A Study of Ultrashort PRS Regimen V in the Treatment of MDR-TB

This is an exploratory, prospective, randomized, active control, and open label clinical trial to evaluate the efficacy and safety of 6-9 months treatment with the ultrashort PRS Regimen V.

Study Overview

• Status: Recruiting
• Conditions: MDR-TB
• Intervention / Treatment: Drug: MDR-TB Treatment Regimen(WHO); Drug: PRS Regimen V

Detailed Description

Shortening the course of treatment based on effective therapy can significantly improve patient compliance and reduce the public health burden.Research on optimal drug combination regimens to further shorten the duration and improve the efficacy of multidrug-resistant tuberculosis treatment is an important research direction.The PRS (parabolic response surface, FSC.II) system is an enhanced use of FSC to better identify and optimize optimal drug combinations.In preliminary studies, it was determined that PRS Regimens V （bedaquiline, delamanid, clofazimine, pyrazinamide）was superior to other regimens and would be a promising combination for XDR-TB because it does not contain fluoroquinolones or aminoglycosides. Preliminary trials have demonstrated that this regimen (PRS Regimens IV) can significantly reduce the duration of treatment required for MDR-TB and achieve a relapse-free cure.

Therefore, the investigators conducted an exploratory, prospective, randomized, positive-controlled, open, multicenter clinical study of this new regimen to observe the efficacy, safety, and recent relapse rate of the new regimen in the treatment of multidrug-resistant tuberculosis.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Shanghai Pulmonary Hospital

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:

1. Untreated newly diagnosed patients with rifampicin resistant (RR) or multidrug resistant (MDR)-TB.
2. Newly treated patients: at least twice confirmed by molecular biology or phenotypic drug susceptibility test to have RR- or MDR-TB; Retreated patients: confirmed once by molecular biology or phenotypic drug susceptibility test to have RR- or MDR-TB.
3. Age between 18 and 65.
4. No abnormality on EKG.
5. Able to understand and sign informed consent form.

Exclusion Criteria:

1. Presence of extrapulmonary TB (including tuberculous pleurisy);
2. History of allergic reaction to any of the drugs used in the study;

3. Presence of any of the following conditions that can lead to prolonged QT:

   1. During screening process, ECG shows QT or QTc interval ≥ 450 ms (permit one non-prescheduled retest within the screening period to re-evaluate the testees' qualification);
   2. Pathological Q waves (any Q wave duration of > 40 ms or depth > 0.4-0.5 mV);
   3. Evidence of ventricular pre-excitation (such as Wolff-Parkinson-White Syndrome);
   4. EKG shows evidence of complete or clinically significant incomplete left or right bundle branch block;
   5. Evidence of 2nd or 3rd degree heart block;
   6. Intraventricular conduction delay, QRS durations > 120 ms;
   7. Slow heart rate, defined as sinus heart rate < 50 bpm;
   8. Having personal or family history of long QT syndrome;
   9. Having heart disease, symptomatic or asymptomatic arrhythmia, excluding sinus arrhythmia;
   10. Fainting (i.e., cardiogenic fainting, not including vasovagal syncope or seizure)
   11. Having risk factors for Torsade de pointes ventricular tachycardia (e.g. heart failure, hypokalemia, hypomagnesemia)
4. Pregnancy or liver, kidney, metabolic, autoimmunity, neurological, psychological or endocrine disease, blood system disease, malignant cancer, long-term users of immunosuppressant drugs.
5. Alcoholism
6. Any patients, based on the judgement of the study medical researchers who are not suitable to participate in the trial or unlikely to complete the trial.
7. Participating in another clinical trial at the same time.
8. History of non-compliance in other clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Group A; Treatment according to WHO MDR-TB treatment guidelines (2019).	Drug: MDR-TB Treatment Regimen(WHO); Treatment according to WHO MDR-TB treatment guidelines (2019); Other Names: WHO Regimen
EXPERIMENTAL: Group B(PRS Regimen V); bedaquiline, delamanid, clofazimine, pyrazinamide	Drug: PRS Regimen V; PRS Regimen V(bedaquiline, delamanid, clofazimine, pyrazinamide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
patient cure rate	Assessment of cure rate : Cure.; Treatment completion.; Treatment failure.; Death.; Loss.; Inconclusive.; Treatment success.	Through study completion, an average of 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early bactericidal activity (EBA)	Collect patient sputum between 16:00 to 8:00 the next morning before taking drugs prior to treatment initiation (Day 0; D0) and on Day 2 (D2), Day 7 (D7), and Day 14 (D14) after the start of treatment	treatment initiation (Day 0; D0) and on Day 2 (D2), Day 7 (D7), and Day 14 (D14) after the start of treatment
Time to culture positivity	culture using MGIT 960 and observe the time to detection of positive growth.	Through study completion, an average of 18 months
Sputum conversion rate	ompare patient sputum conversion rate between the two groups at one month and two months.	Through study completion, an average of 18 months
Radiology changes	"Significant absorption" is defined as lesion absorption ≥ ½. "Absorption" is defined as lesion absorption ≤ ½. "No change" if the original lesion has no clear change. "Worsened" if the original lesion is enlarged or has spread. "Closure" if the original cavity is enclosed or enclosed by blockage. "Shrinkage" if diameter of the original cavity decreased by ≥1/2. "No change" if diameter of the original cavity decreases by <1/2. "Enlarged" if diameter of the original cavity increases by >1/2.	Through study completion, an average of 18 months
Relapse rate one and two years after treatment completion.	follow up at 3, 6, 12, 18, and 24 months after treatment completion	At 3, 6, 12, 18, and 24 months
Time to Cure by Primary Endpoint criteria	Time to Cure by Primary Endpoint criteria	6-9 month

Collaborators and Investigators

• Sponsor: Shanghai Pulmonary Hospital, Shanghai, China
• Collaborators: Huashan Hospital; Shanghai Public Health Clinical Center; Anhui Chest Hospital; No.85 Hospital, Changning, Shanghai, China; Ganzhou Fifth People's Hospital, China; Weifang Second People's Hospital, China; Fourth Taiyuan People's Hospital, China; Shanghai Pudong New Area Pulmonary Hospital, China; Zhengzhou Sixth People's Hospital, China
• Investigators: Principal Investigator: Sha wei, Shanghai Pulmonary Hospital, Shanghai, China

Publications and helpful links

General Publications

• Silva A, Lee BY, Clemens DL, Kee T, Ding X, Ho CM, Horwitz MA. Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):E2172-9. doi: 10.1073/pnas.1600812113. Epub 2016 Mar 28.
• Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014 Oct;18(10):1180-7. doi: 10.5588/ijtld.14.0100.
• Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684-92. doi: 10.1164/rccm.201001-0077OC. Epub 2010 May 4.

Helpful Links

• WHO consolidated guidelines on drug-resistant tuberculosis treatment

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2021
• Primary Completion (ANTICIPATED): September 30, 2024
• Study Completion (ANTICIPATED): September 30, 2024

Study Registration Dates

• First Submitted: February 24, 2022
• First Submitted That Met QC Criteria: March 3, 2022
• First Posted (ACTUAL): March 15, 2022

Study Record Updates

• Last Update Posted (ACTUAL): August 8, 2022
• Last Update Submitted That Met QC Criteria: August 4, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: MDR-TB; bedaquiline; Delamanid
• 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: K21-024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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