TMC278-TiDP6-C209: A Clinical Trial in Treatment Naive HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:
NCT00540449
First received: October 4, 2007
Last updated: May 29, 2015
Last verified: May 2015
Results First Received: June 14, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: HIV Infections
HIV-1
Human Immunodeficiency Virus Type 1
Interventions: Drug: TMC278
Drug: Efavirenz

  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
One hundred and twelve sites in 21 countries randomized participants. In total, 694 participants were randomized: four participants did not start treatment and 690 participants started treatment (346 in the TMC278 group and 344 in the efavirenz [control ] group).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Participant Flow:   Overall Study
    TMC278     Efavirenz  
STARTED     346     344  
COMPLETED     262     266  
NOT COMPLETED     84     78  
Adverse Event                 12                 32  
Sponsor's Decision                 1                 1  
Subject Ineligible To Continue The Trial                 2                 1  
Lost to Follow-up                 19                 17  
Subject Non-Compliant                 7                 5  
Subject Reached A Virologic Endpoint                 32                 8  
Withdrawal by Subject                 10                 10  
Not specified                 1                 4  



  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.
The analysis population included intent to treat (ITT) population defined as all randomized participants who received at least one dose of the study medication.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.
Total Total of all reporting groups

Baseline Measures
    TMC278     Efavirenz     Total  
Number of Participants  
[units: participants]
  346     344     690  
Age  
[units: participants]
     
<=18 years     1     0     1  
Between 18 and 65 years     343     343     686  
>=65 years     2     1     3  
Age  
[units: years]
Mean (Standard Deviation)
  37  (9.68)     36.7  (9.51)     36.8  (9.59)  
Gender  
[units: participants]
     
Female     78     69     147  
Male     268     275     543  
Region Enroll  
[units: participants]
     
Africa     32     31     63  
Asia     47     51     98  
Latin America     60     69     129  
USA, Canada, Europe, Australia     207     193     400  



  Outcome Measures
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1.  Primary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 48   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 48
Measure Description Virological response is defined as confirmed plasma viral load less than (<) 50 human immunodeficiency virus-1 (HIV-1) (ribonucleic acid [RNA]) copies/milliliter (ml) at Week 48. The TLOVR algorithm was used to derive response. Response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Resuppression after confirmed virologic failure was considered as failure. Virologic Failure includes participants who were rebounder (confirmed viral load >= 50 copies/ml after being responder) or who were never suppressed (no confirmed viral load <50 copies/ml).
Time Frame Week 48  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 48  
[units: Participants]
   
Responder     287     285  
Virologic failure     38     15  
Discontinued due to Adverse Event (AE)     6     25  
Discontinued due to other reason than AE     15     19  


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] <0.0001
Difference in proportion of response [5] -0.4
95% Confidence Interval -5.9 to 5.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Assuming a response rate of 75% at 48 weeks for both treatment groups, 340 subjects were needed per treatment (TMC278 or EFV) to establish non-inferiority of TMC278 versus EFV with a maximum allowable difference of 12% and a 1-sided significance level of 2.5%, to yield 95% power.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm as factor and baseline (log10) viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Significance level was set at 2.5% (one-sided). No adjustment of p-value for multiple comparisons, since there was only single comparison for the primary endpoint.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



2.  Secondary:   The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48
Measure Description The analysis is based on the last observed viral load (VL) data within the Week 48 window. Virologic response is defined as a VL<50 copies/ml (observed case). Missing VL was considered as non-response. Virologic Failure includes subjects who had VL>=50 copies/ml in the Wk48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a VL>=50 copies/ml and subjects who had a switch in background regimen that was not permitted by the protocol.
Time Frame Week 48  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48  
[units: Participants]
   
Virologic Response HIV RNA <50 copies/mL at Wk 48     285     281  
Virologic Failure     47     24  
No Viral Load Data in 48 week window     14     39  


Statistical Analysis 1 for The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] <0.0001
Difference in proportion of response [5] 0.3
95% Confidence Interval -5.4 to 5.9
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm as factor and baseline (log10) viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



3.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96  
[units: Participants]
   
Responder     263     271  
Virologic failure     45     16  
Death     0     3  
Discontinued due to AE     10     29  
Discontnued due to other reason than AE     28     25  


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] 0.0055
Difference in proportion of response [5] -3.2
95% Confidence Interval -9.4 to 3.1
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm as factor and baseline (log10) viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



4.  Secondary:   The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

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.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96  
[units: Participants]
   
Virologic Response, <50 copies/ml     265     268  
Virologic failure     54     27  
No viral load data in the 96 week window     27     49  


Statistical Analysis 1 for The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] 0.0013
Difference in proportion of response [5] -1.7
95% Confidence Interval -8.0 to 4.5
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm as factor and baseline (log10) viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.



5.  Secondary:   Number of Participants With Virological Response (Observed, <50 Copies/ml) at Last On-Treatment Post-Week 96 Visit.   [ Time Frame: Variable, ranging from 3 months up to maximum 15 months for TMC278 and 12 months for Efavirenz ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Observed, <50 Copies/ml) at Last On-Treatment Post-Week 96 Visit.
Measure Description Virological response is defined as (observed) plasma viral load less than 50 human immunodeficiency virus-type 1 (HIV-1) ribonucleic acid (RNA) copies per ml at the last on-treatment post-Week 96 visit.
Time Frame Variable, ranging from 3 months up to maximum 15 months for TMC278 and 12 months for Efavirenz  
Safety Issue No  

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.
Participants with at least 1 Post-Week 96 visit were included in the analysis.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  258     271  
Number of Participants With Virological Response (Observed, <50 Copies/ml) at Last On-Treatment Post-Week 96 Visit.  
[units: Participants]
  245     261  

No statistical analysis provided for Number of Participants With Virological Response (Observed, <50 Copies/ml) at Last On-Treatment Post-Week 96 Visit.



6.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 48
Measure Description No text entered.
Time Frame Week 48  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 48  
[units: Participants]
  297     293  

No statistical analysis provided for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 48



7.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 96
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 96  
[units: Participants]
  273     278  

No statistical analysis provided for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 96



8.  Secondary:   Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)   [ Time Frame: Week 48, Week 96 ]

Measure Type Secondary
Measure Title Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)
Measure Description Change from baseline in CD4+ cell count was imputed in case of missing values: in case of premature discontinuation, data were imputed with the baseline value after discontinuation (i.e. change=0, Non-Completer [NC] = Failure); otherwise last observation carried forward was applied.
Time Frame Week 48, Week 96  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  346     344  
Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)  
[units: cellls per microliter]
Mean (Standard Deviation)
   
Absolute cell count, Week 48     195.5  (151.7)     181.6  (156.9)  
Absolute cell count, Week 96     220.7  (167.1)     226.7  (188.9)  
Relative cell count, Week 48     8.6  (5.8)     8.7  (6.0)  
Relative cell count, Week 96     10.1  (7.5)     10.2  (7.2)  

No statistical analysis provided for Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)



9.  Secondary:   Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated Mutations: First Available On-Treatment Genotypic Data After Failure   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated Mutations: First Available On-Treatment Genotypic Data After Failure
Measure Description Virologic failure for the resistance determinations was defined as lack of virologic response (never having had 2 consecutive plasma viral load <50 copies/mL) and plasma viral load increase of >=0.5 log 10 copies/mL above nadir (i.e., never suppressed), or confirmed loss of virologic response (2 consecutive plasma viral load >=50 copies/mL after having had 2 consecutive plasma viral load <50 copies/mL; i.e., rebounder), or discontinued with a last observed on-treatment plasma viral load >=50 copies/mL after having had 2 consecutive plasma viral load <50 copies/mL. For this study, treatment-emergent reverse transcriptase (RT) resistance associated mutations (RAMs) occurring in at least 2 virologic failures (for at least one treatment group) for the following lists are presented: i) Extended list of Non-nucleoside reverse transcriptase inhibitor (NNRTI RAMs) ii) IAS-USA list of Nucleoside/tide reverse transcriptase inhibitor (N[t]RTI RAMs).
Time Frame Week 96  
Safety Issue No  

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.
The ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
    TMC278     Efavirenz  
Number of Participants Analyzed  
[units: participants]
  52     18  
Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated Mutations: First Available On-Treatment Genotypic Data After Failure  
[units: Participants]
   
Any RAM from Extended NNRTI RAMs list     29     9  
NNRTI RAM: E138K     18     0  
NNRTI RAM: K101E     5     0  
NNRTI RAM: Y181C     5     0  
NNRTI RAM: V90I     4     0  
NNRTI RAM: V189I     4     0  
NNRTI RAM: H221Y     4     0  
NNRTI RAM: E138Q     3     0  
NNRTI RAM: K103N     1     8  
Any RAM from IAS-USA N(t)RTI RAMs list     31     5  
N(t)RTI RAM: M184I     24     3  
N(t)RTI RAM: M184V     7     3  
N(t)RTI RAM: K065R     3     0  
N(t)RTI RAM: K219E     3     0  
N(t)RTI RAM: Y115F     2     0  

No statistical analysis provided for Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated Mutations: First Available On-Treatment Genotypic Data After Failure




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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
No text entered.


  More Information
  Hide More Information

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: Medical Leader
Organization: Janssen Infectious Diseases BVBA
e-mail: ClinicalTrialDisclosure@its.jnj.com


No publications provided by Tibotec Pharmaceuticals, Ireland

Publications automatically indexed to this study:

Responsible Party: Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier: NCT00540449     History of Changes
Obsolete Identifiers: NCT00613639
Other Study ID Numbers: CR002689, TMC278-TIDP6-C209
Study First Received: October 4, 2007
Results First Received: June 14, 2011
Last Updated: May 29, 2015
Health Authority: United States: Food and Drug Administration
Ireland: Irish Agriculture and Food Development Authority
Canada: Health Canada
Great Britain: Medicines and Healthcare Products Regulatory Agency
Taiwan: Department of Health
Great Britain: Research Ethics Committee