Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04094012 |
| Other study ID # |
201812127MINB |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
September 24, 2019 |
| Est. completion date |
December 15, 2023 |
Study information
| Verified date |
December 2023 |
| Source |
National Taiwan University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Successful implement of preventive therapy for subjects with latent tuberculosis infection
(LTBI) is the critical step for elimination of tuberculosis (TB). The major obstacle of
traditional preventive therapy is the unacceptable long treatment duration, taking isoniazid
5mg/kg daily for a total of 9 months (9H), thus seriously compromising its acceptability.
With the introduction of 12-doses weekly high-dose (15 mg/kg) rifapentine plus isoniazid (3HP
regimen), the completion rate of 3HP has be shown to be much higher than 9H. However, 4.9% to
9.1% of LTBI cases who received 3HP failed to complete treatment because of side effects.
Systemic drug reactions (SDRs), even hypotension and shock, under 3HP treatment are higher
than 9H treatment.
A recent study in HIV patients demonstrated that a new short-term regimen, consisting of
isoniazid 5mg/kg plus rifapentine 10mg/kg daily for one month (1HP), has a similar risk of
adverse reactions as 3HP. Clinical study with head-to-head comparison between 3HP and 1HP,
however, remains lacking.
The prospective multicenter study is conducted to investigate whether risk of SDRs under 1HP
is lower than that under 3HP.
Hypothesis: 1HP has a lower incidence rate of SDRs than 3HP
Objectives:
1. To compare the risk of SDRs in 1HP treatment and in 3HP treatment
2. To explore side effect profile of 1HP
Methods:
This multicenter randomized control trial will compare the risk of SDRs under conventional
3HP regimen (Arm 1: 3HP), and a new regimen consisting of daily rifapentine (10 mg/kg) plus
isoniazid (5 mg/kg) for 1 month (Arm 2: 1HP).
Description:
Tuberculosis (TB) remains one of the deadliest infectious diseases, with an estimated 10.0
million new cases and 1.6 million deaths in 2017. The World Health Organization (WHO) has set
the goal of eliminating TB as a public health problem, aiming to achieve 90% and 95%
reductions in the TB incidence and number of TB deaths by 2035. Latent tuberculosis infection
(LTBI), a status of persistent immune response to stimulation by Mycobacterium tuberculosis
antigens without clinically manifest active TB, has a 10% risk of progressing to active TB
and has thus emerged as a critical target for improving TB control and elimination.
The effectiveness of LTBI programmes has long been limited. In 1999, real-world data obtained
from an inner-city population in Atlanta, Georgia in the United States revealed that only 27%
of subjects receiving isoniazid (INH) preventive therapy completed their treatment. A 2016
meta-analysis including 748,572 subjects in 58 studies also found poor completion of LTBI
programmes, with a 60% treatment completion rate. With the introduction of rifapentine (RPT),
a rifamycin with much longer half-life than rifampin, the duration of a modern preventive
regimen termed 3HP comprising RPT and INH could be shortened to 12 doses administered weekly,
with the completion rate approaching 90%. However, 3.8% of those receiving 3HP experience
systemic drug reactions (SDRs). The risks of severe adverse event (AE) and SDRs are even
higher among subjects >35 years old.
To date, little has been discovered regarding the risk factors or predictors of SDRs due to
3HP therapy. In a pharmacokinetics study of once-weekly RPT treatment in 35 TB patients
during continuation phase therapy, serious AEs were not linked with a higher area under the
plasma concentration-time curve (AUC0~∞) of RPT. Furthermore, no studies have reported on
plasma INH levels after once-weekly INH treatment or the association between plasma INH level
and AE development. Under the support of the Taiwan Centers for Disease Control (TCDC), a
prospective multicenter observational study was conducted in Taiwan since 2016 to investigate
the correlation between SDRs and plasma concentrations of INH, RPT and their major
metabolites - acetyl-isoniazid (AcINH) and desacetyl-rifapentine (DeAcRPT). Preliminary
results from 129 LTBI cases showed that those with SDRs and those without SDRs had similar
plasma concentrations of the 4 compounds at either post-dose 6 or 24 hours (C6 or C24),
except that the C24 plasma INH concentration was significantly higher in the SDRs group.
Furthermore, generalised estimating equation (GEE) model revealed that C24 plasma INH level
was associated with a higher risk of SDR development (OR [95% CI]: 1.61 [1.15-2.25], p =
0.006). By contrast, C24 plasma RPT level was not associated with a higher risk of SDR
development (OR [95% CI]: 1.01 [1.00-1.02], p = 0.218).
The 3HP regimen is among the four regimens for LTBI that is recommended by the WHO and is
also probably the most promising regimen because of its convenience, with only 12 doses
requried. With its effectiveness well established, the major remaining concern regarding 3HP
may be its AEs. Studies have estimated that 4.9% to 9.1% of those in close contact with
patients with open TB and who received 3HP failed to complete the regimen because of the side
effects.8,10 While on the 3HP regimen, SDRs have generally been linked with RPT, which has a
well-known side effect: flu-like syndrome. Additionally, RPT is a newer agent, making it a
possible contributor to SDRs given that a higher SDR rate was observed compared with other
INH-containing regimens. Some scholars, however, have argued against this point. First, one
study using the 3HP regimen demonstrated that rechallenge with RPT did not necessarily lead
to SDRs. In the same study, rifapentine was better tolerated than isoniazid upon rechallenge.
In another study involving 1200 mg of RPT once weekly as continuation therapy for active TB,
no SDRs were linked with RPT. Finally, in a study of 162 pulmonary TB patients receiving RPT
with a dosage of more than 15mg/kg daily, no patients developed SDRs. In literature review,
we discovered that among reports describing an association between RPT and flu-like symptoms,
RPT was commonly coadministered with INH. Furthermore, in cases describing an association
between INH and flu-like symptoms, the associations were all proven with rechallenge.
Although a less well-known effect than that of RPT, INH can also lead to flu-like syndrome.
Of the patients with active TB who were receiving INH, usually with a dose of 300 mg/day,
1%-9.8% developed flu-like syndrome. Case reports describing the association between INH and
flu-like syndrome have also been published. In the 3HP regimen, INH dosage is 900 mg/week,
and no data exist regarding the proportion of cases developing SDRs under a single INH dosage
higher than this.
Some hypotheses could possibly explain the association between the high INH dose and SDRs
during 3HP therapy. First, since INH could bind to key enzymes in cytokine pathways such as
peroxidase, a high plasma level of INH may activate pathways which are not activated under
usual dose of INH due to low binding affinity. Second, the high plasma INH level may
interfere with or interact with rifapentine metabolite, resulting in SDRs. Rifapentine,
however, did not affect INH pharmacokinetics. Interestingly, a study investigating drug-drug
interactions between dolutegravir and once weekly RPT plus INH also revealed a higher INH AUC
among those who develop toxicities and a higher INH level among two cases experiencing severe
flu-like syndrome. In summary, our preliminary results and recent publications support the
association between INH and SDR development because INH drug level, rather than RPT drug
level, was discovered to be associated with SDR development, and the short duration and rapid
resolution of symptoms in some cases may indicate that a rapidly metabolised drug was the
causative agent.
Because rather high doses of INH and RPT are used in 3HP regimen and safety remains a big
concern in preventive therapy and program roll-out, a new regimen, consisting of daily INH
300 mg and RPT 600 mg (450 mg if body weight <45.0 kg) for one month was compared with 9H in
a large international, open-label RCT enrolling 3000 people living with HIV, so called the
BRIEF TB trial. During follow-up, the incidence of active TB was 0.65 vs. 0.67 per 100
person-years in the 1HP and 9H groups, respectively, showing non-inferiority of the
ultra-short course of preventive therapy. However, the incidence rate of targeted safety
events (liver, gastrointestinal, neurologic, skin or hypersensitivity) was lower with the 1HP
regimen (2.9% [2.2 - 3.9%]) than with 9H regimen (4.7% [3.6 - 6.0%], p = 0.016). Treatment
completion rates were significantly higher among people taking 1HP (97 vs. 91%, p < 0.01).
Because in the PREVENT TB trial the 3HP group had a significantly higher risk of adverse
events than the 9H group, the preliminary results of the BRIEF TB trial suggest that by daily
use of a relative small dose for both INH and RPT, the 1HP regimen, can be more tolerable
than 3HP regimen.
In summary, there remains so many unknowns in rifapentine-based preventive therapy. Further
study is necessary to consolidate the finding that INH may play a role in the development of
SDRs during 3HP therapy, as well as to evaluate the completion rate and safety profile of 1HP
therapy. Therefore, we conduct this prospective multicenter study to investigate whether risk
of SDRs under 1HP is lower than that under 3HP.
Research Hypothesis: 1HP has a lower incidence rate of SDRs than 3HP
Objectives:
1. To compare the risk of SDRs in 1HP treatment and in 3HP treatment
2. To explore side effect profile of 1HP
