A Study to Evaluate the Safety and Efficacy of Raltegravir (MK0518) in HIV-Infected Patients Failing Current Antiretroviral Therapies (MK0518-018 EXT2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00293267
First received: February 14, 2006
Last updated: October 22, 2013
Last verified: October 2013
Results First Received: August 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: raltegravir potassium
Drug: Comparator: Placebo

  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
Phase 3; First Patient In: Mar 2006; Last Patient Last Visit (LPLV) Week 48: Aug 2007; 61 of 63 sites in Australia, Belgium, Denmark, France, Germany, Italy, Peru, Portugal, Spain, Switzerland, Taiwan, Thailand randomized patients. Extension Study LPLV Week 240: June 2011

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 >1000 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
Raltegravir 400 mg b.i.d. + OBT No text entered.
Placebo + OBT No text entered.

Participant Flow for 4 periods

Period 1:   Primary Study - Double-Blind Week 0-48
    Raltegravir 400 mg b.i.d. + OBT     Placebo + OBT  
STARTED     234     118  
Treated     232     118  
Continuing in Double-Blind     193 [1]   50  
COMPLETED     193     50  
NOT COMPLETED     41     68  
Never Treated                 2                 0  
Adverse Event                 1                 1  
Death                 3                 3  
Lack of Efficacy                 0                 2  
Lost to Follow-up                 1                 1  
Withdrawal by Subject                 1                 1  
Entered OLPVF Phase                 33                 60  
[1] Excludes participants who entered the open-label post virological failure (OLPVF) phase

Period 2:   Extension - Double-Blind Week 49-156
    Raltegravir 400 mg b.i.d. + OBT     Placebo + OBT  
STARTED     191 [1]   50  
COMPLETED     139     35  
NOT COMPLETED     52     15  
Adverse Event                 1                 4  
Lack of Efficacy                 7                 1  
Lost to Follow-up                 4                 0  
Withdrawal by Subject                 13                 4  
Death                 3                 0  
Participant relocated or site terminated                 2                 0  
Other Reason                 7                 0  
Entered OLPVF Phase                 15                 6  
[1] 2 participants who completed Week 48 did not enter the extension study

Period 3:   Extension - Open-Label Week 157-240
    Raltegravir 400 mg b.i.d. + OBT     Placebo + OBT  
STARTED     131 [1]   28 [2]
COMPLETED     111     26  
NOT COMPLETED     20     2  
Adverse Event                 5                 0  
Lack of Efficacy                 7                 0  
Lost to Follow-up                 1                 0  
Withdrawal by Subject                 2                 1  
Participant relocated or site terminated                 2                 0  
Other Reason                 3                 1  
[1] 8 of 139 participants who completed the double-blind phase did not enter this open-label phase
[2] 7 of 35 participants who completed the double-blind phase did not enter this open-label phase

Period 4:   Open-Label Post Virologic Failure Phase
    Raltegravir 400 mg b.i.d. + OBT     Placebo + OBT  
STARTED     48 [1]   66 [1]
COMPLETED     15     29  
NOT COMPLETED     33     37  
Adverse Event                 2                 3  
Lack of Efficacy                 23                 19  
Withdrawal by Subject                 2                 4  
Lost to Follow-up                 2                 2  
Laboratory Adverse Event                 0                 2  
Participant Moved or Site Terminated                 0                 2  
Other Reason                 4                 5  
[1] Number of participants who failed treatment and consented to enter the OLPVF phase



  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.
No text entered.

Reporting Groups
  Description
Raltegravir 400 mg b.i.d. + OBT No text entered.
Placebo + OBT No text entered.
Total Total of all reporting groups

Baseline Measures
    Raltegravir 400 mg b.i.d. + OBT     Placebo + OBT     Total  
Number of Participants  
[units: participants]
  232     118     350  
Age  
[units: Years]
Mean ( Full Range )
  46.1  
  ( 16 to 74 )  
  43.7  
  ( 19 to 64 )  
  45.3  
  ( 16 to 74 )  
Gender  
[units: participants]
     
Female     37     15     52  
Male     195     103     298  
Race/Ethnicity, Customized  
[units: participants]
     
White     174     96     270  
Black     18     5     23  
Asian     14     5     19  
Hispanic     6     1     7  
Other     20     11     31  
Cluster of Differentiation 4 (CD4) Cell Count  
[units: cells/mm^3]
Mean ( Full Range )
  156  
  ( 1 to 792 )  
  153  
  ( 3 to 759 )  
  155  
  ( 1 to 792 )  
Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA)  
[units: copies/mL]
Geometric Mean ( Full Range )
  40519  
  ( 441 to 750000 )  
  31828  
  ( 200 to 750000 )  
  37352  
  ( 200 to 750000 )  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 16   [ Time Frame: 16 Weeks ]

2.  Primary:   Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 48   [ Time Frame: 48 Weeks ]

3.  Primary:   Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <400 Copies/mL   [ Time Frame: 156 Weeks ]

4.  Primary:   Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <400 Copies/mL   [ Time Frame: 240 Weeks ]

5.  Secondary:   Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 16   [ Time Frame: 16 Weeks ]

6.  Secondary:   Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 48   [ Time Frame: 48 Weeks ]

7.  Secondary:   Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <50 Copies/mL   [ Time Frame: 156 weeks ]

8.  Secondary:   Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <50 Copies/mL   [ Time Frame: 240 weeks ]

9.  Secondary:   Double-Blind Extension - Week 156: Percentage of Participants Without Loss of Virologic Response   [ Time Frame: 156 weeks ]

10.  Secondary:   Change From Baseline in HIV RNA (log10 Copies/mL) at Week 16   [ Time Frame: Baseline and Week 16 ]

11.  Secondary:   Change From Baseline in HIV RNA (log10 Copies/mL) at Week 48   [ Time Frame: Baseline and Week 48 ]

12.  Secondary:   Double-Blind Extension - Week 156: Change From Baseline in HIV RNA (log10 Copies/mL)   [ Time Frame: Baseline and Week 156 ]

13.  Secondary:   Open-Label Extension - Week 240: Change From Baseline in HIV RNA (log10 Copies/mL)   [ Time Frame: Baseline and Week 240 ]

14.  Secondary:   Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 16   [ Time Frame: Baseline and Week 16 ]

15.  Secondary:   Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 48   [ Time Frame: Baseline and Week 48 ]

16.  Secondary:   Double-Blind Extension - Week 156: Change From Baseline in CD4 Cell Count (Cells/mm^3)   [ Time Frame: Baseline and Week 156 ]

17.  Secondary:   Open-Label Extension - Week 240: Change From Baseline in CD4 Cell Count (Cells/mm^3)   [ Time Frame: Baseline and Week 240 ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame 240 Weeks
Additional Description Adverse events are reported by original treatment group for the entire 240-week study, including double-blind, open-label, and OLPVF phases; 94 of 118 participants in the placebo group also received raltegravir in the open-label or OLPVF phase.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Raltegravir 400 mg b.i.d Plus OBT

Includes all participants initially randomized to raltegravir, including those without virologic failure who

continued into the open-label phase at Week 156 and those who entered the OLPVF phase due to virologic failure. During either open-label phase up to Week 240, these participants continued to receive raltegravir 400 mg b.i.d. plus OBT.

Placebo Plus OBT Includes all participants initially randomized to placebo, including those without virologic failure who continued into the open-label phase at Week 156 and those who entered the OLPVF phase due to virologic failure. During either open-label phase up to Week 240, these participants continued to receive raltegravir 400 mg b.i.d. plus OBT.

Other Adverse Events
    Raltegravir 400 mg b.i.d Plus OBT     Placebo Plus OBT  
Total, other (not including serious) adverse events      
# participants affected / at risk     206/232     104/118  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     9/232 (3.88%)     7/118 (5.93%)  
# events     12     13  
Lymphadenopathy † 1    
# participants affected / at risk     19/232 (8.19%)     5/118 (4.24%)  
# events     19     8  
Gastrointestinal disorders      
Abdominal pain † 1    
# participants affected / at risk     15/232 (6.47%)     11/118 (9.32%)  
# events     16     12  
Diarrhoea † 1    
# participants affected / at risk     74/232 (31.90%)     34/118 (28.81%)  
# events     110     70  
Gastritis † 1    
# participants affected / at risk     8/232 (3.45%)     7/118 (5.93%)  
# events     8     8  
Haemorrhoids † 1    
# participants affected / at risk     12/232 (5.17%)     2/118 (1.69%)  
# events     12     2  
Nausea † 1    
# participants affected / at risk     30/232 (12.93%)     20/118 (16.95%)  
# events     38     25  
Vomiting † 1    
# participants affected / at risk     18/232 (7.76%)     17/118 (14.41%)  
# events     26     25  
General disorders      
Asthenia † 1    
# participants affected / at risk     15/232 (6.47%)     11/118 (9.32%)  
# events     16     11  
Fatigue † 1    
# participants affected / at risk     18/232 (7.76%)     6/118 (5.08%)  
# events     18     9  
Injection site reaction † 1    
# participants affected / at risk     18/232 (7.76%)     14/118 (11.86%)  
# events     19     16  
Pyrexia † 1    
# participants affected / at risk     28/232 (12.07%)     18/118 (15.25%)  
# events     35     23  
Infections and infestations      
Anogenital warts † 1    
# participants affected / at risk     11/232 (4.74%)     6/118 (5.08%)  
# events     14     7  
Bronchitis † 1    
# participants affected / at risk     42/232 (18.10%)     16/118 (13.56%)  
# events     71     23  
Gastroenteritis † 1    
# participants affected / at risk     22/232 (9.48%)     3/118 (2.54%)  
# events     28     4  
Genital herpes † 1    
# participants affected / at risk     10/232 (4.31%)     9/118 (7.63%)  
# events     11     12  
Herpes simplex † 1    
# participants affected / at risk     12/232 (5.17%)     3/118 (2.54%)  
# events     13     6  
Herpes zoster † 1    
# participants affected / at risk     20/232 (8.62%)     7/118 (5.93%)  
# events     23     10  
Influenza † 1    
# participants affected / at risk     25/232 (10.78%)     8/118 (6.78%)  
# events     28     11  
Nasopharyngitis † 1    
# participants affected / at risk     58/232 (25.00%)     21/118 (17.80%)  
# events     96     51  
Oral candidiasis † 1    
# participants affected / at risk     11/232 (4.74%)     15/118 (12.71%)  
# events     14     20  
Pharyngitis † 1    
# participants affected / at risk     15/232 (6.47%)     8/118 (6.78%)  
# events     24     11  
Pneumonia † 1    
# participants affected / at risk     9/232 (3.88%)     9/118 (7.63%)  
# events     12     11  
Respiratory tract infection † 1    
# participants affected / at risk     19/232 (8.19%)     3/118 (2.54%)  
# events     21     5  
Sinusitis † 1    
# participants affected / at risk     11/232 (4.74%)     6/118 (5.08%)  
# events     15     13  
Upper respiratory tract infection † 1    
# participants affected / at risk     20/232 (8.62%)     7/118 (5.93%)  
# events     35     15  
Urinary tract infection † 1    
# participants affected / at risk     14/232 (6.03%)     6/118 (5.08%)  
# events     17     8  
Investigations      
Alanine aminotransferase increased † 1    
# participants affected / at risk     24/232 (10.34%)     9/118 (7.63%)  
# events     40     19  
Aspartate aminotransferase increased † 1    
# participants affected / at risk     24/232 (10.34%)     8/118 (6.78%)  
# events     30     18  
Blood cholesterol increased † 1    
# participants affected / at risk     28/232 (12.07%)     9/118 (7.63%)  
# events     44     20  
Blood triglycerides increased † 1    
# participants affected / at risk     22/232 (9.48%)     11/118 (9.32%)  
# events     30     14  
Weight decreased † 1    
# participants affected / at risk     6/232 (2.59%)     7/118 (5.93%)  
# events     8     7  
Metabolism and nutrition disorders      
Decreased appetite † 1    
# participants affected / at risk     12/232 (5.17%)     6/118 (5.08%)  
# events     13     6  
Diabetes mellitus † 1    
# participants affected / at risk     6/232 (2.59%)     6/118 (5.08%)  
# events     7     6  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     14/232 (6.03%)     7/118 (5.93%)  
# events     15     8  
Back pain † 1    
# participants affected / at risk     26/232 (11.21%)     10/118 (8.47%)  
# events     33     14  
Muscle spasms † 1    
# participants affected / at risk     12/232 (5.17%)     7/118 (5.93%)  
# events     15     7  
Myalgia † 1    
# participants affected / at risk     9/232 (3.88%)     8/118 (6.78%)  
# events     9     9  
Pain in extremity † 1    
# participants affected / at risk     12/232 (5.17%)     6/118 (5.08%)  
# events     16     6  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Skin papilloma † 1    
# participants affected / at risk     16/232 (6.90%)     6/118 (5.08%)  
# events     20     8  
Nervous system disorders      
Dizziness † 1    
# participants affected / at risk     14/232 (6.03%)     2/118 (1.69%)  
# events     15     2  
Headache † 1    
# participants affected / at risk     28/232 (12.07%)     24/118 (20.34%)  
# events     38     29  
Psychiatric disorders      
Depression † 1    
# participants affected / at risk     13/232 (5.60%)     9/118 (7.63%)  
# events     14     10  
Insomnia † 1    
# participants affected / at risk     24/232 (10.34%)     12/118 (10.17%)  
# events     24     14  
Respiratory, thoracic and mediastinal disorders      
Cough † 1    
# participants affected / at risk     20/232 (8.62%)     11/118 (9.32%)  
# events     24     14  
Skin and subcutaneous tissue disorders      
Eczema † 1    
# participants affected / at risk     6/232 (2.59%)     7/118 (5.93%)  
# events     7     7  
Lipodystrophy acquired † 1    
# participants affected / at risk     11/232 (4.74%)     6/118 (5.08%)  
# events     11     6  
Pruritus † 1    
# participants affected / at risk     16/232 (6.90%)     6/118 (5.08%)  
# events     20     6  
Rash † 1    
# participants affected / at risk     20/232 (8.62%)     7/118 (5.93%)  
# events     25     12  
Vascular disorders      
Hypertension † 1    
# participants affected / at risk     32/232 (13.79%)     12/118 (10.17%)  
# events     32     12  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 14.0



  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
Adverse events are reported by original treatment group for the entire 240-week study, including double-blind, open-label, and OLPVF phases; 94 of 118 participants in the placebo group also received raltegravir in the open-label or OLPVF phase.


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


Publications of Results:
Other Publications:

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00293267     History of Changes
Other Study ID Numbers: 0518-018, 2005_096
Study First Received: February 14, 2006
Results First Received: August 18, 2009
Last Updated: October 22, 2013
Health Authority: France: Ministry of Health