Clinical Trial of the Efficacy and Safety of Raphamin in Prevention of Recurrences of Chronic Bacterial Cystitis

Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group Clinical Trial of the Efficacy and Safety of Raphamin in Prevention of the Recurrences of Chronic Bacterial Cystitis

Clinical Trial of the Efficacy and Safety of Raphamin in Prevention of Recurrences of Chronic Bacterial Cystitis

Study Overview

• Status: Recruiting
• Conditions: Cystitis Chronic; Cystitis Bacterial; Recurrence of Chronic Bacterial Cystitis
• Intervention / Treatment: Drug: Placebo; Drug: Raphamin

Detailed Description

Trial design: double blind, placebo-controlled, randomized in parallel groups clinical trial.

The trial includes female outpatients aged 18 years or older with typical symptoms of chronic bacterial cystitis. The severity of typical symptoms of recurrence (exacerbation) should be 7 points or more according to the subscale "Typical symptoms" of the scale "Acute Cystitis Symptom Scale" (ACSS).

At Visit 1 (Day 1), after signing the patient information sheet and the informed consent form for participation in the clinical trial, complaints and medical history are collected, a physical examination is performed, and the severity of typical symptoms of cystitis is assessed using ACSS, collection of urine biosamples for urine analysis with microscopy and bacteriological examination (for identification the sensitivity of microorganisms to antibiotics), ultrasound examination of the urinary system (kidneys, bladder), and concomitant therapy is recorded.

Urinalysis, general and biochemical blood tests are planned in at least 190 patients.

If the patient meets inclusion criteria and does not meets exclusion inclusion criteria at Visit 1 (Day 1), the patient is randomized to one of two groups: patients of Group 1 take Phosphomycin (3 g once) and Raphamin according to the therapeutic and preventive regimen for 10 days; patients of Group 2 use Phosphomycin (3 g once) and Placebo according to the Raphamin regimen for 10 days.

If there is no effect from treatment within 48 hours or phosphomycin-resistant strains are detected, the physician conducts unscheduled visit and gives the patient an alternative drug Cefixime (400 mg). Cefixime is taken 1 times a day at a dose of 400 mg for 5 days or more (the duration of the course is determined by the physician).

All patients are provided with Phosphomycin, if resistance to it is detected - with alternative antibiotic Cefixime.

If microorganisms resistant to both Phosphomycin and Cefixime are detected, the patient is excluded from the trial, and the physician prescribes a treatment strategy in accordance with current standards.

In Electronic Patient Diary (EPD) the patient records the severity of typical cystitis symptoms using ACSS once a day at approximately the same time. Symptoms are recorded in the EPD from the patient's enrollment until Visit 2 (within 10 days of study drug administration), as well as during 10 days of treatment for each subsequent relapse (exacerbation).

In addition, any possible deterioration of the patient's condition (if applicable) is recorded in EDP to assess safety and record adverse events. The study physician instructs patients to complete the diary.

The first ACSS marks in the EDP are made by patient together with physician at Visit 1. EDP is available for filling throughout the patient's participation in the study. Once a week, the patients get SMS reminder: "If you have symptoms of the disease, enter them in the diary and contact the study physician. Don't forget to take your medication." In total, patient's follow-up lasts for 24 weeks. In the process of treatment and observation, 4 visits are scheduled: at day 1 (Visit 1) and day 11 (Visit 2), then at weeks 12 and 24 (Visits 3, 4). Visits 1, 2 and 4 are face-to-face (patient visits trial site); physician conducts physical examination, records symptoms and concomitant therapy, and checks the EPD. At Visit 2 (Day 11+3), the physician gives Phosphomycin/Cefixime and a study drug to patient, to treat a possible subsequent recurrence of cystitis. Blood and urine biosamples are taken from the patient who signed the ICF for taking biological samples (for safety assessment). The study drug received by the patient at Visit 1 should be returned to assess the patient's adherence to the study treatment. Phosphomycin/Cefixime also returns.

Visit 3 (Week 12 ± 3 days) is conducted by correspondence (telephone), in order to interview the patient about her condition.

In case of new recurrence of cystitis, patient contacts with trial physician by phone. On the basis of complaints and symptoms, physician makes conclusion about the onset of chronic cystitis recurrence. Patient completes ACSS in EPD. For a recurrence of cystitis, patient takes Phosphomycin (or Cefixime) and trial product (Raphamin/Placebo for 10 days). At the end of 10 days of treatment, an unscheduled face-to-face visit takes place (Day 11+3 days after the onset of recurrence), at which the patient returns the trial product and Phosphomycin/Cefixime, then the physician dispenses a new pack of trial product and Phosphomycin (or Cefixime) to treat a possible new recurrence of cystitis.

Visit 4 (Week 24 ± 3 days) is the final one; complaints are assessed, the patient undergoes a physical examination, returns the trial product and fills in a visual analogue scale (VAS), which assesses the degree of patient satisfaction with the therapy.

• Study Type: Interventional
• Enrollment (Estimated): 632
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mikhail Putilovskiy, MD, PhD; Phone Number: 302 +74952761575; Email: PutilovskiyMA@materiamedica.ru

Study Locations

• Russian Federation
  • Irkutsk, Russian Federation, 664003
    • Recruiting
    • Scientific Center for Family Health and Human Reproduction Problems/Reproductive Health Department
    • Contact: Larisa Suturina, Prof.
    • Principal Investigator: Larisa Suturina, Prof.
  • Kazan, Russian Federation, 420012
    • Not yet recruiting
    • Kazan State Medical University/Professor's clinic
    • Contact: Ruslan Fatykhov, MD, PhD
    • Principal Investigator: Ruslan Fatykhov, MD, PhD
  • Kemerovo, Russian Federation, 650000
    • Recruiting
    • LLC "Fenareta" Women's and Men's Health Clinic"
    • Contact: Natalia Artymuk, Prof.
    • Principal Investigator: Natalia Artymuk, Prof.
  • Moscow, Russian Federation, 115280
    • Recruiting
    • City Clinical Hospital # 13/Gynecology Department # 1
    • Contact: Felix Grigoryan, PhD
    • Principal Investigator: Felix Grigoryan, PhD
  • Moscow, Russian Federation, 117198
    • Recruiting
    • National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov/Department of Aesthetic Gynecology and Rehabilitation
    • Contact: Inna Apolikhina, Prof.
    • Principal Investigator: Inna Apolikhina, Prof.
  • Moscow, Russian Federation, 111539
    • Recruiting
    • City Clinical Hospital #15 named after O.M. Filatov Department of Health of Moscow
    • Contact: Vladimir Kuzmin, Prof.
    • Principal Investigator: Vladimir Kuzmin, Prof.
  • Moscow, Russian Federation, 115409
    • Recruiting
    • Clinical Hospital # 85 of the Federal Medical and Biological Agency/Central polyclinic
    • Contact: Sergey Levakov, Prof.
    • Principal Investigator: Sergey Levakov, Prof.
  • Moscow, Russian Federation, 115522
    • Recruiting
    • Research Institute of Rheumatology named after V.A. Nasonova
    • Contact: Victoria Gelashvili, MD
    • Principal Investigator: Victoria Gelashvili, MD
  • Moscow, Russian Federation, 117198
    • Withdrawn
    • Peoples' Friendship University of Russia/Department of Obstetrics and Gynecology with a course in perinatology
  • Moscow, Russian Federation, 117997
    • Recruiting
    • Russian National Research Medical University named after N.I. Pirogov/Department of Obstetrics and Gynecology, Faculty of Medicine
    • Contact: Yulia Dobrokhotova, Prof.
    • Principal Investigator: Yulia Dobrokhotova, Prof.
  • Moscow, Russian Federation, 119049
    • Recruiting
    • City Clinical Hospital # 1 named after. N.I. Pirogov of the Moscow City Health Department
    • Contact: Sergey Kotov, PhD, MD
    • Principal Investigator: Sergey Kotov, PhD, MD
  • Moscow, Russian Federation, 119285
    • Not yet recruiting
    • United hospital with clinic of the Administration of the President of the Russian Federation
    • Contact: Nikolay Keshishev, MD, PhD
    • Principal Investigator: Nikolay Keshishev, MD, PhD
  • Moscow, Russian Federation, 121423
    • Not yet recruiting
    • City Clinical Hospital # 67 named after L.A. Vorokhobov
    • Contact: Olga Perevozkina, MD, PhD
    • Principal Investigator: Olga Perevozkina, MD, PhD
  • Moscow, Russian Federation, 123056
    • Withdrawn
    • JSC "MEDSI Group of Companies"
  • Moscow, Russian Federation, 127473
    • Recruiting
    • Moscow State Medical and Dental University named after A.I. Evdokimov/Department of Urologya
    • Contact: Dmitry Pushkar, Prof.
    • Principal Investigator: Dmitry Pushkar, Prof.
  • Nizhny Novgorod, Russian Federation, 603001
    • Recruiting
    • Privolzhsky District Medical Center
    • Contact: Vagif Atduev, Prof.
    • Principal Investigator: Vagif Atduev Vagif, Prof.
  • Obninsk, Russian Federation, 105425
    • Not yet recruiting
    • National Medical Research Center for Radiology/Research Institute of Urology and Interventional Radiology named after. N.A. Lopatkin
    • Contact: Tatyana Perepanova, Prof.
    • Principal Investigator: Tatyana Perepanova, Prof.
  • Pyatigorsk, Russian Federation, 357500
    • Not yet recruiting
    • City Clinical Hospital
    • Contact: Alexander Bardin, MD
    • Principal Investigator: Alexander Bardin, MD
  • Rostov, Russian Federation, 152155
    • Not yet recruiting
    • Rostov Central District Hospital
    • Contact: Ariz Gyulmamedov, MD
    • Principal Investigator: Ariz Gyulmamedov, MD
  • Rostov-on-Don, Russian Federation, 344011
    • Recruiting
    • Clinical and Diagnostic Center "Health" in Rostov-on-Don
    • Contact: Igor Aboyan, Prof.
    • Principal Investigator: Igor Aboyan, Prof.
  • Rostov-on-Don, Russian Federation, 344022
    • Recruiting
    • Rostov State Medical University/Department of Urology and Human Reproductive Health with a course of pediatric urology-andrology
    • Contact: Mikhail Kogan, Prof.
    • Principal Investigator: Mikhail Kogan, Prof.
  • Saint Petersburg, Russian Federation, 190121
    • Recruiting
    • LLC "BioTechService"
    • Contact: Alexander Parshin, PhD
    • Principal Investigator: Alexander Parshin, PhD
  • Saint Petersburg, Russian Federation, 194356
    • Recruiting
    • LLC "Medical Clinic"
    • Contact: Maxim Bushara, MD
    • Principal Investigator: Maxim Bushara, MD
  • Saint Petersburg, Russian Federation, 192071
    • Not yet recruiting
    • City clinic # 44
    • Contact: Farzali Farzaliev, MD
    • Principal Investigator: Farzali Farzaliev, MD
  • Saint Petersburg, Russian Federation, 194044
    • Recruiting
    • All-Russian Center for Emergency and Radiation Medicine named after A.M. Nikiforov/Urology department
    • Contact: Vladislav Grigoriev, PhD
    • Principal Investigator: Vladislav Grigoriev, PhD
  • Saint Petersburg, Russian Federation, 195197
    • Recruiting
    • Medical and sanitary unit No. 70 - branch of the St. Petersburg State Unitary Enterprise of Passenger Road Transport
    • Contact: Vadim Zubarev, PhD, MD
    • Principal Investigator: Vadim Zubarev, PhD, MD
  • Saint Petersburg, Russian Federation, 190013
    • Withdrawn
    • JSC "Polyclinic Complex"
  • Saint Petersburg, Russian Federation, 190013
    • Not yet recruiting
    • LLC "Medical Center Capital-Polis"
    • Contact: Dmitry Gorelov, MD
    • Principal Investigator: Dmitry Gorelov, MD
  • Saint Petersburg, Russian Federation, 194044
    • Recruiting
    • St. Luke's Clinical Hospital
    • Contact: Orlov Igor, PhD
    • Principal Investigator: Orlov Igor, PhD
  • Saint Petersburg, Russian Federation, 194354
    • Withdrawn
    • City Multidisciplinary Hospital # 2/Urology department
  • Saint Petersburg, Russian Federation, 196143
    • Terminated
    • LLC "Research Center Eco-Safety"
  • Saint Petersburg, Russian Federation, 196158
    • Withdrawn
    • Jsc "Northwestern Center of Evidence-Based Medicine"
  • Saint Petersburg, Russian Federation, 198205
    • Not yet recruiting
    • City Hospital # 15
    • Contact: Konstantin Dunets, MD
    • Principal Investigator: Konstantin Dunets, MD
  • Saint Petersburg, Russian Federation, 199034
    • Recruiting
    • Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott/Department of Gynecology and Endocrinology
    • Contact: Maria Yarmolinskaya, Prof.
    • Principal Investigator: Maria Yarmolinskaya, Prof.
  • Saint Petersburg, Russian Federation, 199106
    • Recruiting
    • City Pokrovskaya Hospital/Department of Urology
    • Contact: Andrey Gorelov, Prof.
    • Principal Investigator: Andrey Gorelov, Prof.
  • Sertolovo, Russian Federation, 188650
    • Not yet recruiting
    • Sertolovo City Hospital
    • Contact: Alexander Shvets, MD
    • Principal Investigator: Alexander Shvets, MD
  • Tomsk, Russian Federation, 634050
    • Not yet recruiting
    • Siberian State Medical University/Faculty clinics of Siberian State Medical University
    • Contact: Victor Latypov, MD, PhD
    • Principal Investigator: Victor Latypov, MD, PhD
  • Ufa, Russian Federation, 450008
    • Withdrawn
    • Bashkir State Medical University/Department of Obstetrics and Gynecology # 1
  • Voronezh, Russian Federation, 394036
    • Recruiting
    • Voronezh State Medical University named after N.N. Burdenko/Department of Urology
    • Contact: Andrey Kuzmenko, Prof.
    • Principal Investigator: Andrey Kuzmenko, Prof.
  • Vsevolozhsk, Russian Federation, 188643
    • Recruiting
    • Vsevolozhsk Clinical Interdistrict Hospital/Center for Outpatient Surgery
    • Contact: Nikolay Kanareikin, MD
    • Principal Investigator: Nikolay Kanareikin, MD
  • Yaroslavl, Russian Federation, 150040
    • Recruiting
    • LLC "Medical Center for Diagnosis and Prevention Plus"
    • Contact: Svetlana Isakova, MD
    • Principal Investigator: Svetlana Isakova, MD
  • Yaroslavl, Russian Federation, 150000
    • Not yet recruiting
    • Yaroslavl State Medical University/Department of Urology and Nephrology
    • Contact: Igor Shormanov, Prof.
    • Principal Investigator: Igor Shormanov, Prof.
  • Yaroslavl, Russian Federation, 150001
    • Not yet recruiting
    • LLC "Clinic of Modern Medicine Dr. Bogorodskaya"
    • Contact: Andrey Soloviev, MD, PhD
    • Principal Investigator: Andrey Soloviev, MD, PhD
  • Yaroslavl, Russian Federation, 150062
    • Recruiting
    • Regional Clinical Hospital/Urology department
    • Contact: Dmitry Komlev, PhD
    • Principal Investigator: Dmitry Komlev, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female patients aged 18 years and older.
2. Patients with a confirmed diagnosis of chronic bacterial cystitis.
3. Patients with exacerbation of chronic cystitis based on typical symptoms of exacerbation of the disease with a severity of 7 points or more in accordance wuth ACSS.
4. The first 48 hours from the onset of exacerbation) of chronic bacterial cystitis.
5. Patients who agreed to use an acceptable method of contraception during the study (for women of reproductive potential).
6. Availability of a signed patient information sheet and informed consent form for participation in the clinical trial.

Exclusion Criteria:

1. Presence of urolithiasis, urinary tract obstruction, urothelial cancer, pelvic organ prolapse, neurogenic bladder disorders at the time of examination.
2. Presence of malignant neoplasms of the urinary tract, ureter stone, more than 50 ml of residual urine in the bladder, confirmed by ultrasound examination.
3. Suspicion of bladder tuberculosis.
4. Presence of indications for hospitalization due to a serious condition, macrohematuria, complicated cystitis.
5. Decompensation of diabetes mellitus, immunodeficiency of any etiology, malignant cancer of any localization, severe circulatory insufficiency (cardiovascular disease with functional class IV according to the classification of the New York Heart Association, 1964).
6. Unstable angina pectoris or myocardial infarction within the previous 6 months.
7. Chronic kidney disease (classes С3-5 А3).
8. Hepatic impairment (Child-Pugh class C).
9. Patients who require medicinal products prohibited for use in this study.
10. Exacerbation or decompensation of chronic conditions affecting the patient's ability to participate in the clinical trial.
11. Malabsorption syndrome, including congenital or acquired lactase deficiency or other disaccharidase insufficiency, galactosemia.
12. Hypersensitivity to any component of the medicinal products used in the treatment.
13. Pregnancy, breastfeeding; childbirth less than 3 months prior to study enrollment, unwillingness to comply with contraceptive methods during the study.
14. The medications listed in the Prohibited Concomitant Medication section were administered within 4 weeks prior to enrollment.
15. Patients who, from the investigator's point of view, will not comply with the observation requirements of the study or comply with the administration of the study drug.
16. History of mental diseases, alcoholism, or drug abuse that, in the investigator's opinion, may interfere with the successful completion of trial procedures.
17. Participation in other clinical trials within 3 months prior to enrollment.
18. The patient belongs to the investigational site personnel directly involved in the study, closest relatives of the investigator. The closest relatives are defined as spouse, parents, children or siblings, regardless of whether they are natural or adopted.
19. The patient works for the company OOO "NPF "MATERIA MEDICA HOLDING", being an employee of the company, a temporary contract worker or an appointed official responsible for performing the trial, or their close relative.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Raphamin; Take orally, do not take with meals. Keep the tablets in the mouth until completely dissolved. On the first day of treatment, 8 tablets are taken according to the following scheme: 1 tablet every 30 minutes in the first 2 hours (a total of 5 tablets in 2 hours), then during the same day another 1 tablet is taken 3 times at regular intervals. On the 2nd day and then take 1 tablet 3 times a day. The duration of treatment is 10 days.	Drug: Raphamin; Tablet for oral use.; Other Names: MMH-407
Placebo Comparator: Placebo; Take orally, do not take with meals. Keep the tablets in the mouth until completely dissolved. Placebo is administered according to the Raphamin regimen for 10 days.	Drug: Placebo; Tablet for oral use.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to the first recurrence of chronic bacterial cystitis	Criteria for the diagnosis of chronic bacterial cystitis recurrence are typical symptoms of exacerbation (acute cystitis): frequent urination with small volumes of urine; urgent urination (a sudden and uncontrollable urge to pass urine; feeling pain or burning when passing urine; feeling of incomplete bladder emptying after urination; pain or uncomfortable pressure in the lower abdomen (above the pubis); possible presence of blood in the urine (especially towards the end of urination). Criteria for the diagnosis of chronic bacterial cystitis are 2 and more recurrences during previous 6 months or 3 and more recurrences during previous 12 months.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with a reduction of recurrences of chronic bacterial cystitis	Percentage of patients with a reduction number of recurrences of chronic bacterial cystitis to one episode and less during 6 months of follow-up.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average duration of episodes of recurrences of chronic bacterial cystitis	Average duration of episodes of recurrences of chronic bacterial cystitis after the start of study therapy at inclusion in the study, score 6 or less of typical symptoms of cystitis by the Acute Cystitis Symptom Score (according to the patient's diary).	6 months
Average number of recurrences of chronic bacterial cystitis	Average number of recurrences of chronic bacterial cystitis per patient during 6 months of follow-up.	6 months
Severity of chronic bacterial cystitis recurrences	Severity of chronic bacterial cystitis recurrences within 6 months of follow-up (as measured by the area under the curve for the total score of typical symptoms of cystitis on the Acute Cystitis Symptom Score (ACSS) during 10 days of treatment for each episode of recurrence). ACSS is an 18-item self-reporting questionnaire for clinical diagnosis and follow-up of acute uncomplicated cystitis in women (min 0, max 18 points; 6 typical symptoms are included: urinary frequency, urgent urination, burning feeling when urinating, incomplete bladder empting after urination, pain or uncomfortable pressure in the lower abdomen, visible blood in urine; each symptom is estimated from 0 to 3 points).	6 months
Change in the severity of chronic bacterial cystitis recurrences	Change in the severity of chronic bacterial cystitis recurrences during 6 months of follow-up compared to baseline.	6 months
VAS score at the end of the follow-up period	Visual Analogue Scale (VAS) is used to assess the degree of satisfaction with the treatment. Treatment satisfaction scores are ranged from 0 (no satisfaction with treatment) to 10 points (very significant treatment effect), such that a higher score indicates greater treatment efficacy.	6 months
The Presence of Adverse Events (AEs).	The presence and nature of adverse events, their intensity (severity), causal relationship to the study drug, outcome. Based on medical records.	6 months
Changes in Vital Signs (Blood Pressure measured in mm Hg)	Changes in Blood Pressure at the end of treatment of the initial recurrence of chronic cystitis.	6 months
Changes in Vital Signs (Pulse Rate (Heart Rate) measured in beats per minute)	Changes in Heart Rate at the end of treatment of the initial recurrence of chronic cystitis.	6 months
Changes in Vital Signs (Respiration Rate (Breathing Rate) measured in breaths per minute)	Changes in Respiratory Rate at the end of treatment of the initial recurrence of chronic cystitis. Based on medical records.	6 months
Proportion of patients with clinically significant laboratory abnormalities	Proportion of patients with clinically significant laboratory findings abnormalities at the end of treatment for initial recurrence of chronic cystitis.	6 months

Collaborators and Investigators

• Sponsor: Materia Medica Holding

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 12, 2024
• First Submitted That Met QC Criteria: February 27, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urinary Bladder Diseases; Disease Attributes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cystitis; Recurrence
• Other Study ID Numbers: MMH-407-007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No