Safety of Rifampicin at High Dose for the Treatment of Adult Subjects with Complex Drug Susceptible Pulmonary and Extrapulmonary Tuberculosis

Tuberculosis (TB) is an infectious disease caused by Mycobacterium
tuberculosis. TB primarily affects the lungs but can also cause disease in
other organs. In humans, TB is spread by airborne droplets originating from a
contagious individual while coughing or sneezing.
TB causes more deaths worldwide than any other infectious disease. In 2018, an
estimated 10 million people developed TB and 1.4 million died from TB.
Globally, TB is not uniformly distributed. TB hits harder in developing and
underdeveloped countries which contribute to more than 95% of total diagnosed
cases. Rapid TB diagnosis is based on molecular and microscopic detection of M.
tuberculosis bacilli in biological specimens from patients (sputum,
cerebrospinal fluid, pleural fluid, lymph node aspirate among others). In the
absence of microscopic and/or molecular evidence, TB is also diagnosed based on
the clinical picture, epidemiological data, and morphologic features
(radiological or histological). The growth of M. tuberculosis on solid or
liquid culture media remains the gold standard confirmatory test, and the
colonies are utilized for phenotypic drug susceptibility testing. The time to
sputum culture conversion in liquid media is utilized frequently in clinical
trials as a proxy marker to predict therapeutic efficacy in pulmonary TB.

Therapeutic rationale

By the late 1970s, after a series of trials conducted by the Medical Research
Council, the best drug combinations and the duration of treatment required were
worked out. The best results were achieved using an *intensive* phase of 2
months rifampicin, isoniazid and pyrazinamide, ethambutol followed by a
*continuation* phase of 4 months rifampicin and isoniazid. Rifampicin is the
backbone drug in the treatment of DS-TB due to its potent bactericidal and
sterilizing activity. The 10 mg/kg dose was selected for rifampicin based on
pharmacokinetic, toxicity and cost concerns. The cure rate is estimated at 83%
in HIV negative patients and 78% in HIV-associated TB. Current research results
show that for a concentration dependent drug like rifampicin, doses towards the
upper end of therapeutic window achieve optimal sterilizing activity and
prevent spontaneous mutations related with acquired drug resistance. It is now
widely accepted that rifampicin is currently under-dosed. This has been shown
in murine models and in phase I and phase II clinical studies. In the mouse
models published by Rosenthal and colleagues (doses up to 40mg/kg), Hu and
colleagues (doses of up to 50mg/kg) and), and Steenwinkel and colleagues (doses
up to 160mg/kg/day), a higher rifampicin exposure resulted in a faster and
complete sterilization of visceral cultures. In the studies by Boeree and
colleagues, higher rifampicin doses achieved up to 10-fold higher exposure in
plasma, resulting in a faster time to stable culture conversion in liquid media
in the 35mg/kg rifampicin group than in the 10mg/kg group, and these doses were
safe and well tolerated. The hollow fiber study by Gumbo and colleagues
evaluated the relationship between rifampicin exposure, microbial kill of
log-phase growth and suppression of mutant population and concluded that higher
rifampicin doses than those currently used would optimize the effect of
rifampicin. Therefore, increased doses might have the potential to shorten
DS-TB treatment.
In 2014, the WHO member states endorsed the End TB strategy that has three main
objectives to be accomplished by 2035 compared to the data from 2015: to reduce
the number of TB related deaths by 90%, to reduce TB incidence by 80% and to
eliminate the catastrophic costs associated to TB. In order to achieve these
objectives, the WHO stresses the need of developing innovative ways to deliver
the already available resources as well as the need of developing new
treatment, preventive and diagnostic strategies.

Participant population rationale

DS-TB treatment success rate varies greatly between countries and among
patient*s subgroups. In 2017, treatment success rate of 85% was reported for
new cases of TB with the standard treatment composed of rifampicin, isoniazid,
pyrazinamide, and ethambutol. This regimen combines early bactericidal
activities of isoniazid and rifampicin with rapid sterilizing activities
conferred by rifampicin and pyrazinamide. Nevertheless, treatment outcomes are
worse in certain patient subpopulations such as those with diabetes, liver
disease, persons living with HIV and CNS involvement. As an example, in 2017
success rate was 75% for persons living with HIV. The outcomes of these
difficult to treat patients could be improved using higher doses of rifampicin,
as suggest the results of a trial by Ruslami and colleagues, in which doses of
13 mg/kg with isoniazid and pyrazinamide improved 6-month survival rate in
Indonesian patients with TB meningitis, without an increased risk of toxicity.
Data from clinical daily practice on high-dose rifampicin for a full 6- to
12-month treatment course adds on to the available body of evidence suggesting
that higher doses (32 mg/kg) are safe and well tolerated in difficult to treat
TB patient population.

Rifampicin dose administration rationale

A retrospective observational cohort of 88 patients from Dekkerswald center in
the Netherlands with difficult-to-treat TB or initial low rifampicin plasma
levels (Cmax of <8 mg/L or AUC0-24 <41mg/L) treated with 20-32 mg/kg of
rifampicin, showed that high dose rifampicin was safe and well tolerated. All
patients completed 6-12 months of treatment with high dose rifampicin, without
an increase in rifampicin related adverse events. However, the safety and
tolerability of higher rifampicin doses need further validation in prospective
and adequately powered clinical studies before it can be recommended in the WHO
guidelines for wide use in programmatic settings, especially in patients with a
higher risk of toxicity. The randomized phase II trial in Peruvian patients by
Velásquez et al. showed higher sterilizing activity with no significant
differences in safety with doses of 15 and 20mg/kg as compared to standard
doses. In the study by Ruslami et al., high dose rifampicin showed an
important reduction of mortality in severely ill patients with TB meningitis.
Both studies excluded patients with extrapulmonary disease and, both cohorts
together, only 6 patients were living with HIV and 5 had diabetes. The results
of these studies suggest that higher doses of rifampicin could help to shorten
TB treatment, although this needs to be investigated in large phase III trials
after we have collected sufficient evidence about the safety and tolerability
of the higher dosages in a wider variety of patients.
Therefore, this study will evaluate high dose rifampicin (35 mg/kg) in
combination with standard doses of isoniazid, pyrazinamide and ethambutol in
difficult to treat TB patients, for the first 8 weeks of treatment, as this
period seems to be in which most of the bacterial killing and sterilization
take place. Clearance of M. tuberculosis bacilli from the sputum and culture
conversion during the first two months of treatment serve as a proxy for
evaluating survival rate and cure in DS-TB patients, although the cure
definition for DS-TB from the WHO requires a negative smear or culture at the
end of treatment and there is some evidence that a follow-up after the end of
treatment enhances the detection of treatment failure.

Primary Objective:
To evaluate the safety of high-dose rifampicin (35 mg/kg/d) supplemented with
standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks in adult
subjects with pulmonary or extrapulmonary DS-TB belonging to difficult to treat
subgroups.

Secondary Objective(s):
1. To evaluate the tolerability of high-dose rifampicin (35 mg/kg/d)
supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for
8 weeks in adult subjects with pulmonary or extrapulmonary TB belonging to
difficult to treat patient subgroups.

2. To evaluate the efficacy of high dose rifampicin (35 mg/kg/d) supplemented
with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks by
assessing early sterilizing activity in the sputum of pulmonary TB subjects
belonging to difficult to treat patient subgroups.

3. To compare the bactericidal activity as the proportion of sputum smear
conversion at 8 weeks.

4. To compare the time dynamics of sputum smear bacterial load decline, smear
and culture conversion.

5. To compare the relapse rate 1 year after treatment completion (extended
follow up).

6. To describe pharmacokinetics-pharmacodynamics (PK/PD) of rifampicin at high
doses in difficult-to-treat pulmonary and extrapulmonary TB.

7. To describe the association between genetic polymorphisms and differences in
AUC of rifampicin.

8. To analyse the correlation between the AUC/MIC values and the efficacy
outcomes.

9. To evaluate the response to treatment as measured by exhaled VOCs by means
of an electronic nose device, the AeoNose*.

10. To describe tuberculosis associated costs and the quality of life of DS-TB
participants

This is a phase IIb, interventional, open-label, multi-center, prospective
clinical study of high dose rifampicin (35 mg/kg, intervention group) versus
standard-dose (10mg/kg/day, historical group). High dose rifampicin (35
mg/kg/day) will be given open label during the first 8 weeks of treatment
course supplemented with standard doses of isoniazid, pyrazinamide, and
ethambutol according to the national guidelines and local protocols from the
different participating countries.

High dose rifampicin (35 mg/kg) will be given once daily for 8 weeks. After 8
weeks, participants will be switched to the standard of care as per the local
and national guidelines. Visits, diagnostic and follow-up tests,
questionnaires, and other interventions will be performed as summarized in the
study flow chart in the protocol.
We will whole blood and Dried Blood Spot (DBS) samples to analyze both
pharmacokinetics and pharmacogenetics. To assess pharmacokinetics, we will use
a limited sampling strategy (3 time points after drug dosing) in all
participants per site at week 4 of treatment. The same DBS samples will be used
to conduct a study on genetic polymorphisms and correlate these results with
the safety and tolerability data and with PK and PD data.
We will also assess quality of life and TB associated costs, using SF-12 (all
participants), the St George*s respiratory questionnaire (for pulmonary TB
participants) and the *EUSAT-RCS developed tool* to estimate TB associated
costs (up to 15 participants from the experimental arm per site, see below).

Therapeutic rationale

By the late 1970s, after a series of trials conducted by the Medical Research
Council, the best drug combinations and the duration of treatment required were
worked out. The best results were achieved using an *intensive* phase of 2
months rifampicin, isoniazid and pyrazinamide, ethambutol followed by a
*continuation* phase of 4 months rifampicin and isoniazid. Rifampicin is the
backbone drug in the treatment of DS-TB due to its potent bactericidal and
sterilizing activity. The 10 mg/kg dose was selected for rifampicin based on
pharmacokinetic, toxicity and cost concerns. The cure rate is estimated at 83%
in HIV negative patients and 78% in HIV-associated TB. Current research results
show that for a concentration dependent drug like rifampicin, doses towards the
upper end of therapeutic window achieve optimal sterilizing activity and
prevent spontaneous mutations related with acquired drug resistance. It is now
widely accepted that rifampicin is currently under-dosed. This has been shown
in murine models and in phase I and phase II clinical studies. In the mouse
models published by Rosenthal and colleagues (doses up to 40mg/kg), Hu and
colleagues (doses of up to 50mg/kg) and), and Steenwinkel and colleagues (doses
up to 160mg/kg/day), a higher rifampicin exposure resulted in a faster and
complete sterilization of visceral cultures. In the studies by Boeree and
colleagues, higher rifampicin doses achieved up to 10-fold higher exposure in
plasma, resulting in a faster time to stable culture conversion in liquid media
in the 35mg/kg rifampicin group than in the 10mg/kg group, and these doses were
safe and well tolerated. The hollow fiber study by Gumbo and colleagues
evaluated the relationship between rifampicin exposure, microbial kill of
log-phase growth and suppression of mutant population and concluded that higher
rifampicin doses than those currently used would optimize the effect of
rifampicin. Therefore, increased doses might have the potential to shorten
DS-TB treatment.
In 2014, the WHO member states endorsed the End TB strategy that has three main
objectives to be accomplished by 2035 compared to the data from 2015: to reduce
the number of TB related deaths by 90%, to reduce TB incidence by 80% and to
eliminate the catastrophic costs associated to TB. In order to achieve these
objectives, the WHO stresses the need of developing innovative ways to deliver
the already available resources as well as the need of developing new
treatment, preventive and diagnostic strategies.