Evaluating a New Treatment Regimen for Patients With Multidrug-resistant TB (MDR-TB) - a Prospective Open-label Randomised Controlled Trial

University of Cape Town1 个研究点分布在 1 个国家目标入组 154 人开始时间: 2015年11月12日最近更新: 2021年9月29日

适应症

干预措施

试验速览

阶段: 2 期
状态: 已完成
发起方: University of Cape Town
入组人数: 154
试验地点: 1
主要终点: Treatment success

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This study aims to evaluate the impact of a new injection-free six-to-nine month treatment regimen of linezolid, bedaquiline, levofloxacin, pyrazinamide (PZA) and ethionamide/high dose isoniazid (INH) compared to the conventional empiric injection-based regimen. The secondary aim is to determine if other treatment-related outcomes including adverse events, adherence to treatment, culture conversion, and cure/completion are significantly different in the intervention and conventional arms.

详细描述

Background:

TB is completely out of control in South Africa and is now officially the most common cause of death in this country. Alarmingly, the gravity if this pandemic has now been compounded by the emergence of multidrug-resistant TB (MDR-TB), which constitutes resistance to the two most potent anti-tuberculous drugs, namely rifampicin and isoniazid . XDR-TB refers to resistance to rifampicin, isoniazid, any fluoroquinolone, and any second line injectable drug (amikacin, kanamycin, or capreomycin). MDR-TB is a burgeoning epidemic in South Africa, with rates trebling over the last decade. It is of considerable concern because mortality is high (up to 50% in South Africa) and it often affects economically active young adults. It is also a major threat to health care workers in South Africa. We recently showed a rate in SA health care workers 6 fold higher than the general population further exacerbating the shortage of this critical workforce in the country. The increasing cost to manage this disease is unsustainable.

Although drug-resistant TB comprises less than 2% of the total caseload in the country (approximately ½ million patients with TB treated per year), it consumes almost 40% of the total national TB programme budget, and more than 60% of the total TB drug budget. This is not sustainable and drug-resistant TB therefore has the capacity to destabilise functional TB control programmes in many countries in Africa.

The treatment of MDR-TB is arduous, with a six to eight month intensive phase of daily painful injections of Kanamycin combined with oral pyrazinamide, a fluoroquinolone (moxifloxacin or levofloxacin), prothionamide and either cycloserine or para-aminosalicylic acid (if cycloserine cannot be used). Treatment continues for 18 months after consecutive negative sputum cultures, and lasts at least 20 months. There are substantial drug-associated toxicities and adverse events that frequently lead to interruption or cessation of treatment.

This study proposes to test the efficacy of a new drug regimen for the treatment of MDR-TB which is of short term duration and which does not contain an injectable drug, thus making treatment easier to administer and thereby potentially increasing compliance. All the drugs will be available to the NTP if the study is shown to be successful. This regimen will comprise linezolid, bedaquiline, levofloxacin, PZA and either ethionamide or high dose INH or teridazone. A gene-directed diagnostic approach (mutational analysis) will be used in the interventional arm to individualise therapy and to inform on the use of high dose INH versus ethionamide. If both mutations are present then to administer teridazone.

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 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Newly diagnosed culture and/or GeneXpert positive pulmonary TB.
•Rifampicin resistance detected using at least two susceptibility testing assays (GeneXpert, HainMTBDRplus or phenotypic) using a sputum sample during screening.
•Provide written informed consent prior to all trial-related procedures including HIV testing.
•Male or female aged 18 years and older.
•Body weight between 40 and 90 kg, inclusive.
•Women of non-childbearing potential or participants of either sex who are using or willing to use effective methods of birth control

排除标准

•A participant who in the opinion of the investigator is unlikely to cope with regular visits to the trial site either because of travel constraints, or because of drug or alcohol abuse, or other reason.
•Known at screening to have XDR-TB or pre-XDR-TB (i.e. fluoroquinolone or second-line injectable drug (SLID) resistance i.e. to capreomycin, amikacin and kanamycin).
•Previous history of treatment for MDR-TB or XDR-TB or previous treatment with bedaquiline.
•Currently on MDR-TB treatment for more than 2 weeks.
•Any participant with a Karnofsky score <
•Known allergy to any of the trial drugs or related substances.
•Having participated in other clinical studies within 8 weeks prior to trial start where investigational agents were used that may potentially impact current trial outcome.
•Presence (or evidence) of symptomatic neuropathy grade 3 or higher.
•Epilepsy where drugs prolonging QT interval are used.
•Participant who is pregnant, breast-feeding (and not willing to stop), or planning to conceive a child within 6 months of cessation of treatment.
•Incompatibility between microbiological and clinical/ radiological findings (i.e. where the clinical and/or radiological findings are discordant with microbiological testing suggesting laboratory contamination).
•Participants with ECG abnormalities, in particular QT prolongation.
•Any pre-existing laboratory abnormality which in the opinion of the investigator will place the participant at risk. Patients with any of the following baseline laboratory abnormalities will be excluded from the study:
•Creatinine grade 2 or worse (>1.4 times ULN)
•Hemoglobin level grade 4 (HB <6.5g/dL)
•Platelets grade 3 or worse (<49999 x 109/L)
•ALT grade 3 or worse (>5 times ULN)
•Total bilirubin grade 3 or worse (>2.5 times ULN)
•Specific prior or concurrent medication/treatments (see Restrictions section below, Table 3).
•Rifampicin monoresistant TB.
•Fluoroquinolone and/or SLID resistance. Although in South Africa, the standard of care does not single out MDR-TB with fluoroquinolone or aminoglycoside resistance at initiation of MDR-TB treatment, in this study the Hain MTBDRsl LPA will be used on the sputum sample to exclude any pre-XDR and XDR cases from participation in the study (results from the LPA and phenotypic DST testing on the isolate will be available 3-6 weeks later).
•All inclusion and no exclusion criteria must be met prior to enrolment and randomisation. Whenever the investigator has reason to suspect that there might be a health problem (other than TB) participation should only be considered after discussing the case with the medical monitor. Note: Participants who are currently on, or have previously been on drug-sensitive TB treatment are not excluded from participation.
•Post-randomisation exclusion criteria:
•Fluoroquinolone and/or SLID resistance detected on DST using the isolate. Note: A woman who falls pregnant during the treatment phase of the trial will not be excluded but will be counselled regarding potential termination of pregnancy.

研究组 & 干预措施

Conventional treatment 21-24 months

Active Comparator

Participants will receive a 6-8 month intensive phase of: Kanamycin IM 500-750mg (40-50kg) or 1000mg (51-90kg) daily, Moxifloxacin 400mg od, Pyrazinamide 1000-1750mg (40-50kg) or 1750-2000mg (51-70kg) or 2000-2500mg (71-90kg) daily, Ethionamide 500mg (40-50kg) or 750mg (51-70kg) or 750-1000mg (71-90kg) daily,Terizidone 750mg (40-70kg) or 750-1000mg (71-90kg) daily.

The continuation phase will start after 2 consecutive negative sputum cultures and continue for 18 months with Moxifloxacin, PZA, Ethionamide and Terizidone.

In 2016 the WHO revised the treatment guidelines for MDR-TB. The South African National Tuberculosis Program adopted these recommendations and it was integrated into the study in September 2016: SA NTP recommended shorter regimen(9-12 months):Intensive phase (4-6 months): kanamycin, levofloxacin, clofazimine, pyrazinamide, high-dose isoniazid/ethionamide, ethambutol. Continuation phase (5 months): levofloxacin, clofazimine, pyrazinamide, ethambutol.

干预措施: Pyrazinamide (Drug)

Conventional treatment 21-24 months

Active Comparator

The continuation phase will start after 2 consecutive negative sputum cultures and continue for 18 months with Moxifloxacin, PZA, Ethionamide and Terizidone.

干预措施: Ethionamide (Drug)

Conventional treatment 21-24 months

Active Comparator

The continuation phase will start after 2 consecutive negative sputum cultures and continue for 18 months with Moxifloxacin, PZA, Ethionamide and Terizidone.

干预措施: Terizidone (Drug)

Conventional treatment 21-24 months

Active Comparator

The continuation phase will start after 2 consecutive negative sputum cultures and continue for 18 months with Moxifloxacin, PZA, Ethionamide and Terizidone.

干预措施: Moxifloxacin (Drug)

Conventional treatment 21-24 months

Active Comparator

The continuation phase will start after 2 consecutive negative sputum cultures and continue for 18 months with Moxifloxacin, PZA, Ethionamide and Terizidone.

干预措施: Kanamycin (Drug)