect of scar as erythema or local inflammatory or necrosis or unknitting) at Week 12±2
- and no new surgical procedure requested and no Staphylococcus aureus detected in joint fluid in case of aspiration before Week 12±2

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12 +/-2

E.5.2

Secondary end point(s)

1. Safety parameters: adverse events, physical examination, biological tests as hematology and biochemistry during the whole study;
2. Initial activity of phages: active bacteriophages (PP1493 and/or PP1815) according to phagogram results in regard of the clinical outcome (infection control or relapse) of patients at Week 12±2
3. Clinical control of the infection (as described in primary endpoint) at Week 12±2 for superinfected patients (other species isolated during the surgical procedure)
4. In case of failure before Week 12±2, aspiration of joint fluid at time of failure for microbiological test and identification of Staphylococcus aureus strain: antibiogram and phagogram
5. Microbiology:
- Blood: Staphylococcus aureus quantification (CFU) at D0, D0-T2H, D2, D4, D14±1, D28±2 and Week 12±2;
- Serum: Staphylococcus aureus quantification (qPCR) at D0, D0-T2H, D2, D4, D14±1, D28±2 and Week 12±2
6. Immunology:
- Serum: anti S.aureus phage antibodies, cytokine IL6 at D0, D14±1, D28±2 and Week 12±2
- Joint fluid: anti S.aureus phage antibodies at D0 and at D14±1 only for patients with TKA
7. Pharmacokinetics:
- Serum: quantification of the phages by qPCR at D0, D0T2H, D2, D4, D14±1, D28±2 and Week 12±2
- Blood: quantification of the phages by plaque assay at D0, D0T2H, D2, D4, D14±1, D28±2 and Week 12±2 for patients in sites (France) in Paris, Nantes and Lyon
- Joint Fluid: quantification of the phage by qPCR and plaque assay at D0 and at D14±1 only for patients with TKA; the plaque assay will be performed only for patients in sites (France) in Paris, Nantes and Lyon;
8. Bacteriological Infection Control at D14±1 in joint fluid (only patients with TKA): microbiological culture, quantification of S. aureus by qPCR, WBC count, C-Reactive Protein, IL6;
9. Duration of hospitalization
10. Questionnaire EQ-5D-5L for quality of life at each visit (except D14±1 and D28±2);
11. Evaluation of joint function at D-1 or D0, Week 12±2, Month 6 ±2 weeks, Month 12±1, Month 18±1 and Month 24±2 with:
- Knee: KOOS Knee injury and Osteoarthritis Outcome Score
- Hip: HOOS Hip disability and Osteoarthritis Outcome Score;
12. Clinical control of the infection (as described in primary endpoint) at Month 6±2 weeks, Month 12±1, Month 18±1 and Month 24±2;
13. X Ray at D-1 or D0, Week 12±2, Month6 ±2 weeks, Month 12±1, Month 18±1 and Month 24±2: to check potential appearance of abnormal loosening (border with shifting of the prosthesis), periprosthetic border;
14. In case of rescue treatment: clinical infection control at week 12-RT±2 after the first ultra guided injection, safety parameters, pharmacokinetics, bacteriological and immunological tests.

E.5.2.1

Timepoint(s) of evaluation of this end point

1: end of study
2: Week 12±2
3:Week 12±2
4: Week 12±2
5:D0, D0-T2H, D2, D4, D14±1, D28±2 and Week 12±2
6:Serum: D0, D14±1, D28±2 and Week 12±2; Joint fluid: D0 and at D14±1
7: D0, D0T2H, D2, D4, D14±1, D28±2 and Week 12±2 for Serum; D0, D0T2H, D2, D4, D14±1, D28±2 and Week 12±2 for blood; D0 and at D14±1 for joint fluid
8: D14±1
9: end of study
10: each visit (except D14±1 and D28±2);
11: D-1 or D0, Week 12±2, Month 6 ±2 weeks, Month 12±1, Month 18±1 and Month 24±2
12: Month 6±2 weeks, Month 12±1, Month 18±1 and Month 24±2;
13: t D-1 or D0, Week 12±2, Month6 ±2 weeks, Month 12±1, Month 18±1 and Month 24
14 :week 12-RT±2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1-2

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-11

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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