A Study to Evaluate the Safety and Efficacy of Raltegravir (MK0518) in HIV-Infected Patients Failing Current Antiretroviral Therapies (0518-019 EXT2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00293254
First received: February 15, 2006
Last updated: August 30, 2013
Last verified: August 2013
Results First Received: August 20, 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: 08-Mar-2006; Last Patient Last Visit (LPLV) for Week 48: 31-Jul-2007; Extension Study LPLV Week 240: May 2011

53 sites (US, Brazil, Canada, Colombia, Mexico, and Puerto Rico).


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     232     119  
Treated     230     119  
Continuing in Double-Blind     177 [1]   55 [2]
COMPLETED     177     55  
NOT COMPLETED     55     64  
Never Treated                 2                 0  
Adverse Event                 2                 1  
Death                 5                 2  
Lack of Efficacy                 2                 2  
Lost to Follow-up                 3                 1  
Withdrawal by Subject                 5                 1  
Moved or trial terminated at site                 1                 0  
Entered OLPVF Phase                 35                 57  
[1] Excludes participants who entered the Open-Label Post-Virologic Failure (OLPVF) Phase
[2] Excludes participants who entered the OLPVF phase

Period 2:   Extension - Double-Blind Week 49-156
    Raltegravir 400 mg b.i.d. + OBT     Placebo + OBT  
STARTED     177     54 [1]
COMPLETED     120     25  
NOT COMPLETED     57     29  
Adverse Event                 4                 1  
Death                 4                 1  
Lack of Efficacy                 3                 4  
Lost to Follow-up                 3                 3  
Withdrawal by Subject                 12                 8  
Participant Moved/Site Stopped Trial                 6                 3  
Other Reason                 10                 2  
Entered OLPVF Phase                 15                 7  
[1] 1 of 55 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     120     19 [1]
COMPLETED     110     18  
NOT COMPLETED     10     1  
Adverse Event                 2                 1  
Lack of Efficacy                 1                 0  
Withdrawal by Subject                 1                 0  
Lost to Follow-up                 2                 0  
Other Reason                 4                 0  
[1] 6 of 25 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     50 [1]   64 [1]
COMPLETED     19     37  
NOT COMPLETED     31     27  
Adverse Event                 4                 7  
Lack of Efficacy                 16                 14  
Withdrawal by Subject                 6                 3  
Lost to Follow-up                 3                 0  
Participant Moved/Site Stopped Trial                 1                 1  
Other Reason                 1                 2  
[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]
  230     119     349  
Age  
[units: Years]
Mean ( Full Range )
  45.3  
  ( 16 to 67 )  
  46.5  
  ( 17 to 70 )  
  45.7  
  ( 16 to 70 )  
Gender  
[units: participants]
     
Female     20     12     32  
Male     210     107     317  
Race/Ethnicity, Customized  
[units: Participants]
     
White     127     77     204  
Black     47     21     68  
Asian     2     1     3  
Hispanic     47     18     65  
Native American     1     0     1  
Other     6     2     8  
Cluster of Differentiation 4 (CD4) Cell Count  
[units: cells/mm^3]
Mean ( Full Range )
  146  
  ( 1 to 757 )  
  163  
  ( 0 to 674 )  
  152  
  ( 0 to 757 )  
Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA)  
[units: copies/mL]
Geometric Mean ( Full Range )
  49159  
  ( 200 to 750000 )  
  47850  
  ( 200 to 750000 )  
  48709  
  ( 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 (Log 10 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
  Hide Other Adverse Events

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; 83 of 119 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     214/230     111/119  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     9/230 (3.91%)     9/119 (7.56%)  
# events     9     10  
Lymphadenopathy † 1    
# participants affected / at risk     19/230 (8.26%)     4/119 (3.36%)  
# events     24     4  
Eye disorders      
Conjunctivitis † 1    
# participants affected / at risk     17/230 (7.39%)     2/119 (1.68%)  
# events     18     2  
Gastrointestinal disorders      
Abdominal distension † 1    
# participants affected / at risk     15/230 (6.52%)     6/119 (5.04%)  
# events     18     6  
Abdominal pain † 1    
# participants affected / at risk     25/230 (10.87%)     7/119 (5.88%)  
# events     31     8  
Abdominal pain upper † 1    
# participants affected / at risk     17/230 (7.39%)     11/119 (9.24%)  
# events     19     11  
Constipation † 1    
# participants affected / at risk     15/230 (6.52%)     5/119 (4.20%)  
# events     19     6  
Diarrhoea † 1    
# participants affected / at risk     75/230 (32.61%)     35/119 (29.41%)  
# events     108     41  
Dry mouth † 1    
# participants affected / at risk     2/230 (0.87%)     7/119 (5.88%)  
# events     2     7  
Flatulence † 1    
# participants affected / at risk     17/230 (7.39%)     5/119 (4.20%)  
# events     20     7  
Haemorrhoids † 1    
# participants affected / at risk     8/230 (3.48%)     6/119 (5.04%)  
# events     8     6  
Nausea † 1    
# participants affected / at risk     41/230 (17.83%)     30/119 (25.21%)  
# events     57     40  
Vomiting † 1    
# participants affected / at risk     25/230 (10.87%)     17/119 (14.29%)  
# events     41     19  
General disorders      
Asthenia † 1    
# participants affected / at risk     12/230 (5.22%)     2/119 (1.68%)  
# events     13     2  
Chest pain † 1    
# participants affected / at risk     13/230 (5.65%)     4/119 (3.36%)  
# events     15     4  
Fatigue † 1    
# participants affected / at risk     45/230 (19.57%)     18/119 (15.13%)  
# events     57     22  
Injection site reaction † 1    
# participants affected / at risk     35/230 (15.22%)     14/119 (11.76%)  
# events     41     16  
Oedema peripheral † 1    
# participants affected / at risk     12/230 (5.22%)     9/119 (7.56%)  
# events     13     10  
Pyrexia † 1    
# participants affected / at risk     29/230 (12.61%)     24/119 (20.17%)  
# events     32     35  
Infections and infestations      
Anogenital warts † 1    
# participants affected / at risk     12/230 (5.22%)     4/119 (3.36%)  
# events     15     4  
Bronchitis † 1    
# participants affected / at risk     34/230 (14.78%)     15/119 (12.61%)  
# events     44     18  
Cellulitis † 1    
# participants affected / at risk     11/230 (4.78%)     7/119 (5.88%)  
# events     15     7  
Folliculitis † 1    
# participants affected / at risk     12/230 (5.22%)     4/119 (3.36%)  
# events     14     4  
Furuncle † 1    
# participants affected / at risk     4/230 (1.74%)     6/119 (5.04%)  
# events     4     6  
Gastroenteritis † 1    
# participants affected / at risk     13/230 (5.65%)     6/119 (5.04%)  
# events     14     6  
Herpes zoster † 1    
# participants affected / at risk     27/230 (11.74%)     5/119 (4.20%)  
# events     30     5  
Influenza † 1    
# participants affected / at risk     17/230 (7.39%)     9/119 (7.56%)  
# events     21     14  
Nasopharyngitis † 1    
# participants affected / at risk     29/230 (12.61%)     15/119 (12.61%)  
# events     50     20  
Onychomycosis † 1    
# participants affected / at risk     8/230 (3.48%)     7/119 (5.88%)  
# events     9     8  
Oral candidiasis † 1    
# participants affected / at risk     12/230 (5.22%)     11/119 (9.24%)  
# events     12     12  
Pneumonia † 1    
# participants affected / at risk     14/230 (6.09%)     10/119 (8.40%)  
# events     19     14  
Sinusitis † 1    
# participants affected / at risk     35/230 (15.22%)     15/119 (12.61%)  
# events     50     18  
Upper respiratory tract infection † 1    
# participants affected / at risk     76/230 (33.04%)     29/119 (24.37%)  
# events     114     47  
Urinary tract infection † 1    
# participants affected / at risk     11/230 (4.78%)     11/119 (9.24%)  
# events     12     18  
Investigations      
Alanine aminotransferase increased † 1    
# participants affected / at risk     18/230 (7.83%)     9/119 (7.56%)  
# events     29     11  
Aspartate aminotransferase increased † 1    
# participants affected / at risk     20/230 (8.70%)     9/119 (7.56%)  
# events     27     12  
Blood bilirubin increased † 1    
# participants affected / at risk     6/230 (2.61%)     6/119 (5.04%)  
# events     7     10  
Blood cholesterol increased † 1    
# participants affected / at risk     10/230 (4.35%)     9/119 (7.56%)  
# events     11     11  
Blood creatine phosphokinase increased † 1    
# participants affected / at risk     21/230 (9.13%)     8/119 (6.72%)  
# events     24     8  
Blood creatinine increased † 1    
# participants affected / at risk     18/230 (7.83%)     11/119 (9.24%)  
# events     37     17  
Blood glucose increased † 1    
# participants affected / at risk     13/230 (5.65%)     6/119 (5.04%)  
# events     28     7  
Blood phosphorus decreased † 1    
# participants affected / at risk     3/230 (1.30%)     6/119 (5.04%)  
# events     3     8  
Blood triglycerides increased † 1    
# participants affected / at risk     22/230 (9.57%)     14/119 (11.76%)  
# events     30     15  
Weight decreased † 1    
# participants affected / at risk     14/230 (6.09%)     8/119 (6.72%)  
# events     15     9  
Metabolism and nutrition disorders      
Decreased appetite † 1    
# participants affected / at risk     13/230 (5.65%)     10/119 (8.40%)  
# events     16     10  
Hyperlipidaemia † 1    
# participants affected / at risk     12/230 (5.22%)     1/119 (0.84%)  
# events     12     1  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     24/230 (10.43%)     15/119 (12.61%)  
# events     32     18  
Back pain † 1    
# participants affected / at risk     26/230 (11.30%)     14/119 (11.76%)  
# events     27     17  
Musculoskeletal pain † 1    
# participants affected / at risk     16/230 (6.96%)     5/119 (4.20%)  
# events     17     6  
Myalgia † 1    
# participants affected / at risk     14/230 (6.09%)     13/119 (10.92%)  
# events     16     19  
Pain in extremity † 1    
# participants affected / at risk     27/230 (11.74%)     9/119 (7.56%)  
# events     35     12  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Skin papilloma † 1    
# participants affected / at risk     21/230 (9.13%)     8/119 (6.72%)  
# events     23     10  
Nervous system disorders      
Dizziness † 1    
# participants affected / at risk     22/230 (9.57%)     10/119 (8.40%)  
# events     27     13  
Headache † 1    
# participants affected / at risk     39/230 (16.96%)     19/119 (15.97%)  
# events     62     24  
Hypoaesthesia † 1    
# participants affected / at risk     7/230 (3.04%)     8/119 (6.72%)  
# events     10     10  
Neuropathy peripheral † 1    
# participants affected / at risk     15/230 (6.52%)     9/119 (7.56%)  
# events     19     11  
Paraesthesia † 1    
# participants affected / at risk     10/230 (4.35%)     6/119 (5.04%)  
# events     12     7  
Psychiatric disorders      
Anxiety † 1    
# participants affected / at risk     7/230 (3.04%)     13/119 (10.92%)  
# events     7     14  
Depression † 1    
# participants affected / at risk     15/230 (6.52%)     11/119 (9.24%)  
# events     17     12  
Insomnia † 1    
# participants affected / at risk     22/230 (9.57%)     11/119 (9.24%)  
# events     27     12  
Respiratory, thoracic and mediastinal disorders      
Cough † 1    
# participants affected / at risk     26/230 (11.30%)     21/119 (17.65%)  
# events     32     29  
Dyspnoea † 1    
# participants affected / at risk     4/230 (1.74%)     6/119 (5.04%)  
# events     5     6  
Oropharyngeal pain † 1    
# participants affected / at risk     17/230 (7.39%)     7/119 (5.88%)  
# events     18     8  
Sinus congestion † 1    
# participants affected / at risk     6/230 (2.61%)     8/119 (6.72%)  
# events     7     8  
Skin and subcutaneous tissue disorders      
Night sweats † 1    
# participants affected / at risk     11/230 (4.78%)     6/119 (5.04%)  
# events     15     7  
Pruritus † 1    
# participants affected / at risk     7/230 (3.04%)     7/119 (5.88%)  
# events     8     8  
Rash † 1    
# participants affected / at risk     30/230 (13.04%)     12/119 (10.08%)  
# events     36     17  
Vascular disorders      
Hypertension † 1    
# participants affected / at risk     21/230 (9.13%)     5/119 (4.20%)  
# events     21     6  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 14.0



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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.


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
Adverse events are reported by original treatment group for the entire 240-week study, including double-blind, open-label, and OLPVF phases; 83 of 119 participants in the placebo group also received raltegravir in the open-label or OLPVF phase.  


Results Point of Contact:  
Name/Title: Executive 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: NCT00293254     History of Changes
Other Study ID Numbers: 0518-019, 2005_097
Study First Received: February 15, 2006
Results First Received: August 20, 2009
Last Updated: August 30, 2013
Health Authority: United States: Food and Drug Administration