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Safety and Efficacy of an Investigational Drug in Human Immunodeficiency Virus (HIV)-Infected Patients Failing Current Antiretroviral Therapies (0518-005)(COMPLETED)

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ClinicalTrials.gov Identifier: NCT00105157
Recruitment Status : Completed
First Posted : March 9, 2005
Results First Posted : April 12, 2010
Last Update Posted : December 4, 2015
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions: HIV Infections
Acquired Immunodeficiency Syndrome
Interventions: Drug: Comparator: MK0518
Drug: MK0518
Drug: Placebo

  Participant Flow

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: 22-Apr-2005 to 09-Nov-2006

Multicenter (31) in the United States (15) and outside the United States (16)

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients failed prior antiretroviral therapy (HIV RNA >5000 copies/mL), and had documented resistance to at least one drug in each class of licensed oral antiretroviral therapy (Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase inhibitors and Protease Inhibitors). All patients must have met laboratory criteria.

Reporting Groups
  Description
MK0518 200 mg b.i.d. Optimized background antiretroviral therapy (OBT), if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 200 mg twice a day (b.i.d.). Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
MK0518 400 mg b.i.d. OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 400 mg b.i.d.
MK0518 600 mg b.i.d. OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 600 mg b.i.d.. Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
Placebo OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 matching placebo b.i.d.. Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.

Participant Flow for 3 periods

 Period 1:   Double-Blind (DB)
    MK0518 200 mg b.i.d.   MK0518 400 mg b.i.d.   MK0518 600 mg b.i.d.   Placebo
STARTED   44   45   45   45 
Treated   43   45   45   45 
COMPLETED   30   31   33   6 
NOT COMPLETED   14   14   12   39 
Never Treated                1                0                0                0 
Adverse Event                2                0                1                1 
Lack of Efficacy                11                14                11                38 

Period 2:   Open-Label Continuation of DB
    MK0518 200 mg b.i.d.   MK0518 400 mg b.i.d.   MK0518 600 mg b.i.d.   Placebo
STARTED   30   31   33   6 
COMPLETED   23   21   24   5 
NOT COMPLETED   7   10   9   1 
Adverse Event                3                1                0                0 
Lack of Efficacy                1                4                3                1 
Lost to Follow-up                1                1                1                0 
Withdrawal by Subject                0                1                3                0 
Patient did not continue in extension                1                0                0                0 
Patient moved/site stopped trial                1                3                2                0 

Period 3:   Open-Label Post Virologic Failure(OLPVF)
    MK0518 200 mg b.i.d.   MK0518 400 mg b.i.d.   MK0518 600 mg b.i.d.   Placebo
STARTED   11 [1]   13 [1]   11 [1]   37 [1] 
COMPLETED   2   7   5   19 
NOT COMPLETED   9   6   6   18 
Adverse Event                0                0                0                1 
Lack of Efficacy                7                6                5                10 
Lost to Follow-up                1                0                0                1 
Withdrawal by Subject                0                0                0                5 
Patient moved/Site stopped trial                1                0                1                1 
[1] Number of Patients appropriate for and who consented to enter the OLPVF



  Baseline Characteristics

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.
No text entered.

Reporting Groups
  Description
MK0518 200 mg b.i.d. Optimized background antiretroviral therapy (OBT), if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 200 mg twice a day (b.i.d.). Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
MK0518 400 mg b.i.d. OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 400 mg b.i.d.
MK0518 600 mg b.i.d. OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 600 mg b.i.d.. Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
Placebo OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 matching placebo b.i.d.. Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
Total Total of all reporting groups

Baseline Measures
   MK0518 200 mg b.i.d.   MK0518 400 mg b.i.d.   MK0518 600 mg b.i.d.   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 		 43   45   45   45   178 
Age 
[Units: Years]
Mean (Full Range) 		 44.0 
 (18 to 57)  		 45.1 
 (32 to 69)  		 43.8 
 (25 to 63)  		 43.3 
 (29 to 59)  		 44.1 
 (18 to 69) 
Gender 
[Units: Participants]
 		         
Female   7   5   4   5   21 
Male   36   40   41   40   157 
Race/Ethnicity, Customized 
[Units: Participants]
 		         
White   36   35   32   33   136 
Black   3   5   7   5   20 
Asian   0   0   2   1   3 
Hispanic   4   5   4   5   18 
Others   0   0   0   1   1 
Cluster of Differentiation 4 (CD4) Cell Count 
[Units: Cells/mm3]
Mean (Full Range) 		 244.9 
 (30 to 1153)  		 220.6 
 (68 to 673)  		 220.4 
 (30 to 663)  		 274.0 
 (37 to 880)  		 239.9 
 (30 to 1153) 
Plasma HIV RNA 
[Units: Log10 copies/mL]
Mean (Full Range) 		 4.6 
 (3.5 to 5.9)  		 4.8 
 (3.7 to 5.9)  		 4.7 
 (3.8 to 5.8)  		 4.7 
 (3.6 to 5.8)  		 4.7 
 (3.5 to 5.9) 
Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) 
[Units: Copies/mL]
Mean (Full Range) 		 44642.6 
 (3000 to 750000)  		 59107.9 
 (4770 to 750000)  		 49064.8 
 (7030 to 589000)  		 47432.6 
 (3630 to 611000)  		 49841.6 
 (3000 to 750000) 


  Outcome Measures

1.  Primary:   Change From Baseline in Plasma HIV RNA (log10 Copies/mL) at Week 24   [ Time Frame: Baseline and Week 24 ]
  Show Outcome Measure 1

2.  Secondary:   Number of Patients With Virologic Responses at Week 24   [ Time Frame: 24 weeks ]
  Show Outcome Measure 2

3.  Secondary:   Change From Baseline in CD4 Cell Count at Week 24   [ Time Frame: Baseline and Week 24 ]
  Show Outcome Measure 3

4.  Secondary:   Number of Patients With Clinical Adverse Experiences (CAEs) at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 4

5.  Secondary:   Number of Patients With Serious CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 5

6.  Secondary:   Number of Patients With Drug-related CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 6

7.  Secondary:   Number of Patients With Serious Drug-related CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 7

8.  Secondary:   Number of Patients That Died by 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 8

9.  Secondary:   Number of Patients That Discontinued With CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 9

10.  Secondary:   Number of Patients That Discontinued With Drug-related CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 10

11.  Secondary:   Number of Patients That Discontinued With Serious CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 11

12.  Secondary:   Number of Patients That Discontinued With Serious Drug-related CAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 12

13.  Secondary:   Number of Patients With Laboratory Adverse Experiences (LAEs) at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 13

14.  Secondary:   Number of Patients With Drug-related LAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 14

15.  Secondary:   Number of Patients Discontinued With Laboratory Adverse Experiences (LAEs) at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 15

16.  Secondary:   Number of Patients Discontinued With Drug-related LAEs at 48 Weeks   [ Time Frame: 48 weeks ]
  Show Outcome Measure 16

17.  Secondary:   Number of Patients With Clinical Adverse Experiences (CAEs) at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 17

18.  Secondary:   Number of Patients With Serious CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 18

19.  Secondary:   Number of Patients With Drug-related CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 19

20.  Secondary:   Number of Patients With Serious Drug-related CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 20

21.  Secondary:   Number of Patients That Died by 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 21

22.  Secondary:   Number of Patients That Discontinued With CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 22

23.  Secondary:   Number of Patients That Discontinued With Drug-related CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 23

24.  Secondary:   Number of Patients That Discontinued With Serious CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 24

25.  Secondary:   Number of Patients That Discontinued With Serious Drug-related CAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 25

26.  Secondary:   Number of Patients With Laboratory Adverse Experiences (LAEs) at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 26

27.  Secondary:   Number of Patients With Drug-related LAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 27

28.  Secondary:   Number of Patients Discontinued With Laboratory Adverse Experiences (LAEs) at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 28

29.  Secondary:   Number of Patients Discontinued With Drug-related LAEs at 96 Weeks   [ Time Frame: 96 weeks ]
  Show Outcome Measure 29

30.  Secondary:   Number of Patients With Clinical Adverse Experiences (CAEs) at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 30

31.  Secondary:   Number of Patients With Serious CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 31

32.  Secondary:   Number of Patients With Drug-related CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 32

33.  Secondary:   Number of Patients With Serious Drug-related CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 33

34.  Secondary:   Number of Patients That Died by 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 34

35.  Secondary:   Number of Patients That Discontinued With CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 35

36.  Secondary:   Number of Patients That Discontinued With Drug-related CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 36

37.  Secondary:   Number of Patients That Discontinued With Serious CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 37

38.  Secondary:   Number of Patients That Discontinued With Serious Drug-related CAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 38

39.  Secondary:   Number of Patients With Laboratory Adverse Experiences (LAEs) at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 39

40.  Secondary:   Number of Patients With Serious LAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 40

41.  Secondary:   Number of Patients Discontinued With Drug-related LAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Hide Outcome Measure 41

Measure Type Secondary
Measure Title Number of Patients Discontinued With Drug-related LAEs at 168 Weeks
Measure Description No text entered.
Time Frame 168 weeks  

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 patients who took study medication were included in the analysis (All Patients as Treated approach). Data include patients from the double-blind plus open-label phases.

Reporting Groups
  Description
MK0518 200 mg b.i.d. Optimized background antiretroviral therapy (OBT), if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 200 mg twice a day (b.i.d.). Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
MK0518 400 mg b.i.d. OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 400 mg b.i.d.
MK0518 600 mg b.i.d. OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 600 mg b.i.d.. Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.
Placebo OBT, if possible, based on screening genotypic/phenotypic resistance and past treatment history and MK0518 matching placebo b.i.d.. Once the Phase III dose was determined, all patients were switched to the Phase III dose (400 mg b.i.d.) after completion of at least 24 weeks double-blind therapy.

Measured Values
   MK0518 200 mg b.i.d.   MK0518 400 mg b.i.d.   MK0518 600 mg b.i.d.   Placebo 
Participants Analyzed 
[Units: Participants]
 		 43   45   45   45 
Number of Patients Discontinued With Drug-related LAEs at 168 Weeks 
[Units: Participants]
 		       
Discontinued With Drug-Related LAEs   2   0   0   0 
Did Not Discontinue With Drug-Related LAEs   41   45   45   45 

No statistical analysis provided for Number of Patients Discontinued With Drug-related LAEs at 168 Weeks



42.  Secondary:   Number of Patients With Drug-related LAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 42

43.  Secondary:   Number of Patients With Serious Drug-related LAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 43

44.  Secondary:   Number of Patients Discontinued With LAEs at 168 Weeks   [ Time Frame: 168 weeks ]
  Show Outcome Measure 44

45.  Other Pre-specified:   Change From Baseline in Plasma HIV RNA (log10 Copies/mL) at Week 168 in Combined Substudies   [ Time Frame: Baseline and Week 168 ]
  Show Outcome Measure 45

46.  Other Pre-specified:   Change From Baseline in CD4 Cell Count at Week 168 in Combined Substudies   [ Time Frame: Baseline and Week 168 ]
  Show Outcome Measure 46

47.  Post-Hoc:   Number of Patients With Virologic Responses at Week 168 in Combined Substudies   [ Time Frame: 168 weeks ]
  Show Outcome Measure 47


  Serious Adverse Events


  Other Adverse Events


  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
Due to a 3:1 randomization of MK-0518 to placebo and more discontinuations for placebo in the doubleblind phase, exposure for MK-0518 and placebo differs significantly with follow-up times of 336.3 and 39.7 patient-years, respectively.


  More Information