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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E.1.1.1 | Medical condition in easily understood language |
Pulmonary Multidrug-resistant Tuberculosis (MDR TB) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037443 |
E.1.2 | Term | Pulmonary tuberculosis, unspecified |
E.1.2 | System Organ Class | 100000004862 |
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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 |
The primary objective of this trial is to evaluate the efficacy of delamanid administered orally as 100 mg twice daily (BID) for 2 months followed by 200 mg once daily (QD) for 4 months in combination
with optimized background treatment regimen (OBR) versus placebo with OBR. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the safety of delamanid and placebo as administered in this trial.
•To evaluate the pharmacokinetics (PK) of delamanid as administered in this trial.
•To evaluate the development of resistance to delamanid. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Same title as given in Section 1. Version number is "7.1". Sub-trial will be applicable for South Africa only.
Only sites in South Africa will be eligible and qualified for conducting this clinical trial with HIV co-infected patients. |
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E.3 | Principal inclusion criteria |
1. Provide written, informed consent prior to all trial-related procedures.
2. Male or female patients aged between 18 and 69 years, inclusive.
3. Current Diagnosis of MDR TB from one of the following methods:
• From a single sputum specimen collected no more than 60 days prior to the date of trial enrollment (defined as the date the ICF is signed and screening begins), mycobacterial culture positive for growth of MTB with documented resistance to isoniazid and rifampicin, or
• From a single sputum specimen collected no more than 60 days prior to date of trial enrollment (defined as the date the ICF is signed and screening begins), either sputum smear positive for acid fast bacilli (AFB) or a rapid test positive for MTB, along with a positive rapid test demonstrating resistance to rifampicin alone, or to rifampicin and isoniazid.
4. Findings on screening chest radiograph consistent with TB.
5. Able to produce sputum for mycobacterial culture.
6. Female patients of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control as defined in Section 5.5. .
7. Male patients must agree to use an adequate method of contraception as defined in Section 5.5. |
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E.4 | Principal exclusion criteria |
1. A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.
2. Use of the medications in Section 4.1 including: use of amiodarone at any time during the previous 12 months or use of other anti- arrhythmic drugs for the previous 30 days.
3. Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥1.5 mg/dL or hepatic impairment characterized by ALT and/or AST levels 3 times the upper limit of the laboratory reference range.
4. Current clinically relevant abnormalities in the screening ECG including conduction abnormalities (for example, but not limited to, AV block) or QTcF interval over 450 msec in male patients and 470 msec in female patients.
5. Current clinically relevant/significant cardiovascular disorder such as congestive heart failure, ventricular hypertrophy, coronary artery disease, arrhythmia, or poorly controlled hypertension.
6. BMI < 16 kg/m2.
7. Karnofsky score < 50%.
8. Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
9. Evidence of currently active clinically significant metabolic, gastrointestinal, neurological, psychiatric, or endocrine diseases (eg, poorly controlled diabetes mellitus), currently active malignancy, or other abnormalities (other than those related to 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 −21 to −2]).
12. Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the ICF.
13. Recent use, as determined by urine drug screen, of methadone, benzodiazepines, cocaine, amphetamine/methamphetamine, tetrahydrocannabinol, barbiturates, and opiates which is not
medically authorized and which in the opinion of the investigator would compromise compliance in the study.
14. Any disorder that in the judgment of the investigator makes the patient not a good candidate for the trial or may prevent the patient from reliably participating in the entire course of the trial.
15. Previous exposure to delamanid.
16. Evidence of XDR TB based on the definition from WHO as TB with demonstrated resistance to isoniazid and rifampicin as well to any one of the fluoroquinolones and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin).
17. HIV co-infection for patients screened at sites not participating in the HIV subtrial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the distribution of the time to SCC using the MGIT system during the 6-month Intensive Treatment Period.
SCC during the 6-month Intensive Treatment Period is defined as the observation of a sputum specimen negative for growth of MTB using the MGIT culture system, followed by at least one confirmatory negative sputum culture at least 25 days after the first negative and not followed by a confirmed positive. A confirmed positive is defined as two observed positive results, not taking into account intermittent, missing, or contaminated results. All sputum culture results in between the first negative and confirmatory negative culture 25 days after the first must be negative for growth of MTB. Time to SCC is defined as the interval between the date of the first dose of IMP and the date of collection of the first sputum specimen of 2 consecutive sputum specimens at least 25 days apart that are negative for growth of MTB using the MGIT culture system. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time to SCC is defined as the time elapsed between the date of the first dose of delamanid and the date of collection of the first sputum specimen negative for growth of MTB eligible for SCC using the MGIT culture system. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include the following:
• Proportion of patients with SCC at 2 and 6 months using MGIT and solid culture,
• Distribution of time to SCC by 6 months using solid culture.
• Sustained SCC between Month 18 and Month 30, inclusive, using MGIT and solid culture.
• Treatment outcomes assessed by principal investigators at the end of treatment with OBR (ie, 24 months post randomization).
• Final outcome at Month 30 as a treatment success or failure (including relapse).
• Mean change from baseline in TTD using the MGIT system.
• Mean AUC of change from baseline in time to detection in the MGIT system.
• Proportion of patients who develop resistance to delamanid. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 | No |
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 |
India |
Moldova, Republic of |
Peru |
Philippines |
South Africa |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up CRF page for the last patient completing or withdrawing from the trial. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |