Clinical Trials Register

Summary
EudraCT Number:	2021-000963-54
Sponsor's Protocol Code Number:	FUR-PKPD-05-20
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-06-07
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2021-000963-54

A.3

Full title of the trial

Effectiveness and pharmacokinetic /pharmacodynamic study of Furazidin, prolonged- release tablets, 200 mg in the treatment of patients with uncomplicated lower urinary tract infections (acute or recurrent). FUTURE

Badanie oceniające skuteczność oraz farmakokinetykę/farmakodynamikę Furazydyny 200
mg, w postaci tabletek o przedłużonym uwalnianiu, stosowanych w leczeniu pacjentów z niepowikłanymi
infekcjami dolnych dróg moczowych (ostrymi lub nawracającymi). FUTURE

A.3.1

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

Study to evaluate the microbial response of Furazidin 200 mg prolonged-release tablets in urine collected in patients with clinical symptoms of lower urinary tract infections, and to gain a better understanding of the drug metabolism in patients.

Badanie mające na celu ocenę odpowiedzi drobnoustrojów na tabletki Furazydyny 200 mg o przedłużonym uwalnianiu w moczu pobranym od pacjentów z klinicznymi objawami infekcji dolnych dróg moczowych oraz lepsze zrozumienie metabolizmu leków u pacjentów.

A.3.2

Name or abbreviated title of the trial where available

FUTURE

A.4.1

Sponsor's protocol code number

FUR-PKPD-05-20

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	Adamed Pharma S.A.
B.1.3.4	Country	Poland
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	ADAMED Pharma S.A.
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Adamed Pharma S.A.
B.5.2	Functional name of contact point	Clinical Research Department
B.5.3	Address:
B.5.3.1	Street Address	Pieńków, Ul. Mariana Adamkiewicza 6A
B.5.3.2	Town/ city	CZOSNÓW
B.5.3.3	Post code	05-152
B.5.3.4	Country	Poland
B.5.4	Telephone number	+48227327700
B.5.5	Fax number	+48227165533
B.5.6	E-mail	clinicaltrials@adamed.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	Furazidin prolonged-release tablets
D.3.2	Product code	200 mg
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Furazidine
D.3.9.1	CAS number	1672-88-4
D.3.9.3	Other descriptive name	FURAZIDINE, FURAGINA, FURAGINUM, FURAGIN
D.3.9.4	EV Substance Code	SUB16433MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

uncomplicated lower urinary tract infections (acute or recurrent)

niepowikłane infekcje dolnych dróg moczowych (ostre lub nawracające)

E.1.1.1

Medical condition in easily understood language

urinary tract infections

infekcje dróg moczowych

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10046577
E.1.2	Term	Urinary tract infections
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10046571
E.1.2	Term	Urinary tract infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10024981
E.1.2	Term	Lower urinary tract infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10038140
E.1.2	Term	Recurrent urinary tract infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the effectiveness of Furazidin PR in treatment of uncomplicated UTI (acute or recurrent).

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are:
• to assess pharmacokinetics and pharmacodynamics (PK/PD) of Furazidin PR in general and special patient populations with uncomplicated UTI (acute or recurrent),
• to model PK/PD relationships and assess demographic covariates and/or subpopulations in PK/PD relationships,
• to evaluate safety profile of Furazidin PR,
• to assess quality of life in UTI patients’ population,
• observation of the treatment effectiveness at the Day 5 (First Resolution),
• evaluation of patient compliance with dosing recommendation in respect to the meals,
• evaluation of patients’ compliance with recommended dose regimens of Furazidin PR.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The patients meeting the below mentioned criteria will be included into the study:
1. Informed Consent: Willingness to comply with all the study activities and procedures and provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses. For patients < 18 years old – parents’ informed consent is required.
2. Age: Subject must be ≥ 12 years of age at the time of signing the informed consent form.
3. Sex: female.
4. Patients with diagnosis of uncomplicated lower urinary tract infection (acute or recurrent). For the purposes of this study, urinary tract infection is defined by:
a) presence of at least two of the following clinical symptoms: dysuria, urinary frequency, urinary urgency, suprapubic pain,
and
b) at least a score of 6 of typical symptoms obtained by the Acute Cystitis Symptom Score (ACSS) questionnaire applied as additional tool for the clinical inclusion criteria defined by the draft guideline on the evaluation of medicinal products indicated for treatment of bacterial infections (EMA/844951/2018 Rev. 3)
and
c) presence of pyuria, as determined by a dipstick test positive for leukocyte esterase or at least 10 leukocytes per cubic millimeter (WBC ≥ 10/mm3) as required by the draft EMA Guideline (EMA/844951/2018 Rev. 3).
5. Onset of symptoms of urinary tract infection at least 12 hours but not more than 72 hours prior to Visit 1 (Screening).
6. No prior treatment with systemic antibiotics and/ or chemotherapeutic agents for any reason within 7 days prior to Visit 1;
NOTE: in case of any antimicrobial therapy administrated > 7 days before Visit 1, each treatment should be evaluated individually by the Investigator to assess the risk of PK or PD carryover from previous antibiotics/ chemotherapeutic agents.
7. Negative urine pregnancy test for female subjects of childbearing potential.
8. Female patients must be:
− post-menopausal (i.e.: no menstrual bleeding for at least 12 consecutive months), or
− surgically sterile (i.e. after surgery as bilateral tubal ligation, bilateral ovariectomy or hysterectomy), or
− abstain from sexual intercourse, or
− using an acceptable and highly-effective method of contraception for the duration of the study and for 1 month after the last dose of Furazidin PR to prevent pregnancy, defined as:
• combined oral, transdermal or intravaginal (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation,
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable),
• intrauterine device (IUD), intrauterine hormone-releasing system (IUS),
• bilateral tubal occlusion,
• vasectomised partner,
Additional barrier methods in conjunction with spermicide is recommended.

E.4

Principal exclusion criteria

1. Symptoms suggesting probability of SARS-CoV-2 infection
2. Direct contact with a person suffering from COVID-19 within 14d. before V1
3. Travelled and stayed more than 48 h in the country affected with SARS-CoV-2 transmission within 14d. before V1
4. Any symptoms of complicated urinary tract infections pyelonephritis (i.e., fever T ≥ 38C, flank pain (costovertebral angle pain), chills and / or inflammation of the vulva and vagina and/or abnormal discharge from the vagina or urethra at V 1.
5. Known clinically significant anatomic and functional disorders of the urinary tracts (including, but not limited to: congenital malformations, conditions after surgery within the urogenital tracts during the last 30 d, clinically significant residual urine (more than 100 ml of urine being retained in urinary bladder based on PVR USG examination), neurogenic bladder, urolithiasis, urogenital system malignancies) allowing to recognize complicated urinary tract infection
6. Previous UTI episode treated (resolved or unresolved) within 4 wk before V1
7. Known contraindications for furazidin treatment:
a. severe abdominal pain with special attention to pancreatitis (strong abdominal pain in the area of epi- or mesogastrium, girdle or radiating to back area, nausea and vomiting, diarrhoea)
b. electrolytes disturbances (based on symptoms assessment: irregular heartbeat, tachycardia, fatigue, lethargy, convulsions or seizures, nausea, vomiting, diarrhoea or constipation, abdominal cramping, muscle cramping, muscle weakness, irritability, confusion, headaches, numbness and tingling)
c. polycystic kidney disease, severe pulmonary disease, diagnosed polyneuropathy e.g. diabetic polyneuropathy, known glucose-6-phosphate dehydrogenase deficiency, anemia, known deficiency of vitamins B and folic acid, neutropenia, severe thrombocytopenia, liver failure, porphyria, immunosuppressive or immunomodulatory treatment, HIV/AIDS infection, chemotherapy, steroid therapy, fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency – data obtained on the basis of patient medical history
8. As judged by the investigator, any evidence of disease/condition which in the investigator’s opinion makes it undesirable for the subject to participate in the trial
9. Hypersensitivity to furazidin, nitrofurantoin, nitrofuran derivatives or other drug components
10. Any intake of systemic antibiotics and/or bacteriostatic agents within 7d prior to V1
11. Any intake of systemic OTC drugs within 7d prior to V1 including:
- ibuprofen and other NSAIDs, and/or
- dietary supplements and food preparations used in the UTI
Except for ASA at stable dose of 75or150 mg/d taken over 30 d before V1 to reduce blood clotting
12. Other acute infections (except for acute UTI) requiring antibiotic treatment at V1
13. Catheter in the bladder or any other foreign body in the urinary tracts.
14. Overactive bladder
15. The known history of cancer disease, that is not cured nor stable within 12 months prior to V1
16. Active peptic ulcers. 17. Menstrual bleeding at the day of visit
18. Immunomodulatory prophylaxis due to urinary tract infection within 6 months prior to V1
19. The presence of known severe renal impairment
20. Treatment with vit K antagonists (Warfarin, Acenocumarol) as long the INR test is out of the normal values resulting in significant haematuria (decision about enrolment to be made based on the last INR result), probenecid, sulfinpirazon, alkalising drugs containing magnesium trisilicate, ristomycin, metoclopramide, nalidixic acid, atropine, levomicetin, sulphanilamide within 7d before V1
21. Current or previous history of addiction to alcohol and/or drugs.
22. Patients who are expected to have problems with the insertion of intravenous catheters or venipuncture
23. Investigator’s opinion that the patient should not participate in the study if the subject is unlikely to comply with study procedures, restrictions, and requirements.
24. The legal inability and/or other circumstances that prevent the patient's understanding of the extent and possible influence of the study
25. Sound suspicion that the patient fails to comply with the study protocol directives
26. Are currently enrolled in or discontinued within the last 30d from clinical trial involving an investigational drug including furazidin, nitrofurantoin and/or nitrofuran derivatives or device or off-label use of a drug or device other than the study drug/device used in this study or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
27. Are currently pregnant (confirmed with positive urine pregnancy test) or breast-feeding
28. Are Sponsor’s /CROs employees/relatives or investigator site personnel directly affiliated with this study and/or their immediate families
29. Any conflict of interest or condition that might affect the objective assessments and measurements

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy criterion is defined as a composite endpoint consisting of the resolution or improvement of all clinical symptoms of urinary tract infection without need of additional antibacterial therapy and the efficacy measure according to the ACSS self-assessment scale (a score of typical symptoms of the ACSS ≤ 5 but no item > 1 (mild) and no visible blood in urine) and the demonstration that the bacterial pathogen found at trial entry at CFU > 105/ mL is reduced to fewer than 103 CFU/mL on urine culture during Visit 5 (Test of Cure Visit, 14 (+/-2) days after treatment initiation).

E.5.1.1

Timepoint(s) of evaluation of this end point

14 days (+/- 2 days)

E.5.2

Secondary end point(s)

Assessment of population PK parameters of Furazidin PR in uncomplicated UTI (acute or recurrent) patient population such as clearance and volume of distribution including demographic covariate testing and/or subpopulation analysis,
• Bacteriological assessment (PD) including pathogen identification and observed changes in bacterial count (CFU/mL) during the 7-day therapy with Furazidin PR; [Time Frame: Day 1, Day 2, Day 5, Day 7, Day 14],
• Assessment of population PK/PD relationship and parameters including demographic covariate testing and/or subpopulation analysis,
• Number of patients that achieved resolution or improvement of all clinical symptoms of UTI according to the ACSS self-assessment scale (a score of typical symptoms of ACSS ≤ 5 but no item > 1 (mild)) and no visible blood in urine at Visit 3 (First Resolution), Visit 4 (End ofTreatment), Visit 5 (Test of Cure), and Visit 6 (Follow-up); [Time Frame: Day 5, Day 7, Day 14, Day 28],
• Number of patients that achieved reduction of pathogens count, present at the study entry (at Visit 1), to a level <103 CFU/mL in urine culture at Visit 5; [Time Frame: Day 14], • Number of patients with new infections; [Time Frame: Day 14], • Number of patients with a need of any other antimicrobial medication intake for UTI between Visit 1 and Visit 5 and between Visit 1 and Visit 6; [Time Frame: Day 2, Day 5, Day 7, Day 14, Day 28], • Maintenance of clinical response until Day 28 (Visit 6 - Follow up) based on the ACSS self-assessment scale (a score of typical symptoms of ACSS ≤ 5 but no item > 1 (mild)) and no visible blood in urine); [Time Frame: Day 28],
• Change in the patient self-reporting quality of life using the ACSS questionnaire at Visit 1 (Baseline), Visit 2 (PK/PD sampling), Visit 3 (First Resolution), Visit 4 (End of treatment), Visit 5 (Test of Cure), Visit 6 (Follow-up); [Time Frame: Day 1, Day 2, Day 5, Day 7, Day 14, Day 28],
• Number of Treatment-Emergent AEs/ SAEs collected during the course of the study since Visit 1 until Visit 6; [Time Frame: Day 1 to Day 28], • The susceptibility of infecting strains to Furazidin PR and other antibiotics used for UTI treatment; [Time Frame: Day 1, Day 14],
• Patient compliance with study treatment dosing regimen, defined as the range of 71-129% of total dose of study treatment that should be taken during the course of the study; [Time Frame: Day 14],
• Patient compliance of study treatment administration in respect to meals; compliance defined as at least 71% doses administrated as per recommendations; [Time Frame: Day 14],
• Clinical response to study treatment in relation to patient compliance with study treatment administration in respect to meals; [Time Frame: Day 14].
NOTE: All patients meeting study entry criteria with positive bacteriuria, CFU > 10^3/mL will be assessed for secondary microbiological endpoints.
NOTE: Patients who entered the study and received study medication but failed to fulfill study microbiological inclusion criteria will be evaluated in the same manner as above.

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

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

LVLVS

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Information not present in EudraCT

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

100

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)

Patients will be treated with the prevailing standard of medical care

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-07-18

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-01-16

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