Pharmacokinetic study with a loading dose of clofazimine in adult patients with nontuberculous mycobacterial disease

Current antibiotic treatment regimens of nontuberculous mycobacterial (NTM)
disease are challenging with frequent adverse events and, especially for
pulmonary NTM disease, poor cure rates (50-70%) despite an average treatment
duration of 18 months. Clofazimine (CFZ) is a promising drug for the treatment
of NTM diseases. CFZ is highly active in vitro against M. abscessus and M.
avium, the most common NTM pathogens, and shows synergy with macrolides and
amikacin. The results from limited clinical studies with CFZ-based treatment
regimens are promising. CFZ is currently considered an alternative drug for
patients with M. avium complex infections, who are intolerant of first-line
drugs. CFZ is a first-line oral drug for treatment of M. abscessus infections.
CFZ might prove to be a cornerstone in NTM treatment, but its optimal dosage is
not known. The current dose for adults is 100 mg once daily. However, due to
the complex pharmacokinetics of CFZ - it is highly protein bound, extremely
lipophilic and accumulates in fatty tissues resulting in a long elimination
half-life of ~30 days - it takes several months before steady state, and
presumably effective, concentrations are achieved. With the use of a loading
dose regimen concentrations similar to those at steady state could be reached
faster, possibly leading to improved early treatment efficacy.

The overarching aim of this study is to contribute to dose optimization of CFZ
in the treatment of NTM diseases.

The primary objective of this study is to describe the PK of CFZ, after 4 weeks
of treatment with a loading dose regimen of 300 mg once daily, in adult
patients with pulmonary or extrapulmonary NTM disease.

Secondary objectives are:
• To compare the PK of CFZ after the loading dose phase in this study,
quantified by the highest measured concentrations at approximately 1 and 4
months of treatment, with the same metric measured in a reference study without
loading dose (the PERC study; EudraCT number 2015-003786-28).
• To compare the predicted time to reach steady state concentrations of CFZ
with and without a loading dose.
• To predict PK parameters of CFZ, including AUC0-24, Cmax and C0, based on
sparse sampling at approximately 1 and 4 months of treatment in both this study
and the reference study.
• To evaluate the adequacy of the existing population PK model for CFZ derived
in TB patients for application in the NTM population.
• To assess the safety and tolerability of CFZ in this study.

This will be an explorative, single-center, one-arm, open label,
pharmacokinetic study. A number of 10 patients with pulmonary or extrapulmonary
NTM disease will be included. Patients will receive a loading dose regimen of
300 mg once daily for 4 weeks and will then continue with a standard dose of
100 mg once daily until a total 4 months of treatment with CFZ. In addition,
patients will receive other antimycobacterial drugs as per routine care
throughout the study.

All participants will receive CFZ as a loading dose regimen of 300 mg once
daily for 4 weeks and will then continue with a standard dose of 100 mg once
daily until a total 4 months of treatment with CFZ.

Potential risks:

CFZ frequently causes gastrointestinal (GI) adverse effects (nausea, vomiting,
abdominal pain, diarrhoea) as well as dermatological side-effects (dry skin,
pruritus and ichthyosis). It also frequently causes orange-brown discoloration
of the skin and bodily fluids which can develop within a few weeks and it may
take months to years to resolve after discontinuation of treatment. Depression
and even cases of suicide have been reported as a result of skin discoloration.
In addition, conjunctival and corneal pigmentation occur often.
A potential for QT prolongation has been reported, but no significant QT
prolongation was observed in a recent report of a small cohort of patients with
NTM infection treated with CFZ.
Rare side-effects of CFZ include hepatitis, jaundice, spleen infarction, GI
haemorrhage, hyperbilirubinemia, eosinophilia, anaemia, hyperglycaemia,
hypokalaemia, headache, dizziness, somnolence, fatigue, 'Bull's eye'
maculopathy, generalized retinal degeneration, thromboembolism and
lymphadenopathy.
Even though (mainly) GI and dermatological effects are common, the need for
discontinuation of treatment because of adverse events is uncommon. A recent
large meta-analysis showed that CFZ was among the drugs used for the treatment
of MDR-TB with the lowest incidence of adverse events leading to permanent
discontinuation of treatment (1.6 %; 95% confidence interval (0.5 - 5.3 %).
Limited data on safety of CFZ in patients with NTM disease is available. In two
studies on MAC-PD, skin discoloration was the most observed adverse event due
to CFZ, but otherwise no severe toxicity due to CFZ was observed. In one
retrospective study a large percentage (43 %) of discontinuation due to adverse
events by CFZ was reported - mainly GI disturbances and skin discoloration -
in 42 patients with M. abscessus PD. In another retrospective study 6.5% of the
92 patients treated with CFZ for MAC PD interrupted the drug due to adverse
events.

In the current study a loading dose of 300 mg once daily for 4 weeks will be
used which is higher than the standard dose of 100 mg once daily for NTM
diseases. Adverse events are thought to be dose related, but data regarding
dose-toxicity relationships are lacking. There is experience with higher doses
of CFZ, mainly in the treatment of leprosy. The recommended dose for erythema
nodosum leprosum, a serious complication of leprosy, is 300 mg per day (100 mg
three times a day) for up to 12 weeks, after which the dose is tapered. In
addition, doses of up to 300 mg/day have also been used in the treatment of
DR-TB for long treatment periods of up to 24 months and were tolerated well. In
comparison, a dose of 300 mg per day will be used for a relatively short period
in this study. In addition, the aim of using a loading dose is to achieve
concentrations similar to those at steady state faster, but not to reach
concentrations that are much higher than steady state concentrations with a
standard dose. Therefore, the loading dose in this study is expected to be
safe. Nonetheless, patients will be monitored closely during the study. This
includes monitoring for QT prolongation, because patients with NTM diseases
typically use other drugs that can cause QT prolongation (e.g. macrolides).

Potential benefit:

Clinical studies on dose-response relationships of CFZ are lacking. From a
pharmacological point of view we believe that (early) treatment efficacy could
potentially be improved by using a loading dose to achieve concentrations
similar to steady state faster. Therefore, this study could be an important
step towards dose optimization of CFZ for NTM diseases. If this turns out to be
the case, this could also be of benefit to the participants of this study.
However, this is an explorative study that focusses primarily on the PK of CFZ
and therefore no clinical benefit can be assumed at this stage. This would need
to be studied in larger future studies.

Extent of burden:

Patients with NTM diseases are being monitored closely, including regular
hospital visits, as part of standard clinical care. The study visits at day 1,
day 28, 2 months and after 4 months are in line with the regular follow-up
schedule in clinical care. The monitoring for adverse events by physical
examination (including vital signs), questioning about adverse effects,
withdrawal of a blood chemistry/hematology sample and recording of an ECG
during these visits are all part of regular clinical care. However, the
collection of the PK samples is a study procedure (10 blood samples of 4 ml
throughout the study). Also, patients are asked to keep a medication diary as
part of the study.
Furthermore, the visits on day 7 and Day 28 + 1 (visits 2 and 4) and the phone
call after 3 months of treatment are strictly study procedures.