Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia

• Sponsor: ECOG-ACRIN Cancer Research Group (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01013961
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Locations: 102
• Arms: 2
• Actual Duration (Months): 54.4
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer killing substances to them. Giving rituximab together with alemtuzumab may kill more cancer cells.

PURPOSE: This randomized phase II trial is studying two different doses of rituximab to compare how well they work when given together with alemtuzumab in treating older patients with progressive chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Biological: alemtuzumab; Biological: rituximab	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To compare the rate of complete and overall response in elderly patients with progressive chronic lymphocytic leukemia (CLL) treated with one of two doses of rituximab combined with alemtuzumab to determine if the use of modified-dose rituximab significantly affects outcome.

Secondary

• To monitor and assess toxicity of these regimens.

• To determine the overall and progression-free survival, time to clinical response, time to next treatment, and duration of response in patients treated with these regimens

• To assess the correlation between risk stratification prognostic markers (i.e., CD38, ZAP-70, fluorescent in situ hybridization (FISH), and IgVH mutation) and clinical outcome.

• To assess response to these regimens using both the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria and an expanded definition of response for patients in complete remission, including immunohistochemical examination of the bone marrow and sensitive flow cytometry (4-6 color) of blood for minimal residual disease and computed tomography (CT) scans for residual adenopathy.

• To determine the mechanism of action of rituximab and alemtuzumab and to determine mechanisms of resistance of a subpopulation of CLL cells to these drugs.

OUTLINE: This is a multicenter study. Patients are stratified according to FISH risk (low [13q14-] vs intermediate [12+, no abnormality, all other abnormalities] vs high [17p13-,11q22-]). Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles.

• Arm B: Patients receive alemtuzumab as in arm A. Patients also receive low-dose rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 and on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in cycless 2 and 3. Treatment repeats every 28 days for up to 3 cycles.

Blood and bone marrow samples are collected periodically for cytogenetic and biomarker analysis.

Alemtuzumab dose for Cycle 1 Week 1 of both Arms A and B requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1).

After completion of study therapy, patients are followed up periodically for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized Trial Comparing Standard and Low Dose Rituximab: Initial Treatment of Progressive Chronic Lymphocytic Leukemia in Elderly Patients Using Alemtuzumab and Rituximab
• Actual Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Apr 14, 2015
• Actual Study Completion Date: Apr 14, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A (standard dose) Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Biological: alemtuzumab; Given IV; Biological: rituximab; Given IV
Experimental: Arm B (low dose) Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Biological: alemtuzumab; Given IV; Biological: rituximab; Given IV

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients With Complete Response (CR) [Assessed after 2 cycles of treatment and 2 months after completion of therapy]

   Response was evaluated using NCI-WG96 criteria. A CR requires all of the following for >= 2 months: Absence of lymphadenopathy > 1 cm in diameter by physical examination No hepatomegaly or splenomegaly on physical exam No constitutional symptoms Normal complete blood count (CBC) Patients achieving a clinical CR with negative CT scan after 2 cycles of therapy are re-evaluated using immunohistochemical examination of bone marrow biopsy for residual CLL cells. Patients with no evidence of residual disease and no radiological evidence of residual CLL on CT scan of chest-abdomen-pelvis and no clinical evidence of CLL on clinical evaluation after completion of 2 cycles of therapy will be considered to have a CR with no evidence of residual disease

2. Proportion of Patients With Overall Response (OR) [Assessed after 2 cycles of treatment and 2 months after completion of therapy]

   OR is defined as either CR, clinical CR, or partial response (PR) evaluated by NCI-WG96 criteria. CR has been defined in the other primary endpoint. A clinical CR requires all of the following: Absence of lymphadenopathy by physical examination No hepatomegaly or splenomegaly. Spleen and/or liver, if considered enlarged at baseline, should not be palpable, due to disease, on physical exam Absence of constitutional symptoms Normal CBC as exhibited by: A PR requires all the following for ≥2 months: ≥50% decrease in peripheral blood lymphocyte count from baseline ≥50% reduction in lymphadenopathy ≥50% reduction in size of liver and/or spleen Polymorphonuclear leukocytes ≥1.5x10^9/L or 50% improvement over baseline Platelets >100x10^9/L or 50% improvement over baseline Hemoglobin >11.0 gm/dl or 50% improvement over baseline without transfusions Any constitutional symptoms

Secondary Outcome Measures

1. Overall Survival (OS) [Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years]

   OS is defined to be time from randomization to death from any cause. Those still alive are censored at the date of last contact.

2. Progression-free Survival (PFS) [Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years]

   PFS is defined to be time from randomization to progression (PD) or to death without documentation of progression. For patients without PD, follow-up is censored at the date of last disease assessment without PD, unless death occurs within three months following the date last known progression free. PD is characterized by at least one of the following: ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart (at least 1 node must be >2 cm). Appearance of new palpable lymph nodes (>1 cm in diameter). ≥50% increase in the size of liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly which was not previously present. Absolute number of circulating lymphocytes with a count of >5x10^9/L Transformation to a more aggressive histology

3. Time to Response [Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years]

   Time to response is defined to be time from randomization to first confirmed CR, PR or clinical CR. Those without confirmed CR, PR or clinical CR are censored at the date of last disease assessment.

4. Duration of Response [Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years]

   Duration of response is defined to be time from first confirmed CR, PR or clinical CR to progression or to death without documentation of progression. Patients without confirmed CR, PR or clinical CR are censored at time 0. Those without documentation of progression are censored at the date of last disease assessment without progression, unless death occurs within three months following the date last known progression free.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:

• Minimum threshold peripheral lymphocyte count of 5 x 10^9/L (CLL variant) OR palpable adenopathy > 1 cm or palpable splenomegaly 9small lymphocytic lymphoma [SLL] variant)

• Immunophenotypic demonstrations of a population of B-lymphocytes (as defined by CD19+) that are monoclonal (by light-chain exclusion) AND have ≥ 3 of the following characteristics:

• CD5+

• CD23+

• Dim surface light chain expression

• Dim surface CD20 expression

• FISH analysis is negative for immunoglobulin heavy chain/cyclin D1 gene (IGH/CCND1) and/or immunostaining is negative for cyclin D1 expression (to exclude mantle cell lymphoma)

• Progressive, symptomatic CLL, defined by at least one of the following:

• Weight loss > 10% within the past 6 months attributable to progressive CLL (grade 2 or higher)

• Extreme fatigue attributable to progressive CLL (grade 3 or higher)

• Fevers > 100.5° F for 2 weeks without evidence of infection (grade 1 or higher)

• Night sweats without evidence of infection (drenching)

• Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10^9/L

• Rapidly progressive lymphadenopathy for which the largest node is ≤ 5 cm in any dimension

• Largest lymph nodes involved in the neck, axilla, and groin need to be measured and followed for response

Exclusion Criteria:

• Prior treatment for CLL

• Massive splenomegaly > 6 cm below left costal margin, at rest, on clinical examination

• Lymphadenopathy > 5 cm in any diameter

• New York Heart Association class III or IV heart disease

• Recent myocardial infarction (within the past month)

• Uncontrolled infection

• Infection with the human immunodeficiency virus (HIV/AIDS)

• Serological evidence of active hepatitis B infection (HBsAg or HBeAg positive)

• Positive hepatitis C serology

• Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia

• Other active primary malignancy requiring treatment or that limits survival to ≤ 2 years, except for in situ carcinoma of the cervix or breast or non-metastatic basal cell or squamous cell carcinoma of the skin

• Major surgery within 4 weeks prior to pre-registration

• Concomitant use of continuous systemic corticosteroids

• Prior corticosteroids are allowed but not at time of pre-registration to the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
3	Ella Milbank Foshay Cancer Center at Jupiter Medical Center	Jupiter	Florida	United States	33458
4	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
5	Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler	Savannah	Georgia	United States	31405
6	Rush-Copley Cancer Care Center	Aurora	Illinois	United States	60504
7	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
8	St. Joseph Medical Center	Bloomington	Illinois	United States	61701
9	Graham Hospital	Canton	Illinois	United States	61520
10	Illinois CancerCare - Canton	Canton	Illinois	United States	61520
11	Illinois CancerCare - Carthage	Carthage	Illinois	United States	62321
12	Memorial Hospital	Carthage	Illinois	United States	62321
13	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
14	Eureka Community Hospital	Eureka	Illinois	United States	61530
15	Illinois CancerCare - Eureka	Eureka	Illinois	United States	61530
16	Galesburg Clinic, PC	Galesburg	Illinois	United States	61401
17	Illinois CancerCare - Havana	Havana	Illinois	United States	62644
18	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois	United States	61443
19	Illinois CancerCare - Macomb	Macomb	Illinois	United States	61455
20	McDonough District Hospital	Macomb	Illinois	United States	61455
21	Illinois CancerCare - Monmouth	Monmouth	Illinois	United States	61462
22	OSF Holy Family Medical Center	Monmouth	Illinois	United States	61462
23	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
24	Community Cancer Center	Normal	Illinois	United States	61761
25	Illinois CancerCare - Community Cancer Center	Normal	Illinois	United States	61761
26	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
27	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
28	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois	United States	61554
29	Illinois CancerCare - Pekin	Pekin	Illinois	United States	61603
30	Proctor Hospital	Peoria	Illinois	United States	61614
31	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
32	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
33	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
34	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
35	Illinois CancerCare - Peru	Peru	Illinois	United States	61354
36	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
37	Illinois CancerCare - Princeton	Princeton	Illinois	United States	61356
38	Swedish-American Regional Cancer Center	Rockford	Illinois	United States	61104-2315
39	Illinois CancerCare - Spring Valley	Spring Valley	Illinois	United States	61362
40	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
41	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana	United States	46107
42	Reid Hospital & Health Care Services	Richmond	Indiana	United States	47374
43	McFarland Clinic, PC	Ames	Iowa	United States	50010
44	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa	United States	52403
45	Mercy Regional Cancer Center at Mercy Medical Center	Cedar Rapids	Iowa	United States	52403
46	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
47	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
48	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51102
49	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
50	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana	United States	71315-3198
51	Hematology-Oncology Clinic	Baton Rouge	Louisiana	United States	70809
52	Feist-Weiller Cancer Center at Louisiana State University Health Sciences	Shreveport	Louisiana	United States	71130-3932
53	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
54	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
55	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
56	Upper Michigan Cancer Center at Marquette General Hospital	Marquette	Michigan	United States	49855
57	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
58	Central Care Cancer Center at Carrie J. Babb Cancer Center	Bolivar	Missouri	United States	65613
59	Skaggs Cancer Center at Skaggs Regional Medical Center	Branson	Missouri	United States	65616
60	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
61	Goldschmidt Cancer Center	Jefferson City	Missouri	United States	65109
62	Mercy Clinic Cancer and Hematology - Rolla	Rolla	Missouri	United States	65401
63	Phelps County Regional Medical Center	Rolla	Missouri	United States	65401
64	Missouri Baptist Cancer Center	Saint Louis	Missouri	United States	63131
65	CCOP - Cancer Research for the Ozarks	Springfield	Missouri	United States	65802
66	St. John's Regional Health Center	Springfield	Missouri	United States	65804
67	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
68	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
69	Randolph Hospital	Asheboro	North Carolina	United States	27203-5400
70	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina	United States	27534
71	Moses Cone Regional Cancer Center at Wesley Long Community Hospital	Greensboro	North Carolina	United States	27403-1198
72	Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
73	Kinston Medical Specialists	Kinston	North Carolina	United States	28501
74	Annie Penn Cancer Center	Reidsville	North Carolina	United States	27320
75	Iredell Memorial Hospital	Statesville	North Carolina	United States	28677
76	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota	United States	58501
77	Mid Dakota Clinic, PC	Bismarck	North Dakota	United States	58501
78	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota	United States	58502
79	Aultman Cancer Center at Aultman Hospital	Canton	Ohio	United States	44710-1799
80	Grandview Hospital	Dayton	Ohio	United States	45405
81	Good Samaritan Hospital	Dayton	Ohio	United States	45406
82	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
83	Samaritan North Cancer Care Center	Dayton	Ohio	United States	45415
84	CCOP - Dayton	Dayton	Ohio	United States	45420
85	Blanchard Valley Medical Associates	Findlay	Ohio	United States	45840
86	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
87	Wayne Hospital	Greenville	Ohio	United States	45331
88	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
89	St. Rita's Medical Center	Lima	Ohio	United States	45801
90	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
91	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385
92	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
93	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
94	Mercy Hospital Cancer Center - Scranton	Scranton	Pennsylvania	United States	18501
95	Hematology and Oncology Associates of Northeastern Pennsylvania	Scranton	Pennsylvania	United States	18510
96	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
97	U.T. Medical Center Cancer Institute	Knoxville	Tennessee	United States	37920-6999
98	Danville Regional Medical Center	Danville	Virginia	United States	24541
99	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin	United States	53038
100	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601
101	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
102	Riverview UW Cancer Center at Riverview Hospital	Wisconsin Rapids	Wisconsin	United States	54494

Sponsors and Collaborators

• ECOG-ACRIN Cancer Research Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Clive S. Zent, MD, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ECOG-ACRIN Cancer Research Group
• ClinicalTrials.gov Identifier: NCT01013961
• Other Study ID Numbers: E1908; E1908; U10CA180794
• First Posted: Nov 16, 2009
• Last Update Posted: Jan 14, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by ECOG-ACRIN Cancer Research Group: chronic lymphocytic leukemia; small lymphocytic lymphoma; CLL; elderly; low dose rituximab; alemtuzumab; monoclonal antibodies
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Alemtuzumab

Study Results

Participant Flow

Recruitment Details	This study was activated on October 8, 2010 and closed on October 31, 2013 with a total of 31 patients accrued.
Pre-assignment Detail	Peripheral blood (preferred) or bone marrow must be submitted at pre-registration for FISH risk analysis to determine stratification factor before randomization.

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Period Title: Overall Study
STARTED	16	15
COMPLETED	13	12
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)	Total
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Total of all reporting groups
Overall Participants	16	15	31
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	77	76	76
Sex: Female, Male (Count of Participants)
Female	6 37.5%	7 46.7%	13 41.9%
Male	10 62.5%	8 53.3%	18 58.1%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients With Complete Response (CR)
Description	Response was evaluated using NCI-WG96 criteria. A CR requires all of the following for >= 2 months: Absence of lymphadenopathy > 1 cm in diameter by physical examination No hepatomegaly or splenomegaly on physical exam No constitutional symptoms Normal complete blood count (CBC) Patients achieving a clinical CR with negative CT scan after 2 cycles of therapy are re-evaluated using immunohistochemical examination of bone marrow biopsy for residual CLL cells. Patients with no evidence of residual disease and no radiological evidence of residual CLL on CT scan of chest-abdomen-pelvis and no clinical evidence of CLL on clinical evaluation after completion of 2 cycles of therapy will be considered to have a CR with no evidence of residual disease
Time Frame	Assessed after 2 cycles of treatment and 2 months after completion of therapy

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Measure Participants	16	15
Number (95% Confidence Interval) [proportion of participants]	0.5 3.1%	0.4 2.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Standard Dose), Arm B (Low Dose)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.722
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	Proportion of Patients With Overall Response (OR)
Description	OR is defined as either CR, clinical CR, or partial response (PR) evaluated by NCI-WG96 criteria. CR has been defined in the other primary endpoint. A clinical CR requires all of the following: Absence of lymphadenopathy by physical examination No hepatomegaly or splenomegaly. Spleen and/or liver, if considered enlarged at baseline, should not be palpable, due to disease, on physical exam Absence of constitutional symptoms Normal CBC as exhibited by: A PR requires all the following for ≥2 months: ≥50% decrease in peripheral blood lymphocyte count from baseline ≥50% reduction in lymphadenopathy ≥50% reduction in size of liver and/or spleen Polymorphonuclear leukocytes ≥1.5x10^9/L or 50% improvement over baseline Platelets >100x10^9/L or 50% improvement over baseline Hemoglobin >11.0 gm/dl or 50% improvement over baseline without transfusions Any constitutional symptoms
Time Frame	Assessed after 2 cycles of treatment and 2 months after completion of therapy

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Measure Participants	16	15
Number (95% Confidence Interval) [proportion of participants]	0.875 5.5%	0.933 6.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Standard Dose), Arm B (Low Dose)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined to be time from randomization to death from any cause. Those still alive are censored at the date of last contact.
Time Frame	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Measure Participants	16	15
Median (95% Confidence Interval) [months]	NA	NA

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined to be time from randomization to progression (PD) or to death without documentation of progression. For patients without PD, follow-up is censored at the date of last disease assessment without PD, unless death occurs within three months following the date last known progression free. PD is characterized by at least one of the following: ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart (at least 1 node must be >2 cm). Appearance of new palpable lymph nodes (>1 cm in diameter). ≥50% increase in the size of liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly which was not previously present. Absolute number of circulating lymphocytes with a count of >5x10^9/L Transformation to a more aggressive histology
Time Frame	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Measure Participants	16	15
Median (95% Confidence Interval) [months]	12.8	23.3

5. Secondary Outcome

Title	Time to Response
Description	Time to response is defined to be time from randomization to first confirmed CR, PR or clinical CR. Those without confirmed CR, PR or clinical CR are censored at the date of last disease assessment.
Time Frame	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Measure Participants	16	15
Median (95% Confidence Interval) [months]	4.8	4.7

6. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined to be time from first confirmed CR, PR or clinical CR to progression or to death without documentation of progression. Patients without confirmed CR, PR or clinical CR are censored at time 0. Those without documentation of progression are censored at the date of last disease assessment without progression, unless death occurs within three months following the date last known progression free.
Time Frame	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A (Standard Dose)	Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
Measure Participants	16	15
Median (95% Confidence Interval) [months]	9.8	16.8

Adverse Events

Time Frame	Assessed every 4 weeks while on treatment and for 30 days after the end of treatment
Arm/Group Title	Arm A (Standard Dose)		Arm B (Low Dose)
Arm/Group Description	Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.		Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
All Cause Mortality
	Arm A (Standard Dose)		Arm B (Low Dose)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (Standard Dose)		Arm B (Low Dose)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/16 (100%)		15/15 (100%)
Blood and lymphatic system disorders
Anemia	1/16 (6.3%)		1/15 (6.7%)
Febrile neutropenia	2/16 (12.5%)		1/15 (6.7%)
Gastrointestinal disorders
Mucositis oral	1/16 (6.3%)		0/15 (0%)
General disorders
Fatigue	2/16 (12.5%)		1/15 (6.7%)
Immune system disorders
Serum sickness	0/16 (0%)		1/15 (6.7%)
Infections and infestations
Lung infection	0/16 (0%)		1/15 (6.7%)
Tooth infection	1/16 (6.3%)		0/15 (0%)
Investigations
Lipase increased	1/16 (6.3%)		0/15 (0%)
Lymphocyte count decreased	16/16 (100%)		15/15 (100%)
Lymphocyte count increased	3/16 (18.8%)		6/15 (40%)
Neutrophil count decreased	12/16 (75%)		7/15 (46.7%)
Platelet count decreased	3/16 (18.8%)		1/15 (6.7%)
Weight loss	1/16 (6.3%)		0/15 (0%)
White blood cell decreased	11/16 (68.8%)		9/15 (60%)
Investigations - Other, specify	0/16 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
Hyponatremia	1/16 (6.3%)		1/15 (6.7%)
Nervous system disorders
Nervous system disorders - Other	1/16 (6.3%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/16 (0%)		2/15 (13.3%)
Other (Not Including Serious) Adverse Events
	Arm A (Standard Dose)		Arm B (Low Dose)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/16 (100%)		15/15 (100%)
Blood and lymphatic system disorders
Anemia	16/16 (100%)		14/15 (93.3%)
Cardiac disorders
Atrial fibrillation	0/16 (0%)		1/15 (6.7%)
Gastrointestinal disorders
Mucositis oral	2/16 (12.5%)		0/15 (0%)
Nausea	3/16 (18.8%)		0/15 (0%)
Vomiting	2/16 (12.5%)		0/15 (0%)
General disorders
Chills	3/16 (18.8%)		1/15 (6.7%)
Fatigue	8/16 (50%)		7/15 (46.7%)
Fever	3/16 (18.8%)		2/15 (13.3%)
Injection site reaction	2/16 (12.5%)		1/15 (6.7%)
Malaise	0/16 (0%)		1/15 (6.7%)
Immune system disorders
Allergic reaction	0/16 (0%)		1/15 (6.7%)
Infections and infestations
Bladder infection	0/16 (0%)		1/15 (6.7%)
Mucosal infection	1/16 (6.3%)		0/15 (0%)
Sinusitis	1/16 (6.3%)		0/15 (0%)
Urinary tract infection	1/16 (6.3%)		0/15 (0%)
Infections and infestations - Other	2/16 (12.5%)		4/15 (26.7%)
Investigations
Alanine aminotransferase increased	0/16 (0%)		1/15 (6.7%)
Aspartate aminotransferase increased	1/16 (6.3%)		1/15 (6.7%)
Blood bilirubin increased	0/16 (0%)		1/15 (6.7%)
CD4 lymphocytes decreased	0/16 (0%)		1/15 (6.7%)
Creatinine increased	1/16 (6.3%)		1/15 (6.7%)
Lymphocyte count decreased	6/16 (37.5%)		11/15 (73.3%)
Lymphocyte count increased	7/16 (43.8%)		7/15 (46.7%)
Neutrophil count decreased	9/16 (56.3%)		8/15 (53.3%)
Platelet count decreased	11/16 (68.8%)		10/15 (66.7%)
Weight loss	1/16 (6.3%)		0/15 (0%)
White blood cell decreased	13/16 (81.3%)		15/15 (100%)
Metabolism and nutrition disorders
Anorexia	2/16 (12.5%)		3/15 (20%)
Hyperglycemia	0/16 (0%)		1/15 (6.7%)
Hypoalbuminemia	0/16 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/16 (6.3%)		1/15 (6.7%)
Myalgia	1/16 (6.3%)		0/15 (0%)
Pain in extremity	0/16 (0%)		2/15 (13.3%)
Nervous system disorders
Dizziness	1/16 (6.3%)		1/15 (6.7%)
Dysgeusia	1/16 (6.3%)		0/15 (0%)
Headache	1/16 (6.3%)		0/15 (0%)
Presyncope	0/16 (0%)		1/15 (6.7%)
Tremor	1/16 (6.3%)		0/15 (0%)
Psychiatric disorders
Confusion	1/16 (6.3%)		0/15 (0%)
Renal and urinary disorders
Chronic kidney disease	1/16 (6.3%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/16 (6.3%)		0/15 (0%)
Dyspnea	1/16 (6.3%)		1/15 (6.7%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	3/16 (18.8%)		1/15 (6.7%)
Vascular disorders
Hypotension	1/16 (6.3%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.