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

Human Immunodeficiency Virus Clinical Trial

— REALITY  

Official title:

Reduction of Early mortALITY in HIV-infected African Adults and Children Starting Antiretroviral Therapy: a Randomised Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01825031
• Other study ID #: ISRCTN43622374
• Status: Completed
• Phase: Phase 3
• First received: January 7, 2013
• Last updated: April 19, 2016
• Start date: June 2013
• Est. completion date: March 2016

Study information

• Verified date: April 2016
• Source: Medical Research Council
• Contact: n/a
• Is FDA regulated: No
• Health authority: Kenya: Ethical Review CommitteeKenya: Pharmacy and Poisons BoardMalawi: College of Medicine Research and Ethics CommitteeMalawi: National Health Sciences Research CommitteeUganda: Ministry of HealthUganda: National Council for Science and TechnologyUganda: National Drug AuthorityUganda: Research Ethics CommitteeZimbabwe: Medical Research CouncilZimbabwe: Research Council of ZimbabweZimbabwe: Medicines Control Authority of Zimbabwe
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1805
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years and older

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus
• Immunologic Deficiency Syndromes

Intervention

Drug:
• Raltegravir
400mg twice daily for the first 12 weeks only in addition to 3 standard ARVs
• Fluconazole
100mg once daily for 12 weeks
• Azithromycin
500mg once daily for 5 days
• Albendazole
a single dose 400mg
• 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

Locations

Country	Name	City	State
Kenya	Moi University Clinical Research Centre	Eldoret
Kenya	KEMRI Wellcome Trust Research Programme	Kilifi
Malawi	University of Malawi	Blantyre
Uganda	Joint Clinical Research Centre, Fort Portal	Fort Portal
Uganda	Joint Clinical Research Centre, Gulu	Gulu
Uganda	Joint Clinical Research Centre, Mbale	Mbale
Uganda	Joint Clinical Research Centre, Mbarara	Mbarara
Zimbabwe	University of Zimbabwe Clinical Research Centre	Harare

Sponsors (5)

Lead Sponsor	Collaborator
Anna Griffiths, MRC	Department for International Development, United Kingdom, Medical Research Council, PENTA Foundation, Wellcome Trust

Countries where clinical trial is conducted

Kenya,  Malawi,  Uganda,  Zimbabwe, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause mortality over the first 24 weeks after starting ART		Week 24	No
Secondary	48 week mortality (all-cause)		Week 48	No
Secondary	Safety	serious adverse events; grade 4 adverse events; adverse events leading to modification of ART or other study drugs	Week 0-48	Yes
Secondary	Hospital inpatient episodes and total days admitted		Week 0-48	Yes
Secondary	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.	Week 0-48	No
Secondary	Endpoint relating to anti-infection intervention	Incidence of tuberculosis (TB), cryptococcal and candida disease, severe bacterial infections	0-48 weeks	No
Secondary	Endpoint relating to anti-malnutrition intervention	BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children) and grip strength	0-48 weeks	No
Secondary	Endpoint relating to anti-HIV intervention	Changes in CD4 cell count	0-48 weeks	No