Pilot Clinical Trial of PRS TB Regimen I - Phase II

Tuberculosis (TB) is a major health problem of global proportions. Although drug sensitive TB is a treatable disease, the current standard treatment requires 6 - 8 months of a multi-drug regimen to achieve relapse-free cure. This long course of treatment is often associated with toxicity, poor compliance, and development of drug resistance. A more effective drug combination that provides more rapid sterilization of tissues has the potential to ameliorate these critical problems.

The current drug regimen for treating tuberculosis is lengthy and onerous, and hence complicated by poor compliance leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform, parabolic response surface (PRS, previously called Feedback System control or FSC), and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several new experimental drug regimens among billions of possible drug-dose combinations that outperform the current Standard Regimen. We used the PRS platform to optimize the in vivo drug doses of novel regimens (designated PRS regimen) in a mouse model of pulmonary tuberculosis and then showed that the regimens sterilized much more rapidly than the Standard Regimen and substantially reduced treatment time to relapse-free cure by 25% for PRS regimen, which consists of Clofazimine (Cfz), Ethambutol (E), high dose Pyrazinamide (Z, high), and Prothionamide (Pto). The regimen have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As PRS regimen omit isoniazid, rifampicin, fluoroquinolones, and injectable aminoglycosides, they are suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.

1 Significance of the study Based on results in cell culture in macrophages and in mice we anticipate that PRS regimen will prove to be more effective and will allow a shorter course of treatment than the standard regimen. By allowing a shorter course of treatment, problems with adherence, toxicity, and development of drug resistance can be reduced. Moreover, because the regimen does not include INH or RIF, it can be used in cases of TB that are resistant to those drugs.

2 Methods

1. Summary of Experimental Design This is a randomized, controlled, open-label pilot clinical trial. Previously untreated, smear positive tuberculosis patients (aged 18 - 65 years) with radiographic evidence of TB and whose bacteria are sensitive to first-line drugs will be randomly distributed to group A (standard regimen) and B (new short course PRS regimen). The study will compare sputum conversion rate at the end of treatment between treatment regimens and will evaluate objective indicators of treatment success rate and incidence of adverse events.
2. Identification of Subjects: Potentially eligible subjects will be identified from among subjects seen at or referred to the Shanghai Pulmonary Hospital for treatment of tuberculosis. Subjects will be informed about the study and those who express interest in participation will be provided a written consent form.
3. Consent Process: As described in detail below, Subjects will be informed that participation is voluntary and that they will receive appropriate care for their condition regardless of whether or not they participate in the study. Because subjects have active TB, they will be in isolation in the Shanghai Pulmonary Hospital. The investigator will review the consent form with the subject and ensure that the subject understands the consent form and that all of the subject's questions have been answered. Because timely initiation of treatment is important, subjects will be allowed up to two days to decide whether to participate in the study or to receive standard care.
4. Screening for Eligibility: Screening tests indicated in the Table of Study Procedures (located at the end of this document) and required for assessment of eligibility per inclusion/exclusion criteria will be completed within 14 days prior to study enrollment.
5. Randomization: Eligible subjects will be randomized 1:1 by using a random number generator either to Group A (standard care) or to Group B (the investigational PRS regimen).
6. Study Treatment: Subjects are treated according to their assignment to Group A or Group B as indicated below. Group A, Standard Regimen (2EHRZ/4HR): The standard six-month regimen is eight weeks of daily treatment with isoniazid, rifampin, ethambutol, and pyrazinamide followed by sixteen weeks of isoniazid and rifampin. All drugs are administered orally, seven days/week. Study drugs are dosed by weight as shown in the below. Group B, PRS Regimen (4EZ [high dose] Cfz Pto): The PRS regimen is 4 months of daily Cfz, Emb, Pto, and high dose pyrazinamide, dosed by weight according to below. The drug dosing for both Group A and Group B are summarized in the below: ………………………………………………………………………………………………………………………… Isoniazid (H):daily dose (gm)0.3(weight <50kg);0.3(weight≥50kg),use method: 1 times/day. Rifampin (R):daily dose (gm)0.45(weight <50kg);0.6(weight≥50kg),use method: 1 times/day（Fasting medication）. ethambutol (E):daily dose (gm)0.75(weight <50kg);1.0(weight≥50kg),use method: 1～2 times/day. pyrazinamide (Z):daily dose (gm)1.5(weight <50kg);1.5(weight≥50kg),use method:1～3 times/day. Pyrazinamide (High dose):daily dose (gm)1.75(weight <50kg);2.0(weight≥50kg),use method:1～2 times/day. clofazimine（Cfz）:daily dose (gm)0.15(weight <50kg);0.15(weight≥50kg),use method:1～3times/day. prothionamide（Pto）:daily dose (gm)0.6(weight <50kg);0.6(weight≥50kg),use method: 3 times/day. ……………………………………………………………………………………………………………
7. Patient follow up After 6-months standard treatment or 4-months short term PRS regimen treatment, subjects will have long term follow up to evaluate efficacy and ensure absence of relapse. The checkup times are at 1 month, 3 months, 6 months, 12 months and 24 months.

Evaluation of Efficacy i Bacteriology: sputum smear microscopy, culture using the Becton Dickinson Company mycobacterial growth indicator tube (MGIT) system and Lowenstein-Jensen (LJ) slant culture. MGIT testing will be used to evaluate drug susceptibility .

ii Radiology: All patients undergo chest X-ray and CT scan before treatment. X-ray will be reviewed after 8 weeks of treatment and at end of treatment and during the follow-up period. CT scan will be reviewed at end of treatment.

iii Bacterial load of sputum samples will be evaluated within two weeks after the start of treatment.

iv Time to culture positivity: Time to culture positivity will be performed by MGIT culture within two months after the start of treatment.

v Evaluation of results: We shall employ the World Health Organization (WHO) uniform standards in evaluating cure rate and treatment success rate, the sputum negative conversion rate, incidence of adverse events and patient compliance and other indicators. We shall compare these outcomes between the experimental group and the standard group to analyze the effect of each treatment regime.