Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)

This study has been terminated.

(The study was stopped because of safety concerns)

Sponsor:

Information provided by (Responsible Party):

Sanofi

ClinicalTrials.gov Identifier:

NCT01151137

First received: June 22, 2010

Last updated: October 23, 2012

Last verified: October 2012

History of Changes

Results First Received: September 14, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Atrial Fibrillation
Interventions:	Drug: Dronedarone Drug: Placebo (for Dronedarone)

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
Recruitment initiated in July 2010 was discontinued on July 6, 2011 upon recommendations of the Data Monitoring Committee due to an increased number of observed cardiovascular events in the Dronedarone group. The common study end date [CSED] was defined as July 15, 2011. At that time 494 sites in 37 countries had enrolled at least one patient.

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

Recruitment initiated in July 2010 was discontinued on July 6, 2011 upon recommendations of the Data Monitoring Committee due to an increased number of observed cardiovascular events in the Dronedarone group. The common study end date [CSED] was defined as July 15, 2011.

At that time 494 sites in 37 countries had enrolled at least one patient.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Assignment to groups was done centrally using an Interactive Voice Response System [IVRS] or an Interactive Web Response System [IWRS] in a 1:1 ratio. A total of 3236 participants were randomized at 489 sites (instead of 10800 as initially planned). The median duration of their participation in the study was 3.5 months.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Assignment to groups was done centrally using an Interactive Voice Response System [IVRS] or an Interactive Web Response System [IWRS] in a 1:1 ratio.

A total of 3236 participants were randomized at 489 sites (instead of 10800 as initially planned). The median duration of their participation in the study was 3.5 months.

Reporting Groups

	Description
Placebo	Placebo twice daily until the CSED (median treatment duration of 87.5 days)
Dronedarone	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)

Participant Flow: Overall Study

	Placebo	Dronedarone
STARTED	1617	1619
Treated	1610 ^[1]	1613
Discontinued Treatment	171	342
COMPLETED	1601	1591
NOT COMPLETED	16	28
Death	15	27
Lost to Follow-up	1	1

[1]	One participant randomized to the placebo group received Dronedarone for 7 days by mistake

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.
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Reporting Groups

	Description
Placebo	Placebo twice daily until the CSED (median treatment duration of 87.5 days)
Dronedarone	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Total	Total of all reporting groups

Baseline Measures

	Placebo	Dronedarone	Total
Number of Participants [units: participants]	1617	1619	3236
Age [units: years] Mean (Standard Deviation)	75.0 (5.9)	75.0 (5.9)	75.0 (5.9)
Gender [units: participants]
Female	577	568	1145
Male	1040	1051	2091
Region of Enrollment ^[1] [units: participants]
North America	281	266	547
South America	227	236	463
Western Europe	459	475	934
Eastern Europe	495	488	983
Asia	53	47	100
Rest of the word	102	107	209
Permanent atrial fibrillation [AF] history [units: participants]
6 months to 2 years	490	498	988
> 2 years	1124	1119	2243
Unknown	3	2	5
CHADS2 Score ^[2] [units: participants]
< 2	172	191	363
≥ 2	1444	1427	2871
Unavailable	1	1	2
New York Heart Association [NYHA] class ^[3] [units: participants]
No congestive heart failure [CHF]	535	512	1047
NYHA Class I	209	234	443
NYHA Class II	749	732	1481
NYHA Class III	124	141	265

[1]	Regions were defined as follows: North America: Canada, United States South America: Argentina, Brazil, Chile, Mexico Western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, Russian Federation, Slovakia, Ukraine Asia: Hong Kong, Republic of Korea, Malaysia, Singapore, Taiwan Rest of the World: Australia, Israel, New zealand, South Africa
[2]	CHADS2 is a risk-prediction score ranging from 0 to 6 used estimate Stroke Risk in Atrial Fibrillation patients. CHADS2 score is obtained by adding together the points that correspond to the conditions that are present: C: Congestive Heart Failure history: 1 point H: Hypertension history: 1 point A: Age ≥75 years: 1 point D: Diabetes Mellitus history: 1 point S: Stroke symptoms previously or Transient Ischemic Attack [TIA]: 2 points
[3]	NYHA classification is a functional classification that places the patient in one of 4 categories, based on how much he/she is limited during physical activity: Class I: no limitation of activities; the patient suffers no symptoms from ordinary activities. Class II: slight, mild limitation of activity; the patient is comfortable with rest or with mild exertion. Class III: marked limitation of activity; the patient is comfortable only at rest. Class IV: complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest.

[1]

Regions were defined as follows:

North America: Canada, United States
South America: Argentina, Brazil, Chile, Mexico
Western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom
Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, Russian Federation, Slovakia, Ukraine Asia: Hong Kong, Republic of Korea, Malaysia, Singapore, Taiwan Rest of the World: Australia, Israel, New zealand, South Africa

[2]

CHADS2 is a risk-prediction score ranging from 0 to 6 used estimate Stroke Risk in Atrial Fibrillation patients.

CHADS2 score is obtained by adding together the points that correspond to the conditions that are present:

C: Congestive Heart Failure history: 1 point
H: Hypertension history: 1 point
A: Age ≥75 years: 1 point
D: Diabetes Mellitus history: 1 point
S: Stroke symptoms previously or Transient Ischemic Attack [TIA]: 2 points

[3]

NYHA classification is a functional classification that places the patient in one of 4 categories, based on how much he/she is limited during physical activity:

Class I: no limitation of activities; the patient suffers no symptoms from ordinary activities.
Class II: slight, mild limitation of activity; the patient is comfortable with rest or with mild exertion.
Class III: marked limitation of activity; the patient is comfortable only at rest.
Class IV: complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest.

Outcome Measures

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1. Primary:

Overview of the Two Co-primary Outcomes [ Time Frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) ]

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2. Primary:

Time to First Co-primary Outcome (Cumulative Incidence Function) [ Time Frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) ]

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3. Primary:

Time to Second Co-primary Outcome (Cumulative Incidence Function) [ Time Frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) ]

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4. Secondary:

Deaths [ Time Frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) ]

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5. Secondary:

Time to Cardiovascular Death (Cumulative Incidence Function) [ Time Frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) ]

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6. Other Pre-specified:

Overview of Cardiovascular Events [ Time Frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) ]

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7. Other Pre-specified:

Overview of Adverse Events [AE] [ Time Frame: from first study drug intake up to 10 days after the last study drug intake ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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
Given that the study was prematurely discontinued after 3236 patients were randomized (30% of the initial planned number), p-values were provided for information without any adjustment for multiplicity.

More Information

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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:

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.

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.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:

If no publication has occurred within 12 months after trial completion, the investigator can present or publish trial results. A copy is submitted to the sponsor for review and comment at least 30 days in advance of any presentation or submission for publication.

The sponsor can require to delay the communication for a period not exceeding 90 days to allow for filing a patent application or such other measures as sponsor deems appropriate to establish and preserve its proprietary rights.

Results Point of Contact:

Name/Title: Trial Transparency Team
Organization: sanofi-aventis
e-mail: Contact_US@sanofi.com

Publications of Results:

Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum Á, Blomström P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacrétaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbüchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsányi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2268-76. doi: 10.1056/NEJMoa1109867. Epub 2011 Nov 14. Erratum in: N Engl J Med. 2012 Feb 16;366(7):672.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hohnloser SH, Halperin JL, Camm AJ, Gao P, Radzik D, Connolly SJ; PALLAS investigators. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1019-25. doi: 10.1161/CIRCEP.114.002046. Epub 2014 Nov 6.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT01151137 History of Changes
Other Study ID Numbers:	EFC11405 2010-019791-73 ( EudraCT Number ) U1111-1116-5566 ( Other Identifier: UTN )
Study First Received:	June 22, 2010
Results First Received:	September 14, 2012
Last Updated:	October 23, 2012
Health Authority:	United States: Food and Drug Administration

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