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A Pharmacokinetic Study on Co-administration of Tamiflu (Oseltamivir) and Rimantadine in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT01172847
Recruitment Status : Completed
First Posted : July 30, 2010
Results First Posted : March 21, 2016
Last Update Posted : August 19, 2016
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label)
Condition Healthy Volunteer
Interventions Drug: oseltamivir [Tamiflu]
Drug: rimantadine
Enrollment 24
Recruitment Details This study was conducted at a single center in the United States from 04 August 2009 to 28 September 2009. A total of 40 participants were screened.
Pre-assignment Details Of 40 participants, 24 participants were enrolled.
Arm/Group Title Oseltamivir; Rimantadine; Oseltamivir + Rimantadine
Hide Arm/Group Description Participants received treatments in 3 periods as: Oseltamivir 75 milligram [mg] (twice a day orally for 5 days), Rimantadine 100 mg (twice a day orally for 5 days), and Oseltamivir 75 mg + Rimantadine 100 mg (twice a day orally for 5 days) in a randomly determined sequence with a minimum 7-day wash out period between consecutive treatments periods.
Period Title: Overall Study
Started 24
Oseltamivir 24
Rimantadine 22
Oseltamivir + Rimantadine 21
Completed 21
Not Completed 3
Reason Not Completed
Withdrawal by Subject             3
Arm/Group Title Oseltamivir; Rimantadine; Oseltamivir + Rimantadine
Hide Arm/Group Description Participants received treatments in 3 periods as: Oseltamivir 75 milligram [mg] (twice a day orally for 5 days), Rimantadine 100 mg (twice a day orally for 5 days), and Oseltamivir 75 mg + Rimantadine 100 mg (twice a day orally for 5 days) in a randomly determined sequence with a minimum 7-day wash out period between consecutive treatments periods.
Overall Number of Baseline Participants 24
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants
33.5  (7.34)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
Female
3
  12.5%
Male
21
  87.5%
1.Primary Outcome
Title Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate
Hide Description Oseltamivir carboxylate is active metabolite of oseltamivir. AUC0-12 of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine, using the linear trapezoidal rule.
Time Frame Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetics (PK) analysis population included all participants who were adhered to the protocol.
Arm/Group Title Oseltamivir Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 21 21
Least Squares Mean (90% Confidence Interval)
Unit of Measure: hours (h)*nanogram (ng)/milliliter (mL)
Oseltamivir
5.092
(5.041 to 5.143)
5.070
(5.019 to 5.121)
Oseltamivir Carboxylate
8.008
(7.982 to 8.034)
7.990
(7.964 to 8.017)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Oseltamivir + Rimantadine
Comments Mean exposure ratio of oseltamivir
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter mean exposure ratio
Estimated Value 0.98
Confidence Interval (2-Sided) 90%
0.91 to 1.05
Estimation Comments Estimate of the treatment difference and corresponding 90% CI was derived from the back-transformed model.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Oseltamivir
Comments Mean exposure ratio of oseltamivir carboxylate
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter mean exposure ratio
Estimated Value 0.98
Confidence Interval (2-Sided) 90%
0.95 to 1.02
Estimation Comments Estimate of the treatment difference and corresponding 90% CI was derived from the back-transformed model.
2.Primary Outcome
Title Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Rimantadine
Hide Description AUC0-12 of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir, using the linear trapezoidal rule.
Time Frame Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis population included all participants who were adhered to the protocol.
Arm/Group Title Rimantadine Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 21 21
Least Squares Mean (90% Confidence Interval)
Unit of Measure: h*ng/mL
8.371
(8.349 to 8.394)
8.398
(8.376 to 8.421)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rimantadine, Oseltamivir + Rimantadine
Comments Mean exposure ratio of rimantadine
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter mean exposure ratio
Estimated Value 1.03
Confidence Interval (2-Sided) 90%
1.00 to 1.06
Estimation Comments Estimate of the treatment difference and corresponding 90% CI was derived from the back-transformed model.
3.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate
Hide Description Oseltamivir carboxylate is active metabolite of oseltamivir. Cmax of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine and was directly observed from the data.
Time Frame Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK analysis population included all participants who were adhered to the protocol.
Arm/Group Title Oseltamivir Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 21 21
Least Squares Mean (90% Confidence Interval)
Unit of Measure: ng/mL
Oseltamivir
4.395
(4.317 to 4.472)
4.249
(4.171 to 4.326)
Oseltamivir Carboxylate
5.940
(5.894 to 5.986)
5.921
(5.874 to 5.967)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Oseltamivir + Rimantadine
Comments Mean exposure ratio of oseltamivir
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter mean exposure ratio
Estimated Value 0.86
Confidence Interval (2-Sided) 90%
0.77 to 0.96
Estimation Comments Estimate of the treatment difference and corresponding 90% CI was derived from the back-transformed model.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Oseltamivir + Rimantadine
Comments Mean exposure ratio of oseltamivir carboxylate
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter mean exposure ratio
Estimated Value 0.98
Confidence Interval (2-Sided) 90%
0.92 to 1.05
Estimation Comments Estimate of the treatment difference and corresponding 90% CI was derived from the back-transformed model.
4.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Rimantadine
Hide Description Cmax of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir and was directly observed from the data.
Time Frame Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK analysis population included all participants who were adhered to the protocol.
Arm/Group Title Oseltamivir Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 21 21
Least Squares Mean (90% Confidence Interval)
Unit of Measure: ng/mL
6.036
(6.010 to 6.061)
6.062
(6.036 to 6.087)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oseltamivir, Oseltamivir + Rimantadine
Comments mean exposure ratio of rimantadine
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter mean exposure ratio
Estimated Value 1.03
Confidence Interval (2-Sided) 90%
0.99 to 1.06
Estimation Comments Estimate of the treatment difference and corresponding 90% CI was derived from the back-transformed model.
5.Secondary Outcome
Title Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs)
Hide Description An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect.
Time Frame Up to 11 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
Arm/Group Title Oseltamivir Rimantadine Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received rimantadine 100 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 24 22 21
Measure Type: Number
Unit of Measure: participants
8 6 4
6.Secondary Outcome
Title Number of Participants With Abnormal Vital Signs
Hide Description Vital signs included heart rate (HR), blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), and body temperature. Blood pressure and pulse rate were recorded when participants were rested in a supine position for at least 5 minutes and after standing for 2 minutes. Vital signs values that fall outside the investigator’s normal ranges were recorded.
Time Frame Screening (Days -28 to -2); pre-dose and 2h post-dose on D1 and D5 of each treatment period; at Follow-up visit (10 -14 days after last dose) for blood pressure and HR; Screening; Day -1 of each treatment period; Follow-up visit for temperature
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
Arm/Group Title Oseltamivir Rimantadine Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received rimantadine 100 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 24 22 21
Measure Type: Number
Unit of Measure: participants
High- SBP 6 1 2
High- DBP 2 0 0
High- DBP standing 8 6 2
High- SBP standing 7 4 3
High- HR 2 0 0
High- HR standing 2 1 2
Low- Temperature 7 11 8
7.Secondary Outcome
Title Number of Participants With Marked Abnormality in Laboratory Parameters
Hide Description

Laboratory analysis included hematology (hemoglobin, hematocrit, erythrocytes, platelets counts, leukocytes counts, neutrophils, eosinophils, lymphocytes, basophils, and monocytes);, biochemistry (aspartate aminotransferase , alanine aminotransferase, gamma glutamyl trans peptidase, total bilirubin, alkaline phosphatase, lactate dehydrogenase, albumin, creatinine, urea, creatine phosphokinase, total protein, sodium, chloride, calcium, phosphate, potassium, glucose (fasting), amylase, lipase, total cholesterol, and calculated creatinine clearance); and urinalysis.

Marked laboratory test values (high and low) falling outside the marked reference range and which also represents a clinically relevant change from baseline of at least a designated amount were recoded. In this study, marked abnormality ranges for phosphate as 0.75 – 1.60 millimole (mmol)/L and proteinuria (0 to 4+, and 1).

Time Frame Screening; Day -1 and Day 5 (pre-dose) of each treatment period; Follow-up visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
Arm/Group Title Oseltamivir Rimantadine Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received rimantadine 100 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 24 22 21
Measure Type: Number
Unit of Measure: participants
Phosphate High 1 1 1
Phosphate Low 1 0 0
Proteinuria 1 0 0
8.Secondary Outcome
Title Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG)
Hide Description ECG was recorded when participants were rested in a supine position for at least 5 minutes.
Time Frame Screening; pre-dose on Day 1 and Day 5 of each treatment period; Follow-up visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
Arm/Group Title Oseltamivir Rimantadine Oseltamivir + Rimantadine
Hide Arm/Group Description:
Participants received oseltamivir 75 mg twice a day orally for 5 days.
Participants received rimantadine 100 mg twice a day orally for 5 days.
Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
Overall Number of Participants Analyzed 24 22 21
Measure Type: Number
Unit of Measure: participants
0 0 0
Time Frame Up to 11 weeks
Adverse Event Reporting Description SAEs and other AEs were collected in the safety population which included all participants who received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
 
Arm/Group Title Oseltamivir Rimantadine Oseltamivir + Rimantadine
Hide Arm/Group Description Participants received oseltamivir 75 mg twice a day orally for 5 days. Participants received rimantadine 100 mg twice a day orally for 5 days. Participants received oseltamivir 75 mg + rimantadine 100 mg twice a day orally for 5 days.
All-Cause Mortality
Oseltamivir Rimantadine Oseltamivir + Rimantadine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Oseltamivir Rimantadine Oseltamivir + Rimantadine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/24 (0.00%)   0/22 (0.00%)   0/21 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Oseltamivir Rimantadine Oseltamivir + Rimantadine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/24 (33.33%)   6/22 (27.27%)   4/21 (19.05%) 
Cardiac disorders       
Tachycardia  1  1/24 (4.17%)  0/22 (0.00%)  0/21 (0.00%) 
Gastrointestinal disorders       
Toothache  1  1/24 (4.17%)  1/22 (4.55%)  1/21 (4.76%) 
Nausea  1  1/24 (4.17%)  1/22 (4.55%)  0/21 (0.00%) 
Vomiting  1  0/24 (0.00%)  1/22 (4.55%)  1/21 (4.76%) 
Abdominal pain  1  0/24 (0.00%)  1/22 (4.55%)  0/21 (0.00%) 
Dry mouth  1  1/24 (4.17%)  0/22 (0.00%)  0/21 (0.00%) 
Nervous system disorders       
Headache  1  3/24 (12.50%)  1/22 (4.55%)  0/21 (0.00%) 
Somnolence  1  0/24 (0.00%)  2/22 (9.09%)  0/21 (0.00%) 
Paraesthesia  1  0/24 (0.00%)  0/22 (0.00%)  1/21 (4.76%) 
Psychomotor hyperactivity  1  1/24 (4.17%)  0/22 (0.00%)  0/21 (0.00%) 
Skin and subcutaneous tissue disorders       
Acne  1  0/24 (0.00%)  0/22 (0.00%)  1/21 (4.76%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.1
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
Name/Title: Roche Trial Information Hotline
Organization: F. Hoffmann-La Roche AG
Phone: +41 61 6878333
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01172847     History of Changes
Other Study ID Numbers: NP22770
2009-012742-23
First Submitted: July 29, 2010
First Posted: July 30, 2010
Results First Submitted: January 5, 2016
Results First Posted: March 21, 2016
Last Update Posted: August 19, 2016