E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Multidrug-resistant Tuberculosis (MDR TB) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037440 |
E.1.2 | Term | Pulmonary tuberculosis |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety, efficacy and pharmacokinetics of 200 mg and 300 mg total daily doses of OPC-67683 administered orally as either - 200 mg once daily, 100 mg twice daily, and 150 mg twice daily - in comparison to placebo for 56 consecutive days in combination with an optimized background treatment regimen (OBR) to patients with pulmonary, sputum culture-positive MDR TB. |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Provide written, informed consent prior to all trial-related procedures 2) Male and female patients aged between 18 and 64 years, inclusive. 3) Either mycobacterial culture of sputum positive for growth or sputum smear positive for acid fast bacilli with a positive rapid test for rifampicin resistance on direct sputum within 60 days prior to the expected date of enrollment. 4) Patient with TB caused by isolates of M. tuberculosis complex confirmed to be resistant to treatment with isoniazid and rifampicin, or positive rapid test for rifampicin resistance. 5) Findings on chest radiograph consistent with TB. 6) Able to produce sputum for mycobacterial culture. 7) Female patients of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two 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). 8) Male patients must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30weeks after last dose (to cover duration of spermatogenesis). |
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E.4 | Principal exclusion criteria |
1) A history of allergy to any nitro-imidazoles or nitro-imidazole derivates. 2) Use of the medications in Section 4.1 including: use of amiodarone for the previous 12 months, use of other anti-arrhthymics for the previous 30 days, and use of certain other medications, including certain anti-depressants, antihistamines, and macrolides, for the previous 14 days. 3) Any serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥265 µmol/L or hepatic impairment characterized by ALT and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range. 4) Clinically relevant changes in the ECG such as atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female patients), or of either the QTcF or QTcB interval over 430 milliseconds in male patients and 450 milliseconds in female patients. 5) Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction. 6) For patients with HIV infection, CD4 cell count < 350/mm3 or on treatment with anti-retroviral medication for HIV infection. 7) Karnofsky score < 60%. 8) Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated. 9) Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied). 10) Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the patient in the opinion of the investigator. 11) Administered an IMP within 1-month prior to Visit 1 (Screening [Days -9 to -3]). 12) Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form. 13) Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine, tetrahydrocannabinol, barbiturates, tricyclic antidepressants, and opiates as determined by a urine drug screen unless evidence is provided that the positive drug screen is the result of authorized medications products prescribed by a physician for a non abuse related indication. 14) Any disorder that in the judgment of the investigator makes the subject not a good candidate for the trial or may prevent the patient from reliably participating in the entire course of the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: The primary efficacy endpoint is the proportion of patients who achieve sputum mycobacterial culture conversion within 56 days or less of treatment. Sputum culture conversion is defined to occur at the time of the collection of a sputum specimen with mycobacterial culture negative for growth using the MGIT® culture system followed by at least one additional sputum specimen with mycobacterial culture negative for growth using the MGIT® culture system at least 28 days after the first specimen and not followed by any sputum specimens with a mycobacterial culture positive for growth using the MGIT® culture system at any point during the remainder of the 84-day trial period. PK: For OPC-67683, time to maximal peak plasma concentration (tmax), maximal peak plasma concentration (Cmax), area under the plasma concentration-time curve from 0 to 24 hours (AUC0- 24h) , CL/F (QD dose regimen only), ratios of accumulation for Cmax and AUC0-24h [Rac(Cmax) and Rac(AUC), Day 14, 28 or 56/Day 1] For OPC-67683 metabolites, tmax, Cmax, AUC0-24h , ratios of accumulation for Cmax and AUC0-24h [Rac(Cmax) and Rac(AUC), Day 14, 28 or 56/Day 1] Safety: Reported adverse events, physical examination, vital signs (blood pressure, heart rate, body temperature and weight), standard 12-lead ECG, clinical laboratory assessment results (hematology, chemistry, urinalysis). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of trial date for each individual patient is defined as the last date of contact or the date of final contact attempt as noted on the End of Trial page on the patient’s CRF. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 10 |