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

• ClinicalTrials.gov Identifier: NCT01825031
• Recruitment Status: Completed
• First Posted: April 5, 2013
• Last Update Posted: April 20, 2016
• Sponsor: Anna Griffiths, MRC
• Collaborators: Department for International Development, United Kingdom; Wellcome Trust; Medical Research Council; PENTA Foundation
• Information provided by (Responsible Party): Anna Griffiths, MRC, Medical Research Council

Tracking Information

• First Submitted Date: January 7, 2013
• First Posted Date: April 5, 2013
• Last Update Posted Date: April 20, 2016
• Study Start Date: June 2013
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 2, 2013): All-cause mortality over the first 24 weeks after starting ART [ Time Frame: Week 24 ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 2, 2013)

• 48 week mortality (all-cause) [ Time Frame: Week 48 ]
• Safety [ Time Frame: Week 0-48 ]
  • 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 [ Time Frame: Week 0-48 ]
• Adherence to ART and acceptability of each strategy [ Time Frame: Week 0-48 ]
  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 [ Time Frame: 0-48 weeks ]
  Incidence of tuberculosis (TB), cryptococcal and candida disease, severe bacterial infections
• Endpoint relating to anti-malnutrition intervention [ Time Frame: 0-48 weeks ]
  BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children) and grip strength
• Endpoint relating to anti-HIV intervention [ Time Frame: 0-48 weeks ]
  Changes in CD4 cell count

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy
• Official Title: Reduction of Early mortALITY in HIV-infected African Adults and Children Starting Antiretroviral Therapy: a Randomised Controlled Trial

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:

1. 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);
2. 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
3. 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Human Immunodeficiency Virus

Intervention

• Drug: Raltegravir
  400mg twice daily for the first 12 weeks only in addition to 3 standard ARVs
• Drug: Fluconazole
  100mg once daily for 12 weeks
• Drug: Azithromycin
  500mg once daily for 5 days
• Drug: Albendazole
  a single dose 400mg
• Drug: Isoniazid
  300mg taken immediately in combination with cotrimoxazole
• Dietary Supplement: Ready to Use Supplementary Food
  2x92g packets daily of high energy, low protein lipid-based paste for 12 weeks
  Other Name: RUSF

Study Arms

• Experimental: Antiretroviral Therapy
  Raltegravir twice daily for 12 weeks from antiretroviral therapy (ART) initiation in addition to 3 standard ARVs (2NRTIs/1NNRTI) compared with 3 standard ARVs
  Intervention: Drug: Raltegravir
• Experimental: Opportunistic Infection (OI) Prophylaxis
  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.
  Interventions:

  • Drug: Fluconazole
  • Drug: Azithromycin
  • Drug: Albendazole
  • Drug: Isoniazid
• Experimental: Nutritional Support
  Supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks compared with supplementation for those with severe malnutrition as local practice.
  Intervention: Dietary Supplement: Ready to Use Supplementary Food

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 19, 2016): 1805
• Original Estimated Enrollment (submitted: April 2, 2013): 1800
• Actual Study Completion Date: March 2016
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Kenya, Malawi, Uganda, Zimbabwe

Administrative Information

• NCT Number: NCT01825031
• Other Study ID Numbers: ISRCTN43622374
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Anna Griffiths, MRC, Medical Research Council
• Study Sponsor: Anna Griffiths, MRC

Collaborators

• Department for International Development, United Kingdom
• Wellcome Trust
• Medical Research Council
• PENTA Foundation

Investigators

• Study Director: Diana M Gibb; Medical Research Council

• PRS Account: Medical Research Council
• Verification Date: April 2016