Nexavar® Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer

This study is ongoing, but not recruiting participants.

Sponsor:

Collaborator:

Amgen

Information provided by (Responsible Party):

Bayer

ClinicalTrials.gov Identifier:

NCT00984282

First received: September 24, 2009

Last updated: January 13, 2017

Last verified: January 2017

History of Changes

Results First Received: August 19, 2013

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Thyroid Neoplasms
Interventions:	Drug: Sorafenib (Nexavar, BAY43-9006) Drug: Placebo

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
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 556 enrolled participants, 137 failed screening, 209 were randomized to receive sorafenib, 210 were randomized to placebo. One participant was never treated (placebo) and 2 were randomized by mistake (sorafenib) then re-randomized with different subject numbers. Therefore, 207 participants received sorafenib and 209 received placebo.

Reporting Groups

	Description
DB Sorafenib First, Then Option of OL Sorafenib Treatment	Double-blind period: Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle. Open-label (OL) period: Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle.
DB Placebo First, Then Option of OL Sorafenib Treatment	Double-blind period: participants received matching placebo tablets orally twice daily, 28 days comprised a cycle. Open-label (OL) period: participants on placebo who switched to sorafenib, received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle.

Participant Flow for 3 periods

Period 1: Double Blind Treatment

	DB Sorafenib First, Then Option of OL Sorafenib Treatment	DB Placebo First, Then Option of OL Sorafenib Treatment
STARTED	207	210
Received Treatment	207 ^[1]	209 ^[2]
COMPLETED	103	172
NOT COMPLETED	104	38
Adverse Event	38	6
Progression, recurrence or relapse	24	3
Physician Decision	1	2
Noncompliance with study medication	3	0
Progression by clinical judgment	1	0
Withdrawal by Subject	14	18
Lost to Follow-up	3	0
Death	8	4
Not treated	0	1
Switched to follow-up	12	4

^[1]	Subjects at Risk/Safety Population - in RG1 (RG= Reporting Group for Safety Data)
^[2]	Subjects at Risk/Safety Population - in RG2 (RG= Reporting Group for Safety Data)

Period 2: Open-label Treatment

	DB Sorafenib First, Then Option of OL Sorafenib Treatment	DB Placebo First, Then Option of OL Sorafenib Treatment
STARTED	86	161
Received Treatment	86 ^[1]	161 ^[2]
COMPLETED	0	0
NOT COMPLETED	86	161
Adverse Event	17	29
Withdrawal by Subject	6	21
Death	5	15
Progression, recurrence or relapse	37	77
Lost to Follow-up	1	0
Ongoing with treatment	19	18
Non-compliant with study medication	1	0
Target lesion removed	0	1

^[1]	Subjects at Risk/Safety Population - in RG3 (RG= Reporting Group for Safety Data)
^[2]	Subjects at Risk/Safety Population - in RG4 (RG= Reporting Group for Safety Data)

Period 3: Long Term Follow-up

	DB Sorafenib First, Then Option of OL Sorafenib Treatment	DB Placebo First, Then Option of OL Sorafenib Treatment
STARTED	114 ^[1]	117 ^[1]
COMPLETED	0	0
NOT COMPLETED	114	117
Withdrawal by Subject	18	15
Death	55	72
Lost to Follow-up	8	4
Ongoing with treatment	33	26

^[1]	Participants entered long-term follow-up if terminated double-blind or open-label periods

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
Sorafenib (Nexavar, BAY43-9006)	Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle.
Placebo	Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle.
Total	Total of all reporting groups

Baseline Measures

Sorafenib (Nexavar, BAY43-9006)

Placebo

Total

Overall Participants Analyzed
[Units: Participants]

207

210

417

Age
[Units: Years]
Mean (Standard Deviation)

61.5 (11.2)

62.0 (11.7)

61.8 (11.4)

Age, Customized
[Units: Participants]

< 60 years

161

>= 60 years

127

129

256

Gender
[Units: Participants]
Count of Participants

Female

103 49.8%

115 54.8%

218 52.3%

Male

104 50.2%

95 45.2%

199 47.7%

Geographic region
[Units: Participants]

Europe

124

125

249

North America

Asia

ECOG (Eastern Cooperative Oncology Group) performance status ^[1]
[Units: Participants]

Missing

130

129

259

143

^[1]	The ECOG PS required for the study was 0 (fully active), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), or 2 (ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours)

Site of target/nontarget lesions at baseline - organ class ^[1]
[Units: Participants]

Lung

178

181

359

Lymph node

113

101

214

Bone

113

^[1]	Participants could have had more than one site.

Outcome Measures

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1. Primary:

Progression-free Survival (PFS) Based on Central Assessment Incl. Clinical Progression Due to Bone Irradiation [ Time Frame: Final analysis to be performed when approximately 267 progression-free survival events (centrally assessed) had occurred, study duration approximately three years ]

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2. Secondary:

Overall Survival (OS) [ Time Frame: From randomization of the first subject until the database cut-off (14 Jul 2015), study duration approximately six years ]

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3. Secondary:

Time to Progression (TTP) Based on Central Assessment Incl. Clinical Progression Due to Bone Irradiation [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]

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4. Secondary:

Disease Control Rate (DCR) Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]

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5. Secondary:

Response Rate Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]

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6. Secondary:

Duration of Response (DOR) Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]

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7. Secondary:

Maximum Percent Reduction in Target Lesion Size Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]

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8. Secondary:

AUC(0-12h),ss (Area Under the Concentration Time Curve From Time 0 to 12 Hours at Steady State) [ Time Frame: A single pharmacokinetic plasma sample was collected at steady state (after 14 days of uninterrupted, unmodified sorafenib dosing) ]

Show Outcome Measure 8

Serious Adverse Events

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Other Adverse Events

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Time Frame	Adverse event data were collected after signing the informed consent until the database cut-off (14 Jul 2015), study duration approximately six years
Additional Description	Abbreviations used: Gastrointestinal (GI), Common Terminology Criteria for Adverse Events (CTCAE), Not Otherwise Specified (NOS), Absolute Neutrophil Count (ANC), Central Nervous System (CNS), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Cranial Nerve (CN), Range of Motion (ROM), Cerebrospinal Fluid (CSF), Genitourinary (GU).

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Sorafenib (Double Blind Only)	Reporting Group 1: Participants received 2 tablets of Sorafenib (2x200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle. Data were collected from randomization to the end of double blind period
Placebo (Double Blind Only)	Reporting Group 2: Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle. Data were collected from randomization to the end of double-blind period.
Sorafenib, Open Label Only (Sorafenib Continued)	Reporting Group 3: Participants on sorafenib who continued OL sorafenib treat., received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle. Data were collected from the start of OL period to the data cutoff on 31 Aug
Placebo, Open Label Only (Switch to Sorafenib)	Reporting Group 3: Participants on placebo who switched to sorafenib, received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle. Data were collected from the start of open label period to the data cutoff on 31 Aug 20

Other Adverse Events

	Sorafenib (Double Blind Only)	Placebo (Double Blind Only)	Sorafenib, Open Label Only (Sorafenib Continued)	Placebo, Open Label Only (Switch to Sorafenib)
Total, Other (not including serious) Adverse Events
# participants affected / at risk	202/207 (97.58%)	173/209 (82.78%)	72/86 (83.72%)	159/161 (98.76%)
Blood and lymphatic system disorders
Blood - Other ^* 1
# participants affected / at risk	6/207 (2.90%)	6/209 (2.87%)	5/86 (5.81%)	9/161 (5.59%)
Edema: Limb ^* 1
# participants affected / at risk	13/207 (6.28%)	6/209 (2.87%)	8/86 (9.30%)	8/161 (4.97%)
Hemoglobin ^* 1
# participants affected / at risk	18/207 (8.70%)	10/209 (4.78%)	8/86 (9.30%)	26/161 (16.15%)
Leukocytes ^* 1
# participants affected / at risk	9/207 (4.35%)	4/209 (1.91%)	5/86 (5.81%)	8/161 (4.97%)
Lymphopenia ^* 1
# participants affected / at risk	7/207 (3.38%)	6/209 (2.87%)	0/86 (0.00%)	10/161 (6.21%)
Platelets ^* 1
# participants affected / at risk	8/207 (3.86%)	2/209 (0.96%)	3/86 (3.49%)	10/161 (6.21%)
Cardiac disorders
Hypertension ^* 1
# participants affected / at risk	85/207 (41.06%)	28/209 (13.40%)	8/86 (9.30%)	50/161 (31.06%)
Gastrointestinal disorders
Anorexia ^* 1
# participants affected / at risk	67/207 (32.37%)	11/209 (5.26%)	5/86 (5.81%)	48/161 (29.81%)
Constipation ^* 1
# participants affected / at risk	32/207 (15.46%)	18/209 (8.61%)	4/86 (4.65%)	27/161 (16.77%)
Diarrhea ^* 1
# participants affected / at risk	142/207 (68.60%)	32/209 (15.31%)	21/86 (24.42%)	97/161 (60.25%)
Dry mouth ^* 1
# participants affected / at risk	16/207 (7.73%)	8/209 (3.83%)	2/86 (2.33%)	7/161 (4.35%)
Dysphagia ^* 1
# participants affected / at risk	14/207 (6.76%)	9/209 (4.31%)	5/86 (5.81%)	12/161 (7.45%)
GI - Other ^* 1
# participants affected / at risk	9/207 (4.35%)	4/209 (1.91%)	2/86 (2.33%)	9/161 (5.59%)
Heartburn ^* 1
# participants affected / at risk	10/207 (4.83%)	10/209 (4.78%)	0/86 (0.00%)	13/161 (8.07%)
Mucositis (functional/symptomatic), Oral cavity ^* 1
# participants affected / at risk	49/207 (23.67%)	7/209 (3.35%)	6/86 (6.98%)	40/161 (24.84%)
Nausea ^* 1
# participants affected / at risk	43/207 (20.77%)	25/209 (11.96%)	9/86 (10.47%)	50/161 (31.06%)
Taste Alteration ^* 1
# participants affected / at risk	16/207 (7.73%)	0/209 (0.00%)	0/86 (0.00%)	11/161 (6.83%)
Vomiting ^* 1
# participants affected / at risk	23/207 (11.11%)	13/209 (6.22%)	2/86 (2.33%)	17/161 (10.56%)
General disorders
Fatigue ^* 1
# participants affected / at risk	102/207 (49.28%)	52/209 (24.88%)	18/86 (20.93%)	67/161 (41.61%)
Fever ^* 1
# participants affected / at risk	22/207 (10.63%)	10/209 (4.78%)	8/86 (9.30%)	21/161 (13.04%)
Flu-like syndrome ^* 1
# participants affected / at risk	18/207 (8.70%)	10/209 (4.78%)	2/86 (2.33%)	11/161 (6.83%)
Insomnia ^* 1
# participants affected / at risk	14/207 (6.76%)	6/209 (2.87%)	4/86 (4.65%)	15/161 (9.32%)
Pain, Abdomen NOS ^* 1
# participants affected / at risk	30/207 (14.49%)	10/209 (4.78%)	5/86 (5.81%)	30/161 (18.63%)
Pain, Back ^* 1
# participants affected / at risk	24/207 (11.59%)	21/209 (10.05%)	9/86 (10.47%)	14/161 (8.70%)
Pain, Bone ^* 1
# participants affected / at risk	14/207 (6.76%)	18/209 (8.61%)	7/86 (8.14%)	12/161 (7.45%)
Pain, Chest/Thorax NOS ^* 1
# participants affected / at risk	16/207 (7.73%)	5/209 (2.39%)	1/86 (1.16%)	17/161 (10.56%)
Pain, Dental/Teeth/peridontal ^* 1
# participants affected / at risk	11/207 (5.31%)	4/209 (1.91%)	2/86 (2.33%)	10/161 (6.21%)
Pain, Extremity - limb ^* 1
# participants affected / at risk	30/207 (14.49%)	19/209 (9.09%)	3/86 (3.49%)	28/161 (17.39%)
Pain, Head/Headache ^* 1
# participants affected / at risk	38/207 (18.36%)	16/209 (7.66%)	3/86 (3.49%)	24/161 (14.91%)
Pain, Joint ^* 1
# participants affected / at risk	20/207 (9.66%)	14/209 (6.70%)	4/86 (4.65%)	19/161 (11.80%)
Pain, Muscle ^* 1
# participants affected / at risk	20/207 (9.66%)	15/209 (7.18%)	6/86 (6.98%)	11/161 (6.83%)
Pain, Oral cavity ^* 1
# participants affected / at risk	7/207 (3.38%)	2/209 (0.96%)	0/86 (0.00%)	9/161 (5.59%)
Pain, Other ^* 1
# participants affected / at risk	24/207 (11.59%)	16/209 (7.66%)	8/86 (9.30%)	26/161 (16.15%)
Pain, Throat/Pharynx/Larynx ^* 1
# participants affected / at risk	21/207 (10.14%)	8/209 (3.83%)	1/86 (1.16%)	18/161 (11.18%)
Weight loss ^* 1
# participants affected / at risk	102/207 (49.28%)	29/209 (13.88%)	28/86 (32.56%)	75/161 (46.58%)
Immune system disorders
Rhinitis ^* 1
# participants affected / at risk	9/207 (4.35%)	7/209 (3.35%)	2/86 (2.33%)	9/161 (5.59%)
Infections and infestations
Infection - Other ^* 1
# participants affected / at risk	22/207 (10.63%)	12/209 (5.74%)	8/86 (9.30%)	12/161 (7.45%)
Metabolism and nutrition disorders
ALT ^* 1
# participants affected / at risk	26/207 (12.56%)	9/209 (4.31%)	0/86 (0.00%)	15/161 (9.32%)
AST ^* 1
# participants affected / at risk	23/207 (11.11%)	5/209 (2.39%)	1/86 (1.16%)	11/161 (6.83%)
Hypocalcemia ^* 1
# participants affected / at risk	38/207 (18.36%)	11/209 (5.26%)	12/86 (13.95%)	30/161 (18.63%)
Hypokalemia ^* 1
# participants affected / at risk	14/207 (6.76%)	5/209 (2.39%)	4/86 (4.65%)	14/161 (8.70%)
Hypophosphatemia ^* 1
# participants affected / at risk	7/207 (3.38%)	1/209 (0.48%)	0/86 (0.00%)	10/161 (6.21%)
Metabolic/Lab - Other ^* 1
# participants affected / at risk	79/207 (38.16%)	37/209 (17.70%)	19/86 (22.09%)	55/161 (34.16%)
Musculoskeletal and connective tissue disorders
Musculoskeletal - Other ^* 1
# participants affected / at risk	19/207 (9.18%)	9/209 (4.31%)	7/86 (8.14%)	11/161 (6.83%)
Nervous system disorders
Dizziness ^* 1
# participants affected / at risk	14/207 (6.76%)	7/209 (3.35%)	1/86 (1.16%)	12/161 (7.45%)
Mood Alteration, Anxiety ^* 1
# participants affected / at risk	7/207 (3.38%)	6/209 (2.87%)	0/86 (0.00%)	9/161 (5.59%)
Neuropathy: sensory ^* 1
# participants affected / at risk	32/207 (15.46%)	13/209 (6.22%)	4/86 (4.65%)	21/161 (13.04%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1
# participants affected / at risk	34/207 (16.43%)	34/209 (16.27%)	9/86 (10.47%)	21/161 (13.04%)
Dyspnea (Shortness of breath) ^* 1
# participants affected / at risk	30/207 (14.49%)	27/209 (12.92%)	9/86 (10.47%)	24/161 (14.91%)
Pulmonary - Other ^* 1
# participants affected / at risk	7/207 (3.38%)	7/209 (3.35%)	7/86 (8.14%)	7/161 (4.35%)
Voice changes ^* 1
# participants affected / at risk	25/207 (12.08%)	6/209 (2.87%)	2/86 (2.33%)	12/161 (7.45%)
Skin and subcutaneous tissue disorders
Alopecia ^* 1
# participants affected / at risk	141/207 (68.12%)	18/209 (8.61%)	4/86 (4.65%)	96/161 (59.63%)
Dermatology - Other ^* 1
# participants affected / at risk	30/207 (14.49%)	6/209 (2.87%)	11/86 (12.79%)	31/161 (19.25%)
Dry skin ^* 1
# participants affected / at risk	30/207 (14.49%)	12/209 (5.74%)	6/86 (6.98%)	16/161 (9.94%)
Hand-foot skin reaction ^* 1
# participants affected / at risk	158/207 (76.33%)	20/209 (9.57%)	13/86 (15.12%)	109/161 (67.70%)
Pruritus ^* 1
# participants affected / at risk	44/207 (21.26%)	22/209 (10.53%)	3/86 (3.49%)	21/161 (13.04%)
Rash/desquamation ^* 1
# participants affected / at risk	107/207 (51.69%)	25/209 (11.96%)	9/86 (10.47%)	67/161 (41.61%)
Vascular disorders
Hemorrhage pulmonary, Nose ^* 1
# participants affected / at risk	15/207 (7.25%)	2/209 (0.96%)	2/86 (2.33%)	8/161 (4.97%)

*	Events were collected by non-systematic assessment
1	Term from vocabulary, NCI-CTCAE v.3.0

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
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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: The investigator must discuss any publication with the sponsor prior to release and obtain written consent of the sponsor on the intended publication. He/she must send a draft manuscript of the publication 30 days in advance of submission in order to obtain approval prior to submission of the final version for publication. In case of a difference of opinion, the contents will be discussed in order to find a solution which satisfies both parties.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com

Publications of Results:

Worden F, Fassnacht M, Shi Y, Hadjieva T, Bonichon F, Gao M, Fugazzola L, Ando Y, Hasegawa Y, Park DJ, Shong YK, Smit JW, Chung J, Kappeler C, Meinhardt G, Schlumberger M, Brose MS. Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer. Endocr Relat Cancer. 2015 Dec;22(6):877-87. doi: 10.1530/ERC-15-0252.

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

Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, Pacini F, Paschke R, Shong YK, Sherman SI, Smit JW, Chung J, Kappeler C, Peña C, Molnár I, Schlumberger MJ; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014 Jul 26;384(9940):319-28. doi: 10.1016/S0140-6736(14)60421-9. Epub 2014 Apr 24.

Brose MS, Nutting CM, Sherman SI, Shong YK, Smit JW, Reike G, Chung J, Kalmus J, Kappeler C, Schlumberger M. Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer. 2011 Aug 11;11:349. doi: 10.1186/1471-2407-11-349.

Responsible Party:	Bayer
ClinicalTrials.gov Identifier:	NCT00984282 History of Changes
Other Study ID Numbers:	14295 2009-012007-25 ( EudraCT Number )
Study First Received:	September 24, 2009
Results First Received:	August 19, 2013
Last Updated:	January 13, 2017

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