Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Assessment of the early bactericidal activity (EBA) of tedizolid (200mg / day) at the end of the first 2 days of treatment (D3).
研究概览
简要总结
The objective of this work is to measure the early bactericidal activity of tedizolid, to compare it with the bactericidal activity of linezolid (reference molecule for the treatment of multidrug-resistant tuberculosis) and with that of standard quadruple therapy (reference treatment of drug susceptible tuberculosis).
详细描述
This is a Phase 2, prospective, randomized, open-label controlled trial in 3 parallel groups comparing tedizolid with 2 standard treatments: linezolid (oxazolidinone whose anti-tuberculosis activity has already been demonstrated) and standard treatment for tuberculosis (quadruple therapy: isoniazid, rifampicin, ethambutol, pyrazinamide ). The objective is to measure the early bactericidal activity of tedizolid, to compare it with the bactericidal activity of linezolid and with that of standard quadruple therapy.
Design: A multicentric, open-label, randomized clinical trial
Sample size : 60 patients, 20 in each group
Treatments groups:
- Tedizolid arm:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years old and <75 years old
- •Woman on childbearing age should be on effective contraception during the duration of the study and up to 6 months after treatment; a mechanical contraception (use of condom) will be strongly recommended
- •Male (effective contraception must be used during duration of the study and up to 3 months after treatment)
- •Patient with a first infection with Mycobacterium tuberculosis of pulmonary localization suspected by the presence of a clinical pulmonary symptomatology, a chest X-ray or an abnormal chest computed tomography, and the positive microscopic examination of a sputum (AFB +, presence of AFB) with confirmation of tuberculosis by a genotypic test demonstrating no resistance to rifampicin, without clinical signs of extra-thoracic involvement
- •State medical assistance application being processed ( If patient does not benefit from social security),
- •Signature of informed consent
排除标准
- •Resistance to one of the anti-tuberculosis drugs used detected by a genotypic test in accordance with the recommendations of the High Council of Public Health of 2015;
- •History of anti-tuberculosis treatment (patients with a documented negative genotypic test for isoniazid and rifampicin resistance may be included)
- •History of treatment in the previous two years with one of the antibiotics evaluated in this trial lasting more than one month;
- •Absolute contraindication to the use of at least one of the test molecules (isoniazid, rifampicin, ethambutol, pyrazinamide, linezolid, tedizolid);
- •Tuberculosis having, in the opinion of the investigator, severity criteria not allowing to wait 7 days before starting standard treatment (oxygenorequirement, severe immunosuppression, extra-pulmonary involvement, any sign of severity requiring treatment in intensive care unit);
- •HIV-infected patient receiving protease inhibitors whose antiviral treatment cannot be changed and therefore cannot receive rifampicin; or any other drug contraindicated with one of the study treatments (the list of contraindicated drugs is detailed in the following non-inclusion criteria).
- •Neoplastic pathology during treatment with chemo and / or radiotherapy;
- •Decompensated cirrhosis;
- •Pregnancy, desire to become pregnant, breast-feeding (for women of childbearing potential, contraception should be used for the duration of the study and up to 6 months after treatment, mechanical contraception will be strongly recommended and up to 3 months after treatment);
- •Protected adults (under guardianship, curatorship) and under safeguard of justice
- •Significant laboratory abnormalities (hemoglobin <9g / dl, polynuclear neutrophils <500 / mm3, platelets <50,000 / mm3, creatinine clearance <30ml / min, ASAT or ALAT> 3N, and total bilirubin> 3N)
- •Hyperuricaemia
- •Porphyria
- •Optic neuritis or peripheral neuropathy
- •BMI≤ 16 kg/m2
- •Participation in other interventional research
- •Current treatment with one or more medications contraindicated in combination with linezolid: Linezolid should not be used in patients treated with monoamine oxidase A or B inhibitors (for example: phenelzine, isocarboxacid, selegiline, moclobemide) or who received one of these products in the previous two weeks
- •Current treatment with one or more medications contraindicated in combination with quadritherapy:
- •Combination with bictegravir, cobicistat, daclatasvir, dasabuvir, delamanid, grazoprevir/elbasvir, protease inhibitors boosted by ritonavir, isavuconazole, ledipasvir, lurasidone, midostaurin, ombitasvir/paritaprevir, praziquantel, rilpivirine, sofosbuvir, velpatasvir, voriconazole, voxilaprevir
- •Gastrointestinal topicals, antacids and adsorbents and salts and aluminum hydroxides
研究组 & 干预措施
Tedizolid arm
Patients will be taken 1 tablet per day of 200 mg film-coated of Tedizolid (SIVEXTRO®), in the morning for 7 days. Then, the early bactericidal activity will be measured and compared to the other arms.
干预措施: Tedizolid arm (SIVEXTRO®) (Drug)
Linezolid arm
Patients will be taken 2 tablets per day of 600 mg film-coated of Linezolid (ZYVOXID®) in the morning for 7 days. Then, the early bactericidal activity will be measured and compared to the other arms.
干预措施: Linezolid arm (ZYVOXID®) (Drug)
Standard quadruple therapy arm
Patients will be taken :
ISONIAZIDE :
o A dosage of 3 to 5mg / kg / day for 7 days (to be taken in the morning on an empty stomach) of Isoniazid (RIMIFON®)
RIFAMPICINE :
o A dosage of 10mg / kg / day for 7 days (to be taken in the morning on an empty stomach)
ETHAMBUTOL :
o A dosage of 15-20mg / kg / day for 7 days (to be taken in the morning on an empty stomach) of Ethambutol
PYRAZAMIDE :
o A dosage of 20-25mg / kg / day for 7 days (to be taken in the morning on an empty stomach) of Pyrazinamide
Then, the early bactericidal activity will be measured and compared to the other arms.
干预措施: Standard quadruple therapy arm (Drug)
结局指标
主要结局
Assessment of the early bactericidal activity (EBA) of tedizolid (200mg / day) at the end of the first 2 days of treatment (D3).
时间窗: Day 3
The measurement will be done as follow: EABD1D3= (log10 number of CFU (CFU= colony forming unit) of M. tuberculosis on medium 7H11/mL of sputum on D1) - (log10number of CFU of M. tuberculosis on medium 7H11/mL of sputum on D3)/2.
次要结局
- Evaluation of Tedizolid's tolerance on peripheral neuropathy(30 days)
- Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 1 and Day 3(Day 3)
- Evaluation of Tedizolid's tolerance on platelets(30 days)
- Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 3 and Day 8(Day 8)
- Evaluation of Tedizolid's tolerance on polynuclear neutrophils(30 days)
- Evaluation of Tedizolid's tolerance on AST/ALT(30 days)
- Evaluation of Tedizolid's tolerance on bilirubin(30 days)
- Evaluation of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8(Day 8)
- Comparison of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8(Day 8)
- Evaluation of Tedizolid's tolerance on creatinine clearance(30 days)
- Evaluation of Tedizolid's tolerance on optic neuropathy(30 days)
- Comparison of the early bactericidal activity (EBA) of tedizolid between Day 1 and Day 3(Day 3)
- Tedizolid pharmacokinetics'measurement(24hours)
- Evaluation of Tedizolid's tolerance on hemoglobin(30 days)
- Evaluation of Tedizolid's tolerance on dress syndrome(30 days)