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Submitted by: Quintiles 2016-07-25 00:00:00 Last Updated by: Quintiles 2020-08-14 16:02:08


A Phase 2, Open-label, Multicenter, Single-arm Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Anti-mycobacterial Activity of TMC207 in Combination With a Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) Medications for the Treatment of Children and Adolescents 0 Months to < 18 Years of Age Who Have Confirmed or Probable Pulmonary MDR-TB

PHRR160801-001314

TMC207-C211

2016-CT0344

A Phase 2, Open-label, Multicenter, Single-arm Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Anti-mycobacterial Activity of TMC207 in Combination With a Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) Medications for the Treatment of Children and Adolescents 0 Months to Confirmed or Probable Pulmonary MDR-TB

This is an open-label, multicenter, single-arm Phase 2 study to evaluate the pharmacokinetics, safety, tolerability and anti-mycobacterial activity of TMC207 in combination with a background regimen of MDR-TB medications for the treatment of children from birth (0 months) to < 18 years of age who have been diagnosed with confirmed or probable pulmonary MDR-TB and who will initiate or have already begun MDR-TB treatment.

The study will consist of a screening phase, an open-label treatment phase during which subjects will receive TMC207 in addition to a background regimen of MDR-TB medications, and a follow-up phase. The background regimen will be in accordance with the World Health Organization (WHO) guidelines for treatment of MDR-TB, National Tuberculosis Program (NTP) treatment guidelines and current standard of care at the site. Upon completion of the 24-week treatment with TMC207, all subjects will continue to receive their background regimen under the care of the investigator. All subjects with positive cultures will receive a minimum of 52 weeks of background regimen treatment after sputum conversion. Subjects without positive culture will receive their background regimen treatment according to the WHO or NTP guidelines. All subjects will be followed until 120 weeks post-baseline to collect long-term safety, tolerability, efficacy, pharmacokinetics, and anti-mycobacterial information.

Subjects who prematurely discontinue from study drug and study procedures will be followed up for survival until 120 weeks post-baseline, unless they withdraw from the study (ie, withdraw consent/assent).

At least 60 subjects will be enrolled in this study with 15 subjects planned in each age cohort:
• Cohort 1: ≥12 to • Cohort 2: ≥5 to • Cohort 3: ≥2 to • Cohort 4: 0 months to
Cohorts will be enrolled sequentially, beginning with the oldest age cohort.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2016-10-01 48 2020-10-01 0000-00-00

Ongoing

Institution Classification Region LTO #
Janssen Research and Development LLC Private Business United States of America Not Applicable
Institution Classification Region LTO #
Quintiles Philippines, Inc. Private Business NCR CDRR-NCR-CRO-2
Institution Region
Janssen Research and Development LLC United States of America
Name E-Mail Institution and Institution Address
MARIA INEZ G. PACIA QMNL.HealthRegistrymailbox@quintiles.com 41F Unionbank Plaza Bldg., Meralco Ave., cor. Onyx Road, Ortigas Center, Pasig City, 1600
Name E-Mail Institution and Institution Address
Roberto Salvino rsalvino@its.jnj.com Edison Road,Barrio Ibayo 1700 Paranaque City Philippines
Name Expertise Affiliation
Anjanette O. Reyes-De Leon, MD Pediatrician Lung Center of the Philippines
Melchor Victor Frias, IV MD Pediatrician De La Salle Health Sciences Institute
Project Location Institutional Ethics Review Board
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
De La Salle Health Sciences Institute De La Salle Health Sciences Institute Independent Ethics Committee

Tuberculosis

• to evaluate the safety and tolerability of TMC207 over a 24-week treatment period in each age cohort.
• to evaluate the pharmacokinetics of TMC207 over a 24-week treatment period in the different age cohorts, and to provide guidance on dose selection for each of the age cohorts evaluated in this study.

• to evaluate treatment outcome, including anti-mycobacterial activity of TMC207 in confirmed or probable pulmonary MDR-TB over a 24-week treatment period in each age cohort.
• to evaluate pharmacokinetic-pharmacodynamic relationships for safety and efficacy of TMC207 over a 24-week treatment period in each age cohort.
• to evaluate adherence and palatability of dispersible tablets.
• to evaluate the long-term safety, tolerability, and efficacy of TMC207 in combination with a BR of MDR-TB medications in confirmed or probable pulmonary MDR-TB over 120 weeks post-baseline (including survival follow-up in subjects who prematurely discontinue from study drug and study procedures).

Pending

  • Russia
  • South Africa

Clinical Trial

TMC207-C211

20160211090029

2016-07-19

0000-00-00

60

Unspecified

Unspecified

01 Oct 2016

Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1. Subject must be a boy or girl, aged from birth (0 months) to < 18 years at screening. Infants must be ≥37 weeks gestation at baseline.28
2. Subject must weigh > 4 kg at entry and be within the 5th and 95th percentiles (inclusive) for the subject’s age, based on the WHO child growth standards.38
3. Heterosexually active girls may participate if they are of non-childbearing potential, or if they are using effective birth control methods and are willing to continue practicing birth control methods throughout MDR-TB treatment and for 6 months after stopping TMC207 treatment, or if they are non-heterosexually active or willing to practice sexual abstinence throughout MDR-TB treatment.
4. Boys who engage in sexual activity that could lead to pregnancy of the female partner must use at minimum a male condom throughout MDR-TB treatment and for 3 months after stopping TMC207 treatment.
5. Subject must have confirmed or probable pulmonary MDR-TB (CXR is consistent with intrathoracic TB disease, eg, pleural effusion, fibrotic pleural lesions, intrathoracic lymphadenopathy), including pre-extensively drug-resistant TB (pre-XDR-TB) or XDR-TB infection, based on the case definitions of pediatric pulmonary TB as described in the International Consensus Definitions31 and in accordance with the local standard of care.

Exclusion:
1. Subject has a life expectancy < 6 months.
2. Subject has a clinically significant active medical condition or the presence of any concomitant severe illness or rapidly deteriorating health condition, including immune deficiency, which in the opinion of the investigator would prevent appropriate participation in the study, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the subject a poor candidate for a clinical study.
3. Subject is a girl who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after stopping TMC207 treatment.
4. Subject (or the mother if the potential subject is a child aged < 6 months) has a test positive for HIV at screening or within 1 month before screening.
5. Subject has known or presumed complicated or severe extrapulmonary manifestations of TB, including TB meningitis. Subjects with adenopathy or adenitis are allowed to enter the study.
6. Subject has a significant cardiac arrhythmia that requires medication or a history of risk factors for Torsade de Pointes, eg, heart failure, hypokalemia, known personal or family history of Long QT Syndrome, and untreated hypothyroidism.

Interventional

TMC207

This is an open-label, multicenter, single-arm Phase 2 study to evaluate the pharmacokinetics, safety, tolerability and anti-mycobacterial activity of TMC207 in combination with a background regimen of MDR-TB medications for the treatment of children from birth (0 months) to < 18 years of age who have been diagnosed with confirmed or probable pulmonary MDR-TB and who will initiate or have already begun MDR-TB treatment.

Date Amendment Classification Reason
2016-09-08 Amendments related to the protocol 845-02 dated 14Jul2016 primary reasons for this amendment: 1. Sections 5.2 and 5.2.2: Table 3 Metformin BID dosing was removed and the text was updated to allow the dose frequency to be defined by local labels or clinical practice guidelines. Updated to account for the differences in dose frequency across countries. 2. Sections 5.5.3 and 6: Added text and footnote to state that subjects participating in the CGM sub-study cannot use acetaminophen and/or medications containing acetaminophen for at least 24 hours prior to sensor insertion and while the sensor is being used. Acetaminophen interferes with the signal from the CGM sensor used in the trial and can potentially give falsely high readings.Additional Changes for amendment 02: 1. Section 2.1: Added text to clarify that the interval between Visit 1 and either the combined Visit 2/3/4, or Visit 2, can be no more than 2 weeks. Updated to correct a typographical error and revise allowed timeframe between Visit 1 and Visit 2 or combined Visit 2/3/4. 2. Section 2.1: Table 1 Clarified pre-randomization procedures. Updated to clarify the pre-randomization management of subjects. 3. Section 3.1: Changed ≤3.9 mmol/mol to ≤3.9 mmol/L in four of the objectives/hypotheses. Updated to correct a typographical error. 4. Section 4.1: Added text to clarify that the Investigator Brochure (IB) should be referenced for additional information on sitagliptin, including the Reference Safety Information (RSI). Updated to clarify the source for the Reference Safety Information (RSI).5. Section 5.1.2: Criteria #5: For subjects who qualify for the combined visit, the Screening Visit A1C value can be used to assess eligibility as long as the value was measured within 2 weeks, as opposed to 3 weeks, of the combined visit. Updated to correct a typographical error. 6. Sections 5.1.3, 5.5.1, and 6: Defined criteria for when subjects with elevated triglyceride (TG) levels, must be re-screened after being on a lipid-lowering regimen, as opposed to continuing in the trial. Updated to ensure patients are on a stable lipid-lowering regimen for specified amount of time prior to randomization. 7. Section 5.2: Added text to clarify that if on metformin, another DPP-4 inhibitor and a sulfonylurea, eligible subjects will discontinue the sulfonylurea and switch their other DPP-4i to sitagliptin 100 mg at Visit 2. Added text to clarify the management of subjects at Run-in.8. Section 5.2.1.2: Added text to state that the dose of sitagliptin or matching placebo cannot be modified throughout the 30-week double-blind treatment period. If a subject is suspected of having pancreatitis, study medications should be interrupted; study medications may be re-initiated if pancreatitis is not confirmed. Added to clarify the dose cannot be modified and the actions required with study medication if pancreatitis is suspected. 9. Section 5.2.1.2: Table 4 Corrected, >140 mg/dL is equivalent to >7.8 mmol/L not 10 mmol/L. Updated to correct a typographical error. 10. Section 5.5: Any medications taken by the subject within 15 weeks of Visit 1/Screening, including AHA medications, should be recorded on the appropriate electronic case report form (eCRF). Updated to correct the length of time, prior to Visit 1, for which subjects must documents all medications.11. Sections 5.5.1 and 6: Defined criteria for when subjects with elevated blood pressure, must be re-screened after being on a blood pressure-lowering regimen, as opposed to continuing in the trial. Updated to ensure patients are on a stable blood pressure-lowering regimen for specified amount of time prior to randomization. 12. Section 5.5.2: Added the following: Rapid- and intermediate- acting insulin and other basal insulins should not be taken during the trial. To clarify that only LANTUS® can be taken during this trial. 13. Section 5.8.1.2: Removed statement that subjects who continue to participate in the trial off of study medication are responsible for procurement of AHA background therapy. The sponsor will not cover the cost of non-study medications, but will cover the cost of metformin and LANTUS®.14. Section 6: Increased the visit window between Visit 3 and Visit 4, and Visit 1 to combined Visit 2/3/4 from 5 to 7 days. Updated to Allow sites and subjects a little more flexibility. 15. Section 7.1.1.8: Added the following: LANTUS® will be administered by the subject in the evening and the site will call the subject on Day 2 to record the dose and timing of administration. To clarify that LANTUS® dose administration cannot be witnessed at site on Day 1, but that the site will contact the subject the next day for follow-up.
2016-10-28 Amendments related to the protocol Informed consent
2017-04-03 Amendments related to the protocol Clinical Protocol Amendment 3 dated 07 Dec 2016; ICF - (1) Patient Adolescent Assent Form [English V05PHL01 dated 19 Jan 2017; Tagalog V05PHL(TG)01 dated 06 Feb 2017] (2) Patient Child Assent Form [English V04PHL01 dated 19 Jan 2017; Tagalog - V04PHL(TG)01 dated 06 Feb 2017] (3) Patient Information and ICF [English V06PHL01 dated 19 Jan 2017; Tagalog V06PHL(TG)01 dated 06 Feb 2017] (4) Parent/Legal Guardian Information and Permission Form [English V06PHL01 dated 19 Jan 2017; Tagalog V06PHL(TG)01 dated 06 Feb 2017]
2017-10-04 Amendments related to the protocol [1] Clinical Trial Protocol Amendment 4 dated 13 Jun 2017 [2] ICF (1) Patient Adolescent Assent Form (a) English Patient Adolescent Assent Form V06PHL01 dated 20 Jun 2017 (b) Tagalog Patient Adolescent Assent Form V06PHL(TG)01 dated 28 Jun 2017 (2) Patient Child Assent Form (a) English Patient Child Assent Form V05 PHL01 dated 20 Jun 2017 (b) Tagalog Patient Child Assent Form V05 PHL(TG)01 dated 28 Jun 2017 (3) Patient Information and Informed Consent Form (a) English Patient Information and Informed Consent Form V07 PHL01 dated 26 Jul 2017 (b) Tagalog Patient Information and Informed Consent Form V07 PHL(TG)01 dated 26 Jul 2017 (4) Parent/Legal Guardian Information and Permission Form (a) English Parent/Legal Guardian Information and Permission Form V07 PHL01 dated 26 Jul 2017 (b) Tagalog Parent/Legal Guardian Information and Permission Form V07 PHL(TG)01 dated 26 Jul 2017
2020-09-23 Amendments related to the trial arrangements Site Recruitment Posters cohort 3 v02 and cohort 4 v03
2019-10-21 Amendments related to the protocol TMC207-C211 DOT Card Cohort 3 (age 2 - 4)

Unspecified

Open Label

Unspecified

Unspecified

This is an open-label, multicenter, single-arm Phase 2 study to evaluate the pharmacokinetics, safety, tolerability and anti-mycobacterial activity of TMC207 in combination with a background regimen of MDR-TB medications for the treatment of children from birth (0 months) to < 18 years of age who have been diagnosed with confirmed or probable pulmonary MDR-TB and who will initiate or have already begun MDR-TB treatment.

Phase II

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