Pharmacokinetics and Pharmacodynamics of BI 695500 vs. Rituximab as First Line-treatment in Patients With Low Tumor Burden Follicular Lymphoma

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01950273
• Collaborator: (none)
• Enrollment: 95
• Locations: 29
• Arms: 2
• Actual Duration (Months): 26.8
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of the study is to assess the pharmacokinetic (PK) similarity of Boehringer Ingelheim (BI) 695500 vs. rituximab (MabThera®) in previously untreated patients with low tumor burden follicular lymphoma (LTBFL).

The secondary objective of the study is to evaluate the pharmacodynamics (PD), safety, and anti-tumor activity of BI 695500 vs. rituximab (MabThera®), as well as the presence of anti-drug antibodies (ADAs).

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Follicular	Drug: BI 695500; Drug: MabThera	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-arm, Phase I Study to Evaluate the Pharmacokinetics and Pharmacodynamics of BI 695500 vs. Rituximab (MabThera) Induction Immunotherapy as a First-line Treatment in Patients With Low Tumor Burden Follicular Lymphoma
• Actual Study Start Date: Sep 27, 2013
• Actual Primary Completion Date: Dec 22, 2015
• Actual Study Completion Date: Dec 22, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI695500 BI695500, once a week for 4 weeks (4 administrations in total)	Drug: BI 695500; BI695500, once a week for 4 weeks (4 administrations in total)
Active Comparator: MabThera MabThera, once a week for 4 weeks (4 administration in total)	Drug: MabThera; MabThera, once a week for 4 weeks (4 administrations in total)

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration (AUC) Time Curve of BI 695500 and Rituximab (MabThera®) Over the First Dosing Interval (Pre-infusion on Day 1 to Pre-infusion on Day 8) [Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1.]

   This outcome measure presents area under the concentration time curve of BI 695500 and Rituximab (MabThera®) over the first dosing interval (pre-infusion on Day 1 to pre-infusion on Day 8) (AUCDay 1-Day 8) for assessment of PK (Pharmacokinetics) similarity.

Secondary Outcome Measures

1. AUC of BI 695500 and Rituximab (MabThera®) Over the Fourth Dosing Interval (Pre-infusion on Day 22 to Day 29) (AUC Day 22-Day 29) [Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96 and 168 hours from start of infusion 4.]

   This outcome measure presents area under the concentration of BI 695500 and Rituximab (MabThera®) over the fourth dosing interval (pre-infusion on Day 22 to Day 29).

2. Maximum Measured Concentration of BI 695500 and Rituximab (MabThera®) in Plasma (Cmax) Following Dose 1 [Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1.]

   This outcome measure presents maximum measured concentration of BI 695500 and Rituximab (MabThera®) in plasma (Cmax) following Dose 1

3. Maximum Measured Concentration of Rituximab (MabThera®) and BI 695500 in Plasma (Cmax) Following Dose 4 [Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96, 168, 336, 672, 1344, 2016 and 2880 hours from start of infusion 4.]

   This outcome measure presents maximum measured concentration of Rituximab (MabThera®) and BI 695500 in plasma (Cmax) following Dose 4.

4. Area Under the Depletion-time Curve of the Cluster of Differentiation (CD)19+ B-cell Count (% Change From Baseline (CFB)) in Peripheral Blood From Pre-infusion on Day 1 Until Last Measurement on Day 8 (Pre-infusion) [Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion, and at 24, 48, 72, 96 and 168 hours from start of infusion.]

   This outcome measure presents area under the depletion-time curve of the CD19+ B-cell count (% change from baseline) in peripheral blood from pre-infusion on Day 1 until last measurement on Day 8 (pre-infusion) (AUC Day 1-Day 8, CD19+).

5. Change From Baseline (%) of CD19+ B-cells in Peripheral Blood Measured After Seven Days on Day 8 (Day 8 Pre-infusion Time Point) [Blood sampling was done at 168 hours from start of infusion.]

   This outcome measure presents percent change from baseline of CD19+ B-cells in peripheral blood, measured after 7 days (i.e., Day 8 pre-infusion time point) (PCFBpre,2 CD19+).

6. Overall Response Rate (ORR) (Complete Response (CR) Plus Partial Response (PR)) Evaluated Approximately One Month After Last Dose of BI 695500 or Rituximab (MabThera®) [at Day 50.]

   Overall Response Rate (ORR) comprised Complete Response (CR) plus Partial Response (PR) evaluated approximately one month after last dose of BI 695500 or Rituximab [MabThera®]. Overall Response as defined by the revised International Working Group (IWG) Criteria 2007, using the Investigator's assessment.

7. Percentage of Patients With Treatment Emergent Adverse Events (TEAEs) Selected for Comparability Assessment of BI 695500 and Rituximab (MabThera®) [Adverse Events (AEs) that started or worsened on or after the first dose of study medication and prior to the last date of study medication + 4 months (120 days) inclusive.]

   This outcome measure presents percentage of patients with Treatment Emergent Adverse Events (TEAEs) selected for comparability assessment of BI 695500 and Rituximab (MabThera®).

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Must give written informed consent and be willing to follow this Clinical Trial Protocol.

• Male or female patients, at least 18 years of age at Screening.

• Histologically-confirmed, stage II - IV Non-Hodgkin's lymphoma (CD20+ FL of Grades 1, 2, or 3a).

• Low tumor burden according to the Groupe d'Etudes des Lymphomes Folliculaires (GELF) criteria - no nodal or extranodal involvement of more than 7 cm, no more than 3 nodal sites with a diameter >3 cm, no B symptoms (i.e., fever >38°C, weight loss - unexplained loss of >10 % body weight over the past 6 months, and sweats - the presence of drenching night sweats), no significant splenomegaly, no significant serious effusion, no complications such as organ compression, and less than 5x10^9/L circulating tumor cells.

• Availability of archived tumor sample prior to screening.

• Patients not previously treated for their FL.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

• Have at least 1 measurable lesion as per the International Working Group (IWG) criteria 2007 at Screening (lesion clearly measurable in at least 2 perpendicular dimensions; see Appendix 10.1 for further details).

• Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow) within 28 days prior to randomization, including:

• • hemoglobin =9.0 g/dL (=5.6 mmol/L).
• • absolute neutrophil count =1.5 × 10^9/L.
• • platelet count =100 × 10^9/L.

• Adequate renal and liver function:

• • serum creatinine <2.0 mg/dL (<176.8 micromol/L).
• • total bilirubin <2.0 mg/dL (<34 mcmol/L) except for patient with Gilbert's Syndrome or Hemolysis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x upper limit of normal (ULN) (<5 x ULN is acceptable if abnormalities are thought to be related to hepatic infiltration by FL).

• For participants of reproductive potential (males and females), use of a medically acceptable method of contraception during the trial, i.e., a combination of 2 forms of effective contraception (defined as hormonal contraception, intrauterine device, condom with spermicide, etc.). Females of childbearing potential (includes tubal ligation) and males with female partners of childbearing potential must also agree to use an acceptable method of contraception (see above) for 12 months following completion or discontinuation from the trial medication.

Exclusion criteria:

• Transformation to high-grade lymphoma (secondary to low-grade lymphoma).

• Presence or history of central nervous system lymphoma.

• Patients receiving current treatment with corticosteroids must not be receiving a dose exceeding 20 mg/day prednisone or equivalent.

• Patients with prior or concomitant malignancies within 5 years prior to screening except non-melanoma skin cancer, adequately treated carcinoma in situ of the cervix, adequately treated breast cancer in situ, localized prostate cancer stage T1c - provided that the patient underwent curative treatment, and remains relapse free.

• Major surgery (excluding lymph node biopsy) within 28 days prior to randomization.

• Active, chronic or persistent infection that might worsen with immunosuppressive treatment (e.g., Human Immunodeficiency Virus [HIV], Hepatitis C Virus [HCV], Herpes Zoster); positive for HIV or tuberculosis at Screening.

• Patients with serological evidence of Hepatitis B virus (HBV) infection. Patients seropositive because of HBV vaccine are eligible. HBV positive patients may participate following consultation with a hepatitis expert regarding monitoring and use of HBV antiviral therapy, and provided they agree to receive treatment as indicated.

• Serious underlying medical conditions, which, per the investigator's discretion, could impair the ability of the patient to participate in the trial (including but not limited to ongoing active infection, severe immunosuppression, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease); patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the NYHA classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease.

• Known hypersensitivity or allergy to murine products.

• History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the trial drug.

• Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit.

• Prior treatment with BI 695500 and/or rituximab.

• Patients who received any prior therapy using monoclonal antibodies will be excluded; this does not apply to other biological drugs such as growth factors or anticoagulants.

• Treatment within a clinical trial within 4 weeks prior to initiation of trial treatment. Patients who have received treatment with a drug that has not received regulatory approval for any indication within 4 weeks or a minimum of 5 half-lives, whichever is longer, of the initial dose of trial medication.

• Any other co-existing medical or psychological condition(s) that will preclude participation in the trial or compromise ability to give informed consent and/or comply with study procedures.

• Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit.

• Patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the New York Heart Association (NYHA) classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease; or uncontrolled hypertension.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Canberra Hospital	Canberra	Migration Data	Australia	2605
2	AKH - Medical University of Vienna	Wien		Austria	1090
3	Brussels - UNIV St-Luc	Bruxelles		Belgium	1200
4	UZ Leuven	Leuven		Belgium	3000
5	Namur - HOSP Ste-Elisabeth	Namur		Belgium	5000
6	Clinical Hospital Centre Zagreb	Zagreb		Croatia	10000
7	University Hospital Brno	Brno		Czechia	625 00
8	University Hospital Ostrava	Ostrava-Poruba		Czechia	70852
9	Vseobecna fakultni nemocnice V Praze	Praha 2		Czechia	128 08
10	INS Bergonié	Bordeaux cedex		France	33076
11	HOP Morvan	Brest		France	29609
12	Centre Hospitalier Départemental Les Oudairies	La Roche sur Yon		France	85025
13	HOP Haut-Lévêque	Pessac		France	33600
14	Hôpital la Milétrie - CHU Poitiers	Poitiers		France	86021
15	Gesundheitszentrum Wetterau gGmbH	Bad Nauheim		Germany	61231
16	Universitätsklinikum Carl Gustav Carus Dresden	Dresden		Germany	01307
17	Universitätsklinikum Freiburg	Freiburg		Germany	79106
18	Haemato-Onkologie Hamburg	Hamburg		Germany	21075
19	Klinikum Kassel GmbH	Kassel		Germany	34125
20	General Hospital of Athens "G. Gennimatas"	Athens		Greece	11527
21	Semmelweis University, 1st Dept. Internal Medicine	Budapest		Hungary	1083
22	Auckland Clinical Studies Ltd	Auckland		New Zealand	1010
23	Oncol Centre M Sklodowska-Curie, Dept of Lung & Chest Cancer	Warszawa		Poland	02-781
24	BHI of Omsk region - Clinical Oncology Dispensary	Omsk		Russian Federation	644013
25	St. Petersburg GUZ City Clinical Oncology Dispensary	St. Petersburg		Russian Federation	198255
26	Hospital Germans Trias i Pujol	Badalona		Spain	08916
27	Hospital Puerta del Mar	Cádiz		Spain	11009
28	Fundación Jiménez Díaz	Madrid		Spain	28040
29	Hospital Virgen del Rocío	Sevilla		Spain	41013

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01950273
• Other Study ID Numbers: 1301.5; 2013-001904-12
• First Posted: Sep 25, 2013
• Last Update Posted: Sep 5, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Rituximab

Study Results

Participant Flow

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500 (Test)/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera® (Reference))/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Period Title: Overall Study
STARTED	49	46
COMPLETED	45	46
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	BI 695500	Rituximab (MabThera®)	Total
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.	Total of all reporting groups
Overall Participants	49	46	95
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.6 (12.44)	58.4 (11.48)	59.0 (11.93)
Sex: Female, Male (Count of Participants)
Female	23 46.9%	27 58.7%	50 52.6%
Male	26 53.1%	19 41.3%	45 47.4%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration (AUC) Time Curve of BI 695500 and Rituximab (MabThera®) Over the First Dosing Interval (Pre-infusion on Day 1 to Pre-infusion on Day 8)
Description	This outcome measure presents area under the concentration time curve of BI 695500 and Rituximab (MabThera®) over the first dosing interval (pre-infusion on Day 1 to pre-infusion on Day 8) (AUCDay 1-Day 8) for assessment of PK (Pharmacokinetics) similarity.
Time Frame	Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1.

Outcome Measure Data

Analysis Population Description

The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had an estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	46	43
Geometric Mean (Geometric Coefficient of Variation) [microgram*hour/millilitre (µg*h/mL)]	15700 (69.8)	17600 (27.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard equivalence limit 80% to 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) mean ratio
	Estimated Value	89.53
	Confidence Interval	(2-Sided) 90%; 75.42 to 106.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the adjusted geometric means calculated as (LS mean ratio of BI 695500/Rituximab (MabThera®)).

2. Secondary Outcome

Title	AUC of BI 695500 and Rituximab (MabThera®) Over the Fourth Dosing Interval (Pre-infusion on Day 22 to Day 29) (AUC Day 22-Day 29)
Description	This outcome measure presents area under the concentration of BI 695500 and Rituximab (MabThera®) over the fourth dosing interval (pre-infusion on Day 22 to Day 29).
Time Frame	Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96 and 168 hours from start of infusion 4.

Outcome Measure Data

Analysis Population Description

The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	40	43
Geometric Mean (Geometric Coefficient of Variation) [microgram*hour/millilitre (µg*h/mL)]	41700 (32.3)	44300 (24.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard equivalence limit 80% to 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) means ratio
	Estimated Value	94.60
	Confidence Interval	() 90%; 85.04 to 105.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the adjusted geometric means calculated as (LS mean ratio of BI 695500/Rituximab (MabThera®)).

3. Secondary Outcome

Title	Maximum Measured Concentration of BI 695500 and Rituximab (MabThera®) in Plasma (Cmax) Following Dose 1
Description	This outcome measure presents maximum measured concentration of BI 695500 and Rituximab (MabThera®) in plasma (Cmax) following Dose 1
Time Frame	Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1.

Outcome Measure Data

Analysis Population Description

The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	46	44
Geometric Mean (Geometric Coefficient of Variation) [microgram/millilitre (µg/mL)]	207.882 (58.5)	228.802 (25.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard equivalence limit 80% to 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) means ratio
	Estimated Value	89.94
	Confidence Interval	(2-Sided) 90%; 77.62 to 104.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the adjusted geometric means calculated as (LS mean ratio of BI 695500/Rituximab (MabThera®)).

4. Secondary Outcome

Title	Maximum Measured Concentration of Rituximab (MabThera®) and BI 695500 in Plasma (Cmax) Following Dose 4
Description	This outcome measure presents maximum measured concentration of Rituximab (MabThera®) and BI 695500 in plasma (Cmax) following Dose 4.
Time Frame	Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96, 168, 336, 672, 1344, 2016 and 2880 hours from start of infusion 4.

Outcome Measure Data

Analysis Population Description

The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	39	42
Geometric Mean (Geometric Coefficient of Variation) [microgram/millilitre (µg/mL)]	397.080 (23.1)	412.190 (18.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard equivalence limit 80% to 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) means ratio
	Estimated Value	97.65
	Confidence Interval	(2-Sided) 90%; 90.45 to 105.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the adjusted geometric means calculated as (LS mean ratio of BI 695500/Rituximab (MabThera®)).

5. Secondary Outcome

Title	Area Under the Depletion-time Curve of the Cluster of Differentiation (CD)19+ B-cell Count (% Change From Baseline (CFB)) in Peripheral Blood From Pre-infusion on Day 1 Until Last Measurement on Day 8 (Pre-infusion)
Description	This outcome measure presents area under the depletion-time curve of the CD19+ B-cell count (% change from baseline) in peripheral blood from pre-infusion on Day 1 until last measurement on Day 8 (pre-infusion) (AUC Day 1-Day 8, CD19+).
Time Frame	Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion, and at 24, 48, 72, 96 and 168 hours from start of infusion.

Outcome Measure Data

Analysis Population Description

The PK analysis Set Descriptive (PKSD) consisted of all randomized subjects who received at least one dose of trial medication BI 695500 or Rituximab [MabThera®], had at least one post-treatment PK concentration value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	32	41
Mean (Standard Deviation) [Percentage CFB of CD19+ B-cells*hour]	-16895.2 (1016.9)	-17064.4 (1403.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	249.2
	Confidence Interval	(2-Sided) 90%; -210.6 to 709
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean difference calculated as BI 695500-Rituximab (MabThera®).

6. Secondary Outcome

Title	Change From Baseline (%) of CD19+ B-cells in Peripheral Blood Measured After Seven Days on Day 8 (Day 8 Pre-infusion Time Point)
Description	This outcome measure presents percent change from baseline of CD19+ B-cells in peripheral blood, measured after 7 days (i.e., Day 8 pre-infusion time point) (PCFBpre,2 CD19+).
Time Frame	Blood sampling was done at 168 hours from start of infusion.

Outcome Measure Data

Analysis Population Description

The PK analysis Set Descriptive (PKSD) consisted of all randomized subjects who received at least one dose of trial medication BI 695500 or Rituximab [MabThera®], had at least one post-treatment PK concentration value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	33	42
Mean (Standard Deviation) [Percentage (%) CFB of CD19+ B-cells]	-99.2 (1.7)	-98.8 (4.2)

7. Secondary Outcome

Title	Overall Response Rate (ORR) (Complete Response (CR) Plus Partial Response (PR)) Evaluated Approximately One Month After Last Dose of BI 695500 or Rituximab (MabThera®)
Description	Overall Response Rate (ORR) comprised Complete Response (CR) plus Partial Response (PR) evaluated approximately one month after last dose of BI 695500 or Rituximab [MabThera®]. Overall Response as defined by the revised International Working Group (IWG) Criteria 2007, using the Investigator's assessment.
Time Frame	at Day 50.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAS): The patients who received at least one dose of trial medication and classified as per treatment received.

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	22	25
Number [Percentage of subjects]	44.9	54.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.4
	Confidence Interval	(2-Sided) 95%; -29.4 to 11.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in ORR calculated as ORR (BI695500) - ORR (MabThera®). The confidence interval represented is 95% difference in proportions.

8. Secondary Outcome

Title	Percentage of Patients With Treatment Emergent Adverse Events (TEAEs) Selected for Comparability Assessment of BI 695500 and Rituximab (MabThera®)
Description	This outcome measure presents percentage of patients with Treatment Emergent Adverse Events (TEAEs) selected for comparability assessment of BI 695500 and Rituximab (MabThera®).
Time Frame	Adverse Events (AEs) that started or worsened on or after the first dose of study medication and prior to the last date of study medication + 4 months (120 days) inclusive.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAS): The patients who received at least one dose of trial medication and classified as per treatment received.

Arm/Group Title	BI 695500	Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.	The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
Measure Participants	18	16
Number [Percentage of patients]	36.7	34.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituximab (MabThera®)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -18.0 to 22.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in TEAE incidence calculated as BI695500 - TEAE incidence (MabThera®). The confidence interval represented is 95% difference in proportions.

Adverse Events

Time Frame	From first drug administration until 142 days after last drug administration, up to 156 days.
Arm/Group Title	BI 695500		Rituximab (MabThera®)
Arm/Group Description	The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion.		The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion.
All Cause Mortality
	BI 695500		Rituximab (MabThera®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	BI 695500		Rituximab (MabThera®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/49 (8.2%)		3/46 (6.5%)
Ear and labyrinth disorders
Vertigo	0/49 (0%)		1/46 (2.2%)
Endocrine disorders
Goitre	1/49 (2%)		0/46 (0%)
Immune system disorders
Anaphylactoid reaction	1/49 (2%)		0/46 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/49 (2%)		0/46 (0%)
Psychiatric disorders
Confusional state	0/49 (0%)		1/46 (2.2%)
Renal and urinary disorders
Acute kidney injury	0/49 (0%)		1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Haemothorax	1/49 (2%)		0/46 (0%)
Surgical and medical procedures
Abortion induced	0/49 (0%)		1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	BI 695500		Rituximab (MabThera®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/49 (51%)		28/46 (60.9%)
Blood and lymphatic system disorders
Thrombocytopenia	1/49 (2%)		3/46 (6.5%)
Gastrointestinal disorders
Constipation	0/49 (0%)		3/46 (6.5%)
Diarrhoea	3/49 (6.1%)		3/46 (6.5%)
Gastrooesophageal reflux disease	3/49 (6.1%)		0/46 (0%)
Nausea	2/49 (4.1%)		7/46 (15.2%)
General disorders
Asthenia	6/49 (12.2%)		1/46 (2.2%)
Fatigue	2/49 (4.1%)		4/46 (8.7%)
Pyrexia	4/49 (8.2%)		5/46 (10.9%)
Investigations
Alanine aminotransferase increased	5/49 (10.2%)		3/46 (6.5%)
Aspartate aminotransferase increased	3/49 (6.1%)		3/46 (6.5%)
Blood cholesterol increased	0/49 (0%)		3/46 (6.5%)
Blood lactate dehydrogenase increased	3/49 (6.1%)		1/46 (2.2%)
Gamma-glutamyltransferase increased	3/49 (6.1%)		4/46 (8.7%)
Musculoskeletal and connective tissue disorders
Back pain	4/49 (8.2%)		1/46 (2.2%)
Nervous system disorders
Headache	5/49 (10.2%)		7/46 (15.2%)
Psychiatric disorders
Insomnia	3/49 (6.1%)		1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Cough	2/49 (4.1%)		3/46 (6.5%)
Oropharyngeal pain	1/49 (2%)		4/46 (8.7%)
Skin and subcutaneous tissue disorders
Erythema	3/49 (6.1%)		2/46 (4.3%)
Pruritus	2/49 (4.1%)		7/46 (15.2%)
Vascular disorders
Hypertension	0/49 (0%)		4/46 (8.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.