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Study of Lopinavir/Ritonavir Tablets Comparing Once-Daily Versus Twice-Daily Administration When Coadministered With Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced Human Immunodeficiency Virus Type 1 Infected Subjects

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.
 
ClinicalTrials.gov Identifier: NCT00358917
Recruitment Status : Completed
First Posted : August 1, 2006
Results First Posted : February 1, 2010
Last Update Posted : April 11, 2011
Sponsor:
Information provided by:
Abbott

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Human Immunodeficiency Virus Infections
Intervention Drug: lopinavir/ritonavir (LPV/r) tablet with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Enrollment 599
Recruitment Details  
Pre-assignment Details  
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description lopinavir/ritonavir 800/200 milligram (mg) once daily (QD) tablet lopinavir/ritonavir 400/100 milligram (mg) twice daily (BID) tablet
Period Title: Overall Study
Started 300 299
Completed 234 230
Not Completed 66 69
Reason Not Completed
Adverse Event             14             21
Withdrawal by Subject             5             7
Lost to Follow-up             20             17
Noncompliance             12             11
Death             2             3
Virologic failure             11             8
Unable to Continue Participation             2             2
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet Total
Hide Arm/Group Description lopinavir/ritonavir 800/200 mg once daily (QD) tablet lopinavir/ritonavir 400/100 mg twice daily (BID) tablet Total of all reporting groups
Overall Number of Baseline Participants 300 299 599
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 300 participants 299 participants 599 participants
40.4  (9.22) 40.8  (8.63) 40.6  (8.92)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 300 participants 299 participants 599 participants
Female
103
  34.3%
103
  34.4%
206
  34.4%
Male
197
  65.7%
196
  65.6%
393
  65.6%
Received Prior Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 300 participants 299 participants 599 participants
Received Prior NNRTI 264 241 505
Did Not Receive Prior NNRTI 36 58 94
Received Prior Nucleoside/nucleotide Reverse Transcriptase Inhibitor (NRTI)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 300 participants 299 participants 599 participants
Received Prior NRTI 299 297 596
Did Not Receive Prior NRTI 1 2 3
Received Prior Protease Inhibitor (PI)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 300 participants 299 participants 599 participants
Received Prior PI 140 136 276
Did Not Receive Prior PI 160 163 323
Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Count  
Mean (Standard Deviation)
Unit of measure:  Cells/microliter
Number Analyzed 300 participants 299 participants 599 participants
239.3  (158.39) 268.3  (183.55) 253.9  (171.98)
Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Level  
Mean (Standard Deviation)
Unit of measure:  Log10 copies/milliliter (mL)
Number Analyzed 300 participants 299 participants 599 participants
4.26  (0.826) 4.26  (0.809) 4.26  (0.817)
1.Primary Outcome
Title Percentage of Participants Responding at Week 48 Based on the Food and Drug Administration (FDA) Time to Loss of Virologic Response (TLOVR) Algorithm
Hide Description A participant was classified as a responder at the first of 2 consecutive human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) levels <50 copies/mL. The participant continued to be a responder until 2 consecutive values >=50 copies/mL were reached, until the final value if that value was >=50 copies/mL, or until discontinuation or death.
Time Frame Week 48 (End of Study)
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analysis of all randomized participants who received at least 1 dose of study drug.
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description:
lopinavir/ritonavir 800/200 mg once daily (QD) tablet
lopinavir/ritonavir 400/100 mg twice daily (BID) tablet
Overall Number of Participants Analyzed 300 299
Measure Type: Number
Unit of Measure: Percentage of Participants
55.3 51.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LPV/r 800/200 mg QD Tablet, LPV/r 400/100 mg BID Tablet
Comments The null hypothesis was that the response rate for the once daily (QD) regimen was more than 12% lower than the response rate for the twice daily (BID) regimen. The planned sample size of 600 participants (300 participants in each of the QD and BID treatment regimens) provided 83% power (with a type I error rate of 0.05) to reject the null hypothesis, i.e., to determine noninferiority based on the 12% margin.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The 95% confidence interval for the difference in response rates (once daily [QD] minus twice daily [BID], based on the normal approximation to the binomial distribution) was used to assess noninferiority. The QD regimen was considered noninferior to the BID regimen if the lower limit of the confidence interval remained above -12%.
Statistical Test of Hypothesis P-Value 0.413
Comments [Not Specified]
Method normal approx. to binomial distribution
Comments [Not Specified]
Method of Estimation Estimation Parameter Diff. in Percentage of Subj. Responding
Estimated Value 3.5
Confidence Interval 95%
-4.5 to 11.5
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/Milliliter (mL) at Week 48
Hide Description [Not Specified]
Time Frame Week 48 (End of Study)
Hide Outcome Measure Data
Hide Analysis Population Description
Observed data analysis using all available Week 48 data from all randomized participants who received at least 1 dose of study drug.
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description:
lopinavir/ritonavir 800/200 mg once daily (QD) tablet
lopinavir/ritonavir 400/100 mg twice daily (BID) tablet
Overall Number of Participants Analyzed 225 223
Measure Type: Number
Unit of Measure: Percentage of Participants
76.0 72.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LPV/r 800/200 mg QD Tablet, LPV/r 400/100 mg BID Tablet
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.389
Comments [Not Specified]
Method normal approx. to binomial distribution
Comments [Not Specified]
Method of Estimation Estimation Parameter Diff. in Percentage of Subj. Responding
Estimated Value 3.8
Confidence Interval 95%
-4.3 to 11.9
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Mean Change From Baseline to Week 48 in Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Counts
Hide Description [Not Specified]
Time Frame Week 48 (End of Study)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of study drug and who had CD4+ T cell counts at both the Baseline Visit and Week 48.
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description:
lopinavir/ritonavir 800/200 mg once daily (QD) tablet
lopinavir/ritonavir 400/100 mg twice daily (BID) tablet
Overall Number of Participants Analyzed 195 193
Mean (Standard Error)
Unit of Measure: cells/microliter
135.3  (9.03) 121.5  (9.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LPV/r 800/200 mg QD Tablet, LPV/r 400/100 mg BID Tablet
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.281
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
4.Secondary Outcome
Title Virologic Response (HIV-1 RNA <50 Copies/mL) at Week 48 for Participants With 0-2 Protease Inhibitor Substitutions at Baseline Associated With Reduced Response to Lopinavir/Ritonavir
Hide Description Substitutions considered in the analysis were L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V as defined in the proposed United States Package Insert.
Time Frame Week 48 (End of Study)
Hide Outcome Measure Data
Hide Analysis Population Description
Dropouts-as-censored: participants were responders if they had HIV-1 RNA <50 copies/mL at Week 48. Participants who discontinued (d/c'd) while suppressed or w/o post baseline (BL) levels were excluded. Those d/c'd <Day 85 were excluded unless they had >=1 post BL level & didn't achieve a decrease >=1.0 log10 copies/mL, then they were nonresponders.
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description:
lopinavir/ritonavir 800/200 mg once daily (QD) tablet; 88% NNRTI-experienced, 47% PI-experienced (24% nelfinavir, 19% indinavir, 13% atazanavir).
lopinavir/ritonavir 400/100 mg twice daily (BID) tablet; 81% NNRTI-experienced, 45% PI-experienced (20% nelfinavir, 17% indinavir, 13% atazanavir).
Overall Number of Participants Analyzed 255 250
Measure Type: Number
Unit of Measure: Percentage of Participants
65.5 61.6
5.Secondary Outcome
Title Percentage of Participants With New Primary Protease Mutations at Week 48
Hide Description Emergence of new primary protease inhibitor mutations (i.e., mutations at codons 30, 32, 48, 50, 82, 84, and 90 that were not present at baseline).
Time Frame Week 48 (End of Study)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of study drug and had post baseline genotypic resistance assay results.
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description:
lopinavir/ritonavir 800/200 mg once daily (QD) tablet
lopinavir/ritonavir 400/100 mg twice daily (BID) tablet
Overall Number of Participants Analyzed 75 77
Measure Type: Number
Unit of Measure: Percentage of Participants
8.0 15.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LPV/r 800/200 mg QD Tablet, LPV/r 400/100 mg BID Tablet
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.222
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Hide Arm/Group Description lopinavir/ritonavir 800/200 mg once daily (QD) tablet lopinavir/ritonavir 400/100 mg twice daily (BID) tablet
All-Cause Mortality
LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   27/300 (9.00%)   37/299 (12.37%) 
Blood and lymphatic system disorders     
Anaemia  1  2/300 (0.67%)  0/299 (0.00%) 
Leukocytosis  2  1/300 (0.33%)  0/299 (0.00%) 
Lymphadenopathy  2  0/300 (0.00%)  1/299 (0.33%) 
Cardiac disorders     
Angina pectoris  2  1/300 (0.33%)  0/299 (0.00%) 
Cardiac failure congestive  2  0/300 (0.00%)  1/299 (0.33%) 
Cardiogenic shock  2  1/300 (0.33%)  0/299 (0.00%) 
Tricuspid valve incompetence  1  1/300 (0.33%)  0/299 (0.00%) 
Gastrointestinal disorders     
Abdominal distension  1  0/300 (0.00%)  1/299 (0.33%) 
Abdominal pain  1  1/300 (0.33%)  0/299 (0.00%) 
Diarrhoea  1  1/300 (0.33%)  1/299 (0.33%) 
Gastritis  1  1/300 (0.33%)  0/299 (0.00%) 
Inguinal hernia  1  0/300 (0.00%)  1/299 (0.33%) 
Nausea  1  2/300 (0.67%)  1/299 (0.33%) 
Vomiting  1  1/300 (0.33%)  1/299 (0.33%) 
General disorders     
Asthenia  1  0/300 (0.00%)  1/299 (0.33%) 
Chest pain  1  1/300 (0.33%)  1/299 (0.33%) 
Chills  1  1/300 (0.33%)  0/299 (0.00%) 
Death  1  0/300 (0.00%)  2/299 (0.67%) 
Oedema peripheral  1  0/300 (0.00%)  1/299 (0.33%) 
Pyrexia  1  2/300 (0.67%)  1/299 (0.33%) 
Unevaluable event  1  0/300 (0.00%)  1/299 (0.33%) 
Hepatobiliary disorders     
Cholecystitis  1  1/300 (0.33%)  0/299 (0.00%) 
Cholecystitis chronic  1  0/300 (0.00%)  1/299 (0.33%) 
Jaundice  1  1/300 (0.33%)  0/299 (0.00%) 
Immune system disorders     
Drug hypersensitivity  1  0/300 (0.00%)  1/299 (0.33%) 
Infections and infestations     
Abscess limb  1  1/300 (0.33%)  0/299 (0.00%) 
Appendicitis  1  0/300 (0.00%)  1/299 (0.33%) 
Bacterial disease carrier  1  1/300 (0.33%)  0/299 (0.00%) 
Bronchitis  1  0/300 (0.00%)  1/299 (0.33%) 
Cellulitis  1  0/300 (0.00%)  1/299 (0.33%) 
Cerebral toxoplasmosis  1  1/300 (0.33%)  0/299 (0.00%) 
Cryptococcosis  1  1/300 (0.33%)  0/299 (0.00%) 
Dengue fever  1  1/300 (0.33%)  0/299 (0.00%) 
Disseminated tuberculosis  1  0/300 (0.00%)  1/299 (0.33%) 
Gastroenteritis  1  1/300 (0.33%)  0/299 (0.00%) 
Helicobacter infection  1  0/300 (0.00%)  1/299 (0.33%) 
Herpes zoster  1  0/300 (0.00%)  1/299 (0.33%) 
Meningitis  1  0/300 (0.00%)  1/299 (0.33%) 
Meningitis tuberculous  1  1/300 (0.33%)  0/299 (0.00%) 
Oral candidiasis  1  0/300 (0.00%)  1/299 (0.33%) 
Pneumonia  1  3/300 (1.00%)  5/299 (1.67%) 
Sepsis  1  1/300 (0.33%)  0/299 (0.00%) 
Staphylococcal bacteraemia  1  0/300 (0.00%)  1/299 (0.33%) 
Staphylococcal infection  1  1/300 (0.33%)  1/299 (0.33%) 
Staphylococcal skin infection  1  0/300 (0.00%)  1/299 (0.33%) 
Syphilis  1  1/300 (0.33%)  0/299 (0.00%) 
Tuberculosis  1  1/300 (0.33%)  0/299 (0.00%) 
Urinary tract infection  1  1/300 (0.33%)  0/299 (0.00%) 
Injury, poisoning and procedural complications     
Clavicle fracture  1  1/300 (0.33%)  0/299 (0.00%) 
Head injury  1  0/300 (0.00%)  1/299 (0.33%) 
Hip fracture  1  0/300 (0.00%)  1/299 (0.33%) 
Injury  1  1/300 (0.33%)  0/299 (0.00%) 
Lung injury  1  1/300 (0.33%)  0/299 (0.00%) 
Rib fracture  1  1/300 (0.33%)  0/299 (0.00%) 
Road traffic accident  1  1/300 (0.33%)  0/299 (0.00%) 
Scapula fracture  1  1/300 (0.33%)  0/299 (0.00%) 
Skin laceration  1  0/300 (0.00%)  1/299 (0.33%) 
Upper limb fracture  1  0/300 (0.00%)  1/299 (0.33%) 
Investigations     
Haemoglobin decreased  1  0/300 (0.00%)  1/299 (0.33%) 
Metabolism and nutrition disorders     
Dehydration  1  1/300 (0.33%)  1/299 (0.33%) 
Gout  1  1/300 (0.33%)  0/299 (0.00%) 
Hyperlactacidaemia  1  0/300 (0.00%)  1/299 (0.33%) 
Musculoskeletal and connective tissue disorders     
Flank pain  1  1/300 (0.33%)  0/299 (0.00%) 
Foot deformity  1  1/300 (0.33%)  0/299 (0.00%) 
Lumbar spinal stenosis  1  0/300 (0.00%)  1/299 (0.33%) 
Pain in extremity  1  0/300 (0.00%)  1/299 (0.33%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Ocular neoplasm  1  0/300 (0.00%)  1/299 (0.33%) 
Nervous system disorders     
Cerebral haemorrhage  1  0/300 (0.00%)  1/299 (0.33%) 
Cerebral infarction  1  1/300 (0.33%)  0/299 (0.00%) 
Cerebrovascular accident  1  0/300 (0.00%)  1/299 (0.33%) 
Dizziness  1  0/300 (0.00%)  1/299 (0.33%) 
Encephalitis  1  0/300 (0.00%)  1/299 (0.33%) 
Mononeuritis  1  0/300 (0.00%)  1/299 (0.33%) 
Paraesthesia  1  0/300 (0.00%)  1/299 (0.33%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  1/300 (0.33%)  0/299 (0.00%) 
Ectopic pregnancy  1  0/300 (0.00%)  1/299 (0.33%) 
Psychiatric disorders     
Anxiety  1  1/300 (0.33%)  1/299 (0.33%) 
Major depression  1  1/300 (0.33%)  0/299 (0.00%) 
Personality disorder  1  0/300 (0.00%)  1/299 (0.33%) 
Renal and urinary disorders     
Acute prerenal failure  1  1/300 (0.33%)  0/299 (0.00%) 
Choluria  1  1/300 (0.33%)  0/299 (0.00%) 
Renal failure  1  1/300 (0.33%)  0/299 (0.00%) 
Renal failure acute  1  0/300 (0.00%)  1/299 (0.33%) 
Reproductive system and breast disorders     
Cervical dysplasia  1  0/300 (0.00%)  1/299 (0.33%) 
Epididymitis  1  1/300 (0.33%)  0/299 (0.00%) 
Metrorrhagia  1  0/300 (0.00%)  1/299 (0.33%) 
Vaginal dysplasia  1  0/300 (0.00%)  1/299 (0.33%) 
Vaginal haemorrhage  1  1/300 (0.33%)  0/299 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  0/300 (0.00%)  1/299 (0.33%) 
Chronic obstructive pulmonary disease  1  0/300 (0.00%)  2/299 (0.67%) 
Dyspnoea  1  1/300 (0.33%)  0/299 (0.00%) 
Haemothorax  1  1/300 (0.33%)  0/299 (0.00%) 
Lung disorder  1  0/300 (0.00%)  1/299 (0.33%) 
Pneumothorax  1  1/300 (0.33%)  0/299 (0.00%) 
Pulmonary embolism  1  0/300 (0.00%)  1/299 (0.33%) 
Pulmonary oedema  1  0/300 (0.00%)  1/299 (0.33%) 
Respiratory failure  1  1/300 (0.33%)  0/299 (0.00%) 
Skin and subcutaneous tissue disorders     
Hyperhidrosis  1  1/300 (0.33%)  0/299 (0.00%) 
Stevens-Johnson syndrome  1  0/300 (0.00%)  1/299 (0.33%) 
Vascular disorders     
Arteriosclerosis  1  0/300 (0.00%)  1/299 (0.33%) 
Deep vein thrombosis  1  0/300 (0.00%)  1/299 (0.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
2
Term from vocabulary, MedDRA (11.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4.9%
LPV/r 800/200 mg QD Tablet LPV/r 400/100 mg BID Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   201/300 (67.00%)   180/299 (60.20%) 
Gastrointestinal disorders     
Abdominal pain  1  17/300 (5.67%)  8/299 (2.68%) 
Diarrhoea  1  149/300 (49.67%)  115/299 (38.46%) 
Nausea  1  47/300 (15.67%)  66/299 (22.07%) 
Vomiting  1  36/300 (12.00%)  37/299 (12.37%) 
Infections and infestations     
Influenza  1  21/300 (7.00%)  19/299 (6.35%) 
Nasopharyngitis  1  13/300 (4.33%)  16/299 (5.35%) 
Upper respiratory tract infection  1  29/300 (9.67%)  26/299 (8.70%) 
Nervous system disorders     
Headache  1  20/300 (6.67%)  21/299 (7.02%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  15/300 (5.00%)  15/299 (5.02%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
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.
This study has varying agreements that have been negotiated individually; however, it appears that the most restrictive of the agreements states that following the first publication/presentation of the study by Abbott (or twelve [12] months after the completion of the study at all sites, whichever occurs first), the Principal Investigator (PI) shall, during a period of twelve (12) months, have the right to publish/present the results of the site.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Information Specialist
Organization: Abbott
Phone: 800-633-9110
Layout table for additonal information
Responsible Party: Barry Bernstein, MD, Project Director, Abbott
ClinicalTrials.gov Identifier: NCT00358917     History of Changes
Other Study ID Numbers: M06-802
First Submitted: July 28, 2006
First Posted: August 1, 2006
Results First Submitted: November 12, 2009
Results First Posted: February 1, 2010
Last Update Posted: April 11, 2011