Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis

NCT01131351 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 242-08-2102009-014944-13
• Study Type: interventional
• Target: 10
• Locations: 2 countries
• Sites: 3

Brief Summary

The purpose of this study is:

• To evaluate the safety and tolerability of orally administered OPC-67683 when administered two times daily to MDR tuberculosis (TB) participants refractory to treatment with an optimized background regimen of anti-TB medications (OBR).
• To evaluate the pharmacokinetics (PK) of OPC-67683 and metabolites.

Conditions

Tuberculosis

Keywords

MDR-TB; Dose Escalation; Phase II; Open Label; Non Controlled; Pulmonary Multidrug-Resistant Tuberculosis (MDR TB)

Outcome Measures

Primary Outcomes (14)

• Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs

  Vital signs included body weight \[kilogram (kg)\], body temperature \[degree Celsius (°C)\], heart rate \[beats per minute (BPM)\], respiratory rate (breaths/minute), systolic and diastolic blood pressure \[millimeter of mercury (mmHg)\]. The criteria for clinically significant abnormal value were: body weight (kg): increase \>=5% or decrease \>=5%; body temperature (°C): \>=38.5°C and increase of \>=1.1°C; heart rate (BPM): \>=120 bpm and increase of \>=15 bpm, or \<=60 bpm and decrease of \>=15 bpm; systolic blood pressure (mmHg): \>=160 mmHg and increase of \>=20 mmHg, or \<=90 mmHg and decrease of \>=20 mmHg; diastolic blood pressure (mmHg): \>=105 mmHg and increase of \>=15 mmHg, or \<=50 mmHg and decrease of \>=15 mmHg; respiration rate (breaths per minute) \>30 breaths per minute. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.

  Up to approximately 40 weeks

• Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Results

  The criteria for clinically significant abnormal ECG values were- ventricular rate outlier (\<50 bpm and decrease of \>=25%, \>100 bpm and increase of \>=25%), PR outlier \[increase of \>=25% when PR \>200 milliseconds (ms)\], QRS outlier (increase of \>=25% when QRS \>100 ms), QT (new onset (in treatment period but not at Baseline) \[\>500 ms\]), QT interval corrected by Bazett's formula (QTcB) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), QT interval corrected by Fridericia's formula (QTcF) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Baseline was defined as the average of the ECGs taken at Day -1. Only categories with data for potentially clinically significant abnormal ECG values are reported.

  Up to approximately 40 weeks

• Percentage of Participants With Potentially Clinically Significant Laboratory Values

  Clinical laboratory tests included hematology, coagulation, chemistry, and urinalysis. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.

  Up to approximately 40 weeks

• Percentage of Participants With Abnormal Audiometry Assessment Values

  Up to approximately 40 weeks

• Percentage of Participants With Abnormal Visual Acuity Assessment Values

  Up to approximately 40 weeks

• Percentage of Participants Taking Concomitant Anti-Tuberculosis (TB) Medication During the Trial

  Up to approximately 40 weeks

• Percentage of Participants Taking Concomitant (Excluding Anti-TB) Medication During the Trial

  Up to approximately 40 weeks

• Percentage of Participants With Adverse Events (AEs)

  An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug-related by the investigator.

  Up to approximately 40 weeks

• Percentage of Participants With Immediately Reportable Events (IREs)

  An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-participant hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above. The following were considered as IREs- serious adverse events (SAEs), pregnancies in trial participants or their partners, and all events involving overdose, misuse and abuse.

  Up to approximately 40 weeks

• Cmax: Maximal Peak Plasma Concentration for Delamanid

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid

  AUC0-24h was calculated as 2×AUC0-12h.

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• Rac (Cmax): Ratio of Accumulation for Cmax of Delamanid

  Ratio of accumulation for Cmax was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• Rac (AUC): Ratio of Accumulation for AUC of Delamanid

  Ratio of accumulation for AUC was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

Secondary Outcomes (8)

• Cmax: Maximal Peak Plasma Concentration for Delamanid Metabolites

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid Metabolites

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid Metabolites

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• Rac (Cmax): Ratios of Accumulation for Cmax for Delamanid Metabolites

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

• Rac (AUC): Ratios of Accumulation for AUC for Delamanid Metabolites

  At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196

Study Arms (2)

Delamanid 250 mg BID+ OBR

EXPERIMENTAL

Participants received delamanid five 50 milligrams (mg) (250 mg) tablets, twice a day (BID), along with at least 2 additional anti-TB medications per optimized background regimen (OBR) for up to 28 weeks.

Drug: Delamanid; Drug: Optimized Background Regimen (OBR)

Delamanid 300 mg BID+ OBR

EXPERIMENTAL

Participants received delamanid six 50 mg (300 mg) tablets, BID, along with at least 2 additional anti-TB medications per OBR for up to 28 weeks.

Drug: Delamanid; Drug: Optimized Background Regimen (OBR)

Interventions

Delamanid DRUG

OPC-67683 film-coated tablets

Also known as: OPC-67683

Delamanid 250 mg BID+ OBR; Delamanid 300 mg BID+ OBR

Optimized Background Regimen (OBR) DRUG

OBR was selected at the discretion of the study investigator and included at least 2 anti-TB medications based on World Health Organization (WHO's) guidelines for the programmatic management of drug-resistant TB. Study investigator could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.

Delamanid 250 mg BID+ OBR; Delamanid 300 mg BID+ OBR

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures
• Male or female participants aged between 18 and 64 years, inclusive.
• Able to produce sputum for mycobacterium culture or able to obtain sputum produced through Induction.
• At least three sputum mycobacterium cultures positive for MTB with in-vitro resistance to isoniazid and rifampicin during the previous 270 days (9 months) despite treatment with first and second line anti-TB drugs, including one positive culture within the previous 60 days from the time of sputum collection, prior to date of screening initiation \[defined as the date the informed consent form (ICF) is signed and screening begins\].
• Sputum mycobacterial culture positive for MTB with in-vitro susceptibility to at least one anti-TB medication within the previous 60 days prior to the date of screening initiation.
• Participant judged by the investigator to have potential for clinical benefit from OPC-67683 exposure.
• Female participants of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate) throughout the participation in the trial and for 22 weeks after last dose (to cover duration of ovulation).
• Male participant must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks after last dose (to cover duration of spermatogenesis).

You may not qualify if:

• A history of allergy to any nitro-imidazoles or nitro-imidazole derivatives at any time.
• Use of the medications in Section 4.1 including: use of amiodarone at any time during the previous 12 months, use of other antiarrhythmics for the previous 30 days, as well as use of certain antidepressants, anti-histamines, any macrolides, for the previous 14 days.
• Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels \~265 micromoles (μmol)/L or hepatic impairment characterized by alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.
• Current clinically relevant changes in the Screening electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 msec (in both male and female participants), or of the QT interval with Fridericia's correction (QTcF) interval over 450 msec in male participants and over 470 msec in female participants.
• Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled or poorly controlled hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
• For participants with human immunodeficiency virus (HIV) infection, helper/inducer T-lymphocyte (CD4 cell) count \< 350/mm\^3 or on treatment with anti-retroviral medication for HIV infection.
• Karnofsky score \< 50%.
• Any current diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (3)

Infectology Center of Latvia - Clinic of Tuberculosis and Lung Diseases

Ogre, LV 5015, Latvia

Location

Hospital for Tuberculosis and Lung Diseases

Šiauliai, LT-76231, Lithuania

Location

National Tuberculosis and Infectious Diseases University Hospital

Vilnius, LT-10214, Lithuania

Location

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Multidrug-Resistant

Interventions

OPC-67683

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Limitations and Caveats

The trial was terminated per protocol for lack of efficacy and not for dose limiting toxicity (DLT).

Results Point of Contact

• Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

1-609-524-6788

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 25, 2010
• First Posted: May 26, 2010
• Study Start: February 19, 2010
• Primary Completion: May 12, 2011
• Study Completion: May 12, 2011
• Last Updated: November 11, 2021
• Results First Posted: November 11, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Locations

LI (2); LA (1)