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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)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00105157
First Posted: March 9, 2005
Last Update Posted: December 4, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
Results First Submitted: September 14, 2009  
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
  Hide 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
  Hide 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
  Show All Outcome Measures

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 ]

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

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


  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame 168 weeks: Due to a 3:1 randomization of MK0518 to placebo and more discontinuations for placebo in the double-blind phase, exposure for MK0518 and placebo differs significantly with follow-up times of 336.3 and 39.7 patient-years, respectively.
Additional Description AEs were assessed by the investigators.

Reporting Groups
  Description
MK0518 Includes patients from the MK0518 200 mg, 400 mg, and 600 mg b.i.d. dose groups. Patients who completed at least 24 weeks of double-blind therapy without virologic failure entered the open-label phase to receive open-label MK0518 400 mg b.i.d.
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.

Serious Adverse Events
    MK0518   Placebo
Total, Serious Adverse Events     
# participants affected / at risk   28/133 (21.05%)   3/45 (6.67%) 
Blood and lymphatic system disorders     
Anaemia * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Lymphadenopathy * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Cardiac disorders     
Acute Myocardial Infarction * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Atrioventricular Block Complete * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Bradycardia * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Cardio-Respiratory Arrest * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Coronary Artery Disease * 1     
# participants affected / at risk   2/133 (1.50%)   0/45 (0.00%) 
Myocardial Infarction * 1     
# participants affected / at risk   2/133 (1.50%)   0/45 (0.00%) 
Eye disorders     
Photophobia * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Gastrointestinal disorders     
Anogenital Dysplasia * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Haematemesis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Haematochezia * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Irritable Bowel Syndrome * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Pancreatitis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Pancreatitis Acute * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Varices Oesophageal * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
General disorders     
Oedema Peripheral * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Pyrexia * 1     
# participants affected / at risk   2/133 (1.50%)   0/45 (0.00%) 
Hepatobiliary disorders     
Bile Duct Obstruction * 1     
# participants affected / at risk   1/133 (0.75%)   1/45 (2.22%) 
Cholecystitis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Portal Hypertension * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Infections and infestations     
Anogenital Warts * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Bronchitis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Cellulitis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Herpes Simplex * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Herpes Zoster * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Leishmaniasis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Pneumonia * 1     
# participants affected / at risk   2/133 (1.50%)   0/45 (0.00%) 
Postoperative Wound Infection * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Sepsis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Splenic Abscess * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Staphylococcal Abscess * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Staphylococcal Infection * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Tracheobronchitis * 1     
# participants affected / at risk   0/133 (0.00%)   1/45 (2.22%) 
Injury, poisoning and procedural complications     
Accidental Overdose * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Hip Fracture * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Laceration * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Investigations     
Lipase Increased * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Platelet Count Decreased * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Metabolism and nutrition disorders     
Metabolic Acidosis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Anal Cancer * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Anal Cancer Stage 0 * 1     
# participants affected / at risk   2/133 (1.50%)   0/45 (0.00%) 
Basal Cell Carcinoma * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Hodgkin's Disease * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Nervous system disorders     
Facial Palsy * 1     
# participants affected / at risk   0/133 (0.00%)   1/45 (2.22%) 
Headache * 1     
# participants affected / at risk   1/133 (0.75%)   1/45 (2.22%) 
Lacunar Infarction * 1     
# participants affected / at risk   0/133 (0.00%)   1/45 (2.22%) 
Renal and urinary disorders     
Nephrolithiasis * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Renal Failure * 1     
# participants affected / at risk   2/133 (1.50%)   0/45 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Interstitial Lung Disease * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Lung Disorder * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Pleural Effusion * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Skin and subcutaneous tissue disorders     
Lipoatrophy * 1     
# participants affected / at risk   0/133 (0.00%)   1/45 (2.22%) 
Rash * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
Vascular disorders     
Shock * 1     
# participants affected / at risk   1/133 (0.75%)   0/45 (0.00%) 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA Version 12.0




  Other Adverse Events


  Limitations and Caveats
  Hide 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
  Hide More Information

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:
unchecked 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.
unchecked 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.


Results Point of Contact:  
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372


Publications:

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00105157     History of Changes
Other Study ID Numbers: 0518-005
MK0518-005
2005_007
First Submitted: March 8, 2005
First Posted: March 9, 2005
Results First Submitted: September 14, 2009
Results First Posted: April 12, 2010
Last Update Posted: December 4, 2015