A Study to Evaluate the Safety and Antiretroviral Activity of MK-0518 Versus Efavirenz in Treatment Naive HIV-Infected Patients, Each in Combination With TRUVADA (0518-021 EXT)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Merck Sharp & Dohme Corp.

ClinicalTrials.gov Identifier:

NCT00369941

First received: August 29, 2006

Last updated: February 4, 2015

Last verified: February 2015

History of Changes

Results First Received: September 18, 2009

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	HIV Infections
Interventions:	Drug: MK-0518 Drug: Comparator: efavirenz Drug: Comparator: Truvada Drug: Comparator: Placebo to MK-0518 Drug: Comparator: Placebo to efavirenz

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Primary therapy period: 14-Sep-2006 to 06-May-2009 Multicenter (67) in the United States (18) and Ex-US (49)

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

Primary therapy period: 14-Sep-2006 to 06-May-2009

Multicenter (67) in the United States (18) and Ex-US (49)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

Description

MK-0518 400 mg b.i.d.

MK-0518 400 mg, which can be taken by mouth (PO) twice a day (b.i.d.) without regard to food, and placebo to efavirenz, which will be taken PO at bedtime (q.h.s.) on an empty stomach preferably at bedtime. All participants will take one tablet of TRUVADA® (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) with food, daily with the morning dose of MK-0518. Dosing interval adjustment of TRUVADA® is recommended in all participants with creatinine clearance 30-49 mL/min.

Efavirenz 600 mg q.h.s.

Efavirenz 600 mg, which will be taken by mouth (PO) at bedtime (q.h.s.) on an empty stomach preferably at bedtime, and placebo to MK-0518, which will be taken PO twice a day (b.i.d.) without regard to food. All participants will take one tablet of TRUVADA® with food, daily with the morning dose of placebo. Dosing interval adjustment of TRUVADA® is recommended in all participants with creatinine clearance 30-49 mL/min.

Participant Flow: Overall Study

	MK-0518 400 mg b.i.d.	Efavirenz 600 mg q.h.s.
STARTED	282	284
Treated	281	282
COMPLETED	210	184
NOT COMPLETED	72	100
Never Treated	1	2
Adverse Event	14	28
Lack of Efficacy	6	10
Lost to Follow-up	12	22
Protocol Violation	5	3
Withdrawal by Subject	5	18
Pregnancy	4	2
Completed, Did Not Enter Extension	5	6
Moved	11	5
Treatment with Prohibited Medication	3	1
Employment Interfered with Study Visits	1	0
Study Site Terminated	2	0
Miscellaneous	3	3

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
MK-0518 400 mg b.i.d.	MK-0518 400 mg, which can be taken by mouth (PO) twice a day (b.i.d.) without regard to food, and placebo to efavirenz, which will be taken PO at bedtime (q.h.s.) on an empty stomach preferably at bedtime. All participants will take one tablet of TRUVADA® (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) with food, daily with the morning dose of MK-0518. Dosing interval adjustment of TRUVADA® is recommended in all participants with creatinine clearance 30-49 mL/min.
Efavirenz 600 mg q.h.s.	Efavirenz 600 mg, which will be taken by mouth (PO) at bedtime (q.h.s.) on an empty stomach preferably at bedtime, and placebo to MK-0518, which will be taken PO twice a day (b.i.d.) without regard to food. All participants will take one tablet of TRUVADA® with food, daily with the morning dose of placebo. Dosing interval adjustment of TRUVADA® is recommended in all participants with creatinine clearance 30-49 mL/min.
Total	Total of all reporting groups

Baseline Measures

	MK-0518 400 mg b.i.d.	Efavirenz 600 mg q.h.s.	Total
Number of Participants [units: participants]	281	282	563
Age [units: years] Mean ( Full Range )	38 ( 19 to 67 )	37 ( 19 to 71 )	37 ( 19 to 71 )
Gender [units: participants]
Female	54	51	105
Male	227	231	458
Race/Ethnicity, Customized [units: participants]
White	116	123	239
Black	33	23	56
Asian	36	32	68
Hispanic	60	67	127
Others	36	37	73
Cluster of Differentiation 4 (CD4) Cell Count [units: Cells/mm^3] Mean ( Full Range )	219 ( 1 to 620 )	217 ( 4 to 807 )	218 ( 1 to 807 )
Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) [units: Copies/mL] Geometric Mean ( Full Range )	103205 ( 400 to 750000 )	106215 ( 4410 to 750000 )	104702 ( 400 to 750000 )

Outcome Measures

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1. Primary:

Number of Participants Who Achieved Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) <50 Copies/mL at Week 48 [ Time Frame: 48 Weeks ]

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2. Primary:

Number of Participants With Clinical Adverse Experiences (CAEs) at Week 48 [ Time Frame: 48 Weeks ]

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3. Primary:

Number of Participants With Serious CAEs at Week 48 [ Time Frame: 48 Weeks ]

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4. Primary:

Number of Participants With Drug-related CAEs at Week 48 [ Time Frame: 48 Weeks ]

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5. Primary:

Number of Participants With Serious Drug-related CAEs at Week 48 [ Time Frame: 48 Weeks ]

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6. Primary:

Number of Participants That Died by Week 48 [ Time Frame: 48 Weeks ]

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7. Primary:

Number of Participants That Discontinued With CAEs at Week 48 [ Time Frame: 48 Weeks ]

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8. Primary:

Number of Participants That Discontinued With Serious CAEs at Week 48 [ Time Frame: 48 Weeks ]

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9. Primary:

Number of Participants That Discontinued With Drug-related CAEs at Week 48 [ Time Frame: 48 Weeks ]

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10. Primary:

Number of Participants That Discontinued With Serious Drug-related CAEs at Week 48 [ Time Frame: 48 Weeks ]

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11. Primary:

Number of Participants With Laboratory Adverse Experiences (LAEs) at Week 48 [ Time Frame: 48 Weeks ]

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12. Primary:

Number of Participants With Serious LAEs at Week 48 [ Time Frame: 48 Weeks ]

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13. Primary:

Number of Participants With Drug-related LAEs at Week 48 [ Time Frame: 48 Weeks ]

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14. Primary:

Number of Participants With Serious Drug-related LAEs at Week 48 [ Time Frame: 48 Weeks ]

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15. Primary:

Number of Participants Discontinued With LAEs at Week 48 [ Time Frame: 48 Weeks ]

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16. Primary:

Number of Participants Discontinued With Drug-related LAEs at Week 48 [ Time Frame: 48 Weeks ]

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17. Secondary:

Number of Participants Who Achieved HIV RNA <400 Copies/mL at Week 48 [ Time Frame: 48 Weeks ]

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18. Secondary:

Change From Baseline in Cluster of Differentiation Antigen 4 (CD4) Cell Count at Week 48 [ Time Frame: Baseline and Week 48 ]

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19. Secondary:

Number of Participants Who Achieved HIV RNA <50 Copies/mL at Week 96 [ Time Frame: 96 Weeks ]

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20. Secondary:

Number of Participants Who Achieved HIV RNA <400 Copies/mL at Week 96 [ Time Frame: 96 Weeks ]

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21. Secondary:

Change From Baseline in CD4 Cell Count at Week 96 [ Time Frame: Baseline and Week 96 ]

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22. Secondary:

Number of Participants Who Achieved HIV RNA <50 Copies/mL at Week 156 [ Time Frame: 156 Weeks ]

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23. Secondary:

Number of Participants Who Achieved HIV RNA <400 Copies/mL at Week 156 [ Time Frame: 156 Weeks ]

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24. Secondary:

Change From Baseline in CD4 Cell Count at Week 156 [ Time Frame: Baseline and Week 156 ]

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25. Secondary:

Number of Participants Who Achieved HIV RNA <50 Copies/mL at Week 240 [ Time Frame: 240 Weeks ]

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26. Secondary:

Number of Participants Who Achieved HIV RNA <400 Copies/mL at Week 240 [ Time Frame: 240 Weeks ]

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27. Secondary:

Change From Baseline in CD4 Cell Count at Week 240 [ Time Frame: Baseline and Week 240 ]

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28. Secondary:

Number of Participants With Nervous System Symptoms Assessed by Review of Accumulated Safety Data up to Week 8 [ Time Frame: 8 Weeks ]

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29. Secondary:

Number of Participants With CAEs at Week 96 [ Time Frame: 96 Weeks ]

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30. Secondary:

Number of Participants With CAEs at Week 156 [ Time Frame: 156 Weeks ]

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31. Secondary:

Number of Participants With CAEs at Week 240 [ Time Frame: 240 Weeks ]

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32. Secondary:

Number of Participants With Serious CAEs at Week 96 [ Time Frame: 96 Weeks ]

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33. Secondary:

Number of Participants With Serious CAEs at Week 156 [ Time Frame: 156 Weeks ]

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34. Secondary:

Number of Participants With Serious CAEs at Week 240 [ Time Frame: 240 Weeks ]

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35. Secondary:

Number of Participants With Drug-related CAEs at Week 96 [ Time Frame: 96 Weeks ]

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36. Secondary:

Number of Participants With Drug-related CAEs at Week 156 [ Time Frame: 156 Weeks ]

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37. Secondary:

Number of Participants With Drug-related CAEs at Week 240 [ Time Frame: 240 Weeks ]

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38. Secondary:

Number of Participants With Serious Drug-related CAEs at Week 96 [ Time Frame: 96 Weeks ]

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39. Secondary:

Number of Participants With Serious Drug-related CAEs at Week 156 [ Time Frame: 156 Weeks ]

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40. Secondary:

Number of Participants With Serious Drug-related CAEs at Week 240 [ Time Frame: 240 Weeks ]

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41. Secondary:

Number of Participants That Died by Week 96 [ Time Frame: 96 Weeks ]

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42. Secondary:

Number of Participants That Died by Week 156 [ Time Frame: 156 Weeks ]

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43. Secondary:

Number of Participants That Died by Week 240 [ Time Frame: 240 Weeks ]

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Measure Type	Secondary
Measure Title	Number of Participants That Died by Week 240
Measure Description	All participant deaths in the span of 240 weeks on study were recorded.
Time Frame	240 Weeks
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who took study medication were included in the analysis.

Reporting Groups

Description

MK-0518 400 mg b.i.d.

Efavirenz 600 mg q.h.s.

Measured Values

	MK-0518 400 mg b.i.d.	Efavirenz 600 mg q.h.s.
Number of Participants Analyzed [units: participants]	281	282
Number of Participants That Died by Week 240 [units: Participants]
Died	5	5
Did Not Die	276	277

No statistical analysis provided for Number of Participants That Died by Week 240

44. Secondary:

Number of Participants That Discontinued With CAEs at Week 96 [ Time Frame: 96 Weeks ]

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45. Secondary:

Number of Participants That Discontinued With CAEs at Week 156 [ Time Frame: 156 Weeks ]

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46. Secondary:

Number of Participants That Discontinued With CAEs at Week 240 [ Time Frame: 240 Weeks ]

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47. Secondary:

Number of Participants That Discontinued With Drug-related CAEs at Week 96 [ Time Frame: 96 Weeks ]

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48. Secondary:

Number of Participants That Discontinued With Drug-related CAEs at Week 156 [ Time Frame: 156 Weeks ]

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49. Secondary:

Number of Participants That Discontinued With Drug-related CAEs at Week 240 [ Time Frame: 240 Weeks ]

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50. Secondary:

Number of Participants That Discontinued With Serious CAEs at Week 96 [ Time Frame: 96 Weeks ]

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51. Secondary:

Number of Participants That Discontinued With Serious CAEs at Week 156 [ Time Frame: 156 Weeks ]

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52. Secondary:

Number of Participants That Discontinued With Serious CAEs at Week 240 [ Time Frame: 240 Weeks ]

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53. Secondary:

Number of Participants That Discontinued With Serious Drug-related CAEs at Week 96 [ Time Frame: 96 Weeks ]

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54. Secondary:

Number of Participants That Discontinued With Serious Drug-related CAEs at Week 156 [ Time Frame: 156 Weeks ]

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55. Secondary:

Number of Participants That Discontinued With Serious Drug-related CAEs at Week 240 [ Time Frame: 240 Weeks ]

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56. Secondary:

Number of Participants With LAEs at Week 96 [ Time Frame: 96 Weeks ]

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57. Secondary:

Number of Participants With LAEs at Week 156 [ Time Frame: 156 Weeks ]

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58. Secondary:

Number of Participants With LAEs at Week 240 [ Time Frame: 240 Weeks ]

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59. Secondary:

Number of Participants With Drug-related LAEs at Week 96 [ Time Frame: 96 Weeks ]

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60. Secondary:

Number of Participants With Drug-related LAEs at Week 156 [ Time Frame: 156 Weeks ]

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61. Secondary:

Number of Participants With Drug-related LAEs at Week 240 [ Time Frame: 240 Weeks ]

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62. Secondary:

Number of Participants With Serious LAEs at Week 96 [ Time Frame: 96 Weeks ]

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63. Secondary:

Number of Participants With Serious LAEs at Week 156 [ Time Frame: 156 Weeks ]

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64. Secondary:

Number of Participants With Serious LAEs at Week 240 [ Time Frame: 240 Weeks ]

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65. Secondary:

Number of Participants With Serious Drug-related LAEs at Week 96 [ Time Frame: 96 Weeks ]

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66. Secondary:

Number of Participants With Serious Drug-related LAEs at Week 156 [ Time Frame: 156 Weeks ]

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67. Secondary:

Number of Participants With Serious Drug-related LAEs at Week 240 [ Time Frame: 240 Weeks ]

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68. Secondary:

Number of Participants Discontinued With LAEs at Week 96 [ Time Frame: 96 Weeks ]

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69. Secondary:

Number of Participants Discontinued With LAEs at Week 156 [ Time Frame: 156 Weeks ]

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70. Secondary:

Number of Participants Discontinued With LAEs at Week 240 [ Time Frame: 240 Weeks ]

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71. Secondary:

Number of Participants Discontinued With Drug-related LAEs at Week 96 [ Time Frame: 96 Weeks ]

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72. Secondary:

Number of Participants Discontinued With Drug-related LAEs at Week 156 [ Time Frame: 156 Weeks ]

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73. Secondary:

Number of Participants Discontinued With Drug-related LAEs at Week 240 [ Time Frame: 240 Weeks ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication guidelines.

Results Point of Contact:

Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372
e-mail: ClinicalTrialsDisclosure@merck.com

Publications of Results:

Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ, Barnard RJ, Miller MD, DiNubile MJ, Nguyen BY, Leavitt R, Sklar P; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806. doi: 10.1016/S0140-6736(09)60918-1. Epub 2009 Aug 3. Erratum in: Lancet. 2009 Dec 19-2010 Jan 1;374(9707):2054. Lancet. 2009 Sep 5;374(9692):786.

DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, Wan H, Rodgers AJ, Walker ML, Miller M, DiNubile MJ, Nguyen BY, Teppler H, Leavitt R, Sklar P; STARTMRK Investigators. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012 Jul-Aug;13(4):228-32. doi: 10.1310/hct1304-228. Erratum in: HIV Clin Trials. 2012 Sep-Oct;13(5):preceding 233.

Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, Walker ML, Xu X, Zhao J, Teppler H, Dinubile MJ, Rodgers AJ, Nguyen BY, Leavitt R, Sklar P; STARTMRK Investigators. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. 2011 Oct;53(8):807-16. doi: 10.1093/cid/cir510.

Rockstroh J, Teppler H, Zhao J, Sklar P, Harvey C, Strohmaier K, Leavitt R, Nguyen BY. Safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B and/or C virus coinfection. HIV Med. 2012 Feb;13(2):127-31. doi: 10.1111/j.1468-1293.2011.00933.x. Epub 2011 May 22.

Rockstroh JK, Teppler H, Zhao J, Sklar P, Miller MD, Harvey CM, Strohmaier KM, Leavitt RY, Nguyen BY. Clinical efficacy of raltegravir against B and non-B subtype HIV-1 in phase III clinical studies. AIDS. 2011 Jul 17;25(11):1365-9. doi: 10.1097/QAD.0b013e328348065a.

Nguyen BY, Isaacs RD, Teppler H, Leavitt RY, Sklar P, Iwamoto M, Wenning LA, Miller MD, Chen J, Kemp R, Xu W, Fromtling RA, Vacca JP, Young SD, Rowley M, Lower MW, Gottesdiener KM, Hazuda DJ. Raltegravir: the first HIV-1 integrase strand transfer inhibitor in the HIV armamentarium. Ann N Y Acad Sci. 2011 Mar;1222:83-9. doi: 10.1111/j.1749-6632.2011.05972.x. Review.

Teppler H, Brown DD, Leavitt RY, Sklar P, Wan H, Xu X, Lievano F, Lehman HP, Mast TC, Nguyen BY. Long-term safety from the raltegravir clinical development program. Curr HIV Res. 2011 Jan;9(1):40-53.

Lennox JL, Dejesus E, Berger DS, Lazzarin A, Pollard RB, Ramalho Madruga JV, Zhao J, Wan H, Gilbert CL, Teppler H, Rodgers AJ, Barnard RJ, Miller MD, Dinubile MJ, Nguyen BY, Leavitt R, Sklar P; STARTMRK Investigators. Raltegravir versus Efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr. 2010 Sep;55(1):39-48. doi: 10.1097/QAI.0b013e3181da1287. Erratum in: J Acquir Immune Defic Syndr. 2011 Dec 1;58(4):e120. Dosage error in article text.

Responsible Party:	Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:	NCT00369941 History of Changes
Other Study ID Numbers:	0518-021, MK-0518-021, 2006_519
Study First Received:	August 29, 2006
Results First Received:	September 18, 2009
Last Updated:	February 4, 2015
Health Authority:	United States: Food and Drug Administration

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