FS-1 Drug for Treatment of Multiple Drug-resistant Tuberculosis (FS-1)

Randomized, Placebo-controlled Study of Safety and Therapeutic Efficacy of the Drug FS-1 in the Oral Dosage Form in Drug-resistant Pulmonary Tuberculosis

Drug-resistant tuberculosis is becoming a major problem for the whole humanity, and development of new Anti-TB drugs is of great importance. Since Kazakhstan is a country with the high burden of tuberculosis, the Government of the Republic of Kazakhstan has founded initiative on the development of new Anti-TB drug to treat drug-resistant forms of this infectious disease. JSC "Scientific Center for Anti-infectious Drugs" has developed original drug FS-1 for the treatment of multidrug resistant tuberculosis (MDR-TB).

Study Overview

• Status: Completed
• Conditions: Tuberculosis, MDR
• Intervention / Treatment: Drug: FS-1; Drug: Placebo

Detailed Description

Phase 3 clinical study of FS-1 drug is a randomized, interventional, multicenter, placebo-controlled (add-on), double-blind and two arms trial.

The study consists of two following phases: treatment phase - 6 months and follow-up phase 12 months. It is planned to recruit 480 patients with verified MDR-TB diagnosis.

All data will be compiled in an Electronic Data Capture System with further statistical analysis according to approved Statistical Analytical Plan.

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kazakhstan
  • Almaty, Kazakhstan, 050010
    • National scientific center of phthisiopulmonology Ministry of health of the Republic of Kazakhstan
  • Almaty, Kazakhstan, 050030
    • Center of Phthisiopulmonology of the Public Health Administration of Almaty
  • Karaganda, Kazakhstan
    • Karaganda Medical University
  • East-Kazakhstan Region
    • Semey, East-Kazakhstan Region, Kazakhstan, 071400
      • Semey Medical University
  • West Kazakhstan Region
    • Aktobe, West Kazakhstan Region, Kazakhstan, 030019
      • West Kazakhstan Marat Ospanov Medical University
• Kyrgyzstan
  • Bishkek, Kyrgyzstan, 030019
    • National Center of Phthisiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects suffering from a multidrug-resistant form of pulmonary tuberculosis which is defined by:

  • MDR Tuberculosis confirmed by microbiology test at screening.
  • resistance to isoniazid and rifampicin demonstrated by drug susceptibility test
  • susceptiblity of TB bacteria to fluoroquinolones and aminoglycoside/capreomycin
• all ethnicities, intellectually capable of understanding their own condition and the requirements of the study protocol
• Willing to freely and voluntarily give signed informed consent
• Willing and capable to comply with all requirements of the protocol

Exclusion Criteria:

• Pregnancy and breast-feeding;
• Patients with decompensated concomitant diseases (cardiovascular, renal, hepatic failure) that may affect the conduct of the study;
• Severe mental disorders;
• Allergy to iodine-containing drugs, hypersensitivity to iodine;
• Intolerance to second-line drugs;
• Epidermomycosis
• Socially maladjusted patients suffering from alcoholism and drug addiction;
• Hypothyroidism;
• Hashimoto's thyroiditis;
• TB treatment for more than two months before the start of the study;
• Not willing to adhere to TB therapy;

Exclusion Criteria during the study:

• at the discretion of the researcher, if the continuation of the study is harmful to the patient;
• side effects related with the study drug
• patient's decision to stop participation in study
• appearance of any exclusion criteria during study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; Standard TB treatment+ treatment regiment with FS-1 drug. Study drug was given to the patients orally once per day in dose of 2.5 mg/kg along with other prescribed TB drugs.	Drug: FS-1; FS-1 is a liquid solution for internal intake and has antimicrobial and antibacterial activities.
Placebo Comparator: B; Standard TB treatment + treatment regiment with a placebo. Instead of study drug the placebo was given to the patients orally once per day along with other prescribed TB drugs (in quntity equal to study drug).	Drug: Placebo; Placebo without any active pharmaceutical ingredients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to persistently negative sputum cultures	Time from the start of treatment with study drug to the first negative M. tuberculosis sputum culture on solid medium followed by 4 consecutive negative results with an interval of at least 30 days. Measured in months. Estimated population: randomized subjects who took at least 70% of planned study drug doses; having a positive bacterial culture M. tuberculosis at the baseline; who missed less than 2 consecutive visits or less than 14 consecutive days of study drug treatment (modified ITT analysis).	18 months
Proportion of Patients with persistently negative sputum cultures (SCC)	Sputum culture conversion (SCC) is a persistently negative result of the sputum culture at one year from the patients who had sputum samples positive for growth of M. tuberculosis at baseline and not followed by any positive culture until the end of the trial. SCC corresponds to the outcome "cured" if at least 5 negative bacteriological cultures is recorded (on solid medium) during 12 months with an interval of at least 30 days.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects with relapse of tuberculosis	Relapse is defined when patient received full study drug treatment course (6 months) and bacteriological culture become again positive after 5 negative bacteriological cultures (on solid medium) during 12 months with an interval of at least 30 days.	12 months
Patients body weight dynamics for the period of 18 months.	Comparison of subjects' weight, using as the baseline subjects' weight before the start of the treatment with the subjects' weight during the treatment cycle with the study drug (6 months) and during 12 months of follow-up period.	18 months
The median time to occurrence of negative sputum microscopy result	The average time between positive and negative sputum smear microscopy results during the treatment.	18 months
The time when TB clinical symptoms not observed	Assessment of period between TB clinical symptoms and their disappearance. Observed of TB clinical symptoms are as follows: chest pain, difficulties to breath, cough, sputum, intoxication symptoms.	18 months
Dynamics of the tuberculosis process based on subjects chest x-ray diagnosis.	The positive dynamics of the subject X-ray picture of the tuberculous process is characterized by the closure of TB caused cavities, a decrease of lung infiltration, nodular lesions, pleural effusion and lymphadenopathy.	18 months
The incidence and severity of Adverse Events, Serious Adverse Events and drug related Adverse Drug Reactions	Assessment of Adverse Events and Drug Reactions during the study (6 months of treatment and 12 months of follow-up period). Adverse event (AE) is any untoward medical occurrence in subject administered the study drug and that does not necessarily have a causal relationship with this treatment. AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not related to the study drug. Serious Adverse Event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect. Adverse drug reaction - all noxious and unintended responses to the study drug, when a causal relationship between the study drug and an adverse event is at least a reasonable possibility.	18 months
Assessment of the study drug effect on thyroid gland function	Assessment of thyroid hormones and antibodies in the blood (free triiodothyronine (FT3), free thyroxine (FT4), total thyroxine (TT4),total triiodothyronine (TT3),thyroid stimulating hormone (TSH), antibodies to thyroglobulin and thyroid peroxidase), and results of ultrasound of the thyroid gland before treatment, during treatment (6 months) and during the follow-up period (12 months).	18 months

Collaborators and Investigators

• Sponsor: Scientific Center for Anti-infectious Drugs, Kazakhstan
• Collaborators: Phthisiopulmonology Center of Almaty, Kazakhstan; National Scientific Center of Phthisiopulmonology, Kazakhstan; Karaganda Medical University; West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan; Semey State Medical University; National Center of Phthisiatry, Bishkek, Kyrgyzstan; Invivo laboratory, Kazakhstan
• Investigators: Study Director: Amirkan A Azembayev, Cond.Phar.Sc., JSC "Scientific Center for Anti-infectious Drugs"

Publications and helpful links

Helpful Links

• General information about Sponsor of the study.
• New approach to treatment MDR-TB
• Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multi-Drug Resistant Mycobacterium Tuberculosis Induced by FS-1
• Complete genome sequence of the multi-drug resistant clinical isolate Mycobacterium tuberculosis 187.0 used to study an effect of drug susceptibility reversion by drug FS-1
• Constraints of Drug Resistance - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics
• The effect of the Kazakhstan drug FS-1 on the outcome of multidrug-resistant pulmonary tuberculosis in complex anti-tuberculosis therapy
• Anti-tuberculosis activity of new drug FS-1

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2013
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: November 11, 2015
• First Submitted That Met QC Criteria: November 16, 2015
• First Posted (Estimate): November 18, 2015

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Tuberculosis; Multi-drug resistant TB; TB treatment
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: TP-004 V 5.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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