Fludarabine (Fludara®) Plus Alemtuzumab (CAMPATH®, MabCampath®) vs Fludarabine Alone in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00086580
• Collaborator: (none)
• Enrollment: 335
• Locations: 48
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 3, prospective, multicenter, open-label, randomized, controlled study to evaluate and compare the efficacy and safety of fludarabine plus alemtuzumab versus fludarabine alone as second-line therapy for patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). Patients who meet all eligibility criteria and sign the informed consent document may be entered on the study.

Condition or Disease	Intervention/Treatment	Phase
B-Cell Chronic Lymphocytic Leukemia	Biological: FluCAM [Fludara + Campath]; Biological: fludarabine phosphate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 335 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Trial to Evaluate the Efficacy and Safety of Second-Line Therapy With Fludarabine Plus Alemtuzumab vs. Fludarabine Alone in Patients With B-Cell Chronic Lymphocytic Leukemia
• Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination Arm (FluCAM)	Biological: FluCAM [Fludara + Campath]; Phase A: Escalating Doses of alemtuzumab (Campath) Alone Day 1: alemtuzumab 3 mg intravenously (IV) over 2 hours. Day 2: alemtuzumab 10 mg IV over 2 hours if 3 mg was tolerated, else repeat 3 mg daily until tolerated. Day 3: alemtuzumab 30 mg IV over 2 hours if 10 mg was tolerated, else repeat 10 mg daily until tolerated. Participants were allowed 3-14 days to escalate to 30 mg. Once 30 mg was tolerated, the participant had to begin Phase B within 7 days. Phase B: FluCAM Cycle 1: Days 1,2,3 fludarabine phosphate administered at 30 mg/m^2 over 30 minutes IV, followed within 1 hour by alemtuzumab 30 mg IV over 2 hours. A similar schedule is set for Cycles 2 through 6; duration of alemtuzumab infusions vary from 2-6 hours. Each 28-day period is 1 cycle. Fludarabine phosphate dosage is based on participants' body surface area at the beginning of each cycle. FluCAM administered up to a maximum of 6 cycles, based upon participants' response to therapy and toxicity.; Other Names: alemtuzumab fludarabine phosphate Fludara Campath
Active Comparator: Fludarabine Alone	Biological: fludarabine phosphate; Fludarabine phosphate (Fludara) is administered at a dose of 25 mg/m^2 IV over 15 to 30 minutes daily for 5 consecutive days (days 1 through 5) every 28 days (per package instructions). Each 28-day period is 1 cycle. The dose of fludarabine phosphate will be based on the participant's body surface area as calculated at the beginning of each cycle. Participants treated with fludarabine phosphate up to a maximum of 6 cycles, based upon their response to therapy and toxicity.; Other Names: Fludara

Outcome Measures

Primary Outcome Measures

1. Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment [Up to 6 years]

   Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months.

Secondary Outcome Measures

1. Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) [Up to 9 months]

   Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a >= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology.

2. Kaplan-Meier Estimates of Overall Survival Time [Up to 6 years]

   Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months.

3. Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP) [Up to 6 years]

   Time to disease progression was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease as determined by IRRP. Results are stated in months.

4. Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP) [Up to 6 years]

   Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease as determined by IRRP or death due to any cause. Results are stated in months.

5. Kaplan-Meier Estimates for Time to Alternative Therapy [Up to 6 years]

   Time to alternative therapy was defined as the number of days from the date of randomization to the date of first alternative therapy for chronic lymphocytic leukemia (CLL) or death resulting from any cause. Participants who had not received alternative therapy as of the data cutoff date were censored at the last follow-up visit assessment date plus 1 day. Results are stated in months.

6. Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline [Day 0 (baseline)]

   EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).

7. Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment [up to month 6 (end of treatment)]

   EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).

8. Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline [Day 0 (baseline)]

   The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual "thermometer" with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.

9. Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment [up to month 6 (end of treatment)]

   The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual "thermometer" with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.

10. Summary of Participants With Adverse Experiences (AEs) [Up to 6 years]

    Number of participants with adverse events (AEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (4 point scale from 'not related' to 'definitely related'). Categories reported include participant counts for treatment-emergent AEs, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), and deaths. Related AEs for the combination arm can be related to either fludarabine or alemtuzumab.

11. Mean Systemic Clearance (CL) of Fludarabine [month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)]

    Clearance of drug from plasma is affected by the absorption, distribution, metabolism and elimination of the drug. Mean systemic clearance of fludarabine is derived from plasma concentration versus time data.

12. Total Volume of Distribution (Vss) of Fludarabine [month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)]

    The total volume of distribution (Vss) is the apparent volume in which fludarabine is distributed immediately after it has been injected intravenously and equilibrated between plasma and the surrounding tissues. Total volume of distribution (Vss) of fludarabine is derived from plasma concentration versus time data.

13. Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau) [month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)]

    AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (tau).

14. Maximum Plasma Concentration (Cmax) of Fludarabine [month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)]

    Cmax is the maximum plasma concentration of fludarabine observed.

15. Participants With Minimal Residual Disease (MRD) [up to 9 months]

    MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. MRD was assessed in participants with a clinical complete response (CR) or partial response (PR) without recovery of blood counts. MRD represents a very positive outcome.

Other Outcome Measures

1. Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II [Up to 6 years]

   Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage I or II.

2. Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV [Up to 6 years]

   Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage III or IV.

3. Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II [Up to 6 years]

   Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage I or II.

4. Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV [Up to 6 years]

   Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage III or IV.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• A diagnosis of B-cell chronic lymphocytic leukemia (B-CLL); according to the National Cancer Institute Working Group (NCI WG) criteria.

• Relapsed or refractory disease after 1 prior regimen except patients who were refractory to (i.e., progressed on) fludarabine or alemtuzumab therapy. Patients who previously responded (complete response or partial response) to fludarabine or alemtuzumab therapy, but who have relapsed at the time of study entry, may be eligible but response to fludarabine or alemtuzumab therapy must have lasted >12 months (i.e.,

12 months from a documented response to a documented relapse).

• Binet stage A, stage B, or stage C or Rai Stage I through IV disease with evidence of progression as evidenced by the presence of one or more of the following:

1. Evidence of progressive marrow failure as manifested by: 1) a decrease in hemoglobin to <11g/dL, or 2) a decrease in platelet count to <100 x 10^{9/L within the previous 6 months, or 3) a decrease in absolute neutrophil count (ANC) to <1.0 X 10}9/L.

1. Progressive splenomegaly to >2 cm below the left costal margin or other organomegaly.

2. Progressive lymphadenopathy.

3. Progressive lymphocytosis with an increase of 50% over a 2-month period, or an anticipated doubling time of less than 6 months.

• World Health Organization (WHO) performance status (PS) of 0 or 1.

• Life expectancy >12 weeks.

• Anti-cancer therapy, major surgery, or irradiation was completed >3 weeks before randomization in this study. Patient must have recovered from the acute side effects incurred as a result of previous therapy.

• Serum creatinine less than or equal to 2.0 x institutional upper limits of normal (ULN) and calculated creatinine clearance (CrCl) greater than or equal to 30mL/min using the Cockroft and Gault formula.

• Adequate liver function as indicated by a total bilirubin, AST, and ALT less than or equal to 2 x the institutional ULN value, unless directly attributable to the patient's tumor.

• Female patients with childbearing potential must have a negative serum pregnancy test with 2 weeks of first dose of study drug(s). Male and female patients must agree to use an effective contraceptive method while on study treatment, if appropriate, and for a minimum of 6 months following study therapy.

• Signed, written informed consent.

Exclusion Criteria:

• Previously treated with >1 prior regimen for B-CLL.

• Previously treated with a fludarabine plus alemtuzumab (FluCAM) regimen for B-CLL.

• Positive Coombs test and actively hemolyzing.

• Absolute neutrophil count (ANC) <1.5 x 10^{9/L or platelet count <75 x 10}9/L, unless due to bone marrow involvement.

• Medical condition requiring chronic use of pharmacologic doses of oral corticosteroids, i.e. anything other than replacement dose levels.

• History of anaphylaxis following exposure to monoclonal antibodies.

• Use of investigational agents within 6 weeks prior to study randomization.

• Active infection or history of severe infection (grade 4) within 3 months prior to study randomization.

• Known to be human immunodeficiency virus (HIV) positive.

• Autoimmune thrombocytopenia.

• Active second malignancy.

• Known central nervous system (CNS) involvement with B-CLL.

• Other severe, concurrent diseases, including tuberculosis, mental disorders, serious cardiac functional capacity (Class III or IV as defined by the New York Heart Association Classification), severe diabetes, severe hypertension, pulmonary disease (chronic obstructive pulmonary disease [COPD] with hypoxemia), or major organ malfunction (liver, kidney) that could interfere with the patient's ability to participate in the study.

• Pregnant or nursing women.

• Patients that have progressed with more aggressive B-cell cancers such as Richter's syndrome.

• Active hepatitis or a history of prior viral hepatitis B or hepatitis C, or positive hepatitis B serologies without prior immunization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Fort Myers	Florida	United States	33916
2	Medizinische Universitatsklinik Graz	Graz		Austria	8036
3	Universitat Wien AKH, Innere Medizin I	Wien		Austria	1090
4	University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski	Pleven		Bulgaria	5800
5	UMHAT St. Georgi, Hematology Clinic	Plovdiv		Bulgaria	4000
6	Multiprofile Hospital for Active Treatment "Alexandrovska"	Sofia		Bulgaria	1431
7	National Center for Heamtology and Transfusiology	Sofia		Bulgaria	1756
8	Multiprofile Hospital for Active Treatment, St. Marina	Varna		Bulgaria	9010
9	Cancer Care Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
10	Hopital Notre-Dame du CHUM	Montreal	Quebec	Canada	H2L 4M1
11	Clinical Hospital Center Rijeka, Department of Haematology	Rijeka		Croatia	51000
12	Clinical Hospital Merkur	Zagreb		Croatia	10000
13	University Hospital Dubrava	Zagreb		Croatia	10000
14	CHRU - Hopital Claude Huriez	Lille, Cedex		France	59037
15	Charite-Universitatsmedizin Berlin Campus Benjamin-Franklin	Berlin		Germany	12203
16	Charite Universitatsklinikum der Humboldt-Universitat zu Berlin	Berlin		Germany	13353
17	Klinikum der Universitat zu Koln, Klinik 1 fur Innere Medizin	Koln		Germany	50924
18	Robert-Bosch Krankenhaus GmbH	Stuttgart		Germany	70376
19	"Laikon" General Hospital, University of Athens	Goudi	Athens	Greece	11527
20	U.O. Oncologia Medica Azienda Ospedaliera "Pugliese-Ciaccio"	Cantanzaro		Italy	88100
21	Unita Operativa di Medicina Generale Reumatologia e Oncoematologia	Milano		Italy	20132
22	Istituto di Ematologia Dipartmento di Biotechnologie Celluari ed Ematologia, Universita di Roma "La Sapienza"	Rome		Italy	00161
23	Klinika Hematologii i Transplantacji Szpiku	Katowice		Poland	40-027
24	Klinika Hematologii AM	Lodz		Poland	93-513
25	Klinika Hematologii Pomorskiej Akademii Medycznej w Szczecinie	Szczecin		Poland	71-252
26	Katedra i Klinika Hamatologii, Onkologii I Chorob Wewnetrznych AM	Warszawa		Poland	02-097
27	Klinika Hematologii, Nowotworow Krwii 1 Transplantacji Szpiku	Wroclaw		Poland	50-367
28	Hospital de Santa Maria Servico de Hematologia Clinica/Hospital de dia de Hematologia	Lisboa		Portugal	1649-035
29	Hospital de Sao Teotonio, Servico de Hematologia/Hosptial de Dia Oncologico	Viseu		Portugal	3504-509
30	Institutol Clinic Fundeni, Clinica Heamtologie	Bucharest		Romania	022328
31	State Healthcare Department "Sverdlovsk Regional Clinical Hospital #1",	Ekaterinburg,		Russian Federation	620102
32	GU "Main Military Clinical Hospital named after acad. N.N.Burdenko of MO of Russia", Haematology Centre 3	Moscow		Russian Federation	105229
33	GOUVPO "Saint-Petersburg State Medical University named after acad I.P.Pavlov of Roszdrav", Bone Marrow Transplantology Clinic	Saint-Petersburg		Russian Federation	197089
34	Saint-Petersburg GUZ "City Hospital #31" 3, Dynamo Prospect	Saint-Petersburg		Russian Federation	197110
35	University Hospital, Dept. of Hematology	Lund		Sweden	221 85
36	Orebro University Hospital, Dep. of Medicine	Orebro		Sweden	701 85
37	Universitetssjukhuset	Orebro		Sweden	701 85
38	Medicin kliniken/Hematologsektionen	Sundsvall		Sweden	851 86
39	Akademiska sjukhuset	Uppsala		Sweden	751 85
40	Cherkasskly Oncology Dispensary	Cherkasy		Ukraine	79044
41	City Clinical Hospital #4, Regional Hematology Center	Dnepropetrovsk		Ukraine	49102
42	Donetsk State Medical University	Donetsk		Ukraine	83045
43	Kharkov Regional Clinical Oncology Center, Department of Hematology	Kharkov		Ukraine	61070
44	Khmelnitskiy Regional Hospital, Hematology Department	Khmelnitskiy		Ukraine	29000
45	Institute of Oncology AMS of Ukraine	Kiev		Ukraine	03022
46	Institute of Hematology and Transfusiology AMS of Ukraine, City Clinical Hospital #9	Kiev		Ukraine	04112
47	Scientific Centre for Radiation Medicine AMS of Ukraine, Dept of Hematology and Transplantology	Kyiv		Ukraine	03115
48	Lviv National Medical University named Danilo Galytcky	Lviv		Ukraine	79044

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00086580
• Other Study ID Numbers: CAM314; 2004-000149-39
• First Posted: Jul 8, 2004
• Last Update Posted: Mar 13, 2014
• Last Verified: Feb 1, 2014

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine; Fludarabine; Fludarabine phosphate; Alemtuzumab

Study Results

Participant Flow

Pre-assignment Detail	Treatment was from initiation of study drug(s) to 4 weeks after last administration of study drug. Follow-up was for those without disease progression and ended upon disease progression or primary endpoint analysis whichever came first. Observation included those with disease progression who were observed for alternative rx and overall survival.

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Period Title: Treatment Period
STARTED	168	167
Safety Population	164	165
COMPLETED	103	107
NOT COMPLETED	65	60
Period Title: Treatment Period
STARTED	141	137
COMPLETED	37	18
NOT COMPLETED	104	119
Period Title: Treatment Period
STARTED	95	121
COMPLETED	49	56
NOT COMPLETED	46	65

Baseline Characteristics

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone	Total
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.	Total of all reporting groups
Overall Participants	168	167	335
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.0 (9.25)	60.8 (9.34)	60.4 (9.29)
Sex: Female, Male (Count of Participants)
Female	59 35.1%	59 35.3%	118 35.2%
Male	109 64.9%	108 64.7%	217 64.8%
Race/Ethnicity, Customized (participants) [Number]
White	167 99.4%	167 100%	334 99.7%
Other	1 0.6%	0 0%	1 0.3%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	169.0 (8.88)	169.4 (9.30)	169.2 (9.08)
Body Surface Area (BSA) (meters^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters^2]	1.87 (0.213)	1.90 (0.218)	1.88 (0.216)
Maximum Lymph Node Size (participants) [Number]
<5 centimeters	134 79.8%	136 81.4%	270 80.6%
>= 5 centimeters	34 20.2%	31 18.6%	65 19.4%
World Health Organization (WHO) Performance Status (participants) [Number]
WHO Performance Status = 0	81 48.2%	72 43.1%	153 45.7%
WHO Performance Status = 1	87 51.8%	95 56.9%	182 54.3%
Rai Stage Group (participants) [Number]
Rai Stage 0	2 1.2%	2 1.2%	4 1.2%
Rai Stage I - II	104 61.9%	102 61.1%	206 61.5%
Rai Stage III - IV	62 36.9%	63 37.7%	125 37.3%
Binet Stage (participants) [Number]
Binet Stage A	27 16.1%	25 15%	52 15.5%
Binet Stage B	89 53%	89 53.3%	178 53.1%
Binet Stage C	52 31%	53 31.7%	105 31.3%
Disease Status (participants) [Number]
Relapsed	101 60.1%	101 60.5%	202 60.3%
Refractory	67 39.9%	66 39.5%	133 39.7%
Summary of Prior Therapy by Type of Therapy (participants) [Number]
Fludarabine-containing therapy	25 14.9%	26 15.6%	51 15.2%
Non-fludarabine-containing therapy	143 85.1%	141 84.4%	284 84.8%

Outcome Measures

1. Primary Outcome

Title	Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment
Description	Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	167
Median (95% Confidence Interval) [months]	23.65	16.48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments	Cox proportional hazards model was stratified by Rai Stage Group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.610
	Confidence Interval	(2-Sided) 95%; 0.467 to 0.795
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP)
Description	Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a >= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology.
Time Frame	Up to 9 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	167
Overall Response (CR+PR)	137 81.5%	126 75.4%
Complete Response (CR)	21 12.5%	7 4.2%
Partial Response (PR)	116 69%	119 71.3%
Progressive Disease (PD)	6 3.6%	9 5.4%
Stable Disease (SD)	12 7.1%	21 12.6%
Not Evaluable (NE)	13 7.7%	11 6.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments	Comparison of Overall Response.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.178
	Comments	P-value presented is adjusted for multiple tests using Hochberg procedure for 3 clinically important secondary endpoints: ORR, CR rates and OS.
	Method	Cochran-Mantel-Haenszel
	Comments	CMH chi-square test for a difference in overall response rates between treatments stratified by Rai Stage Group.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference and confidence interval (CI) calculated using the recommended method by Altman et al.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments	Comparison of complete response (CR).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	P-value presented is adjusted for multiple tests using Hochberg procedure for 3 clinically important secondary endpoints: ORR, CR rates and OS.
	Method	Cochran-Mantel-Haenszel
	Comments	CMH chi-square test for a difference in complete response rates between treatments stratified by Rai Stage Group.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference and confidence interval (CI) calculated using the recommended method by Altman et al.

3. Secondary Outcome

Title	Kaplan-Meier Estimates of Overall Survival Time
Description	Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	167
Median (95% Confidence Interval) [months]	NA	52.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.042
	Comments	P-value presented is adjusted for multiple tests using Hochberg procedure for 3 clinically important secondary endpoints: ORR, CR rates and OS.
	Method	Regression, Cox
	Comments	Cox proportional hazards model stratified by Rai Stage Group
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.648
	Confidence Interval	(2-Sided) 95%; 0.449 to 0.937
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP)
Description	Time to disease progression was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease as determined by IRRP. Results are stated in months.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	167
Median (95% Confidence Interval) [months]	27.96	18.68

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments	Cox regression model stratified by Rai Stage Group.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.562
	Confidence Interval	(2-Sided) 95%; 0.420 to 0.752
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)
Description	Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease as determined by IRRP or death due to any cause. Results are stated in months.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set of participants who achieved a complete response or a partial response as determined by the IRRP.

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	135	124
Median (95% Confidence Interval) [months]	25.10	19.14

6. Secondary Outcome

Title	Kaplan-Meier Estimates for Time to Alternative Therapy
Description	Time to alternative therapy was defined as the number of days from the date of randomization to the date of first alternative therapy for chronic lymphocytic leukemia (CLL) or death resulting from any cause. Participants who had not received alternative therapy as of the data cutoff date were censored at the last follow-up visit assessment date plus 1 day. Results are stated in months.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	167
Median (95% Confidence Interval) [months]	25.43	22.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Regression, Cox
	Comments	Cox proportional hazards model stratified by Rai Stage Group.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.718
	Confidence Interval	(2-Sided) 95%; 0.543 to 0.951
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline
Description	EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).
Time Frame	Day 0 (baseline)

Outcome Measure Data

Analysis Population Description

Full analysis dataset. Participants who provided valid answers on questionnaires are included.

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	164
Mean (Standard Deviation) [units on a scale]	0.7959 (0.1868)	0.7822 (0.2023)

8. Secondary Outcome

Title	Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment
Description	EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).
Time Frame	up to month 6 (end of treatment)

Outcome Measure Data

Analysis Population Description

Full analysis dataset. Participants who provided valid answers on questionnaires are included.

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	152	147
Mean (Standard Deviation) [units on a scale]	0.8049 (0.2752)	0.7749 (0.2569)

9. Secondary Outcome

Title	Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline
Description	The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual "thermometer" with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.
Time Frame	Day 0 (baseline)

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants who provided valid answers on questionnaires are included.

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	167	161
Mean (Standard Deviation) [units on a scale]	70.9 (18.01)	70.2 (17.24)

10. Secondary Outcome

Title	Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment
Description	The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual "thermometer" with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.
Time Frame	up to month 6 (end of treatment)

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants who provided valid answers on questionnaires are included.

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	152	146
Mean (Standard Deviation) [units on a scale]	77.1 (19.41)	75.7 (17.98)

11. Secondary Outcome

Title	Summary of Participants With Adverse Experiences (AEs)
Description	Number of participants with adverse events (AEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (4 point scale from 'not related' to 'definitely related'). Categories reported include participant counts for treatment-emergent AEs, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), and deaths. Related AEs for the combination arm can be related to either fludarabine or alemtuzumab.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	164	165
At least 1 treatment emergent AE	161 95.8%	149 89.2%
At least 1 related treatment emergent AE	159 94.6%	125 74.9%
At least 1 treatment-emergent infection	67 39.9%	58 34.7%
At least 1 drug-related infection	44 26.2%	30 18%
At least 1 serious AE	54 32.1%	41 24.6%
At least 1 related serious AE	47 28%	28 16.8%
Discontinuation of study drug due to AE	37 22%	32 19.2%
Discontinuation of study drug due to related AE	32 19%	24 14.4%
Deaths	10 6%	12 7.2%
Patients who died due to a related AE	7 4.2%	6 3.6%
Patients who died within 30 days of the last dose	4 2.4%	7 4.2%

12. Secondary Outcome

Title	Mean Systemic Clearance (CL) of Fludarabine
Description	Clearance of drug from plasma is affected by the absorption, distribution, metabolism and elimination of the drug. Mean systemic clearance of fludarabine is derived from plasma concentration versus time data.
Time Frame	month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	17	12
Mean (Standard Deviation) [liters/hour]	9.46 (4.31)	9.54 (3.10)

13. Secondary Outcome

Title	Total Volume of Distribution (Vss) of Fludarabine
Description	The total volume of distribution (Vss) is the apparent volume in which fludarabine is distributed immediately after it has been injected intravenously and equilibrated between plasma and the surrounding tissues. Total volume of distribution (Vss) of fludarabine is derived from plasma concentration versus time data.
Time Frame	month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	17	12
Mean (Standard Deviation) [liters]	117 (64.3)	172 (91.3)

14. Other Pre-specified Outcome

Title	Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II
Description	Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage I or II.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with Rai stage I or II

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	104	102
Median (95% Confidence Interval) [months]	23.75	20.76

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.102
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.750
	Confidence Interval	(2-Sided) 95%; 0.531 to 1.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Other Pre-specified Outcome

Title	Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV
Description	Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage III or IV.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with Rai stage III or IV

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	62	63
Median (95% Confidence Interval) [months]	20.53	11.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.443
	Confidence Interval	(2-Sided) 95%; 0.292 to 0.671
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Other Pre-specified Outcome

Title	Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II
Description	Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage I or II.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with Rai Stage I or II

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	104	102
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.819
	Comments
	Method	Regression, Cox
	Comments	Cox proportional hazards model
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.066
	Confidence Interval	(2-Sided) 95%; 0.619 to 1.836
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Other Pre-specified Outcome

Title	Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV
Description	Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage III or IV.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with Rai Stage III or IV

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	62	63
Median (95% Confidence Interval) [months]	NA	23.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments	Cox proportional hazards model
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.416
	Confidence Interval	(2-Sided) 95%; 0.250 to 0.690
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau)
Description	AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (tau).
Time Frame	month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	17	12
Mean (Standard Deviation) [ng*h/mL]	8203 (6531)	5669 (3888)

19. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Fludarabine
Description	Cmax is the maximum plasma concentration of fludarabine observed.
Time Frame	month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	17	12
Mean (Standard Deviation) [ng/mL]	4084 (6089)	1847 (1637)

20. Secondary Outcome

Title	Participants With Minimal Residual Disease (MRD)
Description	MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. MRD was assessed in participants with a clinical complete response (CR) or partial response (PR) without recovery of blood counts. MRD represents a very positive outcome.
Time Frame	up to 9 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Combination Arm (FluCAM)	Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.	Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Measure Participants	168	167
Number [participants]	6 3.6%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Arm (FluCAM), Fludarabine Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH chi-square test for a difference in response rates between treatments stratified by Rai Stage Group.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 6 years
Adverse Event Reporting Description	In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
Arm/Group Title	Combination Arm (FluCAM)		Fludarabine Alone
Arm/Group Description	Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.		Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
All Cause Mortality
	Combination Arm (FluCAM)		Fludarabine Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Combination Arm (FluCAM)		Fludarabine Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/164 (32.9%)		41/165 (24.8%)
Blood and lymphatic system disorders
Anaemia	1/164 (0.6%)		6/165 (3.6%)
Anaemia haemolytic autoimmune	2/164 (1.2%)		2/165 (1.2%)
Autoimmune neutropenia	1/164 (0.6%)		0/165 (0%)
Autoimmune thrombocytopenia	0/164 (0%)		1/165 (0.6%)
Disseminated intravascular coagulation	0/164 (0%)		1/165 (0.6%)
Febrile neutropenia	5/164 (3%)		7/165 (4.2%)
Haemolytic anaemia	0/164 (0%)		2/165 (1.2%)
Haemolytic uraemic syndrome	0/164 (0%)		1/165 (0.6%)
Leukopenia	4/164 (2.4%)		1/165 (0.6%)
Neutropenia	8/164 (4.9%)		2/165 (1.2%)
Pancytopenia	2/164 (1.2%)		1/165 (0.6%)
Thrombocytopenia	5/164 (3%)		1/165 (0.6%)
Cardiac disorders
Acute myocardial infarction	0/164 (0%)		1/165 (0.6%)
Angina pectoris	1/164 (0.6%)		0/165 (0%)
Cardiac arrest	1/164 (0.6%)		0/165 (0%)
Cardiac failure	0/164 (0%)		2/165 (1.2%)
Cardiogenic shock	0/164 (0%)		1/165 (0.6%)
Cardiopulmonary failure	1/164 (0.6%)		0/165 (0%)
Cardiovascular insufficiency	1/164 (0.6%)		2/165 (1.2%)
Left ventricular dysfunction	1/164 (0.6%)		0/165 (0%)
Pericardial effusion	1/164 (0.6%)		0/165 (0%)
Supraventricular tachycardia	1/164 (0.6%)		1/165 (0.6%)
Eye disorders
Retinopathy	0/164 (0%)		1/165 (0.6%)
Gastrointestinal disorders
Anal fistula	0/164 (0%)		1/165 (0.6%)
Colitis	1/164 (0.6%)		0/165 (0%)
Diarrhoea	4/164 (2.4%)		0/165 (0%)
Enterocolitis	1/164 (0.6%)		0/165 (0%)
Femoral hernia, obstructive	1/164 (0.6%)		0/165 (0%)
Gastritis	1/164 (0.6%)		0/165 (0%)
Gastrointestinal hypermotility	1/164 (0.6%)		0/165 (0%)
Lower gastrointestinal haemorrhage	0/164 (0%)		1/165 (0.6%)
Nausea	1/164 (0.6%)		0/165 (0%)
Pancreatitis acute	1/164 (0.6%)		0/165 (0%)
Umbilical hernia	0/164 (0%)		1/165 (0.6%)
Vomiting	2/164 (1.2%)		0/165 (0%)
General disorders
Fatigue	1/164 (0.6%)		0/165 (0%)
Infusion related reaction	3/164 (1.8%)		0/165 (0%)
Mucosal inflammation	1/164 (0.6%)		0/165 (0%)
Multi-organ failure	0/164 (0%)		1/165 (0.6%)
Pyrexia	5/164 (3%)		1/165 (0.6%)
Sudden cardiac death	0/164 (0%)		1/165 (0.6%)
Hepatobiliary disorders
Hepatic failure	0/164 (0%)		1/165 (0.6%)
Hepatitis	1/164 (0.6%)		0/165 (0%)
Hepatitis cholestatic	1/164 (0.6%)		0/165 (0%)
Hepatitis toxic	1/164 (0.6%)		0/165 (0%)
Hepatotoxicity	1/164 (0.6%)		0/165 (0%)
Immune system disorders
Hypogammaglobulinaemia	1/164 (0.6%)		0/165 (0%)
Infections and infestations
Bronchitis	3/164 (1.8%)		0/165 (0%)
Cellulitis	0/164 (0%)		1/165 (0.6%)
Cytomegalovirus infection	2/164 (1.2%)		0/165 (0%)
Erysipelas	0/164 (0%)		1/165 (0.6%)
Eye infection toxoplasmal	1/164 (0.6%)		0/165 (0%)
Fungaemia	0/164 (0%)		1/165 (0.6%)
Gastroenteritis escherichia coli	0/164 (0%)		1/165 (0.6%)
Hepatitis c	1/164 (0.6%)		0/165 (0%)
Herpes simplex	0/164 (0%)		1/165 (0.6%)
Herpes zoster	1/164 (0.6%)		0/165 (0%)
Infection	0/164 (0%)		1/165 (0.6%)
Oral fungal infection	0/164 (0%)		1/165 (0.6%)
Orchitis	0/164 (0%)		1/165 (0.6%)
Oropharyngeal candidiasis	1/164 (0.6%)		0/165 (0%)
Peritonsillar abscess	1/164 (0.6%)		0/165 (0%)
Pharyngitis	2/164 (1.2%)		0/165 (0%)
Pharyngitis bacterial	0/164 (0%)		1/165 (0.6%)
Pneumococcal sepsis	0/164 (0%)		1/165 (0.6%)
Pneumocystis jiroveci infection	1/164 (0.6%)		0/165 (0%)
Pneumocystis jiroveci pneumonia	1/164 (0.6%)		0/165 (0%)
Pneumonia	5/164 (3%)		1/165 (0.6%)
Pneumonia bacterial	0/164 (0%)		1/165 (0.6%)
Pneumonia fungal	1/164 (0.6%)		2/165 (1.2%)
Pneumonia streptococcal	0/164 (0%)		1/165 (0.6%)
Pyelonephritis acute	1/164 (0.6%)		1/165 (0.6%)
Respiratory tract infection	0/164 (0%)		1/165 (0.6%)
Salmonella sepsis	1/164 (0.6%)		0/165 (0%)
Sepsis	0/164 (0%)		2/165 (1.2%)
Septic shock	0/164 (0%)		1/165 (0.6%)
Sinusitis	1/164 (0.6%)		1/165 (0.6%)
Tonsillitis	1/164 (0.6%)		0/165 (0%)
Tuberculosis	1/164 (0.6%)		0/165 (0%)
Investigations
Cd4 lymphocytes decreased	1/164 (0.6%)		0/165 (0%)
Cytomegalovirus test positive	3/164 (1.8%)		0/165 (0%)
Pneumocystis test positive	1/164 (0.6%)		0/165 (0%)
Transaminases increased	1/164 (0.6%)		0/165 (0%)
Metabolism and nutrition disorders
Dehydration	1/164 (0.6%)		0/165 (0%)
Hypokalaemia	1/164 (0.6%)		0/165 (0%)
Tumour lysis syndrome	1/164 (0.6%)		0/165 (0%)
Musculoskeletal and connective tissue disorders
Osteochondrosis	0/164 (0%)		1/165 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/164 (0%)		1/165 (0.6%)
Chronic lymphocytic leukaemia transformation	2/164 (1.2%)		0/165 (0%)
Gastric cancer	1/164 (0.6%)		0/165 (0%)
Hodgkin's disease	1/164 (0.6%)		0/165 (0%)
Malignant melanoma	0/164 (0%)		1/165 (0.6%)
Malignant peritoneal neoplasm	0/164 (0%)		1/165 (0.6%)
Malignant pleural effusion	1/164 (0.6%)		1/165 (0.6%)
Neuroendocrine carcinoma of the skin	0/164 (0%)		1/165 (0.6%)
Rectosigmoid cancer	0/164 (0%)		1/165 (0.6%)
Nervous system disorders
Brain oedema	0/164 (0%)		1/165 (0.6%)
Cerebrovascular accident	0/164 (0%)		1/165 (0.6%)
Coma hepatic	1/164 (0.6%)		0/165 (0%)
Ischaemic cerebral infarction	0/164 (0%)		1/165 (0.6%)
Neuropathy peripheral	1/164 (0.6%)		0/165 (0%)
Peripheral sensory neuropathy	0/164 (0%)		1/165 (0.6%)
Radicular pain	1/164 (0.6%)		0/165 (0%)
Renal and urinary disorders
Calculus urinary	1/164 (0.6%)		0/165 (0%)
Cystitis haemorrhagic	0/164 (0%)		1/165 (0.6%)
Nephrolithiasis	1/164 (0.6%)		0/165 (0%)
Renal failure	1/164 (0.6%)		0/165 (0%)
Renal failure acute	0/164 (0%)		1/165 (0.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/164 (0.6%)		0/165 (0%)
Acute respiratory failure	0/164 (0%)		1/165 (0.6%)
Bronchospasm	1/164 (0.6%)		0/165 (0%)
Chronic obstructive pulmonary disease	0/164 (0%)		1/165 (0.6%)
Pulmonary oedema	0/164 (0%)		1/165 (0.6%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/164 (0.6%)		0/165 (0%)
Dermatitis exfoliative	1/164 (0.6%)		0/165 (0%)
Pruritus	1/164 (0.6%)		0/165 (0%)
Urticaria	2/164 (1.2%)		0/165 (0%)
Vascular disorders
Deep vein thrombosis	1/164 (0.6%)		0/165 (0%)
Hypertension	1/164 (0.6%)		0/165 (0%)
Other (Not Including Serious) Adverse Events
	Combination Arm (FluCAM)		Fludarabine Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/164 (97.6%)		147/165 (89.1%)
Blood and lymphatic system disorders
Anaemia	36/164 (22%)		39/165 (23.6%)
Autoimmune thrombocytopenia	0/164 (0%)		1/165 (0.6%)
Eosinophilia	1/164 (0.6%)		3/165 (1.8%)
Febrile neutropenia	1/164 (0.6%)		4/165 (2.4%)
Granulocytopenia	3/164 (1.8%)		1/165 (0.6%)
Haematotoxicity	0/164 (0%)		1/165 (0.6%)
Idiopathic thrombocytopenic purpura	1/164 (0.6%)		0/165 (0%)
Leukopenia	73/164 (44.5%)		25/165 (15.2%)
Lymphopenia	35/164 (21.3%)		7/165 (4.2%)
Neutropenia	82/164 (50%)		84/165 (50.9%)
Pancytopenia	0/164 (0%)		1/165 (0.6%)
Thrombocytopenia	44/164 (26.8%)		44/165 (26.7%)
Cardiac disorders
Angina pectoris	0/164 (0%)		2/165 (1.2%)
Aortic valve calcification	1/164 (0.6%)		0/165 (0%)
Aortic valve incompetence	1/164 (0.6%)		0/165 (0%)
Arrhythmia	1/164 (0.6%)		0/165 (0%)
Arteriosclerosis coronary artery	0/164 (0%)		1/165 (0.6%)
Atrial fibrillation	1/164 (0.6%)		1/165 (0.6%)
Cardiac failure	1/164 (0.6%)		0/165 (0%)
Cardiomyopathy	0/164 (0%)		1/165 (0.6%)
Diastolic dysfunction	1/164 (0.6%)		0/165 (0%)
Hypertensive cardiomyopathy	1/164 (0.6%)		0/165 (0%)
Hypertensive heart disease	1/164 (0.6%)		0/165 (0%)
Left ventricular dysfunction	1/164 (0.6%)		0/165 (0%)
Mitral valve incompetence	1/164 (0.6%)		0/165 (0%)
Myocardial ischaemia	0/164 (0%)		1/165 (0.6%)
Palpitations	1/164 (0.6%)		3/165 (1.8%)
Pericardial effusion	2/164 (1.2%)		0/165 (0%)
Sinus tachycardia	2/164 (1.2%)		0/165 (0%)
Tachycardia	3/164 (1.8%)		0/165 (0%)
Ventricular arrhythmia	1/164 (0.6%)		0/165 (0%)
Ventricular extrasystoles	1/164 (0.6%)		0/165 (0%)
Congenital, familial and genetic disorders
Accessory spleen	1/164 (0.6%)		0/165 (0%)
Kidney malformation	1/164 (0.6%)		0/165 (0%)
Ear and labyrinth disorders
Deafness neurosensory	1/164 (0.6%)		1/165 (0.6%)
Hearing impaired	0/164 (0%)		1/165 (0.6%)
Tinnitus	0/164 (0%)		2/165 (1.2%)
Vertigo	2/164 (1.2%)		1/165 (0.6%)
Endocrine disorders
Goitre	2/164 (1.2%)		1/165 (0.6%)
Hypothyroidism	1/164 (0.6%)		1/165 (0.6%)
Eye disorders
Cataract	0/164 (0%)		1/165 (0.6%)
Conjunctival haemorrhage	0/164 (0%)		1/165 (0.6%)
Conjunctivitis	1/164 (0.6%)		0/165 (0%)
Conjunctivitis allergic	1/164 (0.6%)		0/165 (0%)
Erythema of eyelid	0/164 (0%)		1/165 (0.6%)
Lacrimation increased	1/164 (0.6%)		0/165 (0%)
Retinopathy	0/164 (0%)		1/165 (0.6%)
Retinopathy hypertensive	0/164 (0%)		1/165 (0.6%)
Visual impairment	0/164 (0%)		1/165 (0.6%)
Gastrointestinal disorders
Abdominal discomfort	1/164 (0.6%)		1/165 (0.6%)
Abdominal distension	0/164 (0%)		1/165 (0.6%)
Abdominal pain	4/164 (2.4%)		3/165 (1.8%)
Abdominal pain upper	0/164 (0%)		3/165 (1.8%)
Aphthous stomatitis	1/164 (0.6%)		0/165 (0%)
Ascites	1/164 (0.6%)		0/165 (0%)
Cheilitis	1/164 (0.6%)		0/165 (0%)
Colitis	1/164 (0.6%)		0/165 (0%)
Constipation	6/164 (3.7%)		4/165 (2.4%)
Diarrhoea	15/164 (9.1%)		11/165 (6.7%)
Diverticulum intestinal	0/164 (0%)		1/165 (0.6%)
Dry mouth	1/164 (0.6%)		1/165 (0.6%)
Duodenal ulcer	0/164 (0%)		1/165 (0.6%)
Duodenitis	0/164 (0%)		1/165 (0.6%)
Dyspepsia	3/164 (1.8%)		3/165 (1.8%)
Enterocolitis	1/164 (0.6%)		0/165 (0%)
Erosive duodenitis	1/164 (0.6%)		0/165 (0%)
Flatulence	2/164 (1.2%)		3/165 (1.8%)
Gastric ulcer	1/164 (0.6%)		0/165 (0%)
Gastritis	1/164 (0.6%)		0/165 (0%)
Gastrooesophageal reflux disease	0/164 (0%)		1/165 (0.6%)
Gingival bleeding	0/164 (0%)		1/165 (0.6%)
Gingival pain	0/164 (0%)		1/165 (0.6%)
Gingivitis ulcerative	0/164 (0%)		1/165 (0.6%)
Haemorrhoids	3/164 (1.8%)		0/165 (0%)
Lower gastrointestinal haemorrhage	0/164 (0%)		1/165 (0.6%)
Nausea	20/164 (12.2%)		13/165 (7.9%)
Pancreatic disorder	0/164 (0%)		1/165 (0.6%)
Pancreatitis	3/164 (1.8%)		3/165 (1.8%)
Pancreatitis acute	1/164 (0.6%)		0/165 (0%)
Periodontitis	1/164 (0.6%)		0/165 (0%)
Stomatitis	4/164 (2.4%)		0/165 (0%)
Toothache	1/164 (0.6%)		1/165 (0.6%)
Vomiting	15/164 (9.1%)		3/165 (1.8%)
General disorders
Asthenia	4/164 (2.4%)		6/165 (3.6%)
Catheter site inflammation	1/164 (0.6%)		0/165 (0%)
Chest discomfort	1/164 (0.6%)		0/165 (0%)
Chills	49/164 (29.9%)		2/165 (1.2%)
Face oedema	0/164 (0%)		1/165 (0.6%)
Fatigue	10/164 (6.1%)		9/165 (5.5%)
Generalised oedema	1/164 (0.6%)		0/165 (0%)
Hyperpyrexia	2/164 (1.2%)		0/165 (0%)
Hyperthermia	6/164 (3.7%)		0/165 (0%)
Impaired healing	0/164 (0%)		1/165 (0.6%)
Influenza like illness	2/164 (1.2%)		0/165 (0%)
Infusion related reaction	20/164 (12.2%)		0/165 (0%)
Injection site extravasation	1/164 (0.6%)		0/165 (0%)
Injection site reaction	1/164 (0.6%)		0/165 (0%)
Localised oedema	0/164 (0%)		3/165 (1.8%)
Malaise	1/164 (0.6%)		1/165 (0.6%)
Mucosal inflammation	1/164 (0.6%)		1/165 (0.6%)
Non-cardiac chest pain	2/164 (1.2%)		0/165 (0%)
Oedema	0/164 (0%)		1/165 (0.6%)
Oedema peripheral	6/164 (3.7%)		4/165 (2.4%)
Pyrexia	96/164 (58.5%)		14/165 (8.5%)
Soft tissue inflammation	1/164 (0.6%)		0/165 (0%)
Hepatobiliary disorders
Cholecystitis	1/164 (0.6%)		0/165 (0%)
Cholecystitis chronic	5/164 (3%)		2/165 (1.2%)
Cholelithiasis	0/164 (0%)		1/165 (0.6%)
Hepatic cyst	1/164 (0.6%)		0/165 (0%)
Hepatic steatosis	0/164 (0%)		1/165 (0.6%)
Hepatitis chronic active	0/164 (0%)		1/165 (0.6%)
Hepatitis toxic	1/164 (0.6%)		1/165 (0.6%)
Hepatomegaly	1/164 (0.6%)		0/165 (0%)
Hyperbilirubinaemia	4/164 (2.4%)		0/165 (0%)
Liver disorder	0/164 (0%)		1/165 (0.6%)
Immune system disorders
Allergy to arthropod bite	1/164 (0.6%)		0/165 (0%)
Cytokine release syndrome	7/164 (4.3%)		0/165 (0%)
Drug hypersensitivity	1/164 (0.6%)		0/165 (0%)
Hypersensitivity	5/164 (3%)		1/165 (0.6%)
Mycotic allergy	1/164 (0.6%)		0/165 (0%)
Seasonal allergy	2/164 (1.2%)		0/165 (0%)
Infections and infestations
Acute sinusitis	0/164 (0%)		1/165 (0.6%)
Ascariasis	1/164 (0.6%)		0/165 (0%)
Bronchitis	15/164 (9.1%)		5/165 (3%)
Bronchopneumonia	2/164 (1.2%)		0/165 (0%)
Bullous impetigo	0/164 (0%)		1/165 (0.6%)
Candidiasis	1/164 (0.6%)		0/165 (0%)
Conjunctivitis infective	0/164 (0%)		1/165 (0.6%)
Cystitis	1/164 (0.6%)		1/165 (0.6%)
Cytomegalovirus infection	2/164 (1.2%)		0/165 (0%)
Folliculitis	1/164 (0.6%)		0/165 (0%)
Herpes simplex	2/164 (1.2%)		1/165 (0.6%)
Herpes zoster	4/164 (2.4%)		3/165 (1.8%)
Infection	2/164 (1.2%)		0/165 (0%)
Influenza	2/164 (1.2%)		1/165 (0.6%)
Klebsiella bacteraemia	0/164 (0%)		1/165 (0.6%)
Laryngitis	1/164 (0.6%)		0/165 (0%)
Nasopharyngitis	7/164 (4.3%)		8/165 (4.8%)
Neutropenic infection	2/164 (1.2%)		1/165 (0.6%)
Oral fungal infection	1/164 (0.6%)		2/165 (1.2%)
Oral herpes	3/164 (1.8%)		3/165 (1.8%)
Otitis media	1/164 (0.6%)		0/165 (0%)
Perirectal abscess	0/164 (0%)		1/165 (0.6%)
Pharyngitis	6/164 (3.7%)		5/165 (3%)
Pneumonia	6/164 (3.7%)		3/165 (1.8%)
Pulpitis dental	0/164 (0%)		1/165 (0.6%)
Respiratory tract infection	4/164 (2.4%)		5/165 (3%)
Respiratory tract infection viral	4/164 (2.4%)		2/165 (1.2%)
Rhinitis	3/164 (1.8%)		3/165 (1.8%)
Sinusitis	1/164 (0.6%)		3/165 (1.8%)
Skin candida	0/164 (0%)		1/165 (0.6%)
Staphylococcal infection	0/164 (0%)		1/165 (0.6%)
Tinea versicolour	1/164 (0.6%)		0/165 (0%)
Tonsillitis	1/164 (0.6%)		3/165 (1.8%)
Tooth infection	0/164 (0%)		1/165 (0.6%)
Tracheitis	2/164 (1.2%)		1/165 (0.6%)
Upper respiratory tract infection	3/164 (1.8%)		3/165 (1.8%)
Urinary tract infection	3/164 (1.8%)		1/165 (0.6%)
Urinary tract infection pseudomonal	0/164 (0%)		1/165 (0.6%)
Viral infection	0/164 (0%)		1/165 (0.6%)
Viral upper respiratory tract infection	3/164 (1.8%)		1/165 (0.6%)
Injury, poisoning and procedural complications
Arthropod bite	0/164 (0%)		1/165 (0.6%)
Injury	0/164 (0%)		1/165 (0.6%)
Joint sprain	1/164 (0.6%)		0/165 (0%)
Investigations
Alanine aminotransferase increased	6/164 (3.7%)		5/165 (3%)
Aspartate aminotransferase increased	2/164 (1.2%)		2/165 (1.2%)
Beta 2 microglobulin decreased	1/164 (0.6%)		0/165 (0%)
Blood albumin decreased	0/164 (0%)		1/165 (0.6%)
Blood alkaline phosphatase increased	0/164 (0%)		1/165 (0.6%)
Blood bilirubin increased	2/164 (1.2%)		1/165 (0.6%)
Blood creatinine increased	4/164 (2.4%)		3/165 (1.8%)
Blood lactate dehydrogenase increased	3/164 (1.8%)		0/165 (0%)
Body temperature increased	2/164 (1.2%)		1/165 (0.6%)
Breath sounds abnormal	0/164 (0%)		1/165 (0.6%)
Cd4 lymphocytes decreased	4/164 (2.4%)		2/165 (1.2%)
Creatinine renal clearance decreased	5/164 (3%)		5/165 (3%)
Cytomegalovirus test positive	19/164 (11.6%)		1/165 (0.6%)
Gamma-glutamyltransferase increased	1/164 (0.6%)		2/165 (1.2%)
Haemoglobin decreased	4/164 (2.4%)		5/165 (3%)
Hepatic enzyme increased	0/164 (0%)		1/165 (0.6%)
Lymphocyte count decreased	2/164 (1.2%)		1/165 (0.6%)
Neutrophil count decreased	6/164 (3.7%)		7/165 (4.2%)
Neutrophil pelger-huet anomaly present	1/164 (0.6%)		0/165 (0%)
Platelet count decreased	6/164 (3.7%)		10/165 (6.1%)
Urine uric acid increased	1/164 (0.6%)		0/165 (0%)
Weight decreased	2/164 (1.2%)		2/165 (1.2%)
Weight increased	1/164 (0.6%)		2/165 (1.2%)
White blood cell count decreased	7/164 (4.3%)		3/165 (1.8%)
Metabolism and nutrition disorders
Decreased appetite	2/164 (1.2%)		1/165 (0.6%)
Dehydration	1/164 (0.6%)		0/165 (0%)
Diabetes mellitus	2/164 (1.2%)		0/165 (0%)
Fluid retention	2/164 (1.2%)		0/165 (0%)
Gout	1/164 (0.6%)		0/165 (0%)
Hyperglycaemia	3/164 (1.8%)		2/165 (1.2%)
Hyperkalaemia	0/164 (0%)		1/165 (0.6%)
Hypernatraemia	0/164 (0%)		1/165 (0.6%)
Hyperphosphataemia	0/164 (0%)		1/165 (0.6%)
Hyperproteinaemia	1/164 (0.6%)		0/165 (0%)
Hyperuricaemia	1/164 (0.6%)		4/165 (2.4%)
Hypoalbuminaemia	4/164 (2.4%)		1/165 (0.6%)
Hypokalaemia	4/164 (2.4%)		0/165 (0%)
Hypophosphataemia	1/164 (0.6%)		1/165 (0.6%)
Hypoproteinaemia	1/164 (0.6%)		1/165 (0.6%)
Tumour lysis syndrome	0/164 (0%)		2/165 (1.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/164 (1.8%)		2/165 (1.2%)
Arthritis	0/164 (0%)		1/165 (0.6%)
Arthritis reactive	0/164 (0%)		1/165 (0.6%)
Back pain	4/164 (2.4%)		3/165 (1.8%)
Bone pain	9/164 (5.5%)		0/165 (0%)
Gouty arthritis	0/164 (0%)		1/165 (0.6%)
Groin pain	0/164 (0%)		1/165 (0.6%)
Mastication disorder	1/164 (0.6%)		0/165 (0%)
Musculoskeletal pain	1/164 (0.6%)		2/165 (1.2%)
Myalgia	2/164 (1.2%)		1/165 (0.6%)
Myositis	1/164 (0.6%)		0/165 (0%)
Osteoarthritis	0/164 (0%)		1/165 (0.6%)
Osteochondrosis	3/164 (1.8%)		2/165 (1.2%)
Osteonecrosis of jaw	1/164 (0.6%)		0/165 (0%)
Pain in extremity	2/164 (1.2%)		2/165 (1.2%)
Rheumatoid arthritis	1/164 (0.6%)		0/165 (0%)
Rotator cuff syndrome	0/164 (0%)		1/165 (0.6%)
Scoliosis	0/164 (0%)		1/165 (0.6%)
Spinal deformity	1/164 (0.6%)		0/165 (0%)
Spinal osteoarthritis	1/164 (0.6%)		0/165 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/164 (0%)		1/165 (0.6%)
Benign lung neoplasm	1/164 (0.6%)		0/165 (0%)
Gastrointestinal carcinoma	0/164 (0%)		1/165 (0.6%)
Lipoma	1/164 (0.6%)		1/165 (0.6%)
Malignant pleural effusion	1/164 (0.6%)		1/165 (0.6%)
Metastases to liver	1/164 (0.6%)		0/165 (0%)
Paraneoplastic pemphigus	0/164 (0%)		1/165 (0.6%)
Paraproteinaemia	1/164 (0.6%)		0/165 (0%)
Seborrhoeic keratosis	1/164 (0.6%)		1/165 (0.6%)
Skin papilloma	1/164 (0.6%)		0/165 (0%)
Nervous system disorders
Cognitive disorder	1/164 (0.6%)		0/165 (0%)
Dizziness	4/164 (2.4%)		5/165 (3%)
Dysaesthesia	0/164 (0%)		1/165 (0.6%)
Dysgeusia	1/164 (0.6%)		1/165 (0.6%)
Facial neuralgia	1/164 (0.6%)		0/165 (0%)
Headache	14/164 (8.5%)		4/165 (2.4%)
Hypoaesthesia	0/164 (0%)		2/165 (1.2%)
Memory impairment	1/164 (0.6%)		0/165 (0%)
Neuralgia	0/164 (0%)		1/165 (0.6%)
Neuropathy peripheral	0/164 (0%)		2/165 (1.2%)
Paraesthesia	0/164 (0%)		2/165 (1.2%)
Peripheral sensory neuropathy	1/164 (0.6%)		3/165 (1.8%)
Post herpetic neuralgia	1/164 (0.6%)		0/165 (0%)
Radicular pain	1/164 (0.6%)		0/165 (0%)
Sciatica	0/164 (0%)		1/165 (0.6%)
Somnolence	0/164 (0%)		1/165 (0.6%)
Sphenopalatine neuralgia	1/164 (0.6%)		0/165 (0%)
Syncope	1/164 (0.6%)		0/165 (0%)
Toxic encephalopathy	0/164 (0%)		2/165 (1.2%)
Tremor	1/164 (0.6%)		0/165 (0%)
Psychiatric disorders
Agitation	1/164 (0.6%)		1/165 (0.6%)
Anxiety	1/164 (0.6%)		0/165 (0%)
Confusional state	1/164 (0.6%)		0/165 (0%)
Depression	2/164 (1.2%)		1/165 (0.6%)
Disorientation	0/164 (0%)		1/165 (0.6%)
Hallucination	1/164 (0.6%)		0/165 (0%)
Insomnia	5/164 (3%)		2/165 (1.2%)
Sleep disorder	0/164 (0%)		1/165 (0.6%)
Renal and urinary disorders
Calculus urinary	1/164 (0.6%)		0/165 (0%)
Chromaturia	1/164 (0.6%)		0/165 (0%)
Crystalluria	1/164 (0.6%)		0/165 (0%)
Cystitis haemorrhagic	1/164 (0.6%)		0/165 (0%)
Dysuria	0/164 (0%)		1/165 (0.6%)
Leukocyturia	1/164 (0.6%)		0/165 (0%)
Nephrolithiasis	0/164 (0%)		1/165 (0.6%)
Nephroptosis	2/164 (1.2%)		0/165 (0%)
Pollakiuria	5/164 (3%)		3/165 (1.8%)
Renal failure	1/164 (0.6%)		0/165 (0%)
Renal failure acute	0/164 (0%)		1/165 (0.6%)
Renal impairment	2/164 (1.2%)		0/165 (0%)
Urinary retention	1/164 (0.6%)		0/165 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/164 (0.6%)		2/165 (1.2%)
Calculus prostatic	0/164 (0%)		1/165 (0.6%)
Metrorrhagia	1/164 (0.6%)		0/165 (0%)
Vaginal haemorrhage	0/164 (0%)		1/165 (0.6%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/164 (0%)		1/165 (0.6%)
Bronchitis chronic	1/164 (0.6%)		0/165 (0%)
Bronchospasm	8/164 (4.9%)		0/165 (0%)
Cough	13/164 (7.9%)		8/165 (4.8%)
Dysphonia	1/164 (0.6%)		0/165 (0%)
Dyspnoea	5/164 (3%)		1/165 (0.6%)
Epistaxis	1/164 (0.6%)		2/165 (1.2%)
Haemoptysis	1/164 (0.6%)		0/165 (0%)
Hiccups	3/164 (1.8%)		0/165 (0%)
Laryngeal polyp	1/164 (0.6%)		0/165 (0%)
Lung infiltration	1/164 (0.6%)		0/165 (0%)
Nasal dryness	1/164 (0.6%)		0/165 (0%)
Obstructive airways disorder	0/164 (0%)		1/165 (0.6%)
Oropharyngeal pain	0/164 (0%)		2/165 (1.2%)
Pleural effusion	3/164 (1.8%)		0/165 (0%)
Pleurisy	1/164 (0.6%)		0/165 (0%)
Pneumonitis	1/164 (0.6%)		0/165 (0%)
Pulmonary congestion	1/164 (0.6%)		0/165 (0%)
Respiratory alkalosis	0/164 (0%)		1/165 (0.6%)
Respiratory disorder	1/164 (0.6%)		1/165 (0.6%)
Respiratory failure	0/164 (0%)		1/165 (0.6%)
Sinus congestion	1/164 (0.6%)		0/165 (0%)
Throat irritation	1/164 (0.6%)		0/165 (0%)
Wheezing	0/164 (0%)		1/165 (0.6%)
Skin and subcutaneous tissue disorders
Alopecia	1/164 (0.6%)		0/165 (0%)
Angioedema	0/164 (0%)		1/165 (0.6%)
Dermatitis	1/164 (0.6%)		0/165 (0%)
Dermatitis allergic	13/164 (7.9%)		4/165 (2.4%)
Drug eruption	6/164 (3.7%)		0/165 (0%)
Dry skin	1/164 (0.6%)		0/165 (0%)
Eczema	1/164 (0.6%)		1/165 (0.6%)
Erythema	1/164 (0.6%)		3/165 (1.8%)
Exfoliative rash	1/164 (0.6%)		0/165 (0%)
Hyperhidrosis	3/164 (1.8%)		3/165 (1.8%)
Hyperkeratosis	1/164 (0.6%)		0/165 (0%)
Night sweats	2/164 (1.2%)		0/165 (0%)
Petechiae	0/164 (0%)		1/165 (0.6%)
Pruritus	13/164 (7.9%)		4/165 (2.4%)
Pruritus allergic	3/164 (1.8%)		1/165 (0.6%)
Pruritus generalised	1/164 (0.6%)		0/165 (0%)
Rash	25/164 (15.2%)		5/165 (3%)
Rash erythematous	1/164 (0.6%)		0/165 (0%)
Rash generalised	0/164 (0%)		1/165 (0.6%)
Rash macular	1/164 (0.6%)		0/165 (0%)
Rash maculo-papular	1/164 (0.6%)		0/165 (0%)
Rash papular	1/164 (0.6%)		0/165 (0%)
Seborrhoeic dermatitis	1/164 (0.6%)		0/165 (0%)
Skin exfoliation	0/164 (0%)		2/165 (1.2%)
Skin hyperpigmentation	0/164 (0%)		2/165 (1.2%)
Skin lesion	0/164 (0%)		1/165 (0.6%)
Skin swelling	0/164 (0%)		1/165 (0.6%)
Skin ulcer	0/164 (0%)		1/165 (0.6%)
Swelling face	0/164 (0%)		1/165 (0.6%)
Urticaria	22/164 (13.4%)		4/165 (2.4%)
Urticaria vesiculosa	1/164 (0.6%)		0/165 (0%)
Vascular disorders
Arteriosclerosis obliterans	1/164 (0.6%)		0/165 (0%)
Deep vein thrombosis	2/164 (1.2%)		0/165 (0%)
Flushing	1/164 (0.6%)		0/165 (0%)
Hot flush	1/164 (0.6%)		0/165 (0%)
Hypertension	11/164 (6.7%)		6/165 (3.6%)
Hypertensive crisis	1/164 (0.6%)		0/165 (0%)
Hypotension	3/164 (1.8%)		2/165 (1.2%)
Phlebitis	2/164 (1.2%)		0/165 (0%)
Systolic hypertension	1/164 (0.6%)		1/165 (0.6%)
Temporal arteritis	1/164 (0.6%)		0/165 (0%)
Varicose vein	1/164 (0.6%)		0/165 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

In multi-site studies, PI can publish after an independent multi-investigator publication (in which the PI can participate) or 18 months after study completion. PI gives Genzyme a draft 60 days before publication. Genzyme can ask that confidential information be removed, and can defer publication another 60 days upon notifying PI that it will file a patent application on inventions contained in the draft.