CTRI Number	CTRI/2018/08/015159 [Registered on: 01/08/2018] Trial Registered Prospectively
Last Modified On:	13/10/2023
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Drug
Study Design	Randomized, Parallel Group, Multiple Arm Trial
Public Title of Study Modification(s)	Optimal treatment for a potentially life threatening infection called scrub typhus
Scientific Title of Study Modification(s)	Intravenous Treatment for Scrub Typhus
Secondary IDs if Any	Secondary ID  Registry  NIL  NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)	Name  Dr George M Varghese  Address  Department of Infectious Diseases, Christian Medical College,Ida Scudder Road,Vellore Vellore TAMIL NADU 632004 India  Phone  91-9487393015   Fax     Email  georgemvarghese@hotmail.com
Details Contact Person Scientific Query Modification(s)	Name  Dr George M Varghese  Address  Department of Infectious Diseases, Christian Medical College,Ida Scudder Road,Vellore Vellore TAMIL NADU 632004 India  Phone  91-9487393015   Fax     Email  georgemvarghese@hotmail.com
Details Contact Person Public Query Modification(s)	Name  Roshini G  Address  Department of Infectious Diseases, Chrisitian Medical College, Ida Scudder Road, Vellore Vellore TAMIL NADU 632004 India  Phone  91-9176906501   Fax     Email  roshininair25@gmail.com
Source of Monetary or Material Support Modification(s)	The Wellcome Trust/DBT India Alliance 1110, DLF Tower B, Jasola District Centre Behind Apollo Hospital, New Delhi - 110025
Primary Sponsor	Name  Christian Medical College  Address  Christian Medical College, Ida Scudder Road, Vellore- 632004  Type of Sponsor  Research institution and hospital
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India Lao People's Democratic Republic Thailand
Sites of Study Modification(s)	No of Sites = 6   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr George M Varghese  Christian Medical College  Deaprtment of Infectious Diseases, Christian Medical College, Ida Scudder Road, Vellore Vellore   91-9487393015 georgemvarghese@hotmail.com  Dr Sanjay Mahajan  Indira Gandhi Medical College  Department of Medicine,IGMC, Shimla- 171001 Shimla   91-9418071515 drsanjaymahajan64@gmail.com  Dr Mukta Wyawahare  Jawaharlal Institute of Postgraduate Medical Education and Research  Department of Medicine,JIPMER, Pondicherry-605006 Pondicherry   91-8903307660 mukta.wyawahare@gmail.com  Dr Kavitha Saravu  Kasturba Medical College  Department of Medicine, Manipal Academy of Higher Education( MAHE),KMC, Madhava Nagar, Manipal Udupi   91-9448107636 kavitha.saravu@manipal.edu  Dr Dhruva Chaudhry  Post Graduate Institute of Medical College  Department of Pulmonary care and critical medicine,PGIMS, Rohtak-124001 Rohtak   91-9991101616 dhruvachaudhry@yahoo.co.in  Dr Navneet Sharma  Postgraduate Institute of Medical Education and Research  Department of Internal Medicine, PGIMER,Chandigarh-160012 Chandigarh   91-9872828433 navneetsharma@hotmail.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 6   Name of Committee  Approval Status  Institutional Ethics Committee IGMC  Approved  Institutional Ethics Committee MAHE  Approved  Institutional Ethics Committee PGIMER  Approved  Institutional Ethics Committee SVIMS  Approved  Institutional Ethics Committee( Human Studies), JIPMER  Approved  Institutional Ethics Committee, PGIMS,Rohtak  Approved
Regulatory Clearance Status from DCGI	Status  No Objection Certificate
Health Condition / Problems Studied Modification(s)	Health Type  Condition  Patients  Typhus fever due to Rickettsia tsutsugamushi  Patients  Typhus fever due to Rickettsia tsutsugamushi  Patients  Typhus fever due to Rickettsia tsutsugamushi
Intervention / Comparator Agent Modification(s)	Type  Name  Details  Intervention  Combination of IV Azithromycin and IV Doxycycline  Day 1,Dose 1( Infusion 1):Azithro 500mg In 250ml NS over 1 hr Day 1, Dose 1 ( Infusion 2):Doxy 200mg in 250ml NS over 2 hrs Day 1, Dose 2 ( Infusion 1):Azithro 500mg In 250ml NS over 1 hr Day 1, Dose 2 ( Infusion 2): Doxy 200mg in 250ml NS over 2 hrs Day 2-7: Dose 1 ( Infusion 1):Azithro 500mg In 250ml NS over 1 hr Day 2-7: Dose 1 ( Infusion 2):Doxy 100mg in 100ml NS over 1 hr Day 2-7: Dose 2 ( Infusion 1):Doxy 100mg in 100ml NS over 1 hr  Intervention  IV Azithromycin  Day 1,Dose 1( Infusion 1):Azithro 500mg in 250ml NS over 1 hr Day 1, Dose1 ( Infusion 2):Polybion in 250ml NS over 2 hrs Day 1, Dose 2 ( Infusion 1):Azithro 500mg In 250ml NS over 1 hr Day 1, Dose 2 ( Infusion 2): Polybion in 250ml NS over 2 hrs Day 2-7: Dose 1 ( Infusion 1):Azithro 500mg in 250ml NS over 1 hr Day 2-7: Dose 1 ( Infusion 2):Polybion in 100ml NS over 1 hr Day 2-7: Dose 2 ( Infusion 1):Polybion in 100ml NS over 1 hr  Comparator Agent  IV Doxycycline  Day 1,Dose 1( Infusion 1):Doxy 200mg in 250ml NS over 2 hrs Day 1, Dose1 ( Infusion 2):250 ml NS only over 1 hr Day 1, Dose 2 ( Infusion 1):Doxy 200mg in 250 ml NS over 2 hrs Day 1, Dose 2 ( Infusion 2):250 ml NS only over 1 hr Day 2-7: Dose 1 ( Infusion 1): Doxy 100 mg in 100 ml NS over 1 hr Day 2-7: Dose 1 ( Infusion 2): 250 ml NS only over 1 hr Day 2-7: Dose 2 ( Infusion 1):Doxy 100 mg in 100 ml NS over 1 hr
Inclusion Criteria Modification(s)	Age From  15.00 Year(s) Age To  99.00 Year(s) Gender  Both  Details  All of the following criteria must be met: • Age ≥15 years old presenting with fever • Scrub typhus rapid test (RDT) positivity and/or presence of an eschar • Severe scrub typhus as per the criteria A or requiring IV treatment as decided by the attending physician • Willingness to participate in the study and written informed consent obtained from the patient / the patient’s parent(s), guardian(s) or representative(s) where necessary
ExclusionCriteria	Details  The participant may not enter the study if ANY of the following apply: 1.Pregnancy or breastfeeding 2.Current tuberculosis (rifampicin has activity against O. tsutsugamushi) 3.Documented HIV infection, long term use of steroids, chemotherapy, other immunosuppressant therapy 4.Taking medicines that may interact with study drugs 5.Known allergy to either of the medications 6.Patients who have received azithromycin or doxycycline or chloramphenicol for more than 24 hours within 3 days prior to recruitment
Method of Generating Random Sequence	Computer generated randomization
Method of Concealment	Other
Blinding/Masking	Participant and Outcome Assessor Blinded
Primary Outcome	Outcome  TimePoints  Treatment success as measured as a composite of survival at 28 days, lack of persisting complications at day 7 and lack of fever at day 5  Day28
Secondary Outcome	Outcome  TimePoints  Adverse events   Up to Day 28  Measurement of serial drug levels andO. tsutsugamushi bacterial counts (by qPCR) in blood  Days 1, 3, 7& 10-14   Number of deaths   Day 28
Target Sample Size	Total Sample Size="1509" Sample Size from India="1134"
Phase of Trial	N/A
Date of First Enrollment (India)	10/08/2018
Date of First Enrollment (Global)	10/01/2019
Estimated Duration of Trial	Years="3" Months="0" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Suspended
Recruitment Status of Trial (India)	Completed
Publication Details Modification(s)	This work was published in the New England Journal of Medicine in March, 2023. Citation & link is provided below: Varghese GM, Dayanand D, Gunasekaran K, Kundu D, Wyawahare M, Sharma N, Chaudhry D, Mahajan SK, Saravu K, Aruldhas BW, Mathew BS, Nair RG, Newbigging N, Mathew A, Abhilash KPP, Biswal M, Prasad AH, Zachariah A, Iyadurai R, Hansdak SG, Sathyendra S, Sudarsanam TD, Prakash JAJ, Manesh A, Mohan A, Tarning J, Blacksell SD, Peerawaranun P, Waithira N, Mukaka M, Cheah PY, Peter JV, Abraham OC, Day NPJ; INTREST Trial Investigators. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. N Engl J Med. 2023 Mar 2; 388(9):792-803. Doi: 10.1056/NEJMoa2208449. PMID: 36856615; PMCID: PMC7614458. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2208449
Brief Summary Modification(s)	Background:Scrub typhus caused by bacterium Orientia tsutsugamushi, is a life-threatening acute febrile illness endemic in South and Southeast Asia. Yearly, about one million people are affected with scrub typhus, of which 20% develop severe disease including multi-organ dysfunction and shock leading to fatality rates as high as 30-50%. Although there is evidence to suggest mild scrub typhus can be treated with either azithromycin or doxycycline, the optimal drug treatment and drug dosing for severe cases is still unclear. Also, data on efficacy, pharmaco kinetics and pharmaco dynamics of these drugs in scrub typhus is limited. Methods/Design:We intend to conduct a parallel group; three-arm, participant and   Investigator- blinded multi-center randomized controlled superiority trial across 8 centers in south and south-east Asia to compare the efficacy of  7 days treatment with IV azithromycin vs IV doxycycline vs IV azithromycin + IV doxycycline in the treatment of severe scrub typhus. The primary outcome is treatment success measured as a composite of survival at 28 days, lack of persisting complications at day 7 and lack of fever at day 5. Treatment safety, 28 day all-cause mortality and defined measures of recovery would be assessed as secondary outcomes. Also, we intend to study the pharmacokinetic and pharmacodynamic characteristics of the chosen antibiotic regimens and isolate, characterize human pathogenic Orientia tsutsugamushi  isolates causing scrub typhus.Discussion: Conducting a multi-center, multi-national RCT would make our results generalizable leading to development of evidence-based guidelines that can be disseminated to a range of healthcare settings across the scrub typhus endemic region. It would also facilitate  studying the strain characteristics of the bacteria that influence virulence, diagnostics and treatment.