A Study of MabThera (Rituximab) in Elderly Patients With Untreated Follicular Non-Hodgkin's Lymphoma (NHL)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01144364
• Collaborator: (none)
• Enrollment: 234
• Locations: 45
• Arm: 1
• Actual Duration (Months): 90
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of brief induction therapy with a chemotherapeutic regimen containing MabThera, followed by either maintenance therapy with MabThera or no further therapy. The anticipated time on study treatment is 1-2 years, and the target sample size is 100-500 individuals.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma	Drug: rituximab [Mabthera/Rituxan]	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 234 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label Study of MabThera Maintenance Therapy Compared With no Further Therapy After a Brief Induction With Chemotherapy Plus MabThera on Failure-free Survival in Treatment-naïve Elderly Patients With Advanced Follicular Lymphoma
• Actual Study Start Date: Jan 19, 2004
• Actual Primary Completion Date: Jul 21, 2011
• Actual Study Completion Date: Jul 21, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: rituximab [Mabthera/Rituxan]; Intravenous repeating dose

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Disease Progression or Death [12, 24, and 34 months]

   PFS from randomization was measured from the date of randomization to the date of documented disease progression, relapse, or death from any cause. PFS function was estimated using Kaplan-Meier product-limit method. Responding participants and participants who were lost to follow up were censored at their last assessment date.

2. PFS Randomization- Percentage of Participants Estimated to be Free of Progression at 12, 24, and 34 Months [12, 24, and 34 months]

   PFS from randomization was measured from the date of randomization to the date of documented disease progression, relapse, or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last assessment date. PFS was estimated using Kaplan-Meier methods.

Secondary Outcome Measures

1. Percentage of Participants Estimated to be Free of Progression at 12, 24, and 36 Months [12, 24, and 36 months]

   PFS from enrollment was measured from the date of enrollment to the date of disease progression, relapse, or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last assessment date. Estimates of PFS function were made with the Kaplan-Meier product-limit method.

2. Disease-Free Survival (DFS) From Randomization - Percentage of Participants Disease Free at 12, 24, and 36 Months [12, 24, and 36 months]

   DFS was defined for all participants who achieved a complete response (CR) or unconfirmed CR (CRu) at Month 3 or later, after the completion of induction phase and was measured from the time of randomization to the date of relapse or death as a result of lymphoma or acute toxicity of treatment. Participants without relapse were censored at their last assessment date. Estimates of DFS were made using Kaplan-Meier product-limit method.

3. Overall Survival (OS) From Randomization - Percentage of Participants Estimated to be Alive at 12, 24, and 34 Months [12, 24, and 34 months]

   OS from randomization was defined as the date of randomization to the date of death from any cause. Participants still alive at the time of the final analysis were censored at the date of the last contact. Estimates of the OS function were made by the Kaplan-Meier product-limit method.

4. Overall Survival (OS) From Randomization - Percentage of Participants With Death [12, 24, and 34 months]

   OS from randomization was defined as the date of randomization to the date of death from any cause. Participants still alive at the time of the final analysis were censored at the date of the last contact. Estimates of the OS function were made by the Kaplan-Meier product-limit method.

5. OS From Enrollment - Percentage of Participants Estimated to be Alive at 12, 24, and 36 Months [12, 24, and 36 months]

   OS from enrollment was defined as the date of enrollment to the date of death from any cause. Participants still alive at the time of the final analysis were censored at the date of the last contact. Estimates of the OS function were made by the Kaplan-Meier product-limit method.

6. Percentage of Participants With a Response During the Induction Phase [Months 1 to 8]

   Participants without a response assessment (due to any reasons) were considered as non-responders.

7. Percentage of Participants With a Molecular Response in the Induction Phase [Months 5 and 8]

   Molecular responders were defined as the proportion of CR/CRu participants with a positive bcl-2/IgH (non-Hodgkin's Lymphoma [NHL] marker) at baseline, whose laboratory values were undetectable after treatment.

8. Duration of Response Using a Traditional Approach - Percentage of Participants Estimated to Have a Sustained Response at 12, 24, and 34 Months [Months 12, 24, and 34]

   Duration of response (DOR) was defined for all participants who achieved a response (CR, CRu, and PR) at Month 3 or later, after the completion of induction phase and was measured from the date of randomization until the date of progression, relapse, or death as a result of follicular lymphoma (FL). Participants without relapse, progression, or death for causes other than FL were censored at their last assessment date. Analyses on this endpoint were performed with two different approaches. For the traditional approach, duration of response was estimated as the proportion of participants alive without progression or relapse of disease with the Kaplan-Meier method.

9. Duration of Response Using the Competing Risk Approach - Cumulative Percentage of Participants With Progression, Relapse or Death as a Result of FL at 12, 24, and 34 Months [Months 12, 24, and 34]

   DOR was defined for all participants who achieved a response (CR, CRu, and PR) at Month 3 or later, after the completion of induction phase and was measured from the date of randomization until the date of progression, relapse, or death as a result of FL. Participants without relapse, progression, or death for causes other than FL were censored at their last assessment date. Analyses on this endpoint were performed with two different approaches. For the competing risk approach, deaths for causes other than FL were considered as competing events. DOR was estimated with the cumulative incidence of progression, relapse, or death as a result of FL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• adult patients 60-75 years of age;

• B-cell follicular NHL;

• no previous treatment;

• active disease, with rapid progression.

Exclusion Criteria:

• other cancer within 3 years of study, except carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ of the breast treated with lumpectomy;

• long-term use (>1 month) of systemic corticosteroids;

• central nervous system involvement;

• history of significant cardiovascular disease;

• positive test result for HIV, or hepatitis B or C.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale Civile Dello Spirito Santo; Divisione Di Ematologia	Pescara	Abruzzo	Italy	65100
2	Ospedale Riuniti; Divisione Di Ematologia	Reggio Calabria	Calabria	Italy	89100
3	Istituto Nazionale Tumori Irccs Fondazione g. Pascale;s.c. Ematologia Oncologica	Napoli	Campania	Italy	80131
4	Nuovo Policlinico, Ii Facolta; Divisione Di Ematologia	Napoli	Campania	Italy	80131
5	Ospedale Cardarelli; Divisione Di Ematologia	Napoli	Campania	Italy	80131
6	Presidio Ospedaliero Umberto I; U.O. Di Medicina Interna Ed Oncoematologia	Nocera Inferiore	Campania	Italy	84014
7	A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna	Bologna	Emilia-Romagna	Italy	40138
8	A.O. Universitaria Policlinico Di Modena; Ematologia	Modena	Emilia-Romagna	Italy	41100
9	A.O. Universitaria Policlinico Di Modena; Radiologia	Modena	Emilia-Romagna	Italy	41100
10	Az. Osp. Ospedale Civile; U.O. Di Oncologia Medica Ed Ematologia	Piacenza	Emilia-Romagna	Italy	29100
11	Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia	Ravenna	Emilia-Romagna	Italy	48100
12	Az. Osp. Arcispedale S. Maria Nuova; U.O. Di Ematologia	Reggio Emilia	Emilia-Romagna	Italy	42100
13	Policlinico Universitario; Clinica Oncologia - Padiglione Pennato	Udine	Friuli-Venezia Giulia	Italy	33100
14	Ospedale S. Eugenio; Divisione Di Ematologia	Roma	Lazio	Italy	00144
15	Universita' Degli Studi La Sapienza-Ist.Di Ematologia;Dip. Biotecnologie Cel CELLULARI ED EMATOLOGIA	Roma	Lazio	Italy	00161
16	Uni Cattolica; Divisione Di Ematologia	Roma	Lazio	Italy	00168
17	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia	Italy	24127
18	A.O. Spedali Civili Di Brescia-P.O. Spedali Civili;U.O. Ematologia	Brescia	Lombardia	Italy	25123
19	ASST DI CREMONA; U.O.S. di Ematologia	Cremona	Lombardia	Italy	26100
20	Ospedale Maggiore Di Milano; U.O. Ematologia I - Padiglione Marcora	Milano	Lombardia	Italy	20122
21	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1	Milano	Lombardia	Italy	20133
22	Ist. Nazionale Per Lo Studio E Cura Dei Tumori; Div. Ematologia Trapianto Midollo Osseo Allogenico	Milano	Lombardia	Italy	20133
23	Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia	Milano	Lombardia	Italy	20162
24	ASST DI MONZA; Ematologia	Monza	Lombardia	Italy	20052
25	Ospedale Regionale Di Torrette; Clinica Di Ematologia	Ancona	Marche	Italy	60020
26	Ospedale Civile; S.C. Ematologia	Pesaro	Marche	Italy	61100
27	Ospedale Civile SS. Antonio E Biagio DI Alessandria; Ematologia	Alessandria	Piemonte	Italy	15121
28	Az. Osp. Di Biella; Divisione Di Ematologia	Biella	Piemonte	Italy	13051
29	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte	Italy	10060
30	Az. Osp. S. Croce Ospedale Generale; Sezione Di Ematologia	Cuneo	Piemonte	Italy	12100
31	Az. Osp. S. Luigi Gonzaga; Malattie Apparato Respiratorio 5 Ad Indirizzo Oncologico	Orbassano	Piemonte	Italy	10043
32	A.O. Universitaria S. Giovanni Battista-Molinette Di Torino; Ematologia 1	Torino	Piemonte	Italy	10126
33	A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia	Torino	Piemonte	Italy	10126
34	Uni Degli Studi Di Bari, Policlinico; Cattedra Di Ematologia,Dipart. Di Medicina Interna E Publica	Bari	Puglia	Italy	70124
35	IRCCS Ospedale Casa Sollievo Della Sofferenza; Ematologia E Trapianto Di Midollo Osseo	San Giovanni Rotondo	Puglia	Italy	71013
36	Ospedale Oncologico A Businco-Cagliari; Ematologia Sez.	Cagliari	Sardegna	Italy	09121
37	Az. Osp. Papardo; Struttura Complessa Di Ematologia	Messina	Sicilia	Italy	98165
38	Ospedale V. Cervello; U.O. Ematologia E Trapianti	Palermo	Sicilia	Italy	90146
39	Ospedale Ferrarotto; Divisione Di Ematologia	Via S. Sofia 78	Sicilia	Italy	95123
40	Az. Osp. Di Careggi; Divisione Di Ematologia	Firenze	Toscana	Italy	50135
41	Ospedale Santa Chiara; Unita Operativa Di Ematologia	Pisa	Toscana	Italy	56100
42	Azienda Sanitaria Di Bolzano; Ematologia E Centro Trapianto Mid.Osseo	Bolzano	Trentino-Alto Adige	Italy	39100
43	Dept. Medicina Clinica E Sperimentale; Sez. Medicina Interna E Scienze Oncologiche - Pol. Monteluce	Perugia	Umbria	Italy	06126
44	Ospedale Civile Ss. Giovanni E Paolo; Ematologia	Venezia	Veneto	Italy	30122
45	Uni Di Verona Policlinico G.B. Rossi; Divisione E Cattedra Di Ematologia	Verona	Veneto	Italy	37130

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01144364
• Other Study ID Numbers: ML17638
• First Posted: Jun 15, 2010
• Last Update Posted: Aug 15, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Rituximab

Study Results

Participant Flow

Arm/Group Title	Induction Phase-Immunochemotherapy Rituximab-FND (R-FND)	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Cycles 1 to 4: Participants received rituximab: 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1*, fludarabine (F): 25 mg/m^2 IV on Days 2-4*, mitoxantrone (N): 10 mg/m^2 IV on Day 2*, dexamethasone (D) 10 mg IV (total dose) on Days 2-4*. Cycles were repeated every 28 days for a total of 4 cycles. *In Cycle 1, rituximab was given on Day 8 in order to avoid tumour lysis syndrome. Consequently, in Cycle 1, fludarabine and dexamethasone were given on Days 1, 2, and 3. Mitoxantrone was given on Day 1.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Period Title: Induction Phase
STARTED	234	0	0
COMPLETED	202	0	0
NOT COMPLETED	32	0	0
Period Title: Induction Phase
STARTED	0	101	101
COMPLETED	0	66	60
NOT COMPLETED	0	35	41

Baseline Characteristics

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance	Total
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.	Total of all reporting groups
Overall Participants	101	101	202
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	66	65	66
Sex: Female, Male (Count of Participants)
Female	64 63.4%	56 55.4%	120 59.4%
Male	37 36.6%	45 44.6%	82 40.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Disease Progression or Death
Description	PFS from randomization was measured from the date of randomization to the date of documented disease progression, relapse, or death from any cause. PFS function was estimated using Kaplan-Meier product-limit method. Responding participants and participants who were lost to follow up were censored at their last assessment date.
Time Frame	12, 24, and 34 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	101	101
Number [percentage of participants]	29.7 29.4%	34.7 34.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments	Difference between treatment arms
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.254
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Percentage of Participants Estimated to be Free of Progression at 12, 24, and 36 Months
Description	PFS from enrollment was measured from the date of enrollment to the date of disease progression, relapse, or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last assessment date. Estimates of PFS function were made with the Kaplan-Meier product-limit method.
Time Frame	12, 24, and 36 months

Outcome Measure Data

Analysis Population Description

IP population

Arm/Group Title	Rituximab Induction
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received either no therapy (observation) or rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.
Measure Participants	234
12 months	90.1 89.2%
24 months	77.8 77%
36 months	65.7 65%

3. Secondary Outcome

Title	Disease-Free Survival (DFS) From Randomization - Percentage of Participants Disease Free at 12, 24, and 36 Months
Description	DFS was defined for all participants who achieved a complete response (CR) or unconfirmed CR (CRu) at Month 3 or later, after the completion of induction phase and was measured from the time of randomization to the date of relapse or death as a result of lymphoma or acute toxicity of treatment. Participants without relapse were censored at their last assessment date. Estimates of DFS were made using Kaplan-Meier product-limit method.
Time Frame	12, 24, and 36 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	101	101
12 months	93.0 92.1%	82.5 81.7%
24 months	82.7 81.9%	68.9 68.2%
36 months	69.2 68.5%	62.3 61.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.105
	Comments	Overall DFS
	Method	Cox proportional-hazards
	Comments	Adjusted for randomization stratum and the known prognostic factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.31 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Survival (OS) From Randomization - Percentage of Participants Estimated to be Alive at 12, 24, and 34 Months
Description	OS from randomization was defined as the date of randomization to the date of death from any cause. Participants still alive at the time of the final analysis were censored at the date of the last contact. Estimates of the OS function were made by the Kaplan-Meier product-limit method.
Time Frame	12, 24, and 34 months

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Rituximab Induction, Rituximab Maintenance Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	101	101
12 months	97.0 96%	100 99%
24 months	96.0 95%	96.9 95.9%
34 months	96.0 95%	95.8 94.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.751
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Overall Survival (OS) From Randomization - Percentage of Participants With Death
Description	OS from randomization was defined as the date of randomization to the date of death from any cause. Participants still alive at the time of the final analysis were censored at the date of the last contact. Estimates of the OS function were made by the Kaplan-Meier product-limit method.
Time Frame	12, 24, and 34 months

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	101	101
Number [percentage of participants]	5.0 5%	4.0 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.751
	Comments
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	OS From Enrollment - Percentage of Participants Estimated to be Alive at 12, 24, and 36 Months
Description	OS from enrollment was defined as the date of enrollment to the date of death from any cause. Participants still alive at the time of the final analysis were censored at the date of the last contact. Estimates of the OS function were made by the Kaplan-Meier product-limit method.
Time Frame	12, 24, and 36 months

Outcome Measure Data

Analysis Population Description

IP population

Arm/Group Title	Rituximab Induction, Rituximab Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.
Measure Participants	234
12 months	94.9 94%
24 months	92.7 91.8%
36 months	89.5 88.6%

7. Primary Outcome

Title	PFS Randomization- Percentage of Participants Estimated to be Free of Progression at 12, 24, and 34 Months
Description	PFS from randomization was measured from the date of randomization to the date of documented disease progression, relapse, or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last assessment date. PFS was estimated using Kaplan-Meier methods.
Time Frame	12, 24, and 34 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	101	101
12 months	92.0 91.1%	82.5 81.7%
24 months	81.0 80.2%	68.9 68.2%
34 months	70.4 69.7%	62.3 61.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments	Analysis of overall PFS with Cox proportional-hazards model adjusted for the randomization stratum and the known prognostic factors.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.079
	Comments
	Method	Cox proportional-hazards
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With a Response During the Induction Phase
Description	Participants without a response assessment (due to any reasons) were considered as non-responders.
Time Frame	Months 1 to 8

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	101	101
Complete remission (CR/CRu)	79.2 78.4%	79.2 78.4%
Partial remission	19.8 19.6%	19.8 19.6%
Stable disease	1.0 1%	0.0 0%
Progression disease	0.0 0%	0.0 0%
Missing	0.0 0%	1.0 1%

9. Secondary Outcome

Title	Percentage of Participants With a Molecular Response in the Induction Phase
Description	Molecular responders were defined as the proportion of CR/CRu participants with a positive bcl-2/IgH (non-Hodgkin's Lymphoma [NHL] marker) at baseline, whose laboratory values were undetectable after treatment.
Time Frame	Months 5 and 8

Outcome Measure Data

Analysis Population Description

IP population; only participants with a positive bcl-2/IgH (NHL marker) at baseline were included in the analysis.

Arm/Group Title	Rituximab Induction, Rituximab Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received either no treatment (observation) or rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.
Measure Participants	118
Month 5	36.4 36%
Month 8	58.5 57.9%

10. Secondary Outcome

Title	Duration of Response Using a Traditional Approach - Percentage of Participants Estimated to Have a Sustained Response at 12, 24, and 34 Months
Description	Duration of response (DOR) was defined for all participants who achieved a response (CR, CRu, and PR) at Month 3 or later, after the completion of induction phase and was measured from the date of randomization until the date of progression, relapse, or death as a result of follicular lymphoma (FL). Participants without relapse, progression, or death for causes other than FL were censored at their last assessment date. Analyses on this endpoint were performed with two different approaches. For the traditional approach, duration of response was estimated as the proportion of participants alive without progression or relapse of disease with the Kaplan-Meier method.
Time Frame	Months 12, 24, and 34

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	100	99
12 Months	93.9 93%	82.3 81.5%
24 Months	83.6 82.8%	68.6 67.9%
34 Months	69.9 69.2%	61.9 61.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.103
	Comments	Univariate analysis
	Method	Regression, Cox
	Comments	Cox model stratified for the stratification groups.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.40 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments	Multivariate analysis
	Method	Regression, Cox
	Comments	Adjusted for stratification group, age, sex, Eastern Cooperative Oncology Group Performance Status, FL International prognostic index (FLIPI) score.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.37 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Duration of Response Using the Competing Risk Approach - Cumulative Percentage of Participants With Progression, Relapse or Death as a Result of FL at 12, 24, and 34 Months
Description	DOR was defined for all participants who achieved a response (CR, CRu, and PR) at Month 3 or later, after the completion of induction phase and was measured from the date of randomization until the date of progression, relapse, or death as a result of FL. Participants without relapse, progression, or death for causes other than FL were censored at their last assessment date. Analyses on this endpoint were performed with two different approaches. For the competing risk approach, deaths for causes other than FL were considered as competing events. DOR was estimated with the cumulative incidence of progression, relapse, or death as a result of FL.
Time Frame	Months 12, 24, and 34

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Rituximab Induction, Rituximab Maintenance	Rituximab Induction, Observation Maintenance
Arm/Group Description	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.	Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
Measure Participants	100	99
12 Months	6.1 6%	17.7 17.5%
24 Months	16.2 16%	31.4 31.1%
34 Months	29.5 29.2%	38.0 37.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments	Univariate analysis
	Method	Fine and Gray model
	Comments	Fine and Gray model stratified for the stratification groups.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.39 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rituximab Induction, Rituximab Maintenance, Rituximab Induction, Observation Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.052
	Comments
	Method	Fine and Gray model
	Comments	Fine and Gray model adjusted for stratification group, age, sex, Eastern Cooperative Oncology Group Performance Status, and FLIPI score
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were reported up to Month 15.
Adverse Event Reporting Description	Analyses were performed including all patients receiving at least one dose of planned therapy, both on IP and ITT population. One participant in the Induction Phase did not receive any study drug was not included in the analysis.
Arm/Group Title	Rituximab Induction (Induction Phase Only)		Rituximab Induction, Rituximab Maintenance (Follow-up Phase)		Rituximab Induction, Observation Maintenance (Follow-up Phase)
Arm/Group Description	Rituximab Induction, Rituximab Maintenance Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses).		Rituximab Induction, Rituximab Maintenance Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: 3 months after induction treatment (Month 9), participants who showed at least a partial response after induction treatment received rituximab 375 mg/m^2 IV on Day 1. Doses were repeated every 2 months for a total of 4 doses.		Induction Phase Cycle 1 (4-week cycle): Participants received mitoxantrone 10 mg/m^2 IV on Day 1, fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 1-3, and rituximab 375 mg/m^2 on Day 8. Induction Phase Cycles 2-4 (4-week cycle): Participants received rituximab 375 mg/m^2 IV on Day 1, mitoxantrone 10 mg/m^2 IV on Day 2, and fludarabine 25 mg/m^2 IV and dexamethasone 10 mg IV on Days 2-4. One month after completion of the above 4 cycles, participants were evaluated for tumor response (clinical and molecular evaluation). Responding participants (no progressive disease) received rituximab 375 mg/m^2 IV once weekly for a total of 4 weeks (4 total doses). Maintenance Phase: no further therapy, observation only.
All Cause Mortality
	Rituximab Induction (Induction Phase Only)		Rituximab Induction, Rituximab Maintenance (Follow-up Phase)		Rituximab Induction, Observation Maintenance (Follow-up Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Rituximab Induction (Induction Phase Only)		Rituximab Induction, Rituximab Maintenance (Follow-up Phase)		Rituximab Induction, Observation Maintenance (Follow-up Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/233 (8.2%)		19/101 (18.8%)		17/101 (16.8%)
Blood and lymphatic system disorders
Neutropenia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Disseminated intravascular coagulation	0/233 (0%)		1/101 (1%)		0/101 (0%)
Thrombosis	0/233 (0%)		0/101 (0%)		1/101 (1%)
Cardiac disorders
Atrial fibrillation	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Cardiac ablation	0/233 (0%)		1/101 (1%)		0/101 (0%)
Wolff-Parkinson-White syndrome	0/233 (0%)		1/101 (1%)		0/101 (0%)
Cardiomyopathy	0/233 (0%)		1/101 (1%)		0/101 (0%)
Myocardial infarction	0/233 (0%)		2/101 (2%)		0/101 (0%)
Angina pectoris	0/233 (0%)		0/101 (0%)		2/101 (2%)
Aortic valve stenosis	0/233 (0%)		0/101 (0%)		1/101 (1%)
Cardiac failure	0/233 (0%)		0/101 (0%)		1/101 (1%)
Endocrine disorders
Diabetic vascular disorder	0/233 (0%)		1/101 (1%)		0/101 (0%)
Eye disorders
Cataract operation	0/233 (0%)		0/101 (0%)		1/101 (1%)
Gastrointestinal disorders
Intestinal obstruction	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Intestinal perforation	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Abdominal pain	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Cholecystitis acute	0/233 (0%)		1/101 (1%)		0/101 (0%)
Diarrhoea	0/233 (0%)		1/101 (1%)		0/101 (0%)
Haemorrhoids	0/233 (0%)		1/101 (1%)		0/101 (0%)
Pancreatitis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Cholelithiasis	0/233 (0%)		0/101 (0%)		3/101 (3%)
General disorders
Chest pain	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
General physical health deterioration	0/233 (0%)		0/101 (0%)		1/101 (1%)
Immune system disorders
Hypersensitivity	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pyrexia	2/233 (0.9%)		0/101 (0%)		1/101 (1%)
Infections and infestations
Cytomegalovirus infection	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Febrile neutropenia	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Hepatitis B	1/233 (0.4%)		1/101 (1%)		2/101 (2%)
Pneumonitis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Sepsis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Herpes zoster	0/233 (0%)		1/101 (1%)		0/101 (0%)
Pneumonia	0/233 (0%)		2/101 (2%)		2/101 (2%)
Septic shock	0/233 (0%)		1/101 (1%)		0/101 (0%)
Musculoskeletal and connective tissue disorders
Spinal compression fracture	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Femur fracture	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hip arthroplasty	0/233 (0%)		0/101 (0%)		1/101 (1%)
Upper limb fracture	0/233 (0%)		0/101 (0%)		1/101 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Adenocarcinoma	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Squamous cell carcinoma	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Thyroid cancer	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Colon cancer	0/233 (0%)		0/101 (0%)		1/101 (1%)
Laryngeal cancer	0/233 (0%)		0/101 (0%)		1/101 (1%)
Prostate cancer	0/233 (0%)		0/101 (0%)		1/101 (1%)
Renal cancer	0/233 (0%)		0/101 (0%)		1/101 (1%)
Squamous cell carcinoma of skin	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hodgkin's lymphoma	0/233 (0%)		1/101 (1%)		0/101 (0%)
Plasmablastic lymphoma	0/233 (0%)		1/101 (1%)		0/101 (0%)
Nervous system disorders
Transient ischaemic shock	0/233 (0%)		1/101 (1%)		0/101 (0%)
Cerebrovascular accident	0/233 (0%)		0/101 (0%)		1/101 (1%)
Renal and urinary disorders
Renal cyst	0/233 (0%)		1/101 (1%)		0/101 (0%)
Reproductive system and breast disorders
Ovarian adenoma	0/233 (0%)		0/101 (0%)		1/101 (1%)
Respiratory, thoracic and mediastinal disorders
Lung infiltration	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pleurisy	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pleural effusion	0/233 (0%)		1/101 (1%)		0/101 (0%)
Sarcoidosis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Respiratory failure	0/233 (0%)		0/101 (0%)		1/101 (1%)
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Vascular disorders
Deep vein thrombosis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pulmonary embolism	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Other (Not Including Serious) Adverse Events
	Rituximab Induction (Induction Phase Only)		Rituximab Induction, Rituximab Maintenance (Follow-up Phase)		Rituximab Induction, Observation Maintenance (Follow-up Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	230/233 (98.7%)		73/101 (72.3%)		55/101 (54.5%)
Blood and lymphatic system disorders
Anaemia	103/233 (44.2%)		1/101 (1%)		1/101 (1%)
Neutropenia	225/233 (96.6%)		16/101 (15.8%)		2/101 (2%)
Thrombocytopenia	120/233 (51.5%)		2/101 (2%)		1/101 (1%)
Leukopenia	0/233 (0%)		5/101 (5%)		0/101 (0%)
Lymphopenia	0/233 (0%)		0/101 (0%)		1/101 (1%)
Febrile neutropenia	3/233 (1.3%)		0/101 (0%)		0/101 (0%)
Neutrophilia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Cardiac disorders
Atrial flutter	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Palpitations	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Bradycardia	0/233 (0%)		0/101 (0%)		1/101 (1%)
Extrasystoles	0/233 (0%)		0/101 (0%)		1/101 (1%)
Arrhythmia	0/233 (0%)		2/101 (2%)		0/101 (0%)
Ischaemia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Sinus tachycardia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Ventricular extrasystoles	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Ejection fracture decreased	0/233 (0%)		1/101 (1%)		0/101 (0%)
Ear and labyrinth disorders
Altered hearing	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Deafness	2/233 (0.9%)		1/101 (1%)		0/101 (0%)
Ear pain	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Vertigo	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Endocrine disorders
Diabetes mellitus	2/233 (0.9%)		0/101 (0%)		1/101 (1%)
Diabetic vascular disorder	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Goitre	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Hypothyroidism	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hyperthyroidism	0/233 (0%)		1/101 (1%)		0/101 (0%)
Thyroiditis chronic	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Aptyalism	0/233 (0%)		0/101 (0%)		1/101 (1%)
Eye disorders
Conjunctivitis	1/233 (0.4%)		1/101 (1%)		3/101 (3%)
Cataract	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Glaucoma	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Diplopia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Visual acuity reduced	0/233 (0%)		2/101 (2%)		0/101 (0%)
Vitreous haemorrhage	0/233 (0%)		1/101 (1%)		0/101 (0%)
Gastrointestinal disorders
Gastroenteritis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Choking sensation	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Abdominal ridigity	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Anal ulcer	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Colitis	2/233 (0.9%)		1/101 (1%)		0/101 (0%)
Constipation	24/233 (10.3%)		1/101 (1%)		1/101 (1%)
Diarrhoea	23/233 (9.9%)		2/101 (2%)		1/101 (1%)
Dyspepsia	3/233 (1.3%)		1/101 (1%)		0/101 (0%)
Gastric ulcer	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Gastritis	5/233 (2.1%)		0/101 (0%)		3/101 (3%)
Gastrooesophageal reflux disease	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Gingivitis	2/233 (0.9%)		1/101 (1%)		0/101 (0%)
Haemorrhoids	2/233 (0.9%)		1/101 (1%)		1/101 (1%)
Nausea	43/233 (18.5%)		0/101 (0%)		0/101 (0%)
Oesophagitis	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Pulpitis dental	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Stomatitis	23/233 (9.9%)		2/101 (2%)		0/101 (0%)
Vomiting	8/233 (3.4%)		2/101 (2%)		0/101 (0%)
Anal discomfort	0/233 (0%)		1/101 (1%)		0/101 (0%)
Anal haemorrhage	0/233 (0%)		1/101 (1%)		0/101 (0%)
Diverticulum	0/233 (0%)		1/101 (1%)		0/101 (0%)
Duodenal ulcer	0/233 (0%)		1/101 (1%)		0/101 (0%)
Enteritis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Flatulence	0/233 (0%)		1/101 (1%)		0/101 (0%)
Haematochezia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Pancreatic disorder	0/233 (0%)		1/101 (1%)		0/101 (0%)
Polyp colorectal	0/233 (0%)		1/101 (1%)		0/101 (0%)
Reflux oesophagitis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Aphthous stomatitis	0/233 (0%)		0/101 (0%)		2/101 (2%)
Abdominal pain	10/233 (4.3%)		2/101 (2%)		2/101 (2%)
Abdominal pain upper	12/233 (5.2%)		2/101 (2%)		1/101 (1%)
Hiatus hernia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Ascites	0/233 (0%)		1/101 (1%)		0/101 (0%)
Toothache	0/233 (0%)		1/101 (1%)		0/101 (0%)
Inguinal hernia	0/233 (0%)		0/101 (0%)		1/101 (1%)
General disorders
Edema	11/233 (4.7%)		0/101 (0%)		0/101 (0%)
Hyperpyrexia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Hyperthermia	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Infusion related reaction	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Oedema	2/233 (0.9%)		0/101 (0%)		2/101 (2%)
Oedema peripheral	7/233 (3%)		2/101 (2%)		0/101 (0%)
Pharyngeal oedema	2/233 (0.9%)		8/101 (7.9%)		0/101 (0%)
Pyrexia	44/233 (18.9%)		8/101 (7.9%)		3/101 (3%)
Asthenia	16/233 (6.9%)		4/101 (4%)		5/101 (5%)
Asthenia/fatigue	57/233 (24.5%)		0/101 (0%)		0/101 (0%)
Chills	4/233 (1.7%)		0/101 (0%)		0/101 (0%)
Fatigue	3/233 (1.3%)		1/101 (1%)		1/101 (1%)
Oedema mucosal	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hypothermia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Mucosal inflammation	6/233 (2.6%)		1/101 (1%)		0/101 (0%)
Feeling hot	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Fistula	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Chest pain	4/233 (1.7%)		1/101 (1%)		0/101 (0%)
Pain	31/233 (13.3%)		0/101 (0%)		13/101 (12.9%)
Irritability	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Hepatobiliary disorders
Cholelithiasis	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hepatomegaly	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Immune system disorders
Drug hypersensitivity	6/233 (2.6%)		0/101 (0%)		1/101 (1%)
Hypersensitivity	11/233 (4.7%)		0/101 (0%)		1/101 (1%)
Infections and infestations
Bronchospasm	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Bronchopneumonia	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Cytomegalovirus infection	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Ear infection	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Escherichia infection	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Fungal infection	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Genitourinary tract infection	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Herpes simplex	6/233 (2.6%)		0/101 (0%)		0/101 (0%)
Herpes zoster	4/233 (1.7%)		2/101 (2%)		3/101 (3%)
Klebsiella infection	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Klebsiella sepsis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Onychomycosis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pneumonia	3/233 (1.3%)		2/101 (2%)		0/101 (0%)
Prostate infection	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pseudomonas infection	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Respiratory tract infection	2/233 (0.9%)		0/101 (0%)		1/101 (1%)
Tonsillitis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Tooth abscess	2/233 (0.9%)		2/101 (2%)		1/101 (1%)
Urinary tract infection	2/233 (0.9%)		2/101 (2%)		0/101 (0%)
Vaginal candidiasis	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Viral infection	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Viral DNA test positive	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Hepatitis B	0/233 (0%)		1/101 (1%)		0/101 (0%)
Infection	0/233 (0%)		1/101 (1%)		0/101 (0%)
Pneumonitis	0/233 (0%)		2/101 (2%)		0/101 (0%)
Upper respiratory tract infection	0/233 (0%)		2/101 (2%)		0/101 (0%)
Bronchitis	3/233 (1.3%)		1/101 (1%)		7/101 (6.9%)
Lung infection	0/233 (0%)		0/101 (0%)		1/101 (1%)
Nasopharyngeal disorder	0/233 (0%)		0/101 (0%)		1/101 (1%)
Pharyngitis	0/233 (0%)		2/101 (2%)		2/101 (2%)
Rhinitis	0/233 (0%)		4/101 (4%)		2/101 (2%)
Influenza	7/233 (3%)		5/101 (5%)		9/101 (8.9%)
Diverticulitis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Laryngitis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Gastrointestinal infection	0/233 (0%)		1/101 (1%)		0/101 (0%)
Helicobacter gastritis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Helicobacter pylori identification test positive	0/233 (0%)		1/101 (1%)		0/101 (0%)
Hepatitis viral	0/233 (0%)		1/101 (1%)		0/101 (0%)
Cystitis	5/233 (2.1%)		1/101 (1%)		4/101 (4%)
Bronchitis chronic	0/233 (0%)		1/101 (1%)		0/101 (0%)
Nasopharyngitis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Sinusitis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Tracheitis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Injury, poisoning and procedural complications
Clavicle fracture	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Fracture	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Spinal fracture	2/233 (0.9%)		0/101 (0%)		1/101 (1%)
Ankle fracture	0/233 (0%)		1/101 (1%)		0/101 (0%)
Foot fracture	0/233 (0%)		1/101 (1%)		0/101 (0%)
Humerus fracture	0/233 (0%)		1/101 (1%)		1/101 (1%)
Upper limb fracture	0/233 (0%)		0/101 (0%)		1/101 (1%)
Investigations
Weight increased	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Weight decreased	0/233 (0%)		2/101 (2%)		1/101 (1%)
Blood amylase increased	0/233 (0%)		0/101 (0%)		1/101 (1%)
Liver function test abnormal	0/233 (0%)		0/101 (0%)		1/101 (1%)
Alanine aminotransferase increased	2/233 (0.9%)		2/101 (2%)		1/101 (1%)
Aspartate aminotransferase increased	2/233 (0.9%)		1/101 (1%)		1/101 (1%)
Beta 2 microglobulin increased	0/233 (0%)		1/101 (1%)		1/101 (1%)
Blood immunoglobulin A decreased	0/233 (0%)		0/101 (0%)		1/101 (1%)
Blood immunoglobulin G decreased	0/233 (0%)		0/101 (0%)		1/101 (1%)
Blood immunoglobulin M decreased	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Blood lactate dehydrogenase increased	4/233 (1.7%)		2/101 (2%)		1/101 (1%)
Blood uric acid increased	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Gamma-glutamyltransferase increased	3/233 (1.3%)		1/101 (1%)		1/101 (1%)
Blood alkaline phosphatase increased	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Blood bilirubin increased	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Blood creatinine increased	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Blood glucose increased	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Gamma-glutamyltransferase	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Hyperkalaemia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Red blood cell sedimentation rate increased	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Transaminases abnormal	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Transaminases increased	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Blood alkaline phosphatase	0/233 (0%)		1/101 (1%)		0/101 (0%)
Blood amylase	0/233 (0%)		1/101 (1%)		0/101 (0%)
Alanine aminotransferase	0/233 (0%)		1/101 (1%)		0/101 (0%)
Blood potassium increased	0/233 (0%)		1/101 (1%)		0/101 (0%)
Haemoglobin increaed	0/233 (0%)		1/101 (1%)		0/101 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Anorexia	16/233 (6.9%)		0/101 (0%)		0/101 (0%)
Hypercholesterolaemia	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hypertriglyceridaemia	0/233 (0%)		0/101 (0%)		1/101 (1%)
Hyperuricaemia	4/233 (1.7%)		2/101 (2%)		2/101 (2%)
Hypokalaemia	2/233 (0.9%)		1/101 (1%)		0/101 (0%)
Iron deficiency	0/233 (0%)		1/101 (1%)		0/101 (0%)
Vitamin B12 deficiency	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Hypernatraemia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Musculoskeletal and connective tissue disorders
Osteopenia	2/233 (0.9%)		1/101 (1%)		0/101 (0%)
Osteoporosis	2/233 (0.9%)		0/101 (0%)		5/101 (5%)
Muscle spasms	3/233 (1.3%)		0/101 (0%)		0/101 (0%)
Back pain	10/233 (4.3%)		0/101 (0%)		4/101 (4%)
Bone pain	7/233 (3%)		0/101 (0%)		0/101 (0%)
Musculoskeletal pain	2/233 (0.9%)		2/101 (2%)		1/101 (1%)
Myalgia	9/233 (3.9%)		2/101 (2%)		1/101 (1%)
Pain in extremity	5/233 (2.1%)		4/101 (4%)		1/101 (1%)
Pelvic pain	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Shoulder pain	1/233 (0.4%)		1/101 (1%)		1/101 (1%)
Arthralgia	17/233 (7.3%)		1/101 (1%)		2/101 (2%)
Bone density increased	0/233 (0%)		1/101 (1%)		0/101 (0%)
Neck pain	0/233 (0%)		1/101 (1%)		1/101 (1%)
Osteoarthritis	0/233 (0%)		2/101 (2%)		0/101 (0%)
Groin pain	0/233 (0%)		0/101 (0%)		1/101 (1%)
Intervertebral disc protrusion	0/233 (0%)		0/101 (0%)		1/101 (1%)
Movement disorder	0/233 (0%)		0/101 (0%)		1/101 (1%)
Musculoskeletal discomfort	0/233 (0%)		0/101 (0%)		1/101 (1%)
Exostosis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Osteitis deformans	0/233 (0%)		0/101 (0%)		1/101 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid neoplasm	0/233 (0%)		0/101 (0%)		2/101 (2%)
Laryngeal cancer	0/233 (0%)		1/101 (1%)		0/101 (0%)
Lung neoplasm	0/233 (0%)		1/101 (1%)		0/101 (0%)
Ovarian cancer	0/233 (0%)		1/101 (1%)		0/101 (0%)
Prostate cancer	0/233 (0%)		1/101 (1%)		0/101 (0%)
Nervous system disorders
Syncope	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Dizziness	1/233 (0.4%)		3/101 (3%)		0/101 (0%)
Facial palsy	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Neuropathy	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Neuropathy: motor	5/233 (2.1%)		0/101 (0%)		0/101 (0%)
Neuropathy: sensory	9/233 (3.9%)		0/101 (0%)		0/101 (0%)
Paraesthesia	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Paraesthesia oral	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Peripheral sensory neuropathy	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Headache	7/233 (3%)		3/101 (3%)		0/101 (0%)
Migraine	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Epilepsy	0/233 (0%)		1/101 (1%)		0/101 (0%)
Vagotomy	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Psychiatric disorders
Insomnia	7/233 (3%)		1/101 (1%)		0/101 (0%)
Anxiety	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Confusional state	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Depressed mood	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Depression	2/233 (0.9%)		2/101 (2%)		0/101 (0%)
Amnesia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Renal and urinary disorders
Dysuria	4/233 (1.7%)		0/101 (0%)		1/101 (1%)
Benign prostatic hyperplasia	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Incontinence	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Micturition urgency	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pollakiuria	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Urinary tract disorder	1/233 (0.4%)		0/101 (0%)		1/101 (1%)
Prostate examination abnormal	0/233 (0%)		0/101 (0%)		1/101 (1%)
Reproductive system and breast disorders
Vaginal burning sensation	0/233 (0%)		1/101 (1%)		0/101 (0%)
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	3/233 (1.3%)		0/101 (0%)		0/101 (0%)
Aphonia	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Epistaxis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Pharyngolaryngeal pain	3/233 (1.3%)		1/101 (1%)		0/101 (0%)
Cough	17/233 (7.3%)		13/101 (12.9%)		10/101 (9.9%)
Dyspnoea	7/233 (3%)		1/101 (1%)		5/101 (5%)
Pleural effusion	1/233 (0.4%)		0/101 (0%)		2/101 (2%)
Rhinorrhoea	0/233 (0%)		0/101 (0%)		1/101 (1%)
Chronic obstructive pulmonary disease	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Lung infiltration	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Productive cough	5/233 (2.1%)		0/101 (0%)		0/101 (0%)
Dysphonia	0/233 (0%)		1/101 (1%)		0/101 (0%)
Respiratory disorder	0/233 (0%)		1/101 (1%)		0/101 (0%)
Skin and subcutaneous tissue disorders
Rash erythematous	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Alopecia	15/233 (6.4%)		1/101 (1%)		0/101 (0%)
Dermatitis	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Erythema	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Pruritus	4/233 (1.7%)		0/101 (0%)		3/101 (3%)
Rash	3/233 (1.3%)		0/101 (0%)		1/101 (1%)
Skin	8/233 (3.4%)		0/101 (0%)		0/101 (0%)
Skin lesion	1/233 (0.4%)		1/101 (1%)		0/101 (0%)
Urticaria	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Eczema	0/233 (0%)		1/101 (1%)		0/101 (0%)
Erythema nodosum	0/233 (0%)		1/101 (1%)		0/101 (0%)
Hyperkeratosis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Neck mass	0/233 (0%)		1/101 (1%)		0/101 (0%)
Psoriasis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Skin necrosis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Skin infection	0/233 (0%)		0/101 (0%)		1/101 (1%)
Furuncle	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Vascular disorders
Hypertension	7/233 (3%)		2/101 (2%)		1/101 (1%)
Hypotension	3/233 (1.3%)		1/101 (1%)		1/101 (1%)
Pulse pressure increased	1/233 (0.4%)		0/101 (0%)		0/101 (0%)
Deep vein thrombosis	4/233 (1.7%)		0/101 (0%)		0/101 (0%)
Phlebitis	2/233 (0.9%)		0/101 (0%)		0/101 (0%)
Hypertensive crisis	0/233 (0%)		1/101 (1%)		0/101 (0%)
Blood pressure increased	0/233 (0%)		0/101 (0%)		1/101 (1%)
Carotid artery stenosis	0/233 (0%)		0/101 (0%)		1/101 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The study being conducted under this agreement is part of the overall study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study, but after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.