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Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy (REALITY)

Primary Purpose

Human Immunodeficiency Virus

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Raltegravir
Fluconazole
Azithromycin
Albendazole
Isoniazid
Ready to Use Supplementary Food
Sponsored by
Anna Griffiths, MRC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Human Immunodeficiency Virus focused on measuring HIV

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Aged 5 years or older
  • Documented HIV infection by HIV ELISA or HIV rapid test
  • Naive to ART
  • CD4 T-cell count <100 cells/mm3 on blood test taken at screening for REALITY
  • Results of screening haematology and biochemistry tests available and no contraindications to planned ART according to national guidelines
  • Patient/carer provide informed consent (and children <18 years assent, as appropriate according to their age and knowledge of HIV status)

The lower age limit is because CD4 counts are less reliable predictors of immunodeficiency under 5 years: CD4 counts are recommended by guidelines in older children.

No patient with a CD4 count above 100 cells/mm3 should have ART delayed in order to subsequently meet eligibility criteria. Rather, patients eligible for REALITY will be those testing HIV positive for the first time with a low CD4 count (i.e. those delaying presentation to care), or those who have defaulted before initiating ART and only return to care at an advanced stage of immuno-deficiency.

Exclusion Criteria:

  • Contraindications to any proposed antiretroviral drugs (including integrase inhibitors), isoniazid, fluconazole, albendazole or azithromycin
  • Pregnant or breastfeeding or intending to become pregnant during the first 12 weeks of the study
  • Ever known to have previously received single-dose nevirapine for prevention of mother-to-child transmission (mother or child).

Sites / Locations

  • Moi University Clinical Research Centre
  • KEMRI Wellcome Trust Research Programme
  • University of Malawi
  • Joint Clinical Research Centre, Fort Portal
  • Joint Clinical Research Centre, Gulu
  • Joint Clinical Research Centre, Mbale
  • Joint Clinical Research Centre, Mbarara
  • University of Zimbabwe Clinical Research Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Antiretroviral Therapy

Opportunistic Infection (OI) Prophylaxis

Nutritional Support

Arm Description

Raltegravir twice daily for 12 weeks from antiretroviral therapy (ART) initiation in addition to 3 standard ARVs (2NRTIs/1NNRTI) compared with 3 standard ARVs

Immediate isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole compared with immediate cotrimoxazole (if not already taking this) in all patients plus (not malawi)isoniazid/pyridoxine after 12 weeks.

Supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks compared with supplementation for those with severe malnutrition as local practice.

Outcomes

Primary Outcome Measures

All-cause mortality over the first 24 weeks after starting ART

Secondary Outcome Measures

48 week mortality (all-cause)
Safety
serious adverse events grade 4 adverse events adverse events leading to modification of ART or other study drugs
Hospital inpatient episodes and total days admitted
Adherence to ART and acceptability of each strategy
Adherence to ART, OI drugs and RUSF will be assessed in all participants at each visit by pill counts and short nurse-administered questions. Every 12 weeks, a more detailed adherence questionnaire will be adminstered.
Endpoint relating to anti-infection intervention
Incidence of tuberculosis (TB), cryptococcal and candida disease, severe bacterial infections
Endpoint relating to anti-malnutrition intervention
BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children) and grip strength
Endpoint relating to anti-HIV intervention
Changes in CD4 cell count

Full Information

First Posted
January 7, 2013
Last Updated
April 19, 2016
Sponsor
Anna Griffiths, MRC
Collaborators
Department for International Development, United Kingdom, Wellcome Trust, Medical Research Council, PENTA Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT01825031
Brief Title
Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy
Acronym
REALITY
Official Title
Reduction of Early mortALITY in HIV-infected African Adults and Children Starting Antiretroviral Therapy: a Randomised Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2016
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
March 2016 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Anna Griffiths, MRC
Collaborators
Department for International Development, United Kingdom, Wellcome Trust, Medical Research Council, PENTA Foundation

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A randomised controlled trial to investigate three methods to reduce early mortality in adults, adolescents and children aged 5 years or older starting antiretroviral therapy (ART) with severe immuno-deficiency. The three methods are: (i) increasing the potency of ART with a 12 week induction period using 4 antiretroviral drugs from 3 classes (ii) augmented prophylaxis against opportunistic/bacterial infections and helminths for 12 weeks (iii) macronutrient intervention using ready-to-use supplementary food for 12 weeks.
Detailed Description
REALITY is a open-label randomised trial of 1800 adults, adolescents and children aged 5 years or more with low CD4 counts about to initiate ART. The trial will have a factorial design with 3 randomisations, each to address one of the potential approaches to reduce early mortality in adults and children initiating ART with low CD4, namely: Raltegravir for 12 weeks from ART initiation in addition to 3 standard ART (3-drug 2-class) versus standard of care first-line 3-drug 2-class ART (choice according to national guidelines for ART initiation); Immediate enhanced opportunistic infections (OI) prophylaxis with isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole versus cotrimoxazole prophylaxis alone for the first 12 weeks followed by isoniazid and any prophylaxis and/or treatment prescribed at screening supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks versus standard of care nutritional support to those with poor nutritional status according to local guidelines. All participants will receive cotrimoxazole throughout the trial. The primary objective of the trial is to identify effective, safe and acceptable interventions to reduce early mortality (all-cause) in HIV-infected adults, adolescents, and older children (5 years or more) initiating ART.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus
Keywords
HIV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1805 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Antiretroviral Therapy
Arm Type
Experimental
Arm Description
Raltegravir twice daily for 12 weeks from antiretroviral therapy (ART) initiation in addition to 3 standard ARVs (2NRTIs/1NNRTI) compared with 3 standard ARVs
Arm Title
Opportunistic Infection (OI) Prophylaxis
Arm Type
Experimental
Arm Description
Immediate isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole compared with immediate cotrimoxazole (if not already taking this) in all patients plus (not malawi)isoniazid/pyridoxine after 12 weeks.
Arm Title
Nutritional Support
Arm Type
Experimental
Arm Description
Supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks compared with supplementation for those with severe malnutrition as local practice.
Intervention Type
Drug
Intervention Name(s)
Raltegravir
Intervention Description
400mg twice daily for the first 12 weeks only in addition to 3 standard ARVs
Intervention Type
Drug
Intervention Name(s)
Fluconazole
Intervention Description
100mg once daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Azithromycin
Intervention Description
500mg once daily for 5 days
Intervention Type
Drug
Intervention Name(s)
Albendazole
Intervention Description
a single dose 400mg
Intervention Type
Drug
Intervention Name(s)
Isoniazid
Intervention Description
300mg taken immediately in combination with cotrimoxazole
Intervention Type
Dietary Supplement
Intervention Name(s)
Ready to Use Supplementary Food
Other Intervention Name(s)
RUSF
Intervention Description
2x92g packets daily of high energy, low protein lipid-based paste for 12 weeks
Primary Outcome Measure Information:
Title
All-cause mortality over the first 24 weeks after starting ART
Time Frame
Week 24
Secondary Outcome Measure Information:
Title
48 week mortality (all-cause)
Time Frame
Week 48
Title
Safety
Description
serious adverse events grade 4 adverse events adverse events leading to modification of ART or other study drugs
Time Frame
Week 0-48
Title
Hospital inpatient episodes and total days admitted
Time Frame
Week 0-48
Title
Adherence to ART and acceptability of each strategy
Description
Adherence to ART, OI drugs and RUSF will be assessed in all participants at each visit by pill counts and short nurse-administered questions. Every 12 weeks, a more detailed adherence questionnaire will be adminstered.
Time Frame
Week 0-48
Title
Endpoint relating to anti-infection intervention
Description
Incidence of tuberculosis (TB), cryptococcal and candida disease, severe bacterial infections
Time Frame
0-48 weeks
Title
Endpoint relating to anti-malnutrition intervention
Description
BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children) and grip strength
Time Frame
0-48 weeks
Title
Endpoint relating to anti-HIV intervention
Description
Changes in CD4 cell count
Time Frame
0-48 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged 5 years or older Documented HIV infection by HIV ELISA or HIV rapid test Naive to ART CD4 T-cell count <100 cells/mm3 on blood test taken at screening for REALITY Results of screening haematology and biochemistry tests available and no contraindications to planned ART according to national guidelines Patient/carer provide informed consent (and children <18 years assent, as appropriate according to their age and knowledge of HIV status) The lower age limit is because CD4 counts are less reliable predictors of immunodeficiency under 5 years: CD4 counts are recommended by guidelines in older children. No patient with a CD4 count above 100 cells/mm3 should have ART delayed in order to subsequently meet eligibility criteria. Rather, patients eligible for REALITY will be those testing HIV positive for the first time with a low CD4 count (i.e. those delaying presentation to care), or those who have defaulted before initiating ART and only return to care at an advanced stage of immuno-deficiency. Exclusion Criteria: Contraindications to any proposed antiretroviral drugs (including integrase inhibitors), isoniazid, fluconazole, albendazole or azithromycin Pregnant or breastfeeding or intending to become pregnant during the first 12 weeks of the study Ever known to have previously received single-dose nevirapine for prevention of mother-to-child transmission (mother or child).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diana M Gibb
Organizational Affiliation
Medical Research Council
Official's Role
Study Director
Facility Information:
Facility Name
Moi University Clinical Research Centre
City
Eldoret
Country
Kenya
Facility Name
KEMRI Wellcome Trust Research Programme
City
Kilifi
Country
Kenya
Facility Name
University of Malawi
City
Blantyre
Country
Malawi
Facility Name
Joint Clinical Research Centre, Fort Portal
City
Fort Portal
Country
Uganda
Facility Name
Joint Clinical Research Centre, Gulu
City
Gulu
Country
Uganda
Facility Name
Joint Clinical Research Centre, Mbale
City
Mbale
Country
Uganda
Facility Name
Joint Clinical Research Centre, Mbarara
City
Mbarara
Country
Uganda
Facility Name
University of Zimbabwe Clinical Research Centre
City
Harare
Country
Zimbabwe

12. IPD Sharing Statement

Citations:
PubMed Identifier
34432828
Citation
Kelly C, Tinago W, Alber D, Hunter P, Luckhurst N, Connolly J, Arrigoni F, Garcia Abner A, Kamn'gona R, Sheha I, Chammudzi M, Jambo K, Mallewa J, Rapala A, Mallon PWG, Mwandumba H, Klein N, Khoo S. Inflammatory pathways amongst people living with HIV in Malawi differ according to socioeconomic status. PLoS One. 2021 Aug 25;16(8):e0256576. doi: 10.1371/journal.pone.0256576. eCollection 2021.
Results Reference
derived
PubMed Identifier
32103268
Citation
Kelly C, Tinago W, Alber D, Hunter P, Luckhurst N, Connolly J, Arrigoni F, Abner AG, Kamngona R, Sheha I, Chammudzi M, Jambo K, Mallewa J, Rapala A, Heyderman RS, Mallon PWG, Mwandumba H, Walker AS, Klein N, Khoo S. Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation. Clin Infect Dis. 2020 Dec 3;71(9):2389-2397. doi: 10.1093/cid/ciaa186.
Results Reference
derived
PubMed Identifier
30513108
Citation
Kityo C, Szubert AJ, Siika A, Heyderman R, Bwakura-Dangarembizi M, Lugemwa A, Mwaringa S, Griffiths A, Nkanya I, Kabahenda S, Wachira S, Musoro G, Rajapakse C, Etyang T, Abach J, Spyer MJ, Wavamunno P, Nyondo-Mipando L, Chidziva E, Nathoo K, Klein N, Hakim J, Gibb DM, Walker AS, Pett SL; REALITY trial team. Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial. PLoS Med. 2018 Dec 4;15(12):e1002706. doi: 10.1371/journal.pmed.1002706. eCollection 2018 Dec.
Results Reference
derived
PubMed Identifier
29653915
Citation
Mallewa J, Szubert AJ, Mugyenyi P, Chidziva E, Thomason MJ, Chepkorir P, Abongomera G, Baleeta K, Etyang A, Warambwa C, Melly B, Mudzingwa S, Kelly C, Agutu C, Wilkes H, Nkomani S, Musiime V, Lugemwa A, Pett SL, Bwakura-Dangarembizi M, Prendergast AJ, Gibb DM, Walker AS, Berkley JA; REALITY trial team. Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial. Lancet HIV. 2018 May;5(5):e231-e240. doi: 10.1016/S2352-3018(18)30038-9. Epub 2018 Apr 10. Erratum In: Lancet HIV. 2018 Jul;5(7):e340.
Results Reference
derived

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Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy

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