Trial no.:	PACTR202302799565020	Date of Approval:	09/02/2023
Trial Status:	Registered in accordance with WHO and ICMJE standards

TRIAL DESCRIPTION

Public title

REDUCING MORTALITY IN ADULTS WITH ADVANCED HIV DISEASE (REVIVE) - A randomised, double blinded, placebo-controlled, multicentre trial of Azithromycin prophylaxis for advanced HIV disease

Official scientific title

REDUCING MORTALITY IN ADULTS WITH ADVANCED HIV DISEASE (REVIVE)

Brief summary describing the background and objectives of the trial

A double blinded, placebo-controlled, multicentre trial to evaluate effectiveness of azithromycin prophylaxis for prevention of mortality in advanced HIV. All participants will be randomised (1:1) at the time of study entry to receive azithromycin prophylaxis or placebo for 28 days and will be followed for 24 weeks to determine the primary outcome measure. The primary objective is to determine whether azithromycin is an effective and safe intervention to reduce excess mortality in adults with advanced HIV (CD4 < 100 cells/mm3). Secondary objectives include exploring effects on mortality and hospitalisation at early and late timepoints, impact on incident infection, causes of death, and antimicrobial resistance. Exploratory (in a subgroup of participants at selected sites) Causes of death (using a validated shortened verbal autopsy instrument [94]). Incident severe infection episodes through 24 weeks, defined as a clinical diagnosis of infection leading to hospitalisation and/or isolation of pathogenic bacteria from a sterile site. Carriage and phenotypic macrolide and non-macrolide resistance of bacterial pathogens from upper airway and rectal swabs. The main safety outcome is adverse drug reactions that lead to permanent discontinuation of study drug or that lead to death. Quality of life and cost-effectiveness Social science research (acceptability of intervention, determinants of adherence)

Type of trial

RCT

Acronym (If the trial has an acronym then please provide)

REVIVE

Disease(s) or condition(s) being studied

Infections and Infestations

Sub-Disease(s) or condition(s) being studied

HIV/AIDS

Purpose of the trial

Treatment: Drugs

Anticipated trial start date

01/02/2023

Actual trial start date

08/05/2023

Anticipated date of last follow up

03/08/2026

Actual Last follow-up date

Anticipated target sample size (number of participants)

8000

Actual target sample size (number of participants)

Recruitment status

Recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Parallel: different groups receive different interventions at same time during study	Randomised	Simple randomization using a randomization table created by a computer software program	Allocation was determined by the holder of the sequence who is situated off site	Masking/blinding used	Care giver/Provider,Outcome Assessors,Participants

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Experimental Group	Azithromycin	Azithromycin 250 mg once daily orally	Starting at the time of randomisation, for 4 weeks (28 days)	The azithromycin dosing strategy is selected to balance likelihood of efficacy with cost, any side effects, and adherence. The labelled dose for treatment of respiratory tract infections is a loading dose of 500 mg followed by 250 mg daily for up to 5 days.	4000
Control Group	Placebo Comparator	250mg placebo	starting at the time of randomisation, for 4 weeks (28 days)	Placebo oral tablet	4000	Placebo

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
Age ≥ 18 years Documented HIV infection CD4 count criteria: CD4 count ≤ 100 cells/mm3 within past 30 days if on ART; or Documented CD4 nadir ≤ 100 cells/mm3 and complete interruption of ART for ≥ 6 months; or Documented CD4 count ≤ 100 cells/mm3 if ART-naive Ability to initiate or re-initiate ART, or switch to an effective ART regimen if failing current therapy, within 2 weeks of enrolment	Contraindications to azithromycin: Hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotic; or Personal or family history of QT-prolongation Severe illness requiring immediate or continued hospitalisation* *This will be in the judgement of site investigators.	Adult: 19 Year-44 Year	18 Year(s)	65 Year(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

30/01/2023

UCT Human Research Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
Room G50 Old Main Building, Groote Schuur Hospital, Observatory, 7925	Cape Town	7925	South Africa

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	All-cause mortality at 24 weeks after randomisation	24 weeks after randomisation
Secondary Outcome	 All-cause mortality at 12 weeks  Hospitalisation at 24 weeks  Composite of hospitalisation and all-cause mortality at 24 weeks	12 and 24 weeks

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
New Somerset Hospital	Portswood Road, Greenpoint	Cape Town	8001	South Africa
Steve Biko Academic Hospital	c/o Steve Biko and Malan Street, Capital Park	Pretoria	0001	South Africa
CHRU Clinical HIV Research Unit	Department of Medicine, University of Witwatersrand, Helen Joseph Hospital, Perth Road, Westdene	Johannesburg	2092	South Africa
Site B Clinic	No 1 corner of Bonga and Lwandle Drive, Site B, Khayelitsha	Cape Town	7780	South Africa
Right to Care Esizayo	Corner Malibongwe Drive and Tennessee Avenue Cosmo City	Johannesburg	2087	South Africa
DTHF DCAT Gugulethu	Desmond Tutu Health Foundation Gugulethu Research Offices, Gugulethu Scout Hall,NY79, Gugulethu	Cape Town	7750	South Africa
The Aurum Institute Gavin J Churchyard Legacy Centre	Klerksdorp CRC, 201 Jade Square Centre, Cnr Margaretha Prinsloo and OR Tambo Drive	Klerksdorp	2571	South Africa
The Aurum Institute Rustenburg Clinical Research Centre Heritage Building	178 Beyers Naude Drive	Rustenberg	0299	South Africa
AHRI Main CTU Coordination Site	AHRI Somkhele Via R618 to Hlabisa, Somkhele	Mtubatuba	3935	South Africa
AHRI Satellite Site 1 Mtubatuba Clinic	AHRI Somkhele via R618 to Hlabisa	Mtubatuba	3935	South Africa
AHRI Satellite Site 2 Mpukunyoni Clinic	AHRI Somkhele via R618 to Hlabisa	Mtubatuba	3935	South Africa
AHRI Satellite Site 3 KwaMsane Clinic	Africa Health Research Institute Africa Centre Building, Via R618 to Hlabisa	Mtubatuba	3935	South Africa
AHRI Satellite Site 4 Somkhele Clinic	AHRI Somkhele via R618 to Hlabisa	Mtubatuba	3935	South Africa
AHRI Satellite Site 5 Hluhluwe Clinic	AHRI Somkhele via R618 to Hlabisa	Mtubatuba	3935	South Africa
AHRI Satellite Site 6 Nkundusi Clinic	AHRI Somkhele via R618 to Hlabisa	Mtubatuba	3935	South Africa
Groote Schuur Hospital G26 Infectious Diseases Clinic	G-floor, New Main Building, Groote Schuur Hospital, Main Road, Observatory	Cape Town	7925	South Africa
UCT VUKA Research Clinic	1st floor lsivivana Centre, 8 Mzala street, Khayelitsha	Cape Town	7784	South Africa
lnnoMed Clinical Trial Centre	3rd Floor, Skyscape Terraces, 5 DJ Wood Way, Bellville Business Park, Bellville, 7530, Cape Town, South Africa	Cape Town	7530	South Africa
UBUNTU Clinical Research	Ubuntu Clinical Research - 71 Pretoria Street, Krugersdorp, Gauteng, 1739, South Africa	Gauteng	1739	South Africa
UBUNTU Clinical Research	212 Rose Avenue, Lenasia, Gauteng, 1827, South Africa	Gauteng	1827	South Africa
Livingstone Hospital	Standford Road, Korsten, Gqeberha	Gqeberha	6020	South Africa

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
Population Health Research Institute PHRI	237 Barton Street East, Hamilton, ON L8L 2X2	Ontario	L8L 2X2	Canada

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	Population Health Research Institute	237 Barton Street East, Hamilton,	Ontario	L8L 2X2	Canada	University

COLLABORATORS
Name	Street address	City	Postal code	Country

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	Sean Wasserman	sean.wasserman@uct.ac.za	+27216507220	Room G16.63, New Groote Schuur Hospital, Observatory
City	Postal code	Country	Position/Affiliation
Cape Town	7925	South Africa	Principal Investigator
Role	Name	Email	Phone	Street address
Scientific Enquiries	Veronica Euckermann	veronica.ueckermann@up.ac.za	+27837852343	Steve Biko Academic Hospital, c/o Steve Biko and Malan Street, Capital Park,
City	Postal code	Country	Position/Affiliation
Pretoria	0001	South Africa	Site Principal Investigator
Role	Name	Email	Phone	Street address
Public Enquiries	Meagan McMaster	meagan.mcmaster@uct.ac.za	+27216502602	Faculty of Health Sciences University of Cape Town, Anzio Road
City	Postal code	Country	Position/Affiliation
Cape Town	7925	South Africa	Regulatory Manager

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	Data will be shared with other organizations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by HREC that approved the initial study).	Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol	From the time the final results are published, within 12 months of the study completion date.	Data will be shared with other organizations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by HREC that approved the initial study).
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

Changes to trial information
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Public title	21/11/2024	SAHPRA Suggestion	REDUCING MORTALITY IN ADULTS WITH ADVANCED HIV DISEASE (REVIVE)	REDUCING MORTALITY IN ADULTS WITH ADVANCED HIV DISEASE (REVIVE) - A randomised, double blinded, placebo-controlled, multicentre trial of Azithromycin prophylaxis for advanced HIV disease
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Actual trial start date	19/06/2024	Recruitment commenced		08 May 2023
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Recruitment status	19/06/2024	Recruitment commenced	Not yet recruiting	Recruiting
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Intervention	Intervention List	09/02/2023	Covers experimental group for the enitre trial's sample size. Previous was just for local sites.		Experimental Group, Azithromycin, Azithromycin 250 mg once daily orally, Starting at the time of randomisation, for 4 weeks (28 days), The azithromycin dosing strategy is selected to balance likelihood of efficacy with cost, any side effects, and adherence. The labelled dose for treatment of respiratory tract infections is a loading dose of 500 mg followed by 250 mg daily for up to 5 days. , 4000,
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Intervention	Intervention List	09/02/2023	Covers placebo group for the enitre trial's sample size. Previous was just for local sites.	Control Group, Placebo Comparator, 250mg placebo , starting at the time of randomisation, for 4 weeks (28 days), Placebo oral tablet, 200, Placebo	Control Group, Placebo Comparator, 250mg placebo , starting at the time of randomisation, for 4 weeks (28 days), Placebo oral tablet, 4000, Placebo
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	19/06/2024	Spelling correction	New Somerset Hospitals, Portswood Road, Greenpoint, Cape Town, 8001, South Africa	New Somerset Hospital, Portswood Road, Greenpoint, Cape Town, 8001, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 21Aug2023		CHRU Clinical HIV Research Unit, Department of Medicine, University of Witwatersrand, Helen Joseph Hospital, Perth Road, Westdene , Johannesburg, 2092, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 21Aug2023		Site B Clinic, No 1 corner of Bonga and Lwandle Drive, Site B, Khayelitsha, Cape Town, 7780, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 21Aug2023		Right to Care Esizayo, Corner Malibongwe Drive and Tennessee Avenue Cosmo City, Johannesburg, 2087, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		DTHF DCAT Gugulethu, Desmond Tutu Health Foundation Gugulethu Research Offices, Gugulethu Scout Hall,NY79, Gugulethu, Cape Town, 7750, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		The Aurum Institute Gavin J Churchyard Legacy Centre, Klerksdorp CRC, 201 Jade Square Centre, Cnr Margaretha Prinsloo and OR Tambo Drive, Klerksdorp, 2571, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		The Aurum Institute Rustenburg Clinical Research Centre Heritage Building, 178 Beyers Naude Drive, Rustenberg, 0299, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Main CTU Coordination Site, AHRI Somkhele Via R618 to Hlabisa, Somkhele, Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Satellite Site 1 Mtubatuba Clinic, AHRI Somkhele via R618 to Hlabisa , Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Satellite Site 2 Mpukunyoni Clinic, AHRI Somkhele via R618 to Hlabisa, Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Satellite Site 3 KwaMsane Clinic, Africa Health Research Institute Africa Centre Building, Via R618 to Hlabisa, Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Satellite Site 4 Somkhele Clinic, AHRI Somkhele via R618 to Hlabisa , Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Satellite Site 5 Hluhluwe Clinic, AHRI Somkhele via R618 to Hlabisa , Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 09May2024		AHRI Satellite Site 6 Nkundusi Clinic, AHRI Somkhele via R618 to Hlabisa, Mtubatuba, 3935, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 23Aug2024		Groote Schuur Hospital G26 Infectious Diseases Clinic, G-floor, New Main Building, Groote Schuur Hospital, Main Road, Observatory, Cape Town, 7925, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	21/11/2024	SAHPRA approval received 23Aug2024		UCT VUKA Research Clinic, 1st floor lsivivana Centre, 8 Mzala street, Khayelitsha, Cape Town, 7784, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	24/02/2025	Approved by SAHPRA 21Jan2025		lnnoMed Clinical Trial Centre, 3rd Floor, Skyscape Terraces, 5 DJ Wood Way, Bellville Business Park, Bellville, 7530, Cape Town, South Africa , Cape Town, 7530, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	24/02/2025	Approved by SAHPRA 21Jan2025		UBUNTU Clinical Research, Ubuntu Clinical Research - 71 Pretoria Street, Krugersdorp, Gauteng, 1739, South Africa, Gauteng, 1739, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	24/02/2025	Approved by SAHPRA 21Jan2025		UBUNTU Clinical Research, 212 Rose Avenue, Lenasia, Gauteng, 1827, South Africa, Gauteng, 1827, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	24/02/2025	Approved by SAHPRA 21Jan2025		Livingstone Hospital, Standford Road, Korsten, Gqeberha, Gqeberha, 6020, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	IPD-Sharing time frame	09/02/2023	As per reviewer's comments from the Clinical Trials Registry	From the time the final results are published.	From the time the final results are published, within 12 months of the study completion date.

Pan African Clinical Trials Registry