ORIOLE: Stereotactic Body Radiation for Prostate Oligometastases

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02680587
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 80
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 83.1
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Men with oligometastatic prostate cancer lesions will be randomized (1:2) to observation versus SBRT. The study will NOT be blinded. Within three weeks of the initial treatment planning, SBRT (1-5 fractions) will be administered.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer; Oligometastases	Radiation: SBRT	Phase 2

Detailed Description

This research is being done to determine if we can improve the outcome of prostate cancer patients who have failed primary treatment - surgery or local radiation to the prostate - and have 3 or fewer bone metastases. Patients with metastatic prostate cancer disease will usually be placed on hormonal therapy which can work well for a period of time, but hormonal therapy can have side effects that greatly trouble men. Any effort to delay the start of hormonal therapy would be an advantage to the patient. Radiation treatment usually takes many weeks to deliver and is not given in a high enough doses to metastases to prevent them from coming back locally. Stereotactic body radiation therapy (SBRT) is highly focused radiation, given in a very dose intensive fashion and delivered in usually less than one week. Stereotactic body radiation has been shown to be very effective on bone metastases. Therefore, we are studying the effects of stereotactic body radiation treatment on patients with five or fewer prostate cancer bone metastases to determine if we can stall the use of hormonal therapy and/or prevent other bone metastases from developing elsewhere in the body.

Additionally, fundamental analysis of the oligometastatic state with be achieved through correlation with investigational DCFPyL-positron emission tomography (PET) imaging, which can help us find cancer that has spread (metastatic disease) from its original site in people who have cancer in their prostate to other parts of their body.

Specifically, 54 men with biochemically recurrent, oligometastatic prostate adenocarcinoma will be accrued across 3 centers in the United States. Patients were stratified by primary intervention (surgery vs radiotherapy), prior hormonal therapy, and PSA doubling time, then randomized 2:1 to SBRT or observation. The primary clinical endpoint is progression at 6 months from randomization with the hypothesis that SBRT to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints include local control at 6 months post-SBRT, SBRT-associated toxicity and quality of life, and ADT-free survival (ADT-FS).

Alterations in the biology of the oligometastatic state induced by stereotactic ablative radiotherapy (SABR) will be investigated using leading-edge correlatives, including: analysis of circulating tumor cells (CTCs; Epic Sciences, San Diego, CA), deep sequencing of circulating tumor DNA (ctDNA) using Cancer Personalized Profiling by deep sequencing (CAPP-Seq) to non-invasively assess tumor burden, and ImmunoSEQ profiling of T-cell repertoires to elucidate the immunological response to SABR (Adaptive Technologies, Seattle, WA). Lastly, the use of the Color Genomics platform (Burlingame, CA), a hereditary cancer assay assessing pathogenic mutations in 30 cancer predisposition genes that account for >90% of the germline mutations known to occur in men with castrate resistant metastatic prostate cancer (mCRPC), will help inform and allow for efforts to advance a more personalized medicine approach to tailor screening and therapies in these men.

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Randomized Observation Versus Stereotactic Ablative RadiatIOn for OLigometastatic Prostate CancEr (ORIOLE) Trial
• Actual Study Start Date: Apr 28, 2016
• Actual Primary Completion Date: Aug 30, 2018
• Anticipated Study Completion Date: Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Observational (no SBRT) Men with oligometastatic prostate cancer lesions randomized to observation
Experimental: SBRT Men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT).	Radiation: SBRT; SBRT (1-5 fractions) will be administered.; Other Names: Stereotactic Body Radiation Stereotactic Ablative Radiotherapy

Outcome Measures

Primary Outcome Measures

1. Progression at 6 Months [6 months]

   Number of participants who progressed at 6 months. Progression is defined as either: 1) a ≥ 25% increase in PSA from nadir (and by ≥ 2 ng/mL), requiring confirmation ≥ 4 weeks later (PCWG2 criteria); and/or, 2) clinical/radiographic-progression defined as symptomatic progression (worsening disease-related symptoms or new cancer-related complications), or radiologic progression (on CT scan: ≥ 20% enlargement in sum diameter of soft-tissue target lesions [RECIST1.1 criteria]; on bone scan: ≥ 1 new bone lesions),initiation of ADT or death due to any cause, whichever occurs first.

Secondary Outcome Measures

1. Time to Local Progression [up to 6 months]

   Number of months until local progression in patients with oligometastatic disease.

2. Local Control of SBRT Group [6 months]

   Number of lesions that did not increase in size by at least 20% or more on CT from baseline to 6 months.

3. Toxicity as Assessed by Number of Participants With Adverse Events Grade 3 or Higher [up to 6 months]

   Number of participants experiencing adverse events Grade 3 or higher, as defined by CTCAE.

4. Toxicity as Assessed by Number of Participants With Adverse Events Grades 1 or 2 [up to 6 months]

   Number of participants experiencing adverse events Grades 1 or 2, as defined by CTCAE

5. Change in Quality of Life as Assessed by Brief Pain Inventory [Baseline and 6 months]

   We will assess quality of life following completion of Stereotactic Body Radiation Therapy via Brief Pain Inventory questionnaire made up of 9 questions. Each question scores from 0-10, with higher scores mean worse outcome or more pain. An overall score, calculated by adding the scores for questions 2, 3, 4 and 5 and then dividing by 4, will be calculated pre-treatment and at the time of day 180. The change in score (between baseline and 6 months) will be evaluated.

6. Change of DCFPyL-PET/MRI Positive Lesions [6 months]

   18F-DCFPyL Positron Emission Tomography (PET)/MRI or -PET/CT positive sites that are positive for new or progressive metastatic disease by bone scan/CT at 6-months following SBRT.

7. Change in Survival of Two Groups as Assessed by PSA Level [Baseline and 6 months]

   The PSA levels in blood will be measured in units of nanograms per milliliter (ng/mL).

8. Androgen Deprivation Therapy-free Survival [6 month]

   Androgen Deprivation Therapy-free survival will be assessed using the number of participants deceased at 6 months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the bone or soft tissue develop within the past 6-months that are ≤ 5.0 cm or <250 cm3.

• Patient must have had their primary tumor treated with surgery and/or radiation.

• Histologic confirmation of malignancy (primary or metastatic tumor).

• PSADT <15 months. PSA doubling time (PSADT) will be calculated using as many PSA values that are available from time of relapse (PSA > 0.2). To calculate PSADT, the Memorial Sloan Kettering Cancer Center Prostate Cancer

Prediction Tool will be used. It can be found at the following web site:

https://www.mskcc.org/nomograms/prostate/psa-doubling-time.

• Patient may have had prior systemic therapy and/or ADT associated with treatment of their primary prostate cancer. Patient may have had ADT associated with salvage radiation therapy (to the primary prostate cancer or pelvis is allowed).

• PSA >1 but <50.

• Testosterone > 125 ng/dL.

• Patient must have a life expectancy ≥ 12 months.

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• Patient must have normal organ and marrow function as defined as:

Leukocytes >2,000/μL Absolute Neutrophil Count >1,000/μL Platelets >50,000/μL

• Patient must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• No more than 3 years of ADT is allowed, with the most recent ADT treatment having occurred greater than 6 months prior to enrollment.

• DCFPyL-PET/MRI or DCFPyL-PET/CT scan within the past 6 months with results that demonstrate more disease lesions than baseline CT/Bone Scan

• Castration-resistant prostate cancer (CRPC).

• Suspected pulmonary and/or liver metastases (greater >10 mm in largest axis).

• Patient receiving any other investigational agents.

• Patient is participating in a concurrent treatment protocol.

• Total bilirubin > 3 times the upper limit of normal.

• Liver Transaminases > 5-times the upper limit of normal.

• Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT.

• Liver Transaminases > 5-times the upper limit of normal.

• Prior salvage treatment to the primary prostate cancer or pelvis is allowed.

• Refusal to sign informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Phuoc Tran, M.D., Johns Hopkins Department of Radiation Oncology and Molecular Radiation Sciences

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 11, 2017

More Information

Additional Information:

• Gleason Score Description

Publications

• Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, Rowe SP, Ross AE, Gorin MA, Deville C, Greco SC, Wang H, Denmeade SR, Paller CJ, Dipasquale S, DeWeese TL, Song DY, Wang H, Carducci MA, Pienta KJ, Pomper MG, Dicker AP, Eisenberger MA, Alizadeh AA, Diehn M, Tran PT. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):650-659. doi: 10.1001/jamaoncol.2020.0147.
• Radwan N, Phillips R, Ross A, Rowe SP, Gorin MA, Antonarakis ES, Deville C, Greco S, Denmeade S, Paller C, Song DY, Diehn M, Wang H, Carducci M, Pienta KJ, Pomper MG, DeWeese TL, Dicker A, Eisenberger M, Tran PT. A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE). BMC Cancer. 2017 Jun 29;17(1):453. doi: 10.1186/s12885-017-3455-6.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT02680587
• Other Study ID Numbers: J15180; IRB00079078
• First Posted: Feb 11, 2016
• Last Update Posted: Dec 22, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Prostate Cancer; Stereotactic Body Radiation Therapy; Stereotactic Ablative Radiotherapy; Oligometastasis
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Pre-assignment Detail	26 Excluded from 80, these are: 19 Did not meet inclusion criteria; 5 Declined to participate; 2 Insurance denied

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Period Title: Overall Study
STARTED	18	36
COMPLETED	17	36
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Observational (no SBRT)	SBRT	Total
Arm/Group Description	Evaluating males with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patients will not receive SBRT. They will be observed.	Evaluating males with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.	Total of all reporting groups
Overall Participants	18	36	54
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	68	68	68
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	18 100%	36 100%	54 100%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	18 100%	36 100%	54 100%
Initial T stage (extent of the tumor) (Count of Participants)
cT1c	1 5.6%	3 8.3%	4 7.4%
cT2a	0 0%	2 5.6%	2 3.7%
cT2b	1 5.6%	0 0%	1 1.9%
cT3a	1 5.6%	1 2.8%	2 3.7%
pT2	6 33.3%	12 33.3%	18 33.3%
pT3a	8 44.4%	10 27.8%	18 33.3%
pT3b	1 5.6%	8 22.2%	9 16.7%
Initial N stage (extent of spread to the lymph nodes (Count of Participants)
N0	16 88.9%	31 86.1%	47 87%
N1	1 5.6%	2 5.6%	3 5.6%
NX	1 5.6%	3 8.3%	4 7.4%
Tumor margin status (Count of Participants)
R0	10 55.6%	20 55.6%	30 55.6%
R1	5 27.8%	10 27.8%	15 27.8%
Not applicable	3 16.7%	6 16.7%	9 16.7%
Gleason score (Count of Participants)
3+3=6	0 0%	3 8.3%	3 5.6%
3+4=7	4 22.2%	8 22.2%	12 22.2%
4+3=7	4 22.2%	14 38.9%	18 33.3%
4+4=8	1 5.6%	4 11.1%	5 9.3%
4+5=9	8 44.4%	4 11.1%	12 22.2%
5+4=9	0 0%	3 8.3%	3 5.6%
5+5=10	1 5.6%	0 0%	1 1.9%
Initial management (Count of Participants)
Surgery	15 83.3%	30 83.3%	45 83.3%
Radiotherapy	3 16.7%	6 16.7%	9 16.7%
Time to first recurrence (month) [Median (Full Range) ]
Median (Full Range) [month]	22	22	22
Had received prior ADT (Count of Participants)
Count of Participants [Participants]	5 27.8%	28 77.8%	33 61.1%
Baseline prostate-specific antigen (PSA) (ng/dl) [Median (Full Range) ]
Median (Full Range) [ng/dl]	7	6	6
Baseline prostate-specific antigen doubling time (PSADT) (months) [Median (Full Range) ]
Median (Full Range) [months]	6	8	8

Outcome Measures

1. Primary Outcome

Title	Progression at 6 Months
Description	Number of participants who progressed at 6 months. Progression is defined as either: 1) a ≥ 25% increase in PSA from nadir (and by ≥ 2 ng/mL), requiring confirmation ≥ 4 weeks later (PCWG2 criteria); and/or, 2) clinical/radiographic-progression defined as symptomatic progression (worsening disease-related symptoms or new cancer-related complications), or radiologic progression (on CT scan: ≥ 20% enlargement in sum diameter of soft-tissue target lesions [RECIST1.1 criteria]; on bone scan: ≥ 1 new bone lesions),initiation of ADT or death due to any cause, whichever occurs first.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	18	36
Count of Participants [Participants]	11 61.1%	7 19.4%

2. Secondary Outcome

Title	Time to Local Progression
Description	Number of months until local progression in patients with oligometastatic disease.
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	18	36
Median (Full Range) [Months]	5.8	6

3. Secondary Outcome

Title	Local Control of SBRT Group
Description	Number of lesions that did not increase in size by at least 20% or more on CT from baseline to 6 months.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected from the Observation arm.

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	0	36
Measure lesions	0	89
Number [lesions]	89

4. Secondary Outcome

Title	Toxicity as Assessed by Number of Participants With Adverse Events Grade 3 or Higher
Description	Number of participants experiencing adverse events Grade 3 or higher, as defined by CTCAE.
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	18	36
3 months	0 0%	0 0%
6 months	0 0%	0 0%

5. Secondary Outcome

Title	Toxicity as Assessed by Number of Participants With Adverse Events Grades 1 or 2
Description	Number of participants experiencing adverse events Grades 1 or 2, as defined by CTCAE
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

2 from observation group discontinued intervention because of progression prior to 90 days.

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	16	36
3 month	11 61.1%	30 83.3%
6 month	3 16.7%	15 41.7%

6. Secondary Outcome

Title	Change in Quality of Life as Assessed by Brief Pain Inventory
Description	We will assess quality of life following completion of Stereotactic Body Radiation Therapy via Brief Pain Inventory questionnaire made up of 9 questions. Each question scores from 0-10, with higher scores mean worse outcome or more pain. An overall score, calculated by adding the scores for questions 2, 3, 4 and 5 and then dividing by 4, will be calculated pre-treatment and at the time of day 180. The change in score (between baseline and 6 months) will be evaluated.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	18	36
Median (Inter-Quartile Range) [score on a scale]	0	0

7. Secondary Outcome

Title	Change of DCFPyL-PET/MRI Positive Lesions
Description	18F-DCFPyL Positron Emission Tomography (PET)/MRI or -PET/CT positive sites that are positive for new or progressive metastatic disease by bone scan/CT at 6-months following SBRT.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome measure

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	0	0

8. Secondary Outcome

Title	Change in Survival of Two Groups as Assessed by PSA Level
Description	The PSA levels in blood will be measured in units of nanograms per milliliter (ng/mL).
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Data was not collected

Arm/Group Title	SBRT	Observational (no SBRT)
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.
Measure Participants	0	0

9. Secondary Outcome

Title	Androgen Deprivation Therapy-free Survival
Description	Androgen Deprivation Therapy-free survival will be assessed using the number of participants deceased at 6 months.
Time Frame	6 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observational (no SBRT)	SBRT
Arm/Group Description	Men with oligometastatic prostate cancer lesions randomized to observation	Men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
Measure Participants	18	36
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	up to 6 months
Arm/Group Title	Observational (no SBRT)		SBRT
Arm/Group Description	Evaluating men with oligometastatic prostate cancer lesions randomized to observation Observational (no SBRT): These patient will not receive SBRT. They will be observed.		Evaluating men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT). SBRT: SBRT (1-5 fractions) will be administered.
All Cause Mortality
	Observational (no SBRT)		SBRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/36 (0%)
Serious Adverse Events
	Observational (no SBRT)		SBRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Observational (no SBRT)		SBRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/18 (77.8%)		36/36 (100%)
Gastrointestinal disorders
Constipation	0/18 (0%)	0	1/36 (2.8%)	1
Ascites	0/18 (0%)	0	1/36 (2.8%)	1
Esophageal pain	0/18 (0%)	0	1/36 (2.8%)	1
Perineal pain	0/18 (0%)	0	1/36 (2.8%)	1
Pruritis	1/18 (5.6%)	1	0/36 (0%)	0
Diarrhea	0/18 (0%)	0	2/36 (5.6%)	2
Constipation	0/18 (0%)	0	2/36 (5.6%)	2
Hemorrhoids	0/18 (0%)	0	1/36 (2.8%)	1
Bloating	0/18 (0%)	0	1/36 (2.8%)	1
Gastritis	0/18 (0%)	0	1/36 (2.8%)	1
Nausea	0/18 (0%)	0	1/36 (2.8%)	1
Esophagitis	0/18 (0%)	0	1/36 (2.8%)	1
General disorders
Fatigue	1/18 (5.6%)	1	1/36 (2.8%)	1
Anorexia	1/18 (5.6%)	1	0/36 (0%)	0
Weight loss	0/18 (0%)	0	1/36 (2.8%)	1
Weight gain	0/18 (0%)	0	1/36 (2.8%)	1
Dry mouth	0/18 (0%)	0	1/36 (2.8%)	1
Insomnia	0/18 (0%)	0	1/36 (2.8%)	1
Fatigue	1/18 (5.6%)	1	5/36 (13.9%)	5
Localized Edema	1/18 (5.6%)	1	2/36 (5.6%)	2
Tremor	1/18 (5.6%)	1	0/36 (0%)	0
Weight Loss	0/18 (0%)	0	2/36 (5.6%)	2
Anemia	0/18 (0%)	0	1/36 (2.8%)	1
Dizziness	0/18 (0%)	0	1/36 (2.8%)	1
Dehydration	0/18 (0%)	0	1/36 (2.8%)	1
Nervous system disorders
Neuralgia	0/18 (0%)	0	1/36 (2.8%)	1
Neuralgia	0/18 (0%)	0	1/36 (2.8%)	1
Psychiatric disorders
Depression	0/18 (0%)	0	1/36 (2.8%)	1
Anxiety	1/18 (5.6%)	1	2/36 (5.6%)	2
Depression	1/18 (5.6%)	1	0/36 (0%)	0
Renal and urinary disorders
Urinary Incontinence	1/18 (5.6%)	1	1/36 (2.8%)	1
Urinary retention	0/18 (0%)	0	1/36 (2.8%)	1
Bladder infection	0/18 (0%)	0	1/36 (2.8%)	1
Urinary Incontinence	2/18 (11.1%)	2	2/36 (5.6%)	2
Urinary Retention	1/18 (5.6%)	1	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/18 (0%)	0	1/36 (2.8%)	1
Cough	0/18 (0%)	0	3/36 (8.3%)	3
Skin and subcutaneous tissue disorders
Bruising	0/18 (0%)	0	1/36 (2.8%)	1
Bruising	2/18 (11.1%)	2	0/36 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.