Table S3.
Data Abstraction table A: Study methodology, regimen type and Treatment supervision type.
| References | Country of study | Study design | Inclusion/exclusion criteria | Patient characteristics | Regimen type and frequency | Supervision of treatment (DOT) | Remarks |
|---|---|---|---|---|---|---|---|
| [1] | Taiwan | Randomised clinical trial of two 6 months regimens; one group to fixed dose combination (FDCs) (Rifater/Rifinah) with EHRZ, second group to separate four drugs of EHRZ | Newly diagnosed smear or culture positive pulmonary tuberculosis and with no history of previous anti-tuberculosis treatment. Ineligible were smear negative TB patients and previously treated. | 93 patients were males and 12 were females. Mean age not given. All recruited from an outpatient chest clinic | 2EHRZ/4RHE | Self-administered - FDC | Daily dosages with FDCs consisting of 2Rifater +EMB and 4 of Rifanah +EMB |
| 2EHRZ/4RHE | Self-administered–Loose tabs | Separate formulations of EHRZ | |||||
| [2] | Iran | Experimental clinical trial, with patients randomised to 2EHRZ/2RH and 2EHRZ/4RH | Adults with Newly diagnosed sputum smear positive pulmonary TB, with no cavitation and no abnormality in more than one lobe on plain CXR were eligible while those with concomitant Hypertension, DM, Epilepsy, immunodeficiency and serious forms of EPTB were excluded. | There were 28 females with mean age of 15 years and 39 males with mean age of 52 years. 13 patients were from Afghan and rest from Iran recruited from a health center | 2EHRZ/4RH | All drugs were administered under DOT as daily Single doses | |
| All drugs were administered under DOT as daily Single doses | |||||||
| [3] | Africa and Asia | Multi-centre randomised controlled trial where allocation sequence was independently computer generated and supplied to participating centres in sealed envelopes. | Patients with at least two positive sputum smears for AFFBs, with no previous anti-TB chemotherapy for more than one month, with accessible addresses and those willing to undergo HIV testing were eligible. Ineligible were pregnant women, EPTB and psychiatric patients, the ill and those with concomitant disease (DM, Epilepsy, liver diseases, nephritis, peripheral neuritis, blood disorders, alcoholism) and patients with confirmed Rifampicin resistance | Pre-treatment characteristics were broadly similar and median age was 28 years with 66% of patients being males and 13% of 881 tested being HIV positive. All recruited from participating treatment centers | 2EHRZ/6EH | Facility DOT for the first 2 months, then family or community based DOT in continuation phase. | |
| 2[EHRZ]3/6EH | |||||||
| 2EHRZ/4RH | |||||||
| [4] | South Africa | Prospective controlled clinical trial study comparing Rifater (RHZ) with 2EHRZ/4RH (given 5 days a week for 130 doses) | Adults in Cape town Municipal area with first episode of pulmonary TB diagnosed by chest radiograph and a positive culture where studied while those with additional non-tuberculous pathology as were pregnant women were excluded. | Non-white patients aged over 15 years. No further details on patient characteristics | 3[EHRZ]5/3.5[RH]5 | DOT offered by supervisors at clinic/work and anti-TB drugs given 5 days a week for 130 doses | Study terminated prematurely when EMB became unavailable |
| [5] | Africa, Asia and Latin America | Multi-centre open label non-inferiority randomized controlled trial conducted between 2003 and 2008 in 11 centres in Africa, Asia and Latin America. 798 Patients randomised to 8 weeks of EHRZ and 18 weeks of [RH]3 as FDCs and 787 patients to separate drugs | 18 years and above with Newly diagnosed smear positive pulmonary TB with two by sputum smear on direct smear microscopy and with either no history of previous anti-tuberculosis treatment or for less than 4 weeks for the current episode, with accessible address and has informed consent. Ineligible were pregnant women, EPTB and psychiatric patients, the ill and those with concomitant disease (DM, Epilepsy, liver diseases, nephritis, peripheral neuritis, blood disorders, alcoholism) and patients with confirmed Rifampicin resistance | There were 393 males on FDC and 387 on separate drugs and 198 females on FDC and 192 on separate drugs. Mean age for FDC group was 33.8 and 34.2 for loose formulations. 39 on FDC and 38 patients on separate drugs were HIV positive while 330 on FDC and 317 on loose drugs never smoked. | 2EHRZ/4[RH]3 (FDC) | DOT | |
| 2EHRZ/4[RH]3 (Separate drugs) | |||||||
| [6] | Thailand | Randomized controlled trial where 837 patients were assigned to receive TB treatment -2EHRZ/4RH by DOT or self-administration on basis of daily drug supply in 15 study sites | TB patients with a positive sputum smear for AFBs. Ineligible were patients less than 15 years old, patients with previous history of treatment for TB for > 1 month, known allergy to any of the drugs in treatment regimen, pregnancy, hepatic or renal failure patients. | Mean age was for DOT and self-supervised was 45±17. The male: female ratio was 2.6:1 for DOT and 2.9:1 for self-supervised. Unemployed on DOT were 17 and 20 for self-supervised. All recruited from Zonal Government TB centers and hospitals TB centres | 2EHRZ/4RH | DOT | |
| 2EHRZ/4RH | Self-administered | ||||||
| [7] | Brazil, Philippines and Uganda | Multi-centre phase 3 randomised open label, two sided equivalence trial | HIV uninfected adults with sputum AFB smear positive or negative, non cavitary, drug susceptible TB, with relatively normal hematologic, renal and hepatic function who converted to negative after 2 months of treatment | 120 were males, mean age for study participants was 30.3, average weight 55.2kg, BMI 20.3kg/m2 | 2EHRZ/4RH | DOT Daily for at least 5 days a week | Study was stopped due to high relapse rate and all waiting patients were treated with 6 months regimen |
| [8] | Indonesia | Prospective randomised trial were patients were randomly allocated to the NTP regimen with separate TB drugs and FDC regimen @ with 4 drugs in blister packs | New smear positive patients with body weight between 33kg and 50kg excluded; previously treated, smear negative and body weight < 30kg | There were 96 males and 66 females on loose drugs regimen and 119 males and 79 females on FDC regimen recruited from health center clinics | 2EHRZ/[4RH]3 | DOT | NTP regimen single drug molecules |
| 2EHRZ/[4RH]3 | DOT | FDC regimen (combined formulation) | |||||
| [9] | Argentina, Brazil and Thailand | Multi-centre open label, active controlled randomized, parallel group comparative study to assess efficacy, tolerability and toxicity of regimens: 2EHRZ/4RH, 2Rifabutin150EHZ/4R150H and 2Rifabutin300EHZ/4R300H | HIV negative patients with previously untreated TB that was radiolographically active and bacteriogically confirmed by culture of at least two sputum samples attending outpatient clinic with willingness to participate were included in study. Excluded patients with depressed haematopoietic function (WBC <4000 cells/ml and platelets of < 150,000 cells/ml), patients with severe hepatic impairment, advanced renal dysfunction, malignancies, immunodepressant therapy and pregnancy. |
63 females and 112 males were on rifampicin and 59 females and 115 males were on rifabutin. The median age for rifampicin group was 29 with range of 15–69 years and was the same for rifabutin but with a range of 15–67. 157 from Argentina, 162 from Brazil, 201 from Thailand. 53% had moderately advanced while 41% had advanced disease | 2EHRZ/4RH | DOT for 1st month only | |
| 2Rifabutin150EHZ/4R150H | |||||||
| 2Rifabutin300EHZ/4R300H | |||||||
| [10] | Pakistan | Interventional study comparing DOT by health worker and a family member and self-administered therapy | Newly diagnosed AFB smear positive adult (age 12 years and above) pulmonary TB. Ineligible were patients < 12 years, EPTB, COPD, lung malignancy, decompensated cirrhosis, chronic renal disease or stroke and with suspected MDR-TB. | Recruited from a hospital setting. Baseline characteristics not given | 2EHRZ/4EH | DOT by Health worker | |
| 2EHRZ/4EH | DOT by family member | ||||||
| 2EHRZ/4EH | Self - administration | ||||||
| [11] | Thailand | Prospective open label randomized study with newly diagnosed pulmonary tuberculosis patients randomized to receive six month once daily VS twice a day (split drugs) regimen | Newly diagnosed smear positive pulmonary patients with at least one positive sputum smear for AFB who had never received or received anti-tuberculosis treatment for less than one month with compatible CXR, aged over 20 years, non-pregnant, willing to participate. Excluded were chronic cardiac, lung diseases, hepatitis with liver enzymes raised more than three times, renal disease with greater than 2.0 mg serum creatinine, neurological diseases like dementia and HIV. | There 44 males in group A and 41 in group B, Females were 17 in group A and 20 in B. Age was 37.1±11.4 in A and 37.2±10.9 in B. In A were 11 and B 9 diabetics. Overall, weight was 51.8±9.1kg in A and 51.9±9.9 in B. | 2EHRZ/4RH | DOT by family member | Drugs given once daily RH given in morning and ZE given at bed time |
| 2EHRZ/4RH | DOT by family member | ||||||
| [12] | Britain | Controlled trial of short course chemotherapy in which two 6 month regimens were compared with a control of 9 month where patients were followed up to 36 months | Patients with culture positive pulmonary TB. | All patients had a positive culture on admission, with 58% having a positive smear too. No other baselines are given. | 2EHRZ/4RH | Self-administered | |
| [13] | Egypt, India, Pakistan, Philippines and Thailand | Prospective open randomized multi-centre, multinational study conducted in 26 centres and included 1159 patients randomized to receive daily FDCs or single ant-TB drugs (ST) regimens @ containing 2EHRZ/4RH | Aged 15 years and over with newly diagnosed smear positive pulmonary patients with at least two by sputum smear positive for tubercle bacilli on direct smear microscopy, postero-anterior CXR consistent with PTB, as determined by the clinician and with for less than 4 weeks of previous anti-tuberculosis treatment, with accessible address and has informed consent and willingness to follow protocol. Ineligible were patients < 30 kg, hypersensitivity to used anti-TB drugs, patients with drug induced hepatitis, liver or renal diseases, gout, tuberculous meningitis, (immunosuppressive) treatments (e.g. Corticosteroid) or drug abuse and alcoholism. Any condition that can prove fatal during treatment except HIV. | Age for FDC was 37.4±15.3 and 36.4±14.6 for single tablets. Body weight was 50.3±15 for FDC group and 49.9±10.3kg for single tablets. 18.7% under FDC and 19.4% in single tablet group were previously treated. | 2EHRZ/4RH | Unspecified, on FDC | Although HIV infection was one of the exclusion criteria for the study, six HIV positive patients (one in the 4-FDC group, five in the ST group) were included by investigators |
| 2EHRZ/4RH | Unspecified, on ST | ||||||
| [14] | India | Controlled clinical trial among patients who attended chest clinics of Tuberculosis Research Centre and were treated them with intermittent regimen in initial phase: 2[EHRZ]3/6[EH] | Patients aged 12 years or more who attended chest clinics of Tuberculosis Research Centre and had at least 2 positive sputum smears for AFB who had not received previous chemotherapy for 1 month or more. Excluded patients with severe visual defects other than refractory error | Recruited from TRC chest clinics. 70% were males, mean age was 31.4 years (range 27.4–74.2). Smear grading of 2+ or more was in 70% of patients while a culture grade of 3+ was in 80%. Full susceptibility to both H and R was in 91% of patients, H and HR resistance was 8.4% and 0.9% respectively. | 2[EHRZ]3/6[EH] | DOT in intensive phase and 1st dose under DOT plus six doses of self-administration per week in continuation phase | |
| [15] | India | Controlled randomized trials of oral short course TB regimens: 2EHRZ/6EH, 2[EHRZ]2/4[RH E]2 | OPD patients with respiratory symptoms, aged 12 years or more, free of visual defects other than refractory error with at least two sputum smears positive for AFBs were randomly allocated to regimens of interest irrespective of previous anti-TB chemotherapy | 67% of the patients were males with mean age of 30.3 years (range 12–62 years) with mean weight of 39.9kg (range 15–60kg). All patients had a poor socio-economic background. Smear positivity was similar in all regimens. | 2EHRZ/6EH | self-administration | |
| 2[EHRZ]2/4[RH E]2 | DOT and self-administration | ||||||
| [16] | India | Open label randomized controlled trial comparing intermittent regimens | Newly diagnosed pulmonary TB patients with at least 2 positive sputum cultures and are residents of the study area, willing to test for HIV and ready for supervised outpatient treatment and home visits. Ineligible were those with previous history of TB treatment of >30 days or weighing less than 30kg, pregnant, lactating, those with diabetes, hypertension, epilepsy, EPTB and HIV | 74% were males and 26% females. Patients aged <40 years were 120 and ≥40 were 45. Mean age was 43 years (range 30.2–59,1), average weight 43kg, all were smear positive, 84% susceptible to HRE, non was resistant to HE. 20% were resistant to R. | 2[EHRZ]3/4[RHE]3 | DOT | |
| [17] | Pakistan | Randomized controlled trial of short course chemotherapy comparing direct observation of treatment (DOT) by family member, health worker and self-administration | Newly diagnosed sputum positive pulmonary TB patients living in the study area. Ineligible were those with previous history of TB treatment. Patients from WHO demonstration sites were excluded. | Males constituted 54% of patients on HW-DOT, 52% on Family DOT and 48% on self-administration. Urban dwellers on HW-DOT were 37%, Family DOT-51%, Self-administration 69%. Age range was 15 to ≥55 years | 2EHRZ/6EH | DOT | By Health worker |
| 2EHRZ/6EH | DOT | By family member | |||||
| 2EHRZ/6EH | Self-administration | At home | |||||
| [18] | Indonesia | Comparative study investigating relapse rates among patients randomly allocated and treated with FDC and loose TB drugs | Newly diagnosed sputum positive pulmonary TB adult patients. Ineligible were smear negative and extra-pulmonary TB patients. | Mean age was 36.5 for those on loose drugs with males constituting 59.1% and 37.7 years for those on FDC with 60.2% being males. All were recruited from 15 health center clinics | 2EHRZ/3[RH]3 | DOT and self-administration | FDC |
| 2EHRZ/3[RH]3 | DOT and self-administration | Loose drugs | |||||
| [19] | South Africa | Randomised trial of intermittent regimens | Newly diagnosed pulmonary TB patients aged 15 years or older suitable for twice weekly supervised ambulatory treatment. Excluded smear negative, patients with resistance to 2 or more TB drugs and those with advanced TB, alcoholics and those in poor general conditions or having concomitant diseases including pregnant women. | The male:female ratio was 4.5:1 and mean age 36.7 years (SD 10.3, median 34, range 15–74). Recruitment was from 2 TB hospitals and major urban clinics in Pretoria. | 2EHRZ/4[RHZ]2 | DOT | |
| 2EHRZ/4[EHZ]2 | DOT | ||||||
| [20] | India | Controlled clinical trial among patients who attended chest clinics and were randomised to 3 intermittent regimen | Patients aged 12 years or more who attended chest clinics and had at least 2 positive sputum smears for AFB/cultures and were willing to clinic for DOT for 6 months and had no EPTB or serious non-TB disease. | Recruited through a chest clinic. 930 were previously treated for <1.5 days and 310 for ≥ 1.5 days, all smear positive except two patients. Mean age was 33, 32 and 32 in reg 1, 2 and 3 respectively. Mean weight was 41.4, 40.5 and 40.9 kg respectively | 2[ER] 3[HZ]3/4[RH]2 | DOT | |
| 3[ER] 3[HZ]3/3[RH]2 | DOT | ||||||
| 2[EHRZ]3/4[RH]2 | DOT | ||||||
| [21] | Zaire | Open label controlled clinical trial among patients who attended outpatient clinics and were randomised to partly intermittent regimen | HIV sero-negative patients with first episode of PTB living in study area | Recruited in a study clinic, males constituted 50%. Mean age was 31±7.3. Resistance to H 19.1%, R 0%, E 2.3%, Z 1.2% and RH 0% | 2EHRZ/4[RH]2 | DOT and SA | |
| [22] | Hong Kong | Randomized controlled clinical trial of intermittent and daily six month regimens | Pulmonary smear positive Chinese TB adults aged 15 years or older with no more than two weeks TB chemotherapy | All patients had a positive baseline sputum smear and culture. 72% were males, 32% were more than 45 years, 35% < 25 years. Mean weight was 48kg. TB disease was gross in 1%, extensive in 9% and moderate in 17%, limited in 32% and slight in 41% of the patients | 2[EHRZ]3/4[EHRZ]3 | DOT | |
| 2[EHRZ]7/4[EHRZ]7 | DOT | ||||||
| [23] | Tanzania | Randomized controlled clinical trial of six month regimens, randomization was computer generated | Sputum positive pulmonary TB patients over aged of 18 years. Excluded were patients with renal, hepatic, cardiovascular, epilepsy and severe TB disease, pregnancy/lactation and history of adverse reactions to any study drugs | Mean age was 35.5±12.7, males/females 55/31, mean weight 49.6±7.9, patients with cavity 68% and HIV-32 patients. Recruited from hospital setting. | 2EHRZ/2RHZ-2RH | DOT | |
| [24] | Iran | Controlled clinical trial | Sputum positive pulmonary TB patients over aged of 15 years with cavity less than 5 cm and with no history of previous treatment or for less than 15 days. | All had cavities of less than 5cm. No other characteristics are provided. | 2EHRZ/4RHZ | Unspecified | |
| [25] | South Africa | Randomized comparative open label controlled clinical trial | Sputum positive pulmonary TB patients over aged of 15 years with no history of previous treatment or received treatment for less than 5 days. | Recruited from eight centers, 78.8% and 75.4% males were on RMP and RBT respectively, and corresponding mean age was 36.7±11 versus 34.2±11 while weight was 51.6±7.6 and 50.9±8.2. Extent of disease was minimal in 4 vs 3, advance in 58 vs 51, far advanced in 53 vs 49. | 2EHRZ/4[RHE]2 | Unspecified | Included extra pulmonary but not Tuberculous meningitis patients |
| 2EHRTZ/4[RTHE]2 | |||||||
| [26] | Thailand | Randomized controlled clinical trial | Sputum positive pulmonary TB patients | Recruited from TB clinic. No baseline details available | 2EHRZ/4TH | Unspecified | |
| [27] | Ireland | Randomized controlled clinical trial | Sputum positive new pulmonary TB patients | All were sputum positive new PTB patients recruited from a clinic. | 2EHRZ/4RH | Unspecified |