Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine for Treatment of Patients With MDR-TB

Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least isoniazid and rifampicin, the two most important anti-TB drugs. It occurs in 3.6% of newly diagnosed TB patients in the world and 17% of patients who have been previously treated. In 2017, approximately 558,000 people were estimated to have acquired MDR-TB. However, only 25% of persons with MDR-TB were diagnosed and started on treatment, reflecting inadequate diagnostic capacity and lack of TB treatment capacity.

The investigators propose to randomize participants with MDR-TB to 16 or 24 weeks of treatment with a 5-drug oral experimental regimen or to the standard World Health Organization (WHO) 9-11-month regimen (the "control" regimen). The primary objective is to assess the non-inferiority of the 24-week experimental regimen. In addition, the study also aims to examine the non-inferiority of an even shorter (16-week) regimen. The proposed investigational regimen combines two new drugs, bedaquiline (BDQ) and delamanid (DLM), with three anti-TB agents of known potency, linezolid (LZD), levofloxacin (LFX), and clofazimine (CF), to provide a shorter, better-tolerated and more effective MDR-TB treatment regimen for persons with fluoroquinolone-susceptible MDR-TB. This regimen can be expected to be effective for the vast majority of MDR-TB patients throughout the world.

Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least isoniazid and rifampicin, the two most important anti-TB drugs, and it accounts for 3.6% of newly diagnosed TB patients in the world and 17% of patients who have been treated in the past. In 2017, approximately 558,000 new people were estimated to have developed MDR-TB, and approximately 8.5% of the cases had extensively drug-resistant tuberculosis (XDR-TB).(3) However, only 25% of persons with MDR-TB were diagnosed and started on treatment.The recent roll-out of the genotypic test GeneXpert? has greatly expanded the diagnosis of MDR-TB,(3) and thus a substantial increase in the demand for MDR-TB treatment is anticipated.

In 2016, the World Health Organization (WHO) endorsed a shortened treatment regimen for a subset of patients with MDR-TB.(1, 2) In a recent clinical trial, this regimen was able to achieve 78% cure.(4) This 9-11-month regimen, also known as the "Bangladesh regimen", uses 7 drugs given for 9 months including an injectable agent, which is the cause of the most common and severe toxicities seen when treating MDR-TB. In some reports, the regimen has been found to be associated with as many as 63% of participants experiencing adverse drug reactions.(5) In 2018, WHO updated its guidance recommending consideration of this regimen only in patients who do not have any of the following: resistance to or suspected ineffectiveness of any drug in the regimen (other than isoniazid); exposure to any second-line drug in the regimen for >1 month; intolerance or risk of toxicity to any of the drugs; pregnancy; disseminated TB or extrapulmonary TB in human immunodeficiency virus (HIV) -coinfected patients.(2) Thus, while this regimen is shorter than the WHO 20-24 month regimen, it does not provide an easily tolerated alternative, largely because it contains an injectable agent and because its use is somewhat restricted by the inclusion/exclusion criteria. This regimen is now being rolled out worldwide for eligible patients.

This is a multicenter, randomized, partially blinded, three-arm, phase 3, controlled clinical trial in patients with MDR-TB comparing the efficacy and tolerability of two durations (16 and 24 weeks) of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine (investigational arms) with the WHO-recommended 9 to 11 month regimen containing injectables (control arm).

Primary Aims:

1. Determine if 24 weeks of the investigational regimen is non inferior to the WHO 9 to 11 month regimen.
2. Determine if 16 weeks of the investigational regimen is non inferior to the WHO 9 to 11 month regimen.

3. Describe the safety profiles of the investigational regimens and the standard WHO 9 to 11 month regimen in a randomized trial.

   Secondary Aims:

4. Conduct a QT safety run-in substudy to characterize the frequency, magnitude, and time course of corrected QT interval (QTcF) prolongation associated with the study regimen; and, in the event extreme increases in QTcF and increased proarrhythmic risk are observed, to identify relevant clinical risk factors.
5. Describe the relationship between duration of the oral regimen and safety and tolerability of the regimen.
6. Estimate the minimum duration of the experimental regimen that is non-inferior to the WHO standard 9-month regimen.
7. Describe the relationship between the duration of the oral regimen and the proportion of successful outcomes in the following subpop¬ulations: HIV-infected persons, persons with extensive pulmonary disease, persons with greater baseline bacterial burden in sputum.
8. Collect biospecimens from consenting participants for the purpose of research on discovery and validation of TB biomarkers.
9. Evaluate survival at 132 weeks post randomization.

The proposed study asks an important research question that will yield essential information for improved MDR-TB treatment. Results will inform composition of combination regimens, and reducing the duration of treatment from 9 to 6 months (24 weeks) or less would not only reduce the time over which patients were exposed to potential drug toxicities, but also free up program staff to treat additional TB patients. Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability of programs to keep up with the anticipated increase in patients needing treatment. Moreover, the study can be implemented promptly after funding is awarded. The results of the proposed trial will immediately be applied to reformulating MDR-TB treatment standards throughout the world.

• Drug: Delamanid

  Frequency: daily Route of administration: oral

  Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

  Other Name: Deltyba
• Drug: Levofloxacin

  Frequency: daily Route of administration: oral

  Levofloxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

  Other Name: Levaquin
• Drug: Bedaquiline

  Frequency: daily Route of administration: oral

  Bedaquiline is indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.

  Other Name: Sirturo
• Drug: Clofazimine

  Frequency: daily Route of administration: oral

  Clofazimine has shown activity against multidrug-resistant tuberculosis (MDR-TB) and is now recommended by the World Health Organization (WHO) to treat drug resistant tuberculosis as a "Group B" drug. It is thought that clofazimine acts by inhibiting the formation of matrixes within the DNA and thus delaying the growth of the bacterium. Clofazimine first received FDA approval in 1986, although its use in the treatment of MDR-TB has not been approved by any stringent regulatory authorities and it is therefore used "off-label" for this function.

  Other Name: Lamprene
• Drug: Linezolid

  Frequency: daily Route of administration: oral

  Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

  Other Name: Zyvox
• Combination Product: WHO approved MDR-TB treatment regimens

  In patients with Rifampicin-resistant (RR-TB) or MDR-TB who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of the longer regimens.

  In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines - one chosen from Group A, one from Group B, and at least two from Group C1 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five.

  In patients with RR-TB or MDR-TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (1).

  Other Name: WHO 9-11 month regimen

• Experimental: Investigational: DRAMATIC-16 weeks
  delamanid 200 mg orally, by mouth (PO) once a day (QD), 16 weeks levofloxacin 1000 mg PO QD, 16 weeks clofazimine 100 mg PO QD, 16 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder, 16 weeks linezolid 1200 mg PO QD, 16 weeks
  Interventions:

  • Drug: Delamanid
  • Drug: Levofloxacin
  • Drug: Bedaquiline
  • Drug: Clofazimine
  • Drug: Linezolid
• Experimental: Investigational: DRAMATIC-24 weeks
  delamanid 200 mg PO QD, 24weeks levofloxacin 1000 mg PO QD, 24 weeks clofazimine 100 mg PO QD, 24 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder, 24 weeks linezolid 1200 mg PO QD, 24 weeks
  Interventions:

  • Drug: Delamanid
  • Drug: Levofloxacin
  • Drug: Bedaquiline
  • Drug: Clofazimine
  • Drug: Linezolid
• Active Comparator: Control: WHO 9-11 mo
  World Health Organization (WHO) approved MDR-TB treatment regimens(1)
  Intervention: Combination Product: WHO approved MDR-TB treatment regimens

• 1. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis: 2016 update. Geneva, Switzerland. 2016.
• 2. World Health Organization. Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva, Switzerland. 2018.
• 3. World Health Organization. Global tuberculosis report. 2018.
• 4. International Union Against Tuberculosis and Lung Disease. STREAM clinical trial results provide vital insight into nine-month treatment regimen for multidrug-resistant tuberculosis. 2017. Available from: http://guadalajara.worldlunghealth.org/media/conference-news/updates/st….
• Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, Hanki Y, Van Deun A. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis. 2014 Oct;18(10):1188-94. doi: 10.5588/ijtld.13.0075.

Inclusion Criteria:

1. Males and females age ?12 years. If ?18 years of age, is able to provide informed consent; if <18 years of age, is able to provide informed assent and has a parent or guardian who is able to provide informed consent on the participant's behalf.
2. Has pulmonary tuberculosis (TB) based on investigator assessment of all available information (e.g., chest x-ray, sputum smear, culture, molecular testing).
3. Has a sputum sample that is positive for M. tuberculosis (MTB) that is rifamycin-resistant and fluoroquinolone-susceptible by molecular assay.
4. Is human immunodeficiency virus (HIV) seropositive or seronegative; HIV serostatus must be assessed at screening if either (a) HIV serostatus is unknown, or (b) the last documented negative HIV test was more than two (2) months prior to screening.
5. Willing to attend scheduled follow-up visits and undergo study assessments.
6. Women with child-bearing potential must agree either (a) to practice an adequate birth control (defined as one of the following oral contraceptives, intrauterine devices, contraceptive implants under the skin, contraceptive rings or patches or injections, diaphragms with spermicide or condoms with foam) or (b) to abstain from heterosexual intercourse during study regimen.

Exclusion Criteria:

1. Current MTB isolate is known at screening to be quinolone-resistant.
2. History of allergy (hypersensitivity) or intolerability to one or more agents in the investigational regimens (i.e., Arms 1 and 2)
3. History of serotonin syndrome
4. History of symptomatic ventricular arrhythmia or is taking anti-arrhythmic agents
5. History of optic neuropathy or peripheral neuropathy
6. History of prior treatment with delamanid or linezolid for TB
7. Has at screening received ?14 days of second-line anti-TB drugs
8. Has at screening a Karnofsky score of ?40 or, in the opinion of the Investigator, is unlikely to survive 78 weeks.
9. Has at screening > 40 decibel (dB) hearing at 4000 Hz in either ear

10. Has at screening laboratory results that meet one or more of the following criteria:

    • Hemoglobin concentration <7.0 g/dL (<70 g/L)
    • Platelet count of <80,000/mm3
    • Absolute neutrophil count (ANC) <2000/ mm3
    • Serum creatinine >2.0 mg/dL (>177 µmol/L)
    • Serum Alanine Aminotransferase (ALT) >3x upper limit of normal (ULN)
    • Total bilirubin >3x upper limit of normal (ULN)
    • Serum albumin <2.8 g/dL (<28 g/L)
    • For women of childbearing potential, a positive or indeterminant serum pregnancy test
11. For women of childbearing potential, has a positive or indeterminant urine pregnancy test on the day of randomization.
12. Has at screening a mean QT interval with Fridericia's correction (QTcF) >450 msec based on three electrocardiograms (ECGs).
13. At screening requires ongoing use of prohibited drugs indicated in section 4.2
14. At screening, has weight less than 33 Kg.

• United States Department of Defense
• Novartis Pharmaceuticals
• Pfizer
• Otsuka Pharmaceutical Co., Ltd.