Zoledronate With or Without Thalidomide in Treating Patients With Early Stage Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00432458
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 68
• Locations: 4
• Arms: 2
• Duration (Months): 105
• Patients Per Site: 17
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Zoledronate may prevent bone loss and stop the growth of cancer cells in bone. Thalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. It is not yet know whether giving zoledronate together with thalidomide is more effective than zoledronate alone in treating multiple myeloma.

PURPOSE: This randomized phase III trial is studying zoledronate and thalidomide see how well they work compared with zoledronate alone in treating patients with early stage multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: Thalidomide; Drug: zoledronic acid	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare time to progression in patients with early stage multiple myeloma treated with zoledronate with or without thalidomide.

Secondary

• Compare the response rate, 1-year progression-free survival rate, duration of response, and time to next therapy in patients treated with these regimens.

• Assess differences in toxicity of these regimens in these patients.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to the presence of lytic lesions on metastatic bone survey (yes vs no), beta-2 microglobulin level (high vs normal), and bone marrow labeling index (high [> 1.0%] vs low [≤ 1.0%]). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral thalidomide on days 1-28. Treatment with thalidomide repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive zoledronate IV over 15 minutes on day 1. Treatment with zoledronate repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity.

Blood samples are collected for research studies at baseline and after courses 3, 6, 9, and 12. Bone marrow aspirates are performed at baseline and after courses 6 and 12. Samples are evaluated for bone marrow angiogenesis; vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2 expression; bone marrow angiogenesis-VEGF relationship; bone marrow angiogenesis/apoptosis rate relationship; bone marrow angiogenesis/plasma cell (PC) proliferation rate relationship; VEGF expression/apoptosis rate relationship; and VEGFR expression/PC proliferation rate relationship.

After completion of study treatment, patients are followed every 6 months for up to 5 years.

PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Trial of Thalidomide Plus Zoledronic Acid Versus Zoledronic Acid Alone in Patients With Early Stage Multiple Myeloma
• Study Start Date: Jul 1, 2003
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I: Thal/ZLD Thalidomide (Thal) + Zolendronic acid (ZLD)	Drug: Thalidomide; 200 mg orally on days 1-28 of 28 day cycle; Drug: zoledronic acid; 4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter
Experimental: Arm II: ZLD Zoledronic acid (ZLD)	Drug: zoledronic acid; 4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter

Outcome Measures

Primary Outcome Measures

1. Time to Disease Progression (TTP) [randomization to progression (up to 5 years)]

   Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated.

Secondary Outcome Measures

1. 12-month Progression-free Survival (PFS) [12 months]

   PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization.

2. Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment [12 months]

   Response is defined as follows: CR: Complete disappearance of M-protein from serum & urine on immunofixation, <5% plasma cells in bone marrow (BM) VGPR: >=90% reduction in serum M-component; Urine M-Component <100 mg per 24 hours; <=5% plasma cells in BM PR: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels

3. Duration of Response (Complete Response, Partial Response, and Very Good Partial Response) [time from start of response to progression (up to 5 years)]

   Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method

4. Time to Subsequent Treatment [time from end of treatment to subsequent treatment (up to 5 years)]

   Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method

5. Time to Treatment Failure [time from randomization to treatment failure (up to 5 years)]

   Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method

6. Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events [During treatment (up to 5 years)]

   Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of multiple myeloma (MM)

• Previously untreated asymptomatic disease

• No requirement for immediate chemotherapy for active MM, such as hypercalcemia from myeloma or painful bone lesions

• No solitary plasmacytoma

• Measurable or evaluable disease as defined by one of the following:

• Serum monoclonal protein ≥ 1.0 g by protein electrophoresis

• More than 200 mg of monoclonal protein in the urine by 24-hour electrophoresis

• Measurable soft tissue plasmacytoma by physical exam with ruler or by MRI or positron emission tomography/CT scan

• If the only measurable lesion is the plasmacytoma, it must be ≥ 1.5 cm in 1 dimension

• Must have ≥ 10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index

• No amyloidosis

PATIENT CHARACTERISTICS:

• Performance status 0-2

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 8.0 g/dL

• Creatinine ≤ 2.0 mg/dL (elevation above normal range should not be felt to be related to myeloma)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and for 4 weeks after completion of study treatment

• No uncontrolled infection

• No other active malignancy

• No New York Heart Association class III or IV heart disease

• No pre-existing neuropathy ≥ grade 2

• No concurrent major dental work

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Prior corticosteroids (for nonmalignant disorders) allowed

• Prior therapy with experimental agents not shown to have significant activity in MM, such as clarithromycin, dehydroepiandrosterone, and anakinra allowed

• No prior thalidomide or corticosteroids for MM

• No more than 3 doses of IV zoledronate or pamidronate within the past 12 months

• At least 3 months since prior radiotherapy, including radiotherapy for solitary plasmacytoma

• No concurrent oral bisphosphonate therapy for osteoporosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
3	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Thomas E. Witzig, MD, Mayo Clinic
• Principal Investigator: Craig Reeder, M.D., Mayo Clinic
• Principal Investigator: Vivek Roy, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00432458
• Other Study ID Numbers: CDR0000530050; P30CA015083; MC0289; 421-03
• First Posted: Feb 7, 2007
• Last Update Posted: Jul 4, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Mayo Clinic: stage I multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Zoledronic Acid; Thalidomide

Study Results

Participant Flow

Recruitment Details	Sixty-eight (68) participants were recruited at Mayo Clinic (Rochester) and Memorial Sloan-Kettering between July 2003 and March 2009.
Pre-assignment Detail	All 68 participants were randomized.

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Period Title: Overall Study
STARTED	35	33
COMPLETED	30	32
NOT COMPLETED	5	1

Baseline Characteristics

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD	Total
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)	Total of all reporting groups
Overall Participants	35	33	68
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	63	63
Sex: Female, Male (Count of Participants)
Female	13 37.1%	14 42.4%	27 39.7%
Male	22 62.9%	19 57.6%	41 60.3%
Region of Enrollment (participants) [Number]
United States	35 100%	33 100%	68 100%
Beta-2 Microglobulin (participants) [Number]
High (> upper limit of normal)	29 82.9%	26 78.8%	55 80.9%
Normal (<= upper limit of normal)	6 17.1%	7 21.2%	13 19.1%
Lytic Bone Lesions (participants) [Number]
Present	2 5.7%	2 6.1%	4 5.9%
Not Present	33 94.3%	31 93.9%	64 94.1%
Bone Marrow Labeling Index (participants) [Number]
High (> 1.0%)	3 8.6%	3 9.1%	6 8.8%
Low (<= 1.0%)	31 88.6%	30 90.9%	61 89.7%
Not Applicable	1 2.9%	0 0%	1 1.5%
Anemia (participants) [Number]
< lower limit of normal	14 40%	18 54.5%	32 47.1%
>= lower limit of normal	21 60%	15 45.5%	36 52.9%
Peripheral blood circulating plasma cells (participants) [Number]
Yes	13 37.1%	14 42.4%	27 39.7%
No	20 57.1%	18 54.5%	38 55.9%
Not Applicable	1 2.9%	0 0%	1 1.5%
Not Done	1 2.9%	1 3%	2 2.9%

Outcome Measures

1. Primary Outcome

Title	Time to Disease Progression (TTP)
Description	Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated.
Time Frame	randomization to progression (up to 5 years)

Outcome Measure Data

Analysis Population Description

Time to disease progression was analyzed on all randomized participants on an intent to treat basis.

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	35	33
Median (95% Confidence Interval) [years]	2.4	1.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I: Thal/ZLD, Arm II: ZLD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Log Rank
	Comments	Model was stratified by beta-2 microglobulin (high vs low), lytic bone lesions (present vs not) and bone marrow labeling index (high vs low)

2. Secondary Outcome

Title	12-month Progression-free Survival (PFS)
Description	PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	35	33
Number [participants]	30 85.7%	18 54.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I: Thal/ZLD, Arm II: ZLD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0048
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment
Description	Response is defined as follows: CR: Complete disappearance of M-protein from serum & urine on immunofixation, <5% plasma cells in bone marrow (BM) VGPR: >=90% reduction in serum M-component; Urine M-Component <100 mg per 24 hours; <=5% plasma cells in BM PR: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	35	33
Number [participants]	13 37.1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I: Thal/ZLD, Arm II: ZLD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Duration of Response (Complete Response, Partial Response, and Very Good Partial Response)
Description	Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method
Time Frame	time from start of response to progression (up to 5 years)

Outcome Measure Data

Analysis Population Description

Participants who achieved a confirmed response (CR, VGPR, or PR) as described above were analyzed.

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	13	0
Median (95% Confidence Interval) [years]	3.3

5. Secondary Outcome

Title	Time to Subsequent Treatment
Description	Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method
Time Frame	time from end of treatment to subsequent treatment (up to 5 years)

Outcome Measure Data

Analysis Population Description

This data was not (and will never be) analyzed as it was not submitted consistently across all participants.

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	0	0

6. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method
Time Frame	time from randomization to treatment failure (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	35	33
Median (95% Confidence Interval) [months]	16.5	11.1

7. Secondary Outcome

Title	Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events
Description	Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death
Time Frame	During treatment (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Thal/ZLD	Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)	Zoledronic acid (ZLD)
Measure Participants	35	33
Number [participants]	17 48.6%	13 39.4%

Adverse Events

Arm/Group Title	Arm I: Thal/ZLD		Arm II: ZLD
Arm/Group Description	Thalidomide (Thal) + Zolendronic acid (ZLD)		Zoledronic acid (ZLD)
All Cause Mortality
	Arm I: Thal/ZLD		Arm II: ZLD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I: Thal/ZLD		Arm II: ZLD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/35 (8.6%)		1/33 (3%)
Ear and labyrinth disorders
Vertigo	1/35 (2.9%)	1	0/33 (0%)	0
Infections and infestations
Infection without neutropenia	1/35 (2.9%)	2	0/33 (0%)	0
Renal and urinary disorders
Ureteral Obstruction	1/35 (2.9%)	1	0/33 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/35 (2.9%)	1	0/33 (0%)	0
Dyspnea	1/35 (2.9%)	1	0/33 (0%)	0
Pulmonary	0/35 (0%)	0	1/33 (3%)	2
Other (Not Including Serious) Adverse Events
	Arm I: Thal/ZLD		Arm II: ZLD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/35 (100%)		28/33 (84.8%)
Blood and lymphatic system disorders
Anemia	2/35 (5.7%)	2	1/33 (3%)	5
Cardiac disorders
Cardiovascular	1/35 (2.9%)	1	0/33 (0%)	0
Ischemia/Infarction	2/35 (5.7%)	2	0/33 (0%)	0
Sinus bradycardia	2/35 (5.7%)	3	0/33 (0%)	0
Supraventricular arrhythmias (SVT/atrial fibrillation/flutter)	2/35 (5.7%)	2	0/33 (0%)	0
Ventricular arrhythmia	2/35 (5.7%)	2	0/33 (0%)	0
Ear and labyrinth disorders
Otitis External	0/35 (0%)	0	1/33 (3%)	1
Eye disorders
Conjunctivitis	1/35 (2.9%)	1	0/33 (0%)	0
Vision	0/35 (0%)	0	1/33 (3%)	2
Gastrointestinal disorders
Colitis	1/35 (2.9%)	1	0/33 (0%)	0
Constipation	22/35 (62.9%)	189	6/33 (18.2%)	29
Gastrointestinal disorder	1/35 (2.9%)	1	0/33 (0%)	0
General disorders
Fatigue	27/35 (77.1%)	133	20/33 (60.6%)	64
Fever-No ANC	1/35 (2.9%)	1	3/33 (9.1%)	3
Pain	2/35 (5.7%)	2	1/33 (3%)	1
Rigors	2/35 (5.7%)	2	0/33 (0%)	0
Infections and infestations
Infection	1/35 (2.9%)	1	0/33 (0%)	0
Infection without neutropenia	8/35 (22.9%)	12	2/33 (6.1%)	4
Investigations
Aspartate aminotransferase increased	1/35 (2.9%)	1	0/33 (0%)	0
CD4 lymphocytes decreased	1/35 (2.9%)	3	0/33 (0%)	0
CPK (creatine phosphokinase)	0/35 (0%)	0	1/33 (3%)	3
Creatinine	0/35 (0%)	0	2/33 (6.1%)	2
Leukopenia	3/35 (8.6%)	13	0/33 (0%)	0
Lymphopenia	2/35 (5.7%)	12	1/33 (3%)	1
Neutropenia	13/35 (37.1%)	59	2/33 (6.1%)	6
Prothrombin Time	1/35 (2.9%)	1	1/33 (3%)	1
Metabolism and nutrition disorders
Hyperglycemia	2/35 (5.7%)	4	0/33 (0%)	0
Hypocalcemia	0/35 (0%)	0	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/35 (2.9%)	1	0/33 (0%)	0
Bone pain	0/35 (0%)	0	2/33 (6.1%)	2
Musculoskeletal	1/35 (2.9%)	2	0/33 (0%)	0
Myalgia	1/35 (2.9%)	1	2/33 (6.1%)	2
Nervous system disorders
Ataxia	2/35 (5.7%)	2	0/33 (0%)	0
Depressed level of consciousness	18/35 (51.4%)	48	1/33 (3%)	1
Dizziness	2/35 (5.7%)	2	1/33 (3%)	1
Headache	1/35 (2.9%)	1	0/33 (0%)	0
Ischemia-Cerebral	1/35 (2.9%)	1	1/33 (3%)	1
Neuro-Cranial	1/35 (2.9%)	1	0/33 (0%)	0
Peripheral motor neuropathy	4/35 (11.4%)	5	0/33 (0%)	0
Peripheral sensory neuropathy	28/35 (80%)	304	6/33 (18.2%)	10
Seizure	1/35 (2.9%)	1	0/33 (0%)	0
Syncope	3/35 (8.6%)	5	0/33 (0%)	0
Tremor	1/35 (2.9%)	3	1/33 (3%)	1
Vasovagal Episode	1/35 (2.9%)	1	0/33 (0%)	0
Psychiatric disorders
Depression	1/35 (2.9%)	1	0/33 (0%)	0
Insomnia	0/35 (0%)	0	1/33 (3%)	1
Renal and urinary disorders
Ureteral Obstruction	1/35 (2.9%)	1	0/33 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/35 (2.9%)	1	0/33 (0%)	0
Skin and subcutaneous tissue disorders
Rash/Desquamation	10/35 (28.6%)	24	8/33 (24.2%)	10
Rash/dermatitis associated with high-dose chemotherapy or BMT studies.	0/35 (0%)	0	1/33 (3%)	1
Vascular disorders
Thrombosis	1/35 (2.9%)	1	1/33 (3%)	2

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.