TMC207-TiDP13-C208: Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Participants With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).

Conditions

Tuberculosis

Keywords

Tuberculosis, MDR TB

Brief summary

The objective of this study is to demonstrate that the antibacterial activity of TMC207 is better than placebo when added to a standardized Background Regimen (BR) for treatment of multi-drug resistant TB. Also safety and tolerability will be evaluated.

Detailed description

The trial will be conducted in 2 consecutive stages, an exploratory (investigative) stage (Stage 1) and a proof of effectiveness stage (Stage 2). During Stage 1, a panel of 50 participants will be randomized (participants are assigned different treatments based on chance) to receive either TMC207 or placebo for 8 weeks on top of a BR. In Stage 2, another panel of 150 participants will be randomized to receive either TMC207 or placebo for 24 weeks on top of a BR. TMC207 will be dosed as 400 mg every day for the first 2 weeks, and as 200 mg 3 times/week for the following 6 or 22 weeks during Stages 1 and 2, respectively. When the participants in Stage 1 have completed 8 weeks double-blind (neither theparticipant nor the physician knows whether drug or placebo is being taken, or at what dosage) treatment with TMC207 or placebo (or have discontinued earlier), the primary Stage 1 analysis will be performed on all data of the first 8 weeks of treatment. Following this Stage 1 analysis, Stage 2 will be initiated and a panel of 150 new participants will be enrolled. After the double-blind treatment phase in both Stage 1 and Stage 2, participants will continue to receive MDR-TB treatment as per national treatment guidelines. They will be followed for safety, tolerability, pharmacokinetics, and microbiological efficacy for 96 weeks after receiving their last dose of TMC207 or placebo. The Data Safety Monitoring Board Committee will review these data on a regular basis. The DSMB/DSMC is a group of experts in tuberculosis and clinical trial conduct who have no commercial interests in the development of TMC207 and the company (Tibotec, BVBA) that is developing the new TB drug.

Guglielmetti L, Ardizzoni E, Atger M, Baudin E, Berikova E, Bonnet M, Chang E, Cloez S, Coit JM, Cox V, de Jong BC, Delifer C, Do JM, Tozzi DDS, Ducher V, Ferlazzo G, Gouillou M, Khan A, Khan U, Lachenal N, LaHood AN, Lecca L, Mazmanian M, McIlleron H, Moschioni M, O'Brien K, Okunbor O, Oyewusi L, Panda S, Patil SB, Phillips PPJ, Pichon L, Rupasinghe P, Rich ML, Saluhuddin N, Seung KJ, Tamirat M, Trippa L, Cellamare M, Velásquez GE, Wasserman S, Zimetbaum PJ, Varaine F, Mitnick CD.

2021-09-2522 citations

10.1186/s13063-021-05491-3

Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial

Paul Meyvisch, Chrispin Kambili, Koen Andries, Nacer Lounis, Myriam Theeuwes et al. (10 authors)

PLoS ONE2018-07-1917 citations

10.1371/journal.pone.0200539

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Alexander S. Pym, Andreas H. Diacon, Shenjie Tang, Francesca Conradie, Manfred Danilovitš et al. (16 authors)

European Respiratory Journal2015-12-02333 citations

10.1183/13993003.00724-2015

Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline

Andreas H. Diacon, Alexander S. Pym, Martin P. Grobusch, Jorge M. de los Rios, Eduardo Gotuzzo et al. (16 authors)

New England Journal of Medicine2014-08-20737 citations

10.1056/nejmoa1313865

The diarylquinoline TMC207 for multidrug-resistant tuberculosis.

Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF.

2009-06-01557 citations

10.1056/nejmoa0808427

Interventions

DRUGTMC207

TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.

DRUGPlacebo

Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.

DRUGBackground regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)

Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

No

Inclusion criteria

* Females of non-childbearing potential * Patients with newly diagnosed sputum smear-positive pulmonary MDR-TB infection * Patients must consent to HIV-testing * Patients must be willing to discontinue all TB drugs to allow 7 days washout * Patients having normal weight * Patients are willing to be hospitalized per standard of care.

Exclusion criteria

* Previously having been treated for MDR-TB * Having a significant cardiac arrhythmia that requires medication * For HIV infected patients, having a CD4+ count \< 300 cells/µL * Patients with complicated or severe extrapulmonary manifestations of TB or neurological manifestations of TB * Patients who will require surgical procedure for management of their TB * Evidence of chorioretinitis, optic neuritis, or uveitis at screening * Having had a drug susceptibility test performed prior to screening and being not susceptible to at least 3 of the 5 classes of TB drugs used to treat MDR-TB * Women who are pregnant and/or breastfeeding.

Design outcomes

Primary

Measure	Time frame	Description
The Time to Sputum Culture Conversion at Week 8 (Stage 1)	Week 8, Stage 1	The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
The Time to Sputum Culture Conversion at Week 24 (Stage 2)	Week 24, Stage 2	The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.

Secondary

Measure	Time frame	Description
The Time to Sputum Culture Conversion at Week 24 (Stage 1)	Week 24, Stage 1	The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
The Time to Sputum Culture Conversion at Week 72 (Stage 2)	Week 72, Stage 2	The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 8, 24, and 104 (Stage 1)	The table below shows the percentage of participants in Stage 1 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders.
The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 24, Week 72, and Week 120 (Stage 2)	The table below shows the percentage of participants in Stage 2 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders.

Countries

Brazil, India, Latvia, Peru, Philippines, Russia, South Africa, Thailand

Participant flow

Recruitment details

This trial consisted of an exploratory stage (Stage 1) and a proof-of-efficacy stage (Stage 2). Different participants were enrolled in each stage. Participants in Stage 2 who met protocol-specified criteria were offered open-label treatment with TMC207 after Week 24 (ie, rollover arm).

Pre-assignment details

A total of 208 participants were randomized and 207 (47 participants in Stage 1 and 160 participants in Stage 2) started treatment with placebo or TMC207 (1 participant did not receive study drug). One placebo participant in Stage 2 rolled-over to treatment with TMC207 after Week 24.

Participants by arm

Arm	Count
TMC207 / BR (Stage 1) Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 8.	23
Placebo / BR (Stage 1) Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8.	24
TMC207 / BR (Stage 2) Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24.	79
Placebo / BR (Stage 2) Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 24.	81
Total	207

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	0	0	3	5
Overall Study	Death	1	0	6	1
Overall Study	Inclusion/exclusion criteria not met	0	0	2	6
Overall Study	Lost to Follow-up	1	1	5	3
Overall Study	Other	1	4	1	0
Overall Study	Pregnancy	0	0	3	2
Overall Study	Protocol Violation	4	4	3	7
Overall Study	Rolled-over to treatment with TMC207	0	0	0	1
Overall Study	Withdrawal by Subject	3	4	6	7

Baseline characteristics

Characteristic	TMC207 / BR (Stage 1)	Placebo / BR (Stage 1)	TMC207 / BR (Stage 2)	Placebo / BR (Stage 2)	Total
Age, Continuous	35.6 years STANDARD_DEVIATION 11.66	33.6 years STANDARD_DEVIATION 11.04	36.2 years STANDARD_DEVIATION 13.13	35.8 years STANDARD_DEVIATION 11.01	35.7 years STANDARD_DEVIATION 11.88
Sex: Female, Male Female	5 Participants	7 Participants	27 Participants	32 Participants	71 Participants
Sex: Female, Male Male	18 Participants	17 Participants	52 Participants	49 Participants	136 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	21 / 23	23 / 24	75 / 79	75 / 81
serious Total, serious adverse events	1 / 23	1 / 24	18 / 79	15 / 81

Outcome results

Primary

The Time to Sputum Culture Conversion at Week 24 (Stage 2)

The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.

Time frame: Week 24, Stage 2

Population: The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy.

Arm	Measure	Value (MEDIAN)
TMC207 / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 24 (Stage 2)	83 Days
Placebo / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 24 (Stage 2)	125 Days

p-value: <0.000195% CI: [1.57, 3.8]Cox proportional hazards model

Primary

The Time to Sputum Culture Conversion at Week 8 (Stage 1)

The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.

Time frame: Week 8, Stage 1

Population: The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy.

Arm	Measure	Value (MEDIAN)
TMC207 / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 8 (Stage 1)	51 Days
Placebo / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 8 (Stage 1)	NA Days

p-value: 0.003495% CI: [2.26, 61.23]Cox proportional hazards model

Secondary

The Percentage of Participants With Sputum Culture Conversion (Stage 1)

The table below shows the percentage of participants in Stage 1 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders.

Time frame: Week 8, 24, and 104 (Stage 1)

Population: The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy.

Arm	Measure	Group	Value (NUMBER)
TMC207 / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 8	47.6 Percentage of Participants
TMC207 / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 24	81.0 Percentage of Participants
TMC207 / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 104 (Stage 1 Trial End)	52.4 Percentage of Participants
Placebo / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 8	8.7 Percentage of Participants
Placebo / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 24	65.2 Percentage of Participants
Placebo / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 1)	Week 104 (Stage 1 Trial End)	43.5 Percentage of Participants

Comparison: Week 8p-value: 0.00395% CI: [13.97, 63.88]Regression, Logistic

Comparison: Week 24p-value: 0.23795% CI: [-10.7, 42.17]Regression, Logistic

Comparison: Week 104 (Stage 1 Trial End)p-value: 0.556495% CI: [-21.37, 39.18]Regression, Logistic

Secondary

The Percentage of Participants With Sputum Culture Conversion (Stage 2)

The table below shows the percentage of participants in Stage 2 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders.

Time frame: Week 24, Week 72, and Week 120 (Stage 2)

Population: The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy.

Arm	Measure	Group	Value (NUMBER)
TMC207 / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 24	78.8 Percentage of Participants
TMC207 / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 72	71.2 Percentage of Participants
TMC207 / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 120	62.1 Percentage of Participants
Placebo / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 24	57.6 Percentage of Participants
Placebo / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 72	56.1 Percentage of Participants
Placebo / BR (Stage 1)	The Percentage of Participants With Sputum Culture Conversion (Stage 2)	Week 120	43.9 Percentage of Participants

Comparison: Week 24p-value: 0.00895% CI: [5.59, 36.83]Regression, Logistic

Comparison: Week 72p-value: 0.06995% CI: [-1.21, 31.51]Regression, Logistic

Comparison: Week 120p-value: 0.03595% CI: [1.28, 35.08]Regression, Logistic

Secondary

The Time to Sputum Culture Conversion at Week 24 (Stage 1)

The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.

Time frame: Week 24, Stage 1

Population: The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy.

Arm	Measure	Value (MEDIAN)
TMC207 / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 24 (Stage 1)	70 Days
Placebo / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 24 (Stage 1)	126 Days

p-value: 0.002295% CI: [1.51, 6.53]Cox-proportional hazards model

Secondary

The Time to Sputum Culture Conversion at Week 72 (Stage 2)

The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.

Time frame: Week 72, Stage 2

Population: The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy.

Arm	Measure	Value (MEDIAN)
TMC207 / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 72 (Stage 2)	86 Days
Placebo / BR (Stage 1)	The Time to Sputum Culture Conversion at Week 72 (Stage 2)	168 Days

Comparison: MGIT negative (Responders)p-value: 0.02995% CI: [1.05, 2.59]Cox proportional hazards model

TMC207-TiDP13-C208: Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Participants With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

The Time to Sputum Culture Conversion at Week 24 (Stage 2)

The Time to Sputum Culture Conversion at Week 8 (Stage 1)

The Percentage of Participants With Sputum Culture Conversion (Stage 1)

The Percentage of Participants With Sputum Culture Conversion (Stage 2)

The Time to Sputum Culture Conversion at Week 24 (Stage 1)

The Time to Sputum Culture Conversion at Week 72 (Stage 2)