The evaluation of effectiveness and safety of a shorter standardized treatment regimen for multidrug-resistant tuberculosis

Transcription

1 The evaluation of effectiveness and safety of a shorter standardized treatment regimen for multidrug-resistant tuberculosis A publication of the Global Drug-resistant TB Initiative (GDI) A Working group of the Stop TB Partnership May

2 General information This document describes a protocol for the operational evaluation of a shorter standardized treatment regimen for MDR-TB without additional resistance to either a fluoroquinolone (FQ) and/or second line injectables in (name of country) and provides information about procedures for enrolment and treatment of MDR-TB patients. The protocol is adapted from the STREAM trial (the evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB) by consultants of the International Union Against Tuberculosis and Lung Disease, with input from members of the Global Drug-resistant Tuberculosis Initiative. Countries that are interested in piloting the shorter MDR-TB regimen(s) are encouraged to adapt this generic protocol to their local settings. 2

3 1. Summary Type of study: prospective observational cohort study Disease studied: multidrug-resistant tuberculosis (MDR-TB) Depending on the study design in the country: - Patients determined to have resistance to FQ and/or SL injectables should not be treated with the shorter regimen for MDR-TB. - If LPA testing is done to exclude MDR patients resistant to FQ and/or SL injectables, these cases are excluded from the target population. Goal: to assess the feasibility of achieving the global target of 75% treatment success among MDR-TB patients using shorter MDR-TB regimen in (name of country). Primary objective: To determine the treatment outcomes of patients treated with a shorter MDR-TB regimen Secondary objectives: 1) to assess the safety of the shorter MDR-TB regimen 2) to assess the proportion of MDR-TB patients with recurrent TB after successful treatment with the shorter MDR regimen in (name of country) 1.1 Intervention The proposed regimen consists of two phases: - an intensive phase with kanamycin, high-dose moxifloxacin (or where available, high-dose gatifloxacin), clofazimine, ethambutol, high-dose isoniazid, pyrazinamide and prothionamide given daily for four months. The intensive phase will be extended to a maximum of six months until smear conversion if smear conversion is not achieved within four months. Failure may be declared at six months for those who have a poor response to treatment as defined in the protocol. - a continuation phase consisting of high-dose moxifloxacin (or gatifloxacin), clofazimine, ethambutol, and pyrazinamide given daily for an additional five months. 3

4 1.2 Duration of follow-up Patients with a successful outcome (i.e., cure or treatment completion) will be followed for 12 months after the completion of treatment to assess recurrence of TB. 1.3 Outcome measures Primary outcome is the proportion of patients declared cured, completed treatment, failed, lost-to-follow-up, or who have died by the end of treatment Secondary outcomes are 1) the proportion of patients with serious adverse events, and 2) the proportion of successfully treated cases (cured plus completed treatment) with recurrent tuberculosis within 12 months post-treatment. 2. Introduction 2.1 Background The internationally recommended strategy for tuberculosis (TB) control emphasizes early diagnosis of infectious TB patients and achieving a high cure rate among detected TB cases. 1 Globally, the treatment success rate was 87% among all new TB cases in the 2011 cohort. Unfortunately, the overall proportion of multidrug-resistant TB (MDR-TB) patients in the 2010 cohort who successfully completed treatment was only 48%, due to a substantial proportion of patients who were lost to follow-up, had no outcome information, or in whom treatment failed. 2 The current WHO guidelines on treatment regimens for MDR-TB recommend an intensive phase of treatment of 8 months and a total duration of treatment of 20 months. 3 The guidelines were developed following the GRADE process for guideline development that has been adopted by WHO, and recommendations were based on an analysis of 9,153 cases treated in observational studies. Of the 9153 patients, 4,934 (54%) were judged to have treatment success, 732 (8%) failed or relapsed, 1,392 (15%) died, and 2,095 (23%) were lost to follow-up. 4 A shorter MDR-TB regimen consisting of high dose gatifloxacin (G, Gfx), clofazimine (C, Cfz), pyrazinamide (Z, PZA) and ethambutol (E, EMB) throughout, supplemented 4

5 by kanamycin (K, Km), prothionamide (P, Pto), and high-dose isoniazid (H, INH) in the intensive phase has been piloted in Bangladesh 5. The treatment duration of the intensive phase was four months (extended to a maximum of six months until sputum smear conversion), and the duration of the continuation phase was five months. Treatment success rate in a cohort of 206 patients enrolled in was 87.9% 5 and the success rate in an expanded cohort of 515 MDR-TB patients not previously treated with second line drugs was 84.4%. 6 Shorter MDR-TB regimens were further piloted in Cameroon and Niger (with minor modification of the Bangladesh regimen). Of the 150 patients enrolled in in Cameroon, cure rate was 89%. 7 Of the 65 patients enrolled in in Niger, 58 (89.2%) were cured. 8 Nine countries in West Africa have started to pilot shorter MDR-TB regimens. WHO is advising countries to introduce shorter MDR-TB treatment regimens in projects that adhere to the following criteria 9: approval of the project by a national ethics review committee, ahead of any patient enrolment delivery of treatment under operational research conditions following international standards (including Good Clinical Practice and safety monitoring), with the objective of assessing the effectiveness and safety of these regimens monitoring of the MDR-TB program using shorter regimens, and its corresponding research project, by an independent monitoring board set up by and reporting to WHO 2.2 MDR-TB in (name of country): [Describe the epidemiology of TB, case finding and outcome of treatment of TB, the prevalence of MDR-TB among new and previously treated cases, the prevalence of fluoroquinolone and second line injectable resistance among MDR-TB cases, progress in implementation of the programmatic management of drug resistant TB (PMDT).] [Describe the MDR-TB regimen currently used in the country, outcomes of MDR-TB enrolled on treatment.] 3. Shorter MDR-TB regimen 3.1 Rationale A randomized control trial (the Evaluation of a Standardised Treatment Regimen of 5

6 Anti-Tuberculosis Drugs for Patients with MDR-TB, STREAM) comparing a shorter MDR-TB regimen with WHO recommended longer duration regimens has been launched. However, results will not be available until late 2017 at the earliest. It has been observed that MDR-TB patients might refuse treatment because the treatment duration is long and that health care facilities may not be able to provide treatment to all identified MDR-TB patients because of insufficient treatment capacity. 1 The study in Bangladesh showed higher treatment success with a shorter course regimen than routine MDR-TB treatment. This study nor the subsequent use of similar regimens in the West African cohort studies has revealed any particular safety concerns other than the ones associated with the longer regimens as recommended by WHO. Therefore, it is justifiable to study shorter MDR-TB regimens outside the STREAM trial in countries with good quality MDR-TB treatment programs which nevertheless are struggling with treatment capacity, as they are less demanding on the health care system and offer an alternative life-saving option that might be acceptable to patients. 3.2 The shorter study regimen The shorter MDR-TB regimen has two phases: 1. The intensive phase consists of kanamycin, high-dose moxifloxacin (or high dose gatifloxacin if available)*, clofazimine, ethambutol, high-dose isoniazid, pyrazinamide and prothionamide**) given daily for four months. The intensive phase will be extended until smear conversion if smear conversion is not achieved within four months, with a maximum of six months. Kanamycin will be given thrice-weekly from the fourth month onwards. Failure might be declared at six months for those who have both positive smear at six months and poor clinical response to treatment. 2. The continuation phase consists of high-dose moxifloxacin (or gatifloxacin), clofazimine, ethambutol, and pyrazinamide given daily for an additional five months. * If gatifloxacin is not available, moxifloxacin may be used to replace gatifloxacin. The STREAM trial is evaluating high dose moxifloxacin (800 mg daily) under clinical trial conditions, assuming that moxifloxacin is equivalent to gatifloxacin. Moxifloxacin, gatifloxacin, and high-dose levofloxacin all have excellent EBA, only slightly less than for INH, and greater extended EBA. High dose levofloxacin (1000mg) has a better AUC/MIC ratio than moxifloxacin 400mg and gatifloxacin 400 mg. 10 However, sterilizing effect of levofloxacin has been shown to be inferior to moxifloxacin in mouse models. 11 6

7 ** Prothionamide may be replaced by ethionamide and kanamycin by amikacin in countries where prothionamide and kanamycin are not available. Admission for treatment is not mandatory, but may be advised for specific groups and for very ill people, for instance during the initiation of treatment or when adverse events occur during treatment. Ambulatory treatment from the outset without initial hospitalization may be feasible in settings where management of MDR-TB in the community is strong (daily DOT). 3.3 Risks and benefits A nine-month regimen is substantially shorter than the regimens recommended by the current WHO guidelines. The shorter duration of therapy may come with an increased risk of treatment failure or relapse. However, the opposite has been observed in settings where similar regimens have already been used (Bangladesh and several countries in West Africa). As the total duration of treatment as well as the duration of the injectable is shorter and the regimen is less likely to induce side effects, patients are more likely to complete the whole treatment course. An additional consideration is that the shorter regimens are substantially cheaper than the commonly used regimens. Updated data from Bangladesh reveal that high-level resistance to fluoroquinolones was associated with an unfavourable outcome in MDR-TB patients treated with shorter MDR-TB regimens. 6 Therefore, it is recommended that MDR-TB patients with resistance to fluoroquinolones should not be treated with the shorter course regimen. 4. Objectives of the Study The goal of the study is to determine whether it is feasible to achieve the global target of 75% treatment success among confirmed cases of MDR-TB using a shorter MDR-TB regimen. Primary objective: To determine the treatment outcomes of patients treated with a shorter MDR-TB regimen 7

8 Depending on the study design in the country: Patients determined to have resistance to FQ and/or SL injectables should not treated with the shorter regimen for MDR-TB. If LPA testing is done to exclude MDR patients resistant to FQ and/or SL injectables, these cases are excluded from the target population. Secondary objectives: to assess 1) safety of shorter MDR-TB regimens and 2) the proportion of MDR-TB patients with recurrent TB after successful treatment 5. MDR-TB case finding Patients with presumptive MDR-TB will be identified in health care facilities and tested for at least Rif resistance as follows: [Include here which patients are targeted for DST in your country, and by which genotypic and/or phenotypic method] (Some considerations on case finding: Rapid DST, such as Xpert MTB/RIF (Xpert) test and GenoType MTBDRplus line probe assay (LPA), will be more efficient in the diagnosis of rifampicin resistance than conventional DST. Among those with a high risk of rifampicin resistance, MDR TB treatment can be initiated for those who have rifampicin resistance detected by Xpert without further confirmation of rifampicin resistance. Among those with a low risk of rifampicin resistance (e.g. new TB patients), confirmation using the same test on a different specimen will be done before the initiation of MDR-TB treatment (figure 1). If the second test shows susceptible to rifampicin, the patient will be treated with first line anti-tb drugs; if the second test shows resistance to rifampicin, the patient will be assessed for eligibility for treatment with a shorter MDR-TB regimen(s). In countries with a significant level (to be determined by country) of resistance against FQ and/or second line injectables, second line susceptibility testing by line probe assay should be used in a timely manner, whenever it is possible, to identify patients with high-level quinolone-resistant MDR-TB, injectable-resistant MDR-TB and XDR-TB who would require an individualized approached) 8

9 Figure 1. Algorithm of case finding of rifampicin resistance by rapid test (Xpert or LPA) Rifampicin resistance by rapid test Pre-test probability of rifampicin resistance High Low Repeat the same rapid test on a different specimen Rifampicin resistance Clinical Management: initiation of shorter MDR-TB regimens 6. Patient selection Pulmonary TB patients with evidence of resistance to rifampicin by conventional DST or rapid tests (Xpert or LPA) will be assessed for enrolment. (The effectiveness of 9-month regimens in extrapulmonary MDR-TB is unknown. Countries that decide to enroll extra-pulmonary TB patients would need to adjust the follow-up testing approach for these patients.) 6.1 Patient Inclusion criteria A patient will be eligible for entry into the study if he/she: 1. Is willing and able to give informed consent to be enrolled in the research project and follow-up (signed or witnessed consent if the patient is illiterate) 2. Is aged 18 years or older 3. Has smear-positive or culture-positive or Xpert-positive pulmonary TB with initial laboratory result of resistance to at least rifampicin 4. Is known not to have a strain highly resistant to a fluoroquinolone or injectable when second line DST is performed 5. Has never been previously exposed to second line anti-tuberculosis drugs for more than one month in the setting where second line DST is not performed 6. Is willing to use effective contraception if the patient is a pre-menopausal woman 9

10 7. Is willing to adhere to the follow-up schedule and to study procedures 6.2 Patient exclusion criteria A patient will not be eligible for entry to the study if he/she: (to be adjusted to the diagnostic algorithm used and the selected treatment regimen in the country) 1. Has had a second line DST done and is known to have a strain resistant to fluoroquinolone or second line injectable 2. Has been previously exposed to second line anti-tuberculosis drugs for ant-tuberculosis treatment for more than one month and If second line DST is not done 3. Is pregnant and in the first trimester 4. Is unable to attend or comply with treatment or follow-up schedule 5. Is unable to take oral medication 6. Has AST or ALT >5 times the upper limit of normal 7. Is taking any medications contraindicated with the medicines in the shorter MDR-TB regimen 8. Has a known allergy to any of the study drugs 9. Is currently taking part in another trial of a medicinal product 10. Has a QTcF interval of > 500 msec 11. Has severe renal insufficiency (an estimated creatinine clearance (CrCl) less than 30 ml/min based on the Cockcraft-Gault equation ) 6.3 Screening procedure All pulmonary TB patients with rifampicin resistance detected by conventional DST or rapid tests will be screened for enrolment by using a standard screening form. 6.4 Patient enrolment Patients who are eligible for inclusion in the study will be given information about MDR-TB and the shorter MDR-TB regimen (figure 2). Health education will be provided by qualified staff. If patients are willing to participate in the research study, they will be asked to sign an enrolment consent form (or give a thumb print in the presence of a witness if illiterate). All patients who are not eligible for the study, or 10

11 refuse to be enrolled, or withdraw after enrollment, will be managed by a MDR-TB treatment regimen according to national guidelines. Figure 2. Screening, enrolment, treatment and follow-up Is the patient eligible? Yes Is the patient willing to be enrolled? No No Standard MDR-TB regimen according to national policy Yes Treatment with a shorter MDR-TB regimen Treatment successfully completed? Yes No Individualized approach, treatment in accordance with country protocols Patient follow-up till 12 months after the completion of treatment 11

12 7. Number of patients [describe the number of patients to be enrolled on shorter MDR-TB regimens with sample size calculation and which centers will participate in this research]] 8. Treatment of patients 8.1 Study regimen, dosages The intensive phase consists of kanamycin, high-dose moxifloxacin (or gatifloxacin where available), clofazimine, ethambutol, high-dose isoniazid, pyrazinamide and prothionamide given daily for four months. The intensive phase will be extended to a maximum of six months until smear conversion if smear conversion is not achieved within four months. Kanamycin will be given thrice-weekly from the fourth month onwards. Table 2 shows daily drug dosages used by body weight group; dosages will be modified according to weight change during treatment. Table 2 Daily drug dosages used for standardized shorter multidrug-resistant anti-tuberculosis treatment (to be adjusted to the selected regimen in the country) Drug Weight group Less than 30 kg 30 kg to 50 kg More than 50 kg Gatifloxacin 400 mg 600 mg 800 mg Moxifloxacin 400 mg 600 mg 800 mg Clofazimine 50 mg 100 mg 100 mg Ethambutol 800 mg 800 mg 1200 mg Pyrazinamide 1000 mg 1500 mg 2000 mg Isoniazid 300 mg 400 mg 600 mg Prothionamide 250 mg 500 mg 750 mg Kanamycin 15 mg per kilogram body weight (maximum 1 g) For adults over 59 years of age, the dose will be reduced to 10 mg/kg (max dose 750 mg) Initiation of treatment (Describe the procedures for initiation of treatment in the country, based on the local conditions) 12

13 Some considerations: Hospitalization is not mandatory, but patients may be hospitalized at the initiation of MDR-TB treatment for a short period of time to ensure that patients can tolerate the regimen. Drug ramping is recommended to reduce the gastrointestinal adverse reactions of prothionamide (or ethionamide). Treatment may begin with kanamycin, moxifloxacin (or gatifloxacin), clofazimine, ethambutol, isoniazid, and pyrazinamide at single daily dose (figure 3). If there is no major adverse event on day one, prothionamide 250 mg will be added on day 2. The dosage of prothionamide will be escalated to 500mg on day 5 if patient can tolerate prothionamide 250 mg, and further escalated to 750mg on day 8 if necessary depending on patients body weight. An antiemetic drug may be used if there is gastrointestinal disturbance. Once the regimen has been established, patients can be discharged if community care can be properly arranged, which means Directly Observed Treatment (DOT) daily. Ambulatory treatment from the outset without initial hospitalization may be feasible in settings where management of MDR-TB in the community is strong (daily DOT). 8.3 Continuation phase The continuation phase consists of high-dose moxifloxacin (or gatifloxacin), clofazimine, ethambutol, and pyrazinamide given daily for an additional five months. Transition from the intensive phase to the continuation phase will require that smear results and clinical response are taken into account. Positive smear after four months of treatment will usually indicate non-viable bacilli, but at the same time extensive disease and high bacillary load at start, are both predictors of relapse. Patients with a positive smear at four months of treatment will receive an extended intensive phase to limit the risk of relapse (and acquired resistance) while awaiting the (negative) culture results up to a maximum of six months when they should be placed on to the continuation phase treatment (figure 4). If patients remain smear positive after six months of intensive phase treatment but have good clinical response with decreased severity of symptoms, patients can also proceed to the continuation phase. If clinical response to treatment is poor after six months of intensive phase treatment and patients remain smear positive, treatment failure should be considered. Failure declaration and a switch to an individualized treatment will be considered earlier in cases with clear lack of response (clinically, smear grading, culture). At the moment when failure is declared, culture and susceptibility testing (including second line drugs) 13

14 must be (re)done. Retreatment with an individualized salvage MDR-TB regimen should take results of susceptibility testing into account. Figure 3. Steps in the establishment of treatment regimen (example of drug ramping) Day1 : Kanamycin, moxifloxacin (or gatifloxacin), clofazimine, ethambutol, isoniazid, and pyrazinamide at single daily Address adverse event Day 2: Add prothionamide 250 mg qd Address adverse event Day 5: Increase prothionamide to 500mg qd Address adverse event Day 8: Increase prothionamide to 750mg (500mg in the morning, 250mg in the evening), if indicated 14

15 Figure 4. Transition from the intensive phase to the continuation phase Smear result at 4 months Negative Proceed to continuation phase Positive Extend intensive phase by one month and ensure culture & SL DST are done Smear result at 5 months Negative Proceed to continuation phase Positive Extend intensive phase by one month Smear result at 6 months Negative Proceed to continuation phase Positive Based on clinical and bacteriological evidence, failure is likely No Proceed to continuation phase Yes Declare failure; prepare for treatment with salvage regimen 15

16 8.3 Management of patients in the Community Directly Observed Therapy (DOT) should be administered throughout the whole treatment course by a trained independent treatment supporter who is not directly related to the patient. DOT services could be either facility-based in which patients visit a health care facility daily for treatment or community-based in which a trained treatment supporter visits the patients daily for drug administration (or vice versa), accompanies the patient to follow-up visits and liaises with the clinical staff. Enablers and incentives (such as travel expenditure, food) during the whole treatment course are helpful, and should be consistently provided whenever possible and relevant. 8.4 Treatment supporter A treatment supporter must be identified for each patient. [describe here organization of treatment management, DOT and treatment support in practice in the country] Some suggestions: The treatment supporter has the following responsibilities: Strictly administer DOT on a daily basis. Monitor adverse events closely and address adverse events in a timely manner. Maintain patients treatment cards on a daily basis. Initiate patient tracing if patients fail to return for treatment as per schedule. Ensure that there is sufficient buffer stock of drugs for patients who are currently on treatment. 8.5 Procedure following missed treatment Any days missed in either the intensive or the continuation phase should be made up by extending this phase of the regimen by the number of days missed (up to two consecutive months which will be classified as loss-to-follow-up). Reasons of missed treatment must be identified and addressed. 8.6 Examinations at baseline and monitoring during treatment (depending on the countries choice of regimen) 16

17 Examinations at baseline and monitoring during treatment should adapt national guidelines with modifications for the shorter duration of treatment. Examinations at baseline include body weight and height, temperature, sputum smear and culture, DST, serum liver enzymes, serum creatinine, haemoglobin, platelet count, white blood count, serum glucose, serum potassium, thyroid stimulating hormone (TSH), HIV, pregnancy test (female only), electrocardiogram (ECG), hearing and visual test. A chest radiograph should be taken at baseline if possible. All HIV infected patients should be offered antiretroviral therapy and co-trimoxazole preventive therapy according to national policy. Table 3-1 shows examinations at baseline and during the intensive phase; Table 3-2 shows examinations during the continuation phase. Sputum smears and cultures should be done monthly until completion of treatment. Frequency of other examinations may be increased as needed according to the decision of clinicians. ECG will be performed before treatment, on day two, on day seven, at month one, month three and during the first month of the continuation phase. An ECG should be performed more frequently in cases with a significant increase of QTc interval after the initiation of treatment and in patients with a QTcF interval > 450 msec. DSTs of first and second line drugs should be done at baseline and on all positive cultures from month four onwards whenever it is possible. Table 3-1 Examination at baseline and during the intensive phase (IP) Month in the intensive phase 0 IP1 IP2 IP3 IP4 IP5 IP6 Body weight Sputum smear Sputum culture Sputum DST Serum liver enzymes/uric acid Serum creatinine Haemoglobin/platelet/white blood count Serum glucose* Serum potassium Thyroid stimulating hormone (TSH) Audiogram Visual test HIV Pregnancy test (female only) ECG Consider adding body temperature 17

18 * Check serum glucose of all patients if gatifloxacin is used, check serum glucose in diabetic patients if moxifloxacin is used Table 3-2 Examination during the continuation phase (CP) Month in the continuation phase CP1 CP2 CP3 CP4 CP5 Body weight Sputum smear Sputum culture Sputum DST Serum liver enzymes/uric acid Serum creatinine Haemoglobin/platelet/white blood count Serum glucose* Serum potassium Thyroid stimulating hormone (TSH) Audiogram Visual test ECG * Check serum glucose of all patients if gatifloxacin is used, check serum glucose in diabetic patients if moxifloxacin is used 9. Monitoring and management of adverse events Adverse events should be monitored in a systematic and timely manner. At every DOT encounter, health workers should ask the patient about clinical symptoms of common adverse effects including skin rashes, gastrointestinal disturbances, psychiatric disturbance (headache, anxiety, depression, irritability, behaviour change), jaundice, vestibular toxicity (nausea, vertigo, ataxia), peripheral neuropathy and symptoms of electrolyte wasting (muscle cramping, palpitations). Ototoxicity (hearing loss) needs particular attention. Laboratory screening outlined in Table 3-1 and Table 3-2 should be performed to detect occult adverse effects. As moxifloxacin (gatifloxacin) and clofazimine may induce QT prolongation, monitoring of ECG is essential. Skin discolouration due to clofazimine will always occur, but it is not considered to be an adverse event, and will disappear slowly after treatment. Management of adverse events should take patient safety and treatment need into consideration. For minor adverse events, re-assurance to enhance adherence is needed. If the offending drug(s) need to be removed from the regimen, replacement 18

19 might be required, especially in the intensive phase when the bacillary load is high. Replacement of drugs should take the clinical condition and bacteriological status of patients into account. Any decision must be made on the basis of careful case review. 10. Data analysis and statistics 10.1 Outcome measurement Primary outcome is the proportion of patients with successful treatment (cured plus completed treatment), failed, loss-to-follow-up, and died. Secondary outcomes are 1) the proportion of patients with serious adverse drug reaction, and 2) the proportion of successfully treated patients with recurrent TB in 12 months post-treatment follow-up. Outcome analysis should follow Definitions and reporting framework for tuberculosis revision released by WHO in 2013: Cured: Treatment completed without evidence of failure AND three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment completed: Treatment completed without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment failed: Treatment terminated or need for permanent regimen change of 2 anti-tb drugs because of lack of conversion by the end of the intensive phase, or bacteriological reversion in the continuation phase after conversion to negative, or serious adverse events evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs decision made by clinician to terminate the study treatment due to poor response Died: A patient who dies for any reason during the course of treatment. Lost to follow-up: A patient whose treatment was interrupted for 2 consecutive months or more. (This category was previously known as defaulted.) Not evaluated: A patient for whom no treatment outcome is assigned. (This includes cases transferred out to another treatment unit and whose treatment outcome is unknown) 19

20 Treatment success: The sum of cured and treatment completed The terms conversion and reversion of culture results are defined as follows: Conversion (to negative): culture is considered to have converted to negative when two consecutive cultures taken at least 30 days apart are found to be negative. In such case, the specimen collection date of the first negative culture is used as the date of conversion. Reversion (to positive): culture is considered to have reverted to positive when, after an initial conversion, two consecutive cultures taken at least 30 days apart are found to be positive. For the purpose of defining Treatment failed, reversion is only considered when it occurs in the continuation phase. Recurrent TB is defined as 1) two consecutive positive cultures or 2) one positive culture with clinical signs and symptoms and radiographic deterioration after cure or completion of treatment. An isolated positive smear or culture without clinical deterioration after treatment completion provides insufficient evidence to define recurrent TB. If genotyping is available, recurrent TB may be further classified as 1) relapse, 2) reinfection, or 3) unclassified. Relapse: isolates of the recurrent episode share the same genotype pattern with isolates of the first episode of MDR-TB. Reinfection: isolates of the recurrent episode and isolates of the first episode of MDR-TB have different genotype patterns. Undetermined: there is insufficient information to determine whether the recurrent episode is due to relapse or reinfection Post treatment follow-up After completion of treatment, patients will be informed of the risk of recurrent TB and advised to return for clinical assessment. Patients will also be advised to return for sputum examinations at 6 and 12 months after completion of treatment. A single sputum specimen for smear and culture will be collected at each follow-up visit. 11 Procedures for assessing safety After initiation of treatment, patients will be closely monitored for signs and symptoms 20

21 of drug toxicity. It is recommended to grade all symptoms and laboratory findings according to severity using The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events ( DAIDS AE Grading Table ). 12 All adverse events leading to the study therapy being temporarily or permanently discontinued and all Grade 3 or greater toxicity effects will require thorough investigation with relevant clinical and laboratory tests, and must be reported. See also section 15.2 (Note here the country specific roles and responsibilities regarding the monitoring, grading, administration and reporting of adverse events- by whom, to whom and when) 12. Bacteriology [Describe smear, culture, conventional DST, Xpert test, LPA and proficiency testing] 13 Individually adapted regimen Study treatment will be permanently discontinued in patients experiencing: - Intolerable severe toxicity of 2 or more drugs (see section 9) - Pregnant during treatment - Treatment failure When study treatment will be permanently discontinued, patients will be evaluated by a clinical committee and initiated on an individually adapted treatment, based on the WHO guidelines for regimen design. 14. Data management and project monitoring (Here the country should describe the data management of the study) Considerations: A data management and monitoring plan should be developed before the launch of the study project. Susceptibility testing of first line and second line anti-tb drugs at baseline and during treatment, examination at baseline and during the intensive phase (Table 3-1), examination during the continuation phase (table 3-2), adverse 21

22 drug reactions, and treatment change of each patient must be recorded. Enrolment and progress of patients treatment should be reviewed on a quarterly basis. Monitoring indicators are given in Chapter 2 of the WHO's 2014 PMDT Companion Handbook and the related Annexes. The objectives of project monitoring are: 1. To ensure that the rights of human subjects are protected and that the conduct of the operational research is in compliance with the approved protocol, the principles of Good Clinical Practice, and the applicable regulatory requirement 2. To identify constraints in the identification of MDR-TB suspects, sputum examinations, diagnosis of patients with rifampicin resistance, timely enrolment, pre-treatment assessment, initiation of treatment, management of adverse events, monitoring examinations during treatment, DOT services in the community, tracing of late patients, and assessment of outcome of treatment. 3. To verify that the reported data are complete, timely and accurate. 15. Quality assurance and human subjects protection 15.1 Quality assurance Good Clinical Practice (GCP) is a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected (ICH topic E6 (R1) Guideline for GCP). GCP training should be provided for all staff involved in the operational research of shorter MDR-TB regimens. Quality assured by regular internal monitoring and/or reporting: Overall adherence to protocols Monitoring study reports submitted: completeness; accuracy checks comparing with registers and treatment cards during supervision visits On-site supervision of MDR treatment centres: accuracy of filling cards; prescriptions and DOT; completeness of toxicity monitoring and reporting of serious adverse events (SAE) Referring centers (treatment and diagnosis): completeness and appropriateness of referral of patients under evaluation for MDR-TB; arrival of results and action taken 22

23 On-site supervision of Xpert and reference labs: completeness and accuracy of registration; turnaround time and communication of results; MDR diagnosed versus enrolled; strain collection (if applicable) Smear microscopy quality, by regular rechecking of smears as part of the routine TB lab network Quality Assurance; by regular reporting of routine performance, including positivity rates differentiating between individuals who have smear examinations for diagnosis and for follow-up (Rapid) DST performance and quality reports: numbers done, resistance proportion by type of case; resistance profiles; non-tb detected; error and failure rates Culture quality: culture lab reports on overall contamination rate (counted as tubes); yield of TB, NTM, contamination and the proportion culture negative among samples from smear-positive cases not on treatment (= only counts from new and relapse cases, specimens before start of treatment) Conventional DST: performance in proficiency testing rounds performed by WHO/IUATLD Safety reporting All serious adverse events (SAEs) should be reported immediately to the investigators and the relevant national pharmacovigilance authority. Definitions: 1. Adverse Drug Reaction (ADR): All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. 2. Adverse Event (AE): Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 3. Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR): any untoward medical occurrence that at any dose - results in death - is life-threatening - requires inpatient hospitalization or prolongation of existing hospitalization - results in persistent or significant disability/incapacity The severity (i.e. intensity) of all AEs/ADRs (serious and non-serious) in this operational research should be graded using the DAIDs criteria. When an AE/ADR occurs, the investigator responsible for the care of the patient must first assess 23

24 whether the event is serious. If it is serious (SAE or serious ADR), then an SAE form must be completed and sent to the principle investigator and the relevant pharmacovigilance authority. 6. Ethics considerations The study will follow the principles of the Declaration of Helsinki. The study protocol should be submitted to and approved by a national or local ethics review committee prior to initiation of the study. The Investigators must ensure that the study is carried out in accordance with the principles of Good Clinical Practice. No patient may be enrolled into this study until the investigator has obtained the patient s informed consent. Patients will be provided with information about the study in a language that is understandable to patients. Consent for enrolment should be based on a Patient Information Sheet (PIS). Patients should have the opportunity to discuss the PIS with the medical officer/treatment supporter. The patients will be assured that their decision to participate in the study or not will not affect the quality of care they will receive. Once the patient has understood the PIS and agrees to participate in the pilot project, the patient will be asked to sign the consent form. 24

25 References 1. Chiang C-Y, Van Deun A, Enarson D A. Bad drug-resistant tuberculosis programme is worse than no programme: time for a change. Int J Tuberc Lung Dis 2013;17: World Health Organization. Global tuberculosis report World Health Organization Document 2013;WHO/HTM/TB/ World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis update. World Health Organization Document 2011;WHO/HTM/TB/2011.6: Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, et al. (2012) Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PloS Med 9(8): e : doi: /journal.pmed Van Deun A, Kya Jai Maug A, Halim M A, Kumar Das P, Ranjan Sarker M, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010;182: Aung KJM, Van Deun A, Declercq E, et al. Successful 9-month Bangladesh regimen for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014; 18: Kuaban C, Noeske J, Rieder HL, Ait-Khaled N, Abena Foe JL, Trebucq A. High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. Int J Tuberc Lung Dis 2015; 19: Piubello A, Hassane Harouna S, Souleymane MB, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis 2014; 18: WHO. The use of short regimens for treatment of multidrug-resistant tuberculosis. Available at Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10: J eziris N, Truffot-Pernot C, Aubry A, Jarlier V, Lounis N. Fluoroquinolone-containing third-line regimen against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother. 2003;47: The Division of AIDS, National Institute of Allergy and Infectious DIseases. Table for Grading the Severity of Adult and Pediatric Adverse Events. Available at 25