A Study to Evaluate the Safety and Efficacy of an Investigational Drug in HIV Infected Patients (0518-004)(COMPLETED)

This study has been completed.

Sponsor:

Information provided by:

Merck

ClinicalTrials.gov Identifier:

NCT00100048

First received: December 22, 2004

Last updated: February 2, 2012

Last verified: February 2012

History of Changes

Results First Received: January 21, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Conditions:	HIV Infections Acquired Immunodeficiency Syndrome
Interventions:	Drug: Comparator: MK0518 monotherapy Drug: Comparator: MK0518 combination therapy Drug: Comparator: efavirenz Drug: Comparator: tenofovir Drug: Comparator: lamivudine Drug: Placebo monotherapy

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: For Part I (10 day monotherapy): 24-Jan-2005 to 04-May-2005 Part II (Dose Ranging): 14-Jun-2005 to 04-Oct-2006 (48 weeks); 14-Jun-2005 to 12-Jul-2010 (240 weeks) Multicenter (29) in the United States (14) and Ex-US (15)

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

Primary therapy period:

For Part I (10 day monotherapy): 24-Jan-2005 to 04-May-2005 Part II (Dose Ranging): 14-Jun-2005 to 04-Oct-2006 (48 weeks); 14-Jun-2005 to 12-Jul-2010 (240 weeks) Multicenter (29) in the United States (14) and Ex-US (15)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients with Human Immunodeficiency Virus (HIV) Ribonucleic acid (RNA) of at least 5000 copies/mL and cluster of differentiation 4 (CD4) cell counts of at least 100 cells/mm3. All patients must have met laboratory criteria. 206 enrolled; 5 from Cohort I did not continue to the combination phase. Therefore 201 entered the combination phase.

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

Patients with Human Immunodeficiency Virus (HIV) Ribonucleic acid (RNA) of at least 5000 copies/mL and cluster of differentiation 4 (CD4) cell counts of at least 100 cells/mm3. All patients must have met laboratory criteria.

206 enrolled; 5 from Cohort I did not continue to the combination phase. Therefore 201 entered the combination phase.

Reporting Groups

	Description
MK0518 100 mg b.i.d.	Cohort I-Monotherapy Phase MK0518 100 mg twice daily (b.i.d.) Cohort II Combined-Combination Therapy Phase MK0518 100 mg + tenofovir + lamivudine
MK0518 200 mg b.i.d	Cohort I-Monotherapy Phase MK0518 200 mg b.i.d Cohort II Combined-Combination Therapy Phase MK0518 200 mg + tenofovir + lamivudine
MK0518 400 mg b.i.d.	Cohort I-Monotherapy Phase MK0518 400 mg b.i.d. Cohort II Combined-Combination Therapy Phase MK0518 400 mg + tenofovir + lamivudine
MK0518 600 mg b.i.d.	Cohort I-Monotherapy Phase MK0518 600 mg b.i.d. Cohort II Combined-Combination Therapy Phase MK0518 600 mg + tenofovir + lamivudine
Placebo	Cohort I-Monotherapy Phase Placebo to MK0518 b.i.d.
Efavirenz 600 mg q.h.s.	Cohort II Combined-Combination Therapy Phase efavirenz 600 mg every night at bedtime (q.h.s.)

Participant Flow for 2 periods

Period 1: Cohort I-Monotherapy Phase 10 Days

	MK0518 100 mg b.i.d.	MK0518 200 mg b.i.d	MK0518 400 mg b.i.d.	MK0518 600 mg b.i.d.	Placebo	Efavirenz 600 mg q.h.s.
STARTED	7	7	6	8	7	0 ^[1]
Treated	7	7	6	8	7	0
COMPLETED	7 ^[2]	7 ^[2]	6 ^[3]	8 ^[3]	7 ^[4]	0
NOT COMPLETED	0	0	0	0	0	0

[1]	participants only assigned Efavirenz 600 mg q.h.s in Cohort II Combined-Combination Therapy Phase
[2]	7 Subjects Continued to Cohort II Combined-Combination Therapy Phase (48 Weeks)
[3]	6 Subjects Continued to Cohort II Combined-Combination Therapy Phase (48 Weeks)
[4]	4 Subjects Continued to Cohort II, as part of the Efavirenz 600 mg q.d. arm

Period 2: Cohort I & II-Combination Therapy Phase

	MK0518 100 mg b.i.d.	MK0518 200 mg b.i.d	MK0518 400 mg b.i.d.	MK0518 600 mg b.i.d.	Placebo	Efavirenz 600 mg q.h.s.
STARTED	41 ^[1]	40 ^[2]	41 ^[3]	40 ^[4]	0 ^[5]	39 ^[6]
Treated	39	40	41	40	0	38
Never Treated	2 ^[7]	0	0	0	0	1 ^[7]
COMPLETED	27	31	28	30	0	26
NOT COMPLETED	14	9	13	10	0	13
Never Treated	2	0	0	0	0	1
Adverse Event	0	1	2	0	0	1
Lack of Efficacy	1	3	0	0	0	2
Lost to Follow-up	2	1	3	2	0	3
Withdrawal by Subject	1	2	2	5	0	4
Other Reason	7	1	4	2	0	0
Completed Base Study, Did Not Continue	1	1	2	0	0	2
Laboratory Adverse Experience	0	0	0	1	0	0

[1]	7 subjects from the Monotherapy Phase and 34 new subjects
[2]	7 subjects from the Monotherapy Phase and 33 new subjects
[3]	6 subjects from the Monotherapy Phase and 35 new subjects
[4]	8 subjects from the Monotherapy Phase and 32 new subjects
[5]	participants only assigned Placebo in Cohort I-Monotherapy Phase.
[6]	4 subjects from the Monotherapy Phase (Placebo)and 35 new subjects
[7]	Randomised in Cohort II did not start Period

Baseline Characteristics

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Reporting Groups

	Description
MK0518 100 mg b.i.d.	Cohort I-Monotherapy Phase (10 Days) MK0518 100 mg twice daily (b.i.d.) Cohort II Combined-Combination Therapy Phase (48 Weeks) MK0518 100 mg b.i.d
MK0518 200 mg b.i.d	Cohort I-Monotherapy Phase (10 Days) MK0518 200 mg b.i.d Cohort II Combined-Combination Therapy Phase (48 Weeks) MK0518 200 mg + tenofovir + lamivudine
MK0518 400 mg b.i.d.	Cohort I-Monotherapy Phase (10 Days) MK0518 400 mg b.i.d. Cohort II Combined-Combination Therapy Phase (48 Weeks) MK0518 400 mg + tenofovir + lamivudine
MK0518 600 mg b.i.d.	Cohort I-Monotherapy Phase (10 Days) MK0518 600 mg b.i.d. Cohort II Combined-Combination Therapy Phase (48 Weeks) MK0518 600 mg + tenofovir + lamivudine
Placebo / Efavirenz 600 mg Once Daily (q.d.)	Cohort I-Monotherapy Phase (10 Days) Placebo to MK0518 b.i.d. Cohort II Combined-Combination Therapy Phase (48 Weeks) Efavirenz + Tenofovir + Lamivudine
Total	Total of all reporting groups

Baseline Measures

	MK0518 100 mg b.i.d.	MK0518 200 mg b.i.d	MK0518 400 mg b.i.d.	MK0518 600 mg b.i.d.	Placebo / Efavirenz 600 mg Once Daily (q.d.)	Total
Number of Participants [units: participants]	41	40	41	42	42	206
Age ^[1] [units: Years] Mean ( Full Range )
Cohort I	46 ( 31 to 68 )	37 ( 22 to 57 )	41 ( 25 to 55 )	39 ( 30 to 49 )	36 ( 21 to 51 )	40 ( 21 to 68 )
Cohort II	34 ( 19 to 58 )	31 ( 21 to 56 )	34 ( 19 to 50 )	36 ( 20 to 49 )	36 ( 22 to 54 )	35 ( 19 to 58 )
Cohort I & II Combined	37 ( 19 to 68 )	34 ( 21 to 57 )	36 ( 19 to 55 )	37 ( 20 to 49 )	36 ( 22 to 54 )	36 ( 19 to 68 )
Gender, Customized [units: participants]
Female (Cohort I)	0	1	0	0	1	2
Male (Cohort I)	7	6	6	8	6	33
Female (Cohort II)	6	10	4	11	8	39
Male (Cohort II)	27	23	31	23	26	130
Never Treated Cohort II	1	0	0	0	1	2
Race/Ethnicity, Customized [units: participants]
White (Cohort I)	4	4	3	8	3	22
Black (Cohort I)	1	1	0	0	0	2
Asian (Cohort I)	0	0	0	0	1	1
Hispanic (Cohort I)	2	2	3	0	3	10
White (Cohort II)	4	10	11	8	10	43
Black (Cohort II)	1	1	1	0	0	3
Asian (Cohort II)	3	6	8	7	8	32
Hispanic (Cohort II)	12	9	10	9	10	50
Other (Cohort II)	13	7	5	10	6	41
Never Treated (Cohort II)	1	0	0	0	1	2
Cluster of differentiation 4 (CD4) Cell Count ^[1] [units: cells/mm^3] Mean ( Full Range )
Cohort I	415 ( 138 to 745 )	343 ( 149 to 624 )	256 ( 96 to 602 )	569 ( 241 to 1034 )	343 ( 115 to 599 )	394 ( 96 to 1034 )
Cohort II	293 ( 76 to 736 )	292 ( 70 to 723 )	348 ( 95 to 1017 )	245 ( 99 to 734 )	276 ( 77 to 744 )	291 ( 70 to 1017 )
Cohort I and II Combined	272 ( 76 to 758 )	277 ( 70 to 723 )	293 ( 95 to 1017 )	244 ( 99 to 786 )	225 ( 77 to 744 )	266 ( 70 to 1017 )
Plasma Human Immunodeficiency Virus (HIV) Ribonucleic acid (RNA) ^[1] [units: copies/mL] Geometric Mean ( Full Range )
Cohort I	44989 ( 3890 to 225000 )	34143 ( 5420 to 168000 )	37728 ( 6850 to 152000 )	93911 ( 17100 to 388000 )	58412 ( 7630 to 456000 )	51496 ( 3890 to 456000 )
Cohort II	65982 ( 4200 to 750000 )	73646 ( 7490 to 750000 )	47019 ( 2440 to 499000 )	61929 ( 3450 to 750000 )	76752 ( 7500 to 675000 )	63965 ( 2440 to 750000 )
Cohort I and II Combined	58206 ( 4200 to 750000 )	64715 ( 7490 to 750000 )	43083 ( 2440 to 499000 )	57919 ( 3450 to 750000 )	67554 ( 3340 to 675000 )	57437 ( 2440 to 750000 )

[1]	Cohort I Participants: MK0518 100 mg b.i.d. (7); MK0518 200 mg b.i.d. (7); MK0518 400 mg b.i.d. (6); MK0518 600 mg b.i.d. (8); Placebo Cohort (7) Cohort II Participants: MK0518 100 mg b.i.d. (33); MK0518 200 mg b.i.d. (33); MK0518 400 mg b.i.d. (35); MK0518 600 mg b.i.d. (34); Efavirenz 600 mg q.d. (34) Cohort I & II Participants Combined: MK0518 100 mg b.i.d. (39); MK0518 200 mg b.i.d. (40); MK0518 400 mg b.i.d. (41); MK0518 600 mg b.i.d. (40); Efavirenz 600 mg q.d. (38)

[1]

Cohort I Participants: MK0518 100 mg b.i.d. (7); MK0518 200 mg b.i.d. (7); MK0518 400 mg b.i.d. (6); MK0518 600 mg b.i.d. (8); Placebo Cohort (7)

Cohort II Participants: MK0518 100 mg b.i.d. (33); MK0518 200 mg b.i.d. (33); MK0518 400 mg b.i.d. (35); MK0518 600 mg b.i.d. (34); Efavirenz 600 mg q.d. (34)

Cohort I & II Participants Combined: MK0518 100 mg b.i.d. (39); MK0518 200 mg b.i.d. (40); MK0518 400 mg b.i.d. (41); MK0518 600 mg b.i.d. (40); Efavirenz 600 mg q.d. (38)

Outcome Measures

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1. Primary:

Change From Baseline in Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) on Day 10 (Cohort I) [ Time Frame: Baseline and Day 10 ]

Show Outcome Measure 1

2. Primary:

Number of Patients With Clinical Adverse Experiences (CAEs) and Number of Patients With Serious CAEs at Day 10 (Cohort I) [ Time Frame: 10 days ]

Show Outcome Measure 2

3. Primary:

Number of Participants With HIV RNA Levels Below 400 Copies/mL at Week 24 (Cohort II) [ Time Frame: Week 24 ]

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4. Primary:

Number of Patients With Clinical Adverse Experiences (CAEs) [ Time Frame: 48 weeks ]

Show Outcome Measure 4

5. Primary:

Number of Patients With Serious CAEs (Cohort I and II Combined) [ Time Frame: 48 weeks ]

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6. Primary:

Number of Patients With Serious CAEs and Non-serious CAEs at Week 144 [ Time Frame: 144 Weeks ]

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7. Primary:

Number of Participants With Clinical Adverse Experiences (AEs)and Serious Adverse Experiences (SAEs) [ Time Frame: Week 240 ]

Show Outcome Measure 7

8. Primary:

Number of Participants With HIV RNA (Human Immunodeficiency Virus Ribonucleic Acid) Levels Below 50 Copies/mL at Week 240 [ Time Frame: Week 240 ]

Show Outcome Measure 8

9. Secondary:

Number of Participants With HIV RNA Levels Below 50 Copies/mL at Week 24 (Cohort II) [ Time Frame: Week 24 ]

Show Outcome Measure 9

10. Secondary:

Change From Baseline in Plasma HIV RNA at Week 24 (Cohort II) [ Time Frame: Baseline and Week 24 ]

Show Outcome Measure 10

11. Secondary:

Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 24 (Cohort II) [ Time Frame: Baseline and Week 24 ]

Show Outcome Measure 11

12. Secondary:

Number of Patients With HIV RNA Level Below 50 Copies/mL and HIV RNA Level Below 400 Copies/mL at Week 96 [ Time Frame: 96 Weeks ]

Show Outcome Measure 12

13. Secondary:

Change From Baseline in Plasma HIV RNA at Week 96 [ Time Frame: Baseline and Week 96 ]

Show Outcome Measure 13

14. Secondary:

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

Show Outcome Measure 14

15. Secondary:

Number of Participants With HIV RNA Levels Below 400 Copies/mL at Week 240 [ Time Frame: Week 240 ]

Show Outcome Measure 15

16. Secondary:

Change From Baseline in Plasma HIV RNA at Week 240 [ Time Frame: Baseline and Week 240 ]

Show Outcome Measure 16

17. Secondary:

Change From Baseline in CD4 (T-helper) Cell Count at Week 240 [ Time Frame: Baseline and Week 240 ]

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Measure Type	Secondary
Measure Title	Change From Baseline in CD4 (T-helper) Cell Count at Week 240
Measure Description	Change in number of CD4 cells/mm^3 from baseline to Week 240.
Time Frame	Baseline and Week 240
Safety Issue	No

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.
Modified-Intention-to-Treat (MITT): participants were included in the treatment group to which they were randomized, regardless of adherence to the entry criteria, treatment actually received, and deviation from the protocol. Participants who were randomized but never dosed were not included in the analyses.

Reporting Groups

	Description
MK-0518 b.i.d.	Cohort I-Monotherapy Phase (10 Days) MK0518 100, 200, 400, or 600 mg b.i.d. Cohort II Combined-Combination Therapy Phase (48 Weeks) MK0518 100, 200, 400, or 600 mg + tenofovir + lamivudine
EVF Combo Therapy	EFV Combo Therapy Phase - Cohort II efavirenz 600 mg daily at bedtime (qhs) + tenofovir + lamivudine This arm included participants from Cohort I who were randomized to placebo.

Description

MK-0518 b.i.d.

Cohort I-Monotherapy Phase (10 Days) MK0518 100, 200, 400, or 600 mg b.i.d.

Cohort II Combined-Combination Therapy Phase (48 Weeks) MK0518 100, 200, 400, or 600 mg + tenofovir + lamivudine

EVF Combo Therapy

EFV Combo Therapy Phase - Cohort II efavirenz 600 mg daily at bedtime (qhs) + tenofovir + lamivudine

This arm included participants from Cohort I who were randomized to placebo.

Measured Values

	MK-0518 b.i.d.	EVF Combo Therapy
Number of Participants Analyzed [units: participants]	123	31
Change From Baseline in CD4 (T-helper) Cell Count at Week 240 [units: cells/mm^3] Mean ( 95% Confidence Interval )	301.7 ( 268.0 to 335.5 )	275.6 ( 209.9 to 341.3 )

No statistical analysis provided for Change From Baseline in CD4 (T-helper) Cell Count at Week 240

18. Other Pre-specified:

Number of Participants With HIV RNA Levels Below 400 Copies/mL at Week 48 [ Time Frame: 48 weeks ]

Show Outcome Measure 18

19. Other Pre-specified:

Number of Patients With Drug-related CAEs [ Time Frame: 48 weeks ]

Show Outcome Measure 19

20. Other Pre-specified:

Number of Patients With Serious Drug-related CAEs [ Time Frame: 48 Weeks ]

Show Outcome Measure 20

21. Other Pre-specified:

Number of Patients That Discontinued With CAEs [ Time Frame: 48 Weeks ]

Show Outcome Measure 21

22. Other Pre-specified:

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

Show Outcome Measure 22

23. Other Pre-specified:

Number of Patients With Serious LAEs [ Time Frame: 48 Weeks ]

Show Outcome Measure 23

24. Other Pre-specified:

Number of Patients With Drug-related LAEs [ Time Frame: 48 Weeks ]

Show Outcome Measure 24

25. Other Pre-specified:

Number of Patients With Serious Drug-related LAEs [ Time Frame: 48 Weeks ]

Show Outcome Measure 25

26. Other Pre-specified:

Number of Patients That Discontinued With LAEs [ Time Frame: 48 Weeks ]

Show Outcome Measure 26

Serious Adverse Events

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Other Adverse Events

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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: Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

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
No text entered.

Results Point of Contact:

Name/Title: Vice President, Late Stage Development Group Leader
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372
e-mail: ClinicalTrialsDisclosure@merck.com

Publications:

Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15. Erratum in: J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):492.

Murray JM, Emery S, Kelleher AD, Law M, Chen J, Hazuda DJ, Nguyen BY, Teppler H, Cooper DA. Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS. 2007 Nov 12;21(17):2315-21.

Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33.

Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Campbell H, Strohmaier KM, Wan H, Danovich RM, Teppler H; Protocol 004 Part II Study Team. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr. 2009 Nov 1;52(3):350-6.

Responsible Party:	Vice President, Late Stage Development Group Leader, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00100048 History of Changes
Other Study ID Numbers:	MK-0518-004, 2004_096
Study First Received:	December 22, 2004
Results First Received:	January 21, 2010
Last Updated:	February 2, 2012
Health Authority:	United States: Food and Drug Administration

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