A Dose-Ranging Study to Compare Doravirine (MK-1439) Plus TRUVADA® Versus Efavirenz Plus TRUVADA® in Human Immunodeficiency Virus (HIV)-1 Infected Participants (MK-1439-007)

• ClinicalTrials.gov Identifier: NCT01632345
• Recruitment Status: Completed
• First Posted: July 2, 2012
• Results First Posted: December 13, 2017
• Last Update Posted: July 18, 2019
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

The hypothesis tested in this study is that doravirine (MK-1439) at the final dose selected is superior to efavirenz, each given in combination with TRUVADA®, as measured by the percentage of participants with CNS events by Week 8. If superiority is established at Week 8, the same hypothesis will be tested for Week 24.

Condition or disease	Intervention/treatment	Phase
HIV Infections	Drug: Doravirine; Drug: Efavirenz; Drug: TRUVADA®; Drug: Placebo for Doravirine; Drug: Placebo for Efavirenz	Phase 2

Detailed Description:

Part I - Dose-Ranging. Part I will evaluate the (1) safety and tolerability and (2) efficacy (antiretroviral activity) of 4 doses of doravirine compared with efavirenz, when each is given in combination with TRUVADA® for at least 24 weeks in approximately 200 participants. A single dose of doravirine will be selected for further study after all participants complete the Week 24 visit in Part I. Participants receiving any dose of doravirine in Part I will be switched to the selected doravirine dose and continue in the study for up to 96 weeks, but will not be randomized to Part II.

Part II - Selected Dose. Part II will be initiated after the doravirine dose has been selected as indicated above for Part 1. Approximately 120 additional participants will be randomized in 1:1 ratio to the selected dose of doravirine or efavirenz, each in combination with TRUVADA® for 96 weeks of blinded treatment. Part II will evaluate the safety of the selected dose compared with efavirenz, particularly with regard to central nervous system (CNS) adverse events.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 342 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Multicenter, Double-Blind, Randomized, 2-Part, Dose Ranging Study to Compare the Safety, and Antiretroviral Activity of MK-1439 Plus TRUVADA Versus Efavirenz Plus TRUVADA in Antiretroviral Treatment-Naive, HIV-1 Infected Patients
• Actual Study Start Date: October 12, 2012
• Actual Primary Completion Date: December 3, 2014
• Actual Study Completion Date: March 21, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Doravirine 25 mg; Doravirine 25 mg + TRUVADA® Participants in this arm will receive doravirine 25 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz.	Drug: Doravirine; Part I: Doravirine 25 mg, 50 mg (25 mg X 2), 100 mg, or 200 mg (100 mg X 2) depending upon randomization, taken orally every morning with or without food for at least 24 weeks. Part II: Selected dose of doravirine depending upon randomization (either 25 mg, 50 mg, 100 mg, or 200 mg) tablet orally every morning with or without food for 96 weeks.; Other Name: MK-1439; Drug: TRUVADA®; Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks; Drug: Placebo for Doravirine; Placebo tablets matching doravirine
Experimental: Doravirine 50 mg; Doravirine 50 mg + TRUVADA® Participants in this arm will receive doravirine 50 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz.	Drug: Doravirine; Part I: Doravirine 25 mg, 50 mg (25 mg X 2), 100 mg, or 200 mg (100 mg X 2) depending upon randomization, taken orally every morning with or without food for at least 24 weeks. Part II: Selected dose of doravirine depending upon randomization (either 25 mg, 50 mg, 100 mg, or 200 mg) tablet orally every morning with or without food for 96 weeks.; Other Name: MK-1439; Drug: TRUVADA®; Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks; Drug: Placebo for Doravirine; Placebo tablets matching doravirine
Experimental: Doravirine 100 mg; Doravirine 100 mg + TRUVADA® Participants in this arm will receive doravirine 100 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz.	Drug: Doravirine; Part I: Doravirine 25 mg, 50 mg (25 mg X 2), 100 mg, or 200 mg (100 mg X 2) depending upon randomization, taken orally every morning with or without food for at least 24 weeks. Part II: Selected dose of doravirine depending upon randomization (either 25 mg, 50 mg, 100 mg, or 200 mg) tablet orally every morning with or without food for 96 weeks.; Other Name: MK-1439; Drug: TRUVADA®; Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks; Drug: Placebo for Doravirine; Placebo tablets matching doravirine
Experimental: Doravirine 200 mg; Doravirine 200 mg + TRUVADA® Participants in this arm will receive doravirine 200 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz.	Drug: Doravirine; Part I: Doravirine 25 mg, 50 mg (25 mg X 2), 100 mg, or 200 mg (100 mg X 2) depending upon randomization, taken orally every morning with or without food for at least 24 weeks. Part II: Selected dose of doravirine depending upon randomization (either 25 mg, 50 mg, 100 mg, or 200 mg) tablet orally every morning with or without food for 96 weeks.; Other Name: MK-1439; Drug: TRUVADA®; Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks; Drug: Placebo for Doravirine; Placebo tablets matching doravirine
Active Comparator: Efavirenz; Efavirenz + TRUVADA® Participants in this arm will receive efavirenz in Part I and in Part II. These participants also receive placebo that matches doravirine.	Drug: Efavirenz; Efavirenz 600 mg tablet orally at bedtime taken without food on an empty stomach for 96 weeks; Drug: TRUVADA®; Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks; Drug: Placebo for Efavirenz; Placebo tablets matching efavirenz

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With At Least 1 AE in Weeks 0-24: Doravirine (All Doses) vs Efavirenz (Part I) [ Time Frame: Up to Week 24 ]
   Assessment of the percentage of participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, or 200 mg), compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group with at least 1 AE was primarily assessed for Weeks 0-24.
2. Percentage of Participants Who Discontinued Study Therapy Due to AEs in Weeks 0-24: Doravirine (All Doses) vs Efavirenz (Part I) [ Time Frame: Up to Week 24 ]
   Assessment of the percentage of participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, or 200 mg), compared with participants receiving efavirenz 600 mg, who discontinued therapy due to an AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group who discontinued therapy due to an AE was primarily assessed for Weeks 0-24.
3. Percentage of Participants With At Least 1 AE in Weeks 0-24: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Up to Week 24 ]
   Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group with at least 1 AE was assessed for Weeks 0-24.
4. Percentage of Participants With CNS Events by Week 8: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Up to Week 8 ]
   Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had CNS events over 8 weeks of treatment. CNS events were pooled and evaluated as pre-specified by the protocol (depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, disturbance in attention, somnolence, dizziness, or concentration impaired). The percentage of participants in either treatment group with CNS events was assessed over Weeks 0-8.
5. Percentage of Participants With CNS Events by Week 24: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Up to Week 24 ]
   Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had CNS events over 24 weeks of treatment. CNS events were pooled and evaluated as pre-specified by the protocol (depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, disturbance in attention, somnolence, dizziness, or concentration impaired). The percentage of participants in either treatment group with CNS events was assessed over Weeks 0-24.
6. Percentage of Participants With Virologic Response (HIV-1 RNA) < 40 Copies/mL) at Week 24: Doravirine (All Doses) vs Efavirenz (Part I) [ Time Frame: Week 24 ]
   Assessment of the virologic response to doravirine at all studied doses (25 mg, 50 mg, 100 mg, and 200 mg), compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with plasma HIV-1 RNA <40 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification of 40 copies/mL. The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The Non-Completer = Failure (NC=F) approach, in which participants who prematurely discontinued assigned treatment for any reason and were considered as failures thereafter, was used as the primary approach to handle missing data this analysis of efficacy.This primary outcome was analyzed for HIV-1 RNA <40 copies/mL in Part I.
7. Percentage of Participants With Virologic Response (HIV-1 RNA <40 Copies/mL) at Week 24: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Week 24 ]
   Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with HIV-1 RNA <40 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification of 40 copies/mL. The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The NC=F approach was used as the primary approach to handle missing data this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA <40 copies/mL in Part I & Part II combined.

Secondary Outcome Measures :

1. Percentage of Participants With Virologic Response (HIV-1 RNA <40 Copies/mL) at Week 48: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Week 48 ]
   Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with HIV-1 RNA <40 copies/mL at Week 48. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay. The percentage of participants in any treatment group with a virologic response was primarily assessed for Weeks 0-24. The NC=F approach was used as the primary approach to handle missing data this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA <40 copies/mL in Part I & Part II combined.
2. Percentage of Participants With Virologic Response (HIV-1 RNA <40 Copies/mL) at Week 96: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Week 96 ]
   Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with HIV-1 RNA <40 copies/mL at Week 96. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay. The percentage of participants in any treatment group with a virologic response was primarily assessed for Weeks 0-24. The NC=F approach was used as the primary approach to handle missing data this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA <40 copies/mL in Part I & Part II combined.
3. Percentage of Participants With Virologic Response (HIV-1 RNA <200 Copies/mL) at Week 24: Doravirine (All Doses) vs Efavirenz (Part I) [ Time Frame: Week 24 ]
   Assessment of the virologic response to doravirine at all studied doses (25 mg, 50 mg, 100 mg, and 200 mg), compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with plasma HIV-1 RNA <200 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay.The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The NC=F approach was used as the primary approach to handle missing data for this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA <200 copies/mL in Part I.
4. Percentage of Participants With Virologic Response (HIV-1 RNA <200 Copies/mL) at Week 24: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Week 24 ]
   Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with plasma HIV-1 RNA <200 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay. The percentage of participants in any treatment group with a virologic response was primarily assessed for Weeks 0-24. The NC=F approach was used as the primary approach to handle missing data for this analysis of efficacy. This secondary outcome was analyzed for HIV-1 RNA <200 copies/mL in Part I & Part II combined.
5. Percentage of Participants With Virologic Response (HIV-1 RNA <200 Copies/mL) at Week 48: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Week 48 ]
   Evaluation of the antiretroviral activity of doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA for 24 weeks, as measured by the percentage of participants with HIV-1 RNA <200 copies/mL at Week 48. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay. This primary outcome was analyzed for RNA <200 copies/mL in Part I & Part II combined.
6. Percentage of Participants With Virologic Response (HIV-1 RNA <200 Copies/mL) at Week 96: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Week 96 ]
   Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with plasma HIV-1 RNA <200 copies/mL at Week 96. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay. The percentage of participants in any treatment group with a virologic response was primarily assessed for Weeks 0-96. The Non-Completer = Failure (NC=F) approach, in which participants who prematurely discontinued assigned treatment for any reason and were considered as failures thereafter, was used as the primary approach to handle missing data this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA <200 copies/mL in Part I & Part II combined.
7. Change From Baseline in CD4 T Lymphocyte Cell Count at Week 24: Doravirine (All Doses) vs Efavirenz (Part I) [ Time Frame: Baseline, Week 24 ]
   Evaluation of the change from baseline in the CD4 cell count at Week 24 in participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, and 200 mg), compared with participants receiving efavirenz 600 mg. The Observed Failure (OF) approach was used to handle missing data, and the Baseline CD4 cell count was carried forward for participants who discontinued assigned treatment due to lack of efficacy.
8. Change From Baseline in CD4 Cell Count at Week 24: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Baseline, Week 24 ]
   Assessment of the change from baseline in the CD4 cell count at Week 24 in participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg. The OF approach was used to handle missing data, and the Baseline CD4 cell count was carried forward for participants who discontinued assigned treatment due to lack of efficacy.
9. Change From Baseline in CD4 Cell Count at Week 48: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Baseline, Week 48 ]
   Assessment of the change from baseline in the CD4 count at Week 48 in participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg. The OF approach was used to handle missing data, and the Baseline CD4 cell count was carried forward for subjects who discontinued assigned treatment due to lack of efficacy.
10. Change From Baseline in CD4 Cell Count at Week 96: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Baseline, Week 96 ]
    A secondary endpoint in Part I/II combined was the change from baseline in the CD4 count at Week 96 in participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg. The OF approach was used to handle missing data, and the Baseline CD4 cell count was carried forward for subjects who discontinued assigned treatment due to lack of efficacy.
11. Percentage of Participants With At Least 1 AE in Weeks 0-48: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Up to Week 48 ]
    A secondary outcome in Part I/II combined was the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 48 weeks of treatment. The percentage of participants in any treatment group with at least 1 AE was primarily assessed for Weeks 0-48.
12. Percentage of Participants With At Least 1 AE in Weeks 0-96: Doravirine 100 mg vs Efavirenz (Part I & Part II Combined) [ Time Frame: Up to Week 96 ]
    A secondary outcome in Part I/II combined was the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 96 weeks of treatment. The percentage of participants in any treatment group with at least 1 AE was primarily assessed for Weeks 0-96.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• HIV-1 positive
• No previous use of antiretroviral therapy (ART)
• No signs of active pulmonary disease within 45 days before the start of study treatment
• Clinically stable with no signs or symptoms of acute infection
• No change in clinical status or chronic medications for at least 2 weeks before the start of study treatment
• Participants of reproductive potential agree to remain abstinent in line with their preferred and usual lifestyle or use (or have their partner use) 2 acceptable methods of birth control throughout the study and for 12 weeks post study.
• Participants not of reproductive potential, not sexually active, whose current partner(s) is not of reproductive potential, or whose sexual activity is exclusively homosexual are eligible without requiring the use of contraception.

Exclusion Criteria:

• Males planning to impregnate or provide sperm donation for the duration of the study plus an additional 12 weeks. Females pregnant or breast-feeding or expecting to conceive or donate eggs for the duration of the study plus an additional 12 weeks.
• Received any approved or experimental antiretroviral agents or is anticipated to receive such medications during the study.
• Use of any immunomodulators or immunosuppressive therapy within one month before the study. Short courses of corticosteroids (e.g., for asthma exacerbation) are allowed.
• Treatment for a viral infection other than HIV, such as hepatitis B, with an agent that is active against HIV
• HIV resistance to emtricitabine, tenofovir disoproxil fumarate, and/or efavirenz.
• History of renal or urinary obstructive disease or requires dialysis
• Active Hepatitis C virus (HCV) or Hepatitis B virus (HBV) co-infection
• History of alcohol or other substance abuse
• Participation in a study with an investigational compound/device within one month or is anticipating to participate in such a study during this study

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gatell JM, Morales-Ramirez JO, Hagins DP, Thompson M, Arasteh K, Hoffmann C, Raffi F, Osiyemi O, Dretler R, Harvey C, Xu X, Plettenberg A, Smith DE, Portilla J, Rugina S, Kumar S, Frobose C, Wan H, Rodgers A, Hwang C, Teppler H. Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial. Antivir Ther. 2019;24(6):425-435. doi: 10.3851/IMP3323.

Thompson M, Orkin C, Molina JM, Sax P, Cahn P, Squires K, Xu X, Rodgers A, Kumar S, Teppler H, Martin E, Hanna G, Hwang C. Once-daily Doravirine for Initial Treatment of Adults Living With Human Immunodeficiency Virus-1: An Integrated Safety Analysis. Clin Infect Dis. 2020 Mar 17;70(7):1336-1343. doi: 10.1093/cid/ciz423.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01632345
• Other Study ID Numbers: 1439-007; MK-1439-007 ( Other Identifier: Merck ); 2012-001573-93 ( EudraCT Number )
• First Posted: July 2, 2012
• Results First Posted: December 13, 2017
• Last Update Posted: July 18, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Efavirenz; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Anti-HIV Agents; Anti-Retroviral Agents