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Trial record 82 of 730 for:    Area Under Curve AND Bioavailability

A Study to Evaluate the Effect of a Proton-Pump Inhibitor (Rabeprazole) on the Relative Bioavailability of Cobimetinib in Healthy Participants

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ClinicalTrials.gov Identifier: NCT01277718
Recruitment Status : Completed
First Posted : January 17, 2011
Results First Posted : July 7, 2016
Last Update Posted : May 10, 2017
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy Volunteer
Interventions Drug: Cobimetinib
Drug: Rabeprazole
Enrollment 20
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Treatment A First, Then Treatment B, Followed by Treatment C Treatment A First, Then Treatment C, Followed by Treatment B
Hide Arm/Group Description Treatment A in Period 1: One 20-mg tablet of cobimetinib administered orally with 240 milliliters (mL) room temperature water after at least an 8-hour fast. Treatment B in Period 2: 20 mg oral rabeprazole administered once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state followed by one 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. Treatment C in Period 3: 20 mg oral rabeprazole administered once daily for 4 days starting on Day -4. On Day 1, 20 mg rabeprazole was administered in fasted state. Approximately 30 minutes later, participants were provided a standardized Food and Drug Administration (FDA) high-fat meal, and approximately 30 minutes after starting the meal, one 20-mg tablet of cobimetinib was administered orally with 240 mL room temperature water. There was minimum of a 13-day washout between cobimetinib doses of each period. Treatment A in Period 1: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. Treatment C in Period 2: 20 mg oral rabeprazole administered once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state. Approximately 30 minutes later, participants were provided a standardized FDA high-fat meal, and approximately 30 minutes after starting the meal, one 20-mg tablet of cobimetinib was administered orally with 240 mL room temperature water. Treatment B in Period 3: 20 mg oral rabeprazole administered once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state followed by one 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. There was minimum of a 13-day washout between cobimetinib doses of each period.
Period Title: Period 1 - First Intervention
Started 10 10
Completed 10 10
Not Completed 0 0
Period Title: Washout Period of 13 Days
Started 10 10
Completed 10 10
Not Completed 0 0
Period Title: Period 2 - Second Intervention
Started 10 10
Completed 10 7
Not Completed 0 3
Reason Not Completed
Protocol Violation             0             1
Physician Decision             0             2
Period Title: Washout Period of 13 Days
Started 10 7
Completed 10 7
Not Completed 0 0
Period Title: Period 3 - Third Intervention
Started 10 7
Completed 10 7
Not Completed 0 0
Arm/Group Title Entire Study Population
Hide Arm/Group Description All participants randomized to any treatment.
Overall Number of Baseline Participants 20
Hide Baseline Analysis Population Description
All enrolled participants
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 20 participants
31
(22 to 53)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
Female
4
  20.0%
Male
16
  80.0%
1.Primary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Cobimetinib
Hide Description AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf).
Time Frame Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
Arm/Group Title Cobimetinib [Fasted] Cobimetinib [Fasted] + Rabeprazole Cobimetinib [Fed] + Rabeprazole
Hide Arm/Group Description:
One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast.
Participants received 20 mg oral rabeprazole once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state followed by one 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast.
Participants received 20 mg oral rabeprazole once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state. Approximately 30 minutes later, participants were provided a standardized FDA high-fat meal, and approximately 30 minutes after starting the meal, one 20-mg tablet of cobimetinib was administered orally with 240 mL room temperature water.
Overall Number of Participants Analyzed 20 16 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms*hours/milliliter (ng*hr/mL)
778
(32.8%)
864
(39.1%)
846
(48.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cobimetinib [Fasted], Cobimetinib [Fasted] + Rabeprazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Least Squares (LS) Means (in %)
Estimated Value 111
Confidence Interval (2-Sided) 90%
98.02 to 124.99
Estimation Comments LS mean was calculated from Analysis of variance (ANOVA). Data for AUCinf were natural log-transformed prior to analysis. Ratio of AUCinf LS means for log-transformed parameter (expressed as a percent).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cobimetinib [Fasted] + Rabeprazole, Cobimetinib [Fed] + Rabeprazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS Means (in %)
Estimated Value 96.2
Confidence Interval (2-Sided) 90%
85.06 to 108.77
Estimation Comments LS mean was calculated from ANOVA. Data for AUCinf were natural log-transformed prior to analysis. Ratio of AUCinf LS means for log-transformed parameter (expressed as a percent).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cobimetinib [Fasted], Cobimetinib [Fed] + Rabeprazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS Means (in %)
Estimated Value 106
Confidence Interval (2-Sided) 90%
94.53 to 119.91
Estimation Comments LS mean was calculated from ANOVA. Data for AUCinf were natural log-transformed prior to analysis. Ratio of AUCinf LS means for log-transformed parameter (expressed as a percent).
2.Primary Outcome
Title Maximum Observed Concentration of Cobimetinib
Hide Description [Not Specified]
Time Frame Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
Arm/Group Title Cobimetinib [Fasted] Cobimetinib [Fasted] + Rabeprazole Cobimetinib [Fed] + Rabeprazole
Hide Arm/Group Description:
One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast.
Participants received 20 mg oral rabeprazole once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state followed by one 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast.
Participants received 20 mg oral rabeprazole once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state. Approximately 30 minutes later, participants were provided a standardized FDA high-fat meal, and approximately 30 minutes after starting the meal, one 20-mg tablet of cobimetinib was administered orally with 240 mL room temperature water.
Overall Number of Participants Analyzed 20 17 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms per milliliter (ng/mL)
17.0
(35.3%)
17.2
(36.0%)
14.8
(51.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cobimetinib [Fasted], Cobimetinib [Fasted] + Rabeprazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS Means (in %)
Estimated Value 100
Confidence Interval (2-Sided) 90%
85.09 to 118.03
Estimation Comments LS mean was calculated from ANOVA. Data for Cmax were natural log-transformed prior to analysis. Ratio of Cmax LS means for log-transformed parameter (expressed as a percent).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cobimetinib [Fasted] + Rabeprazole, Cobimetinib [Fed] + Rabeprazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS Means (in %)
Estimated Value 85.7
Confidence Interval (2-Sided) 90%
72.51 to 101.33
Estimation Comments LS mean was calculated from ANOVA. Data for Cmax were natural log-transformed prior to analysis. Ratio of Cmax LS means for log-transformed parameter (expressed as a percent).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cobimetinib [Fasted], Cobimetinib [Fed] + Rabeprazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS Means (in %)
Estimated Value 85.9
Confidence Interval (2-Sided) 90%
72.94 to 101.17
Estimation Comments LS mean was calculated from ANOVA. Data for Cmax were natural log-transformed prior to analysis. Ratio of Cmax LS means for log-transformed parameter (expressed as a percent).
Time Frame Adverse events were recorded from start of study treatment in first period to end of last period (up to 36 days)
Adverse Event Reporting Description Three participants discontinued study in second period and did not receive Cobimetinib [Fasted] + Rabeprazole in third period. Therefore, only 17 participants were evaluable for adverse events in the Cobimetinib [Fasted] + Rabeprazole treatment arm.
 
Arm/Group Title Cobimetinib [Fasted] Cobimetinib [Fasted] + Rabeprazole Cobimetinib [Fed] + Rabeprazole
Hide Arm/Group Description One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. Participants received 20 mg oral rabeprazole once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state followed by one 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. Participants received 20 mg oral rabeprazole once daily for 4 days starting on Day -4. On Day 1 of the treatment period, 20 mg rabeprazole was administered in fasted state. Approximately 30 minutes later, participants were provided a standardized FDA high-fat meal, and approximately 30 minutes after starting the meal, one 20-mg tablet of cobimetinib was administered orally with 240 mL room temperature water.
All-Cause Mortality
Cobimetinib [Fasted] Cobimetinib [Fasted] + Rabeprazole Cobimetinib [Fed] + Rabeprazole
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Cobimetinib [Fasted] Cobimetinib [Fasted] + Rabeprazole Cobimetinib [Fed] + Rabeprazole
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/17 (0.00%)   0/20 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cobimetinib [Fasted] Cobimetinib [Fasted] + Rabeprazole Cobimetinib [Fed] + Rabeprazole
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/20 (40.00%)   10/17 (58.82%)   9/20 (45.00%) 
Blood and lymphatic system disorders       
Lymphadenopathy * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Ear and labyrinth disorders       
Hyperacusis * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Vertigo * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Eye disorders       
Eye irritation * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Eye pain * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Ocular hyperaemia * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Photophobia * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Scleral hyperaemia * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Vision blurred * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Gastrointestinal disorders       
Nausea * 1  0/20 (0.00%)  2/17 (11.76%)  2/20 (10.00%) 
Diarrhoea * 1  0/20 (0.00%)  0/17 (0.00%)  2/20 (10.00%) 
Vomiting * 1  0/20 (0.00%)  0/17 (0.00%)  2/20 (10.00%) 
Abdominal pain * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Abdominal pain lower * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Flatulence * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
General disorders       
Chills * 1  0/20 (0.00%)  0/17 (0.00%)  2/20 (10.00%) 
Asthenia * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Feeling cold * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Vessel puncture site haematoma * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Infections and infestations       
Gastroenteritis viral * 1  0/20 (0.00%)  1/17 (5.88%)  1/20 (5.00%) 
Oral herpes * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Respiratory tract infection viral * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Upper respiratory tract Infection * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Viral pharyngitis * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Viral upper respiratory tract infection * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Injury, poisoning and procedural complications       
Muscle strain * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Skin laceration * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Musculoskeletal and connective tissue disorders       
Neck pain * 1  0/20 (0.00%)  2/17 (11.76%)  1/20 (5.00%) 
Arthralgia * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Back pain * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Musculoskeletal pain * 1  0/20 (0.00%)  1/17 (5.88%)  0/20 (0.00%) 
Myalgia * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Nervous system disorders       
Headache * 1  2/20 (10.00%)  2/17 (11.76%)  2/20 (10.00%) 
Dizziness * 1  0/20 (0.00%)  2/17 (11.76%)  2/20 (10.00%) 
Depressed level of consciousness * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Psychiatric disorders       
Insomnia * 1  1/20 (5.00%)  1/17 (5.88%)  0/20 (0.00%) 
Renal and urinary disorders       
Haematuria * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Reproductive system and breast disorders       
Dysmenorrhoea * 1  0/20 (0.00%)  1/17 (5.88%)  1/20 (5.00%) 
Respiratory, thoracic and mediastinal disorders       
Dry throat * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
Skin and subcutaneous tissue disorders       
Papule * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Pruritus * 1  1/20 (5.00%)  0/17 (0.00%)  0/20 (0.00%) 
Rash * 1  0/20 (0.00%)  0/17 (0.00%)  1/20 (5.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 13.1
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.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
EMail: genentech@druginfo.com
Layout table for additonal information
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01277718     History of Changes
Other Study ID Numbers: MEK4954g
First Submitted: January 7, 2011
First Posted: January 17, 2011
Results First Submitted: May 27, 2016
Results First Posted: July 7, 2016
Last Update Posted: May 10, 2017