Trial Outcomes & Findings for Tuberculosis Treatment Shortening Trial (NCT NCT00130247)

Last Updated: 2018-11-08

Results Overview

Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive \[defined as at least 1 of the following\]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

394 participants

Primary outcome timeframe

30 months

Results posted on

2018-11-08

Participant Flow

HIV-uninfected 18 to 60 year old adults with suspected or newly diagnosed pulmonary tuberculosis were eligible for enrollment at participating sites in Kampala, Uganda; Vitória, Brazil; and Manila/Makati City, the Philippines. Screening began in April 2002 in Uganda, December 2002 in Brazil, and November 2003 in the Philippines.

Subjects who met eligibility criteria were started on standard chemotherapy and routinely followed during anti-TB therapy. Patients with drug-susceptible TB who were sputum culture negative after 2 months of treatment were randomly assigned at 4 months to stop treatment or received an additional 2 months of daily isoniazid (INH) and rifampicin.

Participant milestones

Participant milestones
Measure	4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Overall Study STARTED	196	198
Overall Study COMPLETED	194	194
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Reasons for withdrawal
Measure	4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Overall Study Pregnancy	1	0
Overall Study Post-randomization exclusion	1	2
Overall Study Not compliant with DOT	0	2

Baseline Characteristics

Tuberculosis Treatment Shortening Trial

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	4-Month Arm n=196 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=198 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.	Total n=394 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	196 Participants n=5 Participants	198 Participants n=7 Participants	394 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	31.2 years STANDARD_DEVIATION 10 • n=5 Participants	30.3 years STANDARD_DEVIATION 10 • n=7 Participants	30.8 years STANDARD_DEVIATION 10 • n=5 Participants
Sex: Female, Male Female	77 Participants n=5 Participants	78 Participants n=7 Participants	155 Participants n=5 Participants
Sex: Female, Male Male	119 Participants n=5 Participants	120 Participants n=7 Participants	239 Participants n=5 Participants
Region of Enrollment Philippines	47 participants n=5 Participants	48 participants n=7 Participants	95 participants n=5 Participants
Region of Enrollment Brazil	81 participants n=5 Participants	81 participants n=7 Participants	162 participants n=5 Participants
Region of Enrollment Uganda	68 participants n=5 Participants	69 participants n=7 Participants	137 participants n=5 Participants

PRIMARY outcome

Timeframe: 30 months

Population: The intention to treat (ITT) analysis included all 394 fully eligible and randomized patients allocated to the shortened 4-month treatment group (N=196) or the standard 6-month treatment group (N=198). There were no allocated patients excluded in the ITT analysis dataset.

Outcome measures

Outcome measures
Measure	4-Month Arm n=196 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=198 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat	13 Participants	3 Participants

PRIMARY outcome

Timeframe: 30 months

Population: The per-protocol analysis included all 370 patients (185 per treatment arm) who received the intervention, completed treatment and full follow-up and did not have exogenous reinfection of TB. The 24 excluded subjects included 2 patients with exogenous reinfection of TB, 12 lost to follow-up, 4 deaths, and 6 who did not receive the intervention.

Outcome measures

Outcome measures
Measure	4-Month Arm n=185 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=185 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol	13 Participants	3 Participants

SECONDARY outcome

Timeframe: 2 years

A culture-positive treatment failure was defined as initial culture conversion but subsequent reversion to culture positivity. A clinical treatment failure was defined as a patient with clinical and/or radiographic evidence of progressive tuberculosis not confirmed by a positive culture after 4 or more months of anti-TB treatment while still receiving treatment. Patients who defaulted before completing study treatment and returned later with culture-positive tuberculosis were termed failures after non-adherence.

Outcome measures

Outcome measures
Measure	4-Month Arm n=196 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=198 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat Treatment Failures	0 Participants	0 Participants
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat Relapses	13 Participants	3 Participants

SECONDARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	4-Month Arm n=185 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=185 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol Treatment Failures	0 Participants	0 Participants
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol Relapses	13 Participants	3 Participants

SECONDARY outcome

Timeframe: 1 and 2 years after successful completion of initial anti-TB treatment

Population: Analysis includes the 386 patients who received the intervention, completed treatment, and started post-treatment follow-up (193 patients in each treatment arm). Two subjects were lost after completing treatment and contributed no follow-up time, and 6 subjects did not receive the intervention so were not included in the analysis.

Outcome measures

Outcome measures
Measure	4-Month Arm n=193 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=193 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Relapses at 1 and 2 Years Relapses at 1 year	10 Participants	3 Participants
Relapses at 1 and 2 Years Relapses at 2 years	13 Participants	3 Participants

SECONDARY outcome

Timeframe: 2 years

Population: This analysis was per protocol and looked for acquired drug resistance among the 13 patients in the 4-Month Arm who relapsed and the 3 patients in the 6-Month Arm who relapsed.

Outcome measures

Outcome measures
Measure	4-Month Arm n=13 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=3 Participants Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Acquired Drug Resistance in Patients Who Relapsed	0 Participants	0 Participants

SECONDARY outcome

Timeframe: After 2 and 6 months of anti-TB treatment and upon relapse

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-treatment and serum pre-treatment after 2 and 6 months of anti-TB treatment, and at the time of relapse for future immunologic analysis

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 1 and 2 months of anti-TB treatment

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 1 and 2 months of anti-TB treatment, and upon relapse

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30

Outcome measures

Outcome data not reported

Adverse Events

4-Month Arm

Serious events: 19 serious events

Other events: 170 other events

Deaths: 0 deaths

6-Month Arm

Serious events: 22 serious events

Other events: 164 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

John L. Johnson, M.D., Principal Investigator

Case Western Reserve University, Tuberculosis Research Unit

Phone: (216) 368-1949

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	4-Month Arm n=196 participants at risk Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=198 participants at risk Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Cardiac disorders Acute Myocardial Infarction (Death)	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Psychiatric disorders Bipolar Affective Disorder	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Bronchopneumonia	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Cardiac disorders Coronary Arery Occlusion	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Cystocele and Perineal Rupture	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Endometrial Polyp	0.00% 0/77 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	1.3% 1/78 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Fetal Death	1.3% 1/77 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	1.3% 1/78 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Eye disorders Glaucoma in Right Eye	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Injury, poisoning and procedural complications Gunshot Wound (Abdomen)	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Injury, poisoning and procedural complications Gunshot Wound to Head (Death)	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Nervous system disorders Headache (Severe Post-operative)	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Hemoptysis	0.51% 1/196 • Number of events 2 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Investigations Hospitalization (Unknown Cause of Abdominal Pain)	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
General disorders Hyperhidrosis	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Skin and subcutaneous tissue disorders Malignant Melanoma (Death)	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Musculoskeletal and connective tissue disorders Other Acquired Calcaneus Deformity	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Ovarian Cyst	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Ovarian Teratoma (Benign)	1.3% 1/77 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	1.3% 1/78 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Eye disorders Panuveitis	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Pelvic Abcess	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Pre-eclampsia	0.00% 0/77 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	1.3% 1/78 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Pregnancy, puerperium and perinatal conditions Pregnancy	13.0% 10/77 • Number of events 10 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	16.7% 13/78 • Number of events 14 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Nervous system disorders Seizure	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Injury, poisoning and procedural complications Suffocation (Death)	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Surgical and medical procedures Surgical Intervention on Right Shoulder	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Surgical and medical procedures Tracheal Plastic Repair	0.00% 0/196 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.51% 1/198 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Reproductive system and breast disorders Uterine Myoma	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Vocal Cord Cyst	0.51% 1/196 • Number of events 1 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	0.00% 0/198 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site

Measure	4-Month Arm n=196 participants at risk Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.	6-Month Arm n=198 participants at risk Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Gastrointestinal disorders Abdominal Pain	24.5% 48/196 • Number of events 63 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	24.7% 49/198 • Number of events 59 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Skin and subcutaneous tissue disorders Acne	7.1% 14/196 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	8.1% 16/198 • Number of events 17 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Metabolism and nutrition disorders Appetite Lost	19.9% 39/196 • Number of events 49 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	15.2% 30/198 • Number of events 35 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Musculoskeletal and connective tissue disorders Arthralgia	32.7% 64/196 • Number of events 92 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	32.3% 64/198 • Number of events 87 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Musculoskeletal and connective tissue disorders Back Pain	17.3% 34/196 • Number of events 46 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	15.7% 31/198 • Number of events 36 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Chest Pain	35.7% 70/196 • Number of events 115 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	26.3% 52/198 • Number of events 77 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Coryza	5.6% 11/196 • Number of events 11 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	5.1% 10/198 • Number of events 11 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Cough	53.1% 104/196 • Number of events 186 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	45.5% 90/198 • Number of events 162 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Gastrointestinal disorders Diarrhea	7.7% 15/196 • Number of events 20 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	5.1% 10/198 • Number of events 10 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Nervous system disorders Dizziness	9.2% 18/196 • Number of events 20 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	8.6% 17/198 • Number of events 18 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Dyspnea	8.7% 17/196 • Number of events 18 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	4.5% 9/198 • Number of events 9 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
General disorders Fever	44.4% 87/196 • Number of events 148 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	33.8% 67/198 • Number of events 103 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Infections and infestations Flu	20.4% 40/196 • Number of events 63 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	13.6% 27/198 • Number of events 46 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Nervous system disorders Headache	32.7% 64/196 • Number of events 102 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	23.2% 46/198 • Number of events 66 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Blood and lymphatic system disorders Hemoptysis	7.7% 15/196 • Number of events 19 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	7.6% 15/198 • Number of events 19 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Psychiatric disorders Insomnia	4.1% 8/196 • Number of events 11 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	5.6% 11/198 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
General disorders Malaise	8.7% 17/196 • Number of events 22 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	7.6% 15/198 • Number of events 18 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Infections and infestations Malaria	4.6% 9/196 • Number of events 12 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	1.0% 2/198 • Number of events 3 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Musculoskeletal and connective tissue disorders Myalgia	2.6% 5/196 • Number of events 5 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	7.6% 15/198 • Number of events 16 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Gastrointestinal disorders Nausea	10.2% 20/196 • Number of events 31 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	16.2% 32/198 • Number of events 41 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Musculoskeletal and connective tissue disorders Pain in Limb	3.1% 6/196 • Number of events 8 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	5.6% 11/198 • Number of events 14 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Produce Sputum	24.5% 48/196 • Number of events 57 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	19.7% 39/198 • Number of events 50 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Skin and subcutaneous tissue disorders Pruritis	23.5% 46/196 • Number of events 57 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	21.7% 43/198 • Number of events 52 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Purulent Sputum	17.3% 34/196 • Number of events 40 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	13.6% 27/198 • Number of events 33 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Skin and subcutaneous tissue disorders Rash	9.2% 18/196 • Number of events 20 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	7.6% 15/198 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Rhinorrhea	6.1% 12/196 • Number of events 17 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	8.6% 17/198 • Number of events 19 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
General disorders Rigors	6.6% 13/196 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	6.1% 12/198 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Skin and subcutaneous tissue disorders Skin Lesion	7.7% 15/196 • Number of events 21 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	4.5% 9/198 • Number of events 22 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Sore Throat	7.1% 14/196 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	5.1% 10/198 • Number of events 10 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
General disorders Sweating	6.6% 13/196 • Number of events 15 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	8.6% 17/198 • Number of events 22 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Infections and infestations Tinea Infection	5.1% 10/196 • Number of events 12 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	3.0% 6/198 • Number of events 9 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Respiratory, thoracic and mediastinal disorders Upper Respiratory Tract Infection	16.8% 33/196 • Number of events 50 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	13.6% 27/198 • Number of events 39 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Gastrointestinal disorders Vomiting	7.7% 15/196 • Number of events 18 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	8.1% 16/198 • Number of events 19 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Metabolism and nutrition disorders Weight Loss	12.2% 24/196 • Number of events 29 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site	10.1% 20/198 • Number of events 26 • 6 years Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site