A Trial to Evaluate Safety, Tolerability, and Efficacy of Orally Administered OPC-67683

NCT02573350 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 242-07-2082008-005107-26
• Study Type: interventional
• Target: 213
• Locations: 6 countries
• Sites: 8

Brief Summary

A phase 2, multicenter, uncontrolled, open-label trial in participants with Multi-drug Resistant Tuberculosis (MDR-TB). Only participants who completed Trial 242-07-204 (NCT00685360) were eligible. The trial was performed globally at 14 sites qualified to treat MDR-TB. All 434 participants who completed Trial 242-07-204 were eligible for this trial if there was still potential clinical benefit to them and all inclusion criteria and no exclusion criteria were met.

Conditions

Tuberculosis, Multidrug-Resistant

Outcome Measures

Primary Outcomes (11)

• Number of Participants With Clinically Significant Abnormality in Vital Signs

  Vital signs included weight (kg), body temperature (degree Celsius), heart rate \[beats/minute (bpm)\], systolic and diastolic blood pressure \[millimetre of mercury (mm Hg)\]. The criteria for clinically significant abnormal value for: weight was decrease or increase of \>=5% in body weight, heart rate was \<=60 bpm and decrease of \>=15 bpm; \>=120 bpm and Increase of \>=15 bpm, systolic blood pressure (SBP) \<=90 mm Hg and decrease of \>=20 mm Hg; diastolic blood pressure (DBP) \<=50 mm Hg and decrease of \>=15 mm Hg, all vital signs relative to Baseline. Baseline is Study 204 completion visit (Day 84) for participants who complete the baseline visit within 7 days of completing Study 204. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.

  From first dose of study drug up to Week 26

• Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values

  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. Only categories with data are reported.

  From first dose of study drug up to Week 26

• Number of Participants With Clinical Significant Abnormality in Laboratory Test

  Laboratory assessments included parameters for serum chemistry (alkaline phosphatase, alanine aminotransferase, alanine transaminase, total bilirubin, cholesterol, gamma-glutamyl transferase, glucose, lactic dehydrogenase, potassium, sodium, triglycerides, uric acid), hematology (white blood cell count eosinophils, absolute, hematocrit, hemoglobin, lymphocytes, absolute, mean corpuscular volume, neutrophil, bands, neutrophils, neutrophils, absolute, platelet count, red blood cell (RBC) count, reticulocyte count) and urinalysis (blood, epithelial cast, granular cast, hyaline cast, RBCs per high power field (RBC/HPF)). The participants were categorized based on the clinically significant laboratory values as per predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.

  From first dose of study drug up to Week 26

• Number of Participants With Abnormality in Audiometry at Baseline

  Audiometry assessments were done at Baseline.

  Baseline

• Number of Participants With Abnormality in Visual Acuity

  From first dose of study drug up to Week 26

• Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)

  Participants with abnormal neurological and psychiatric assessments were reported. An adverse event (AE) is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug.

  From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

• Number of Participants With Clinical Significant Abnormality in Thyroid Function Test Reported as TEAE

  Participants with abnormal thyroid free T4 nanograms per deciliter (ng/dL) and thyroid-stimulating hormone (\>=3 OR \<=0.3 micro-international units per litre (uIU/mL). An AE is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug.

  From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

• Number of Participants With Any Concomitant Medication Usage

  Concomitant medications are defined as medications that started on or after the first day of study treatment or were started prior to study treatment but were ongoing on the first day of study treatment.

  From first dose of study drug up to Week 26

• Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)

  An adverse event (AE) is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug. An SAE is an AE that resulted in death, inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event.

  From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

• Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE

  Participants with clinically significant abnormal coagulation (prothrombin time (PT) \>17.5 seconds and activated partial thromboplastin time (aPTT) \>45 seconds) were reported.

  From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

• Number of Participants With Clinical Significant Abnormality in Cortisol

  Participants with clinically significant cortisol \>=26 micrograms/decilitre (ug/dL) were reported.

  From first dose of study drug up to Week 26

Secondary Outcomes (13)

• Percentage of Treatment Responders Using the Mycobacterial Growth Indicator Tube (MGIT) Culture System

  Week 26

• Percentage of Treatment Responders Using Solid Culture Medium

  Week 26

• Percentage of Treatment Non-responders Using the MGIT Culture System

  Week 26

• Percentage of Treatment Non-responders Using Solid Culture Medium

  Week 26

• Percentage of Sustained Converters Using the MGIT Culture System

  Week 26

Study Arms (2)

Delamanid 100 mg BID + OBR

EXPERIMENTAL

Participants received Delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) along with at least 4 additional anti-TB medications per optimized background regimen (OBR) from Week 0 to Week 26. Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment.

Drug: Delamanid; Drug: OBR

Delamanid 200 mg BID + OBR

EXPERIMENTAL

Participants received Delamanid 200 mg (4x50 mg tablets), orally, BID along with at least 4 additional anti-TB medications per OBR up to Week 26. Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment. A participant might have been titrated to Delamanid 200 mg BID after an initial hospitalization of 2 weeks. Participants were grouped according to the longest duration of Delamanid dose administered during the study.

Drug: Delamanid; Drug: OBR

Interventions

Delamanid DRUG

Delamanid was administered orally twice daily as 50-mg tablets under fed conditions in the morning and evening.

Also known as: OPC-67683, Deltyba

Delamanid 100 mg BID + OBR; Delamanid 200 mg BID + OBR

OBR DRUG

Selection and administration of the treatment medications (i.e. OBRs) was based on World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines. Study investigators could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.

Delamanid 100 mg BID + OBR; Delamanid 200 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, at the time of enrollment into the 242-07-204 trial. Participants who were 64 years at the time of 204 enrollment and who are now 65 years, are eligible for this trial.
• Participants who have completed trial 242-07-204
• Participants judged by the investigator to have the potential for clinical benefit from OPC-67683 exposure
• Able to produce sputum for mycobacterial culture or able to obtain sputum produced through induction
• Female participants of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control throughout the participation in the trial and for 22 weeks after last dose.
• Male participants must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks after last dose.

You may not qualify if:

• Greater than 30 days has elapsed from the participant's date of completion in the 242-07-204 trial or greater than 30 days has elapsed since the patient's trial investigator's site was initiated in this trial, whichever is later.
• A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.
• Use of the medications in Section 5.4.7 including: use of amiodarone at any time during the previous 12 months, use of other anti-arrhythmics for the previous 30 days, and use of certain other medications, including certain anti-depressants, anti-histamines, and macrolides, for the previous 14 days.
• Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥265 moles per liter (mol/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 from the screening lab results.
• Current clinically relevant changes in the electrocardiogram (ECG) (between Trial 242-07-204 Day 56 assessment and baseline) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (msec) (in both male and female participants), or the corrected QT interval using Fridericia's method (QTcF) interval over 450 msec in male participants and 470 msec in female participants.
• Current clinically relevant cardiovascular disorders such as heart failure, coronary artery disease, uncontrolled or poorly controlled hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
• Any participants with known or reported significant psychiatric history.
• For participants with human immunodeficiency virus (HIV) infection, CD4 cell count less than 350/cubic millimeter (mm\^3) or on treatment with antiretroviral medication for HIV infection.
• Karnofsky score under 50 percent (%) while hospitalized and less than 60% while not hospitalized.
• Any current diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
• Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
• Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the participants in the opinion of the investigator.
• Administered an investigational medicinal product (IMP) within 1 month prior to Visit 1 other than OPC-67683 given as IMP in trial 242-07-204.
• Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form.
• Recent use of methadone, benzodiazepines, cocaine, amphetamine/methamphetamine, tetrahydrocannabinol, barbiturates, and opiates as determined by a urine drug screen, unless evidence is provided that the positive drug screen is the result of authorized medications or products prescribed by a physician for a non-abuse related indication.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (8)

Beijing Chest Hospital

Beijing, 101149, China

Location

North Estonian Medical Centre Foundation Center of Pulmonology

Tallinn, 13419, Estonia

Location

Tartu University Lung Hospital

Tartu, 51014, Estonia

Location

State Agency of Tuberculosis and Lung Disease

Riga, LV2118, Latvia

Location

Hospital Nacional Sergio E. Bernales

Lima, 41, Peru

Location

Tropical Disease Foundation

Makati City, 1229, Philippines

Location

Younsei University Medical Center

Seoul, 120-752, South Korea

Location

Asan Medical Center

Seoul, 138-736, South Korea

Location

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Interventions

OPC-67683

Condition Hierarchy (Ancestors)

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

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: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2015
• First Posted: October 9, 2015
• Study Start: March 26, 2009
• Primary Completion: October 27, 2011
• Study Completion: October 27, 2011
• Last Updated: November 1, 2021
• Results First Posted: November 1, 2021

Record last verified: 2021-09

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

ES (2); PE (1); PH (1); KR (2); LA (1); CN (1)