A Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil (MMF) in Participants With Pemphigus Vulgaris (PV)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02383589
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 135
• Locations: 68
• Arms: 2
• Actual Duration (Months): 53.1
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Phase III, randomized, double-blind, double-dummy, active-comparator, parallel-arm, multicenter study to evaluate the efficacy and safety of rituximab compared with MMF in participants with moderate-to-severely active PV requiring 60-120 milligrams per day (mg/day) oral prednisone or equivalent. Participants must have a confirmed diagnosis of PV within the previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of active disease at screening.

Approximately 135 participants will be enrolled at up to 60 centers worldwide. Participants will be randomized in a 1:1 ratio to receive either rituximab plus MMF placebo or rituximab placebo plus MMF. Randomization will be stratified by duration of illness.

The study will consist of three periods: a screening period of up to 28 days, a 52-week double-blind treatment period, and a 48-week safety follow up period that begins at the time of study treatment completion or discontinuation.

Condition or Disease	Intervention/Treatment	Phase
Pemphigus Vulgaris	Drug: Mycophenolate Mofetil Placebo; Drug: Mycophenolate Mofetil; Drug: Rituximab; Drug: Rituximab Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Double-Dummy, Active-Comparator, Multicenter Study to Evaluate the Efficacy and Safety of Rituximab Versus MMF in Patients With Pemphigus Vulgaris
• Actual Study Start Date: May 26, 2015
• Actual Primary Completion Date: Nov 28, 2018
• Actual Study Completion Date: Oct 29, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Mycophenolate Mofetil (MMF) Participants will receive MMF orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants will also receive rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met.	Drug: Mycophenolate Mofetil; MMF will be administered at a starting dose of 500 milligrams (mg) Q12H and the dose will be titrated to achieve a goal of 1 gram (gm) Q12H.; Other Names: MMF, CellCept ; Drug: Rituximab Placebo; Rituximab matching placebo will be administered via IV infusion.; Other Names: MabThera/Rituxan
Experimental: Rituximab (RTX) Participants will receive rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met. Participants will also receive MMF matching placebo orally twice daily Q12H from Day 1 to Week 52.	Drug: Mycophenolate Mofetil Placebo; MMF matching placebo will be administered orally Q12H.; Drug: Rituximab; Rituximab will be administered at a dose of 1000 mg via IV infusion.; Other Names: MabThera/Rituxan

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants (Excluding Telemedicine [TM] Participants) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score [From Baseline up to 52 Weeks (up to clinical cut-off date (CCOD) of 28 November 2018)]

Secondary Outcome Measures

1. Cumulative Oral Corticosteroid Dose [From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

2. Total Number of Protocol Defined Disease Flares [From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

   Disease flare is defined as appearance of three or more new lesions a month that do not heal spontaneously within 1 week, or by the extension of established lesions, in a participant who has achieved disease control.

3. Time to Initial Sustained Complete Remission [From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

4. Time to Protocol Defined Disease Flare [From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

   Disease flare is defined as the appearance of three or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a participant who has achieved disease control.

5. Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score [From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

   Total DLQI scores range from 0 to 30 with higher DLQI scores reflecting greater impairment in a participant's health-related quality of life. The DLQI score is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. The measure type mean is the estimated mean from adjusted MMRM.

6. Percentage of Participants With Adverse Events, Serious Adverse Events, and Corticosteroid-Related Adverse Events [Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

   An adverse event is any untoward medical occurrence in a participant to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment. A serious adverse event is an adverse event that results in death or is life-threatening or requires/prolongs hospitalization or results in persistent/significant disability/incapacity or congenital abnormality/birth defect. Adverse events of Grade 3 of higher are severe and life-threatening adverse events CS-related adverse events - causality as determined by the investigator.

7. Percentage of Participants With Anti-Drug Antibodies (ADA) [Baseline up to 52 Weeks (up to CCOD of 28 November 2018)]

   Participants with treatment-induced and treatment-enhanced anti-drug antibodies. The clinical relevance of anti-rituximab antibody formation in RITUXAN treated pemphigus vulgaris (PV) participants is unclear.

8. Percentage of Participants With Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN) [Baseline; Weeks 16, 24, 40 and 52; (end of treatment: up to Week 52) (up to CCOD of 28 November 2018)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of PV within the previous 24 months, based on the presence of histological features of acantholysis via skin or mucosal biopsy and one of the following: tissue bound immunoglobulin G (IgG) antibodies by direct immunofluorescence on the surface of affected epithelium or serological detection of serum desmoglein-3 (DSg3) autoantibodies against epithelial cell surface either by indirect immunofluorescence microscopy or by enzyme-linked immunosorbent assay

• Presence of moderate-to-severely active disease, defined as overall PDAI activity score of greater than or equal to (>/=)15

• Receiving standard-of-care corticosteroids consisting of 60-120 mg/day oral prednisone or equivalent and, in the judgment of the investigator, expected to benefit from the addition of immunosuppressive therapy

• For women who are not postmenopausal (>/=12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two effective methods of contraception, including at least one method with a failure rate of less than (<) 1 percent (%) per year, during the treatment period and for at least 12 months after the last dose of study treatment

Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Barrier methods must always be supplemented with the use of a spermicide

Examples of contraceptive methods with a failure rate of < 1% per year (highly effective contraceptive methods) include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices

• For men (including those who have undergone a vasectomy): agreement to remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of study treatment and agreement to refrain from donating sperm during this same period

Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the participant

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. In addition to male contraception, agreement to advise female partners of childbearing potential to use highly effective contraception during the study and for at least 12 months after the last dose of study treatment

• Agreement to avoid excessive exposure to sunlight during study participation

• Able to comply with the study protocol, in the investigator's judgment

Exclusion Criteria:

• Diagnosis of pemphigus foliaceus or evidence of paraneoplastic pemphigus or other non-PV autoimmune blistering disease

• History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies, or known hypersensitivity to any component of rituximab

• Known hypersensitivity or contraindication to MMF, mycophenolic acid, polysorbate, or oral corticosteroids

• Lack of peripheral venous access

• Pregnant or lactating, or intending to become pregnant during the study

Women who are not postmenopausal (>/=12 months of non-therapy-induced amenorrhea) or surgically sterile must have two negative results with a sensitivity of >/=25 milli-international units per milliliter (mIU/mL): one from a serum pregnancy test at Day -8 to Day -10 of screening and another from a urine pregnancy test at Day 1 prior to randomization

• Participated in another interventional clinical trial within 28 days prior to randomization

• Use of any investigational agent within 28 days or 5 elimination half-lives prior to randomization (whichever is the longer)

• Significant cardiovascular or pulmonary disease (including obstructive pulmonary disease)

• Evidence of any new or uncontrolled concomitant disease that, in the investigator's judgment, would preclude participant participation, including but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders

• Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization

• Treatment with intravenous (IV) immunoglobulin (Ig), plasmapheresis, or other similar procedure within 8 weeks prior to randomization

• Treatment with immunosuppressive medications (e.g., azathioprine, MMF) within 1 week prior to randomization

• Treatment with cyclophosphamide within 12 weeks prior to randomization

• History of or currently active primary or secondary immunodeficiency, including known history of HIV infection and other severe immunodeficiency blood disorders

• Known active infection of any kind (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to randomization; entry into this study may be reconsidered once the infection has fully resolved

• History of or current cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except complete excision of basal cell of the skin and squamous cell carcinoma of the skin that have been treated or excised and cured)

• Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening

• Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery

• Treatment with rituximab or a B cell-targeted therapy (e.g., anti-cluster of differentiation [CD] 20 [CD20], anti CD22, or anti-B-lymphocyte stimulator [BLyS]) within 12 months prior to randomization

• Treatment with a live or attenuated vaccine within 28 days prior to randomization; it is recommended that a participant's vaccination record and the need for immunization prior to study entry be carefully investigated

• Evidence of abnormal liver enzymes or hematology laboratory values

• Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) serology at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Birmingham	Birmingham	Alabama	United States	35294
2	University of Arizona Medical Research Office	Tucson	Arizona	United States	85724
3	UC Davis Department of Dermatology	Sacramento	California	United States	95816
4	Univ of Calif-San Francisco	San Francisco	California	United States	94115
5	Los Angeles Biomedical Research Institute	Torrance	California	United States	90502
6	Northwestern University	Chicago	Illinois	United States	60611
7	Massachusetts General Hospital Dermatology	Boston	Massachusetts	United States	02114
8	University of Minnesota	Minneapolis	Minnesota	United States	55455
9	St Louis University Hospital	Saint Louis	Missouri	United States	63104
10	Uni of NY and Roswell Cancer	Buffalo	New York	United States	14203
11	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
12	Wake Forest Baptist Hospital Center for Dermatology Research	Winston-Salem	North Carolina	United States	27104
13	Cleveland Clinic	Cleveland	Ohio	United States	44195
14	Oregon Health Sciences Uni	Portland	Oregon	United States	97239
15	Penn University	Philadelphia	Pennsylvania	United States	19104
16	Hospital Italiano	Buenos Aires		Argentina	C1181ACH
17	Centro de Investigaciones Médicas - CIM	Florencio Varela		Argentina	1888
18	Hospital Luis Lagomaggiore	Mendoza		Argentina	5500
19	Hospital Austral	Pilar, Pcia De Buenos Aires		Argentina	1500
20	St George Hospital	Kogarah, New South Wales	New South Wales	Australia	2217
21	Veracity Clinical Research	Woolloongabba	Queensland	Australia	4102
22	Faculdade de Medicina de Botucatu - Hospital das Clínicas	Botucatu	SP	Brazil	18618-970
23	Hospital das Clinicas - FMUSP	Sao Paulo	SP	Brazil	05403-000
24	Santa Casa de São Paulo Hospital Central X	São Paulo	SP	Brazil	01221-020
25	University of Alberta	Edmonton	Alberta	Canada	T6G 2G3
26	Guildford Dermatology	Surrey	British Columbia	Canada	V3R 6A7
27	Lynde Institute for Dermatology	Markham	Ontario	Canada	L3P 1X2
28	Department of Dermatology Avicenne Hospital & University	Bobigny		France	93000
29	CHU Hopitaux de Bordeaux	CHU Hopitaux De Bordeaux		France	33000
30	Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez	Lille		France	59037
31	Les Hospices Civils de Lyon Dermatologie inflammatoire et médecine interne	Lyon / Pierre Bénite		France	69495
32	CHU de Reims	Reims		France	51100
33	CHU de Rennes - Hopital de Pontchaillo	Rennes		France	35033
34	CHU de Rouen - Hôpital Charles Nicolle	Rouen		France	76031
35	CHU Saint Etienne - Hôpital Nord	Saint Etienne		France	42055
36	University Hospital for Dermatology	Dresden		Germany	01304
37	Kompetenzzentrum Fragile Haut Klinik fur Dermatologie und Venerologie	Freiburg		Germany	79104
38	Universitätsklinikum Heidelberg	Heidelberg		Germany	69120
39	Klinik und Poliklinik für Dermatologie und Venerologie Universitätsklinikum Köln	Koeln		Germany	50937
40	University Hospital Schleswig-Holstein	Lübeck		Germany	23538
41	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR, Hautklinik und Poliklinik	Mainz		Germany	55131
42	University of Munster	Muenster		Germany	48149
43	HaEmek MC	Afula		Israel	18341
44	Rambam Medical Centre; Dept. of Dermatology	Haifa		Israel	31096
45	Rabin Medical Centre; Dept. of Dermatology	Petach Tikva		Israel	49100
46	Sheba Medical Center	Ramat Gan		Israel	5262100
47	Sourasky Medical Centre	Tel-Aviv		Israel	6423906
48	Ambulatorio di Malattie Rare e Immunopatologia Cutanea	Florence	Lazio	Italy	50125
49	Università di Parma Clinica Dermatologica	Parma	Lazio	Italy
50	U.O. Dermatologia Dipartimento Malattie Infettive Fondazione IRCCS Policlinico San Matteo	Pavia	Lazio	Italy	27100
51	Centro Clinico per le genodermatosi Dipartimento di Dermatologia dell'Immacolata - IRCCS	Rome	Lazio	Italy	00167
52	S.C. Dermatologia 2 - Ambulatorio Malattie Rare	Turin	Lazio	Italy	10126
53	ASST DEGLI SPEDALI CIVILI DI BRESCIA; Clinica Dermatologica	Brescia	Lombardia	Italy	25123
54	Clinica Universitaria de Navarra	Pamplona	Navarra	Spain	31008
55	Hospital Clínic. Barcelona	Barcelona		Spain	08036
56	Hosp. G. U Gregorio Marañón	Madrid		Spain	28007
57	Hospital de la Victoria	Malaga		Spain	29010
58	Gülhane Military Medical Academy in Ankara	Ankara		Turkey
59	Akdeniz University Medical Faculty	Antalya		Turkey	07059
60	Gaziantep University Medical Faculty Sahinbey Hospital	Gaziantep		Turkey
61	Bezm-i Alem University Medical Faculty	Istanbul		Turkey	34093
62	Istanbul Uni Istanbul Medical Faculty	Istanbul		Turkey	34093
63	Haydarpasa Numune Training and Research Hospital	Istanbul		Turkey	34668
64	Marmara Uni	Istanbul		Turkey
65	Celal Bayar University Medical Faculty Hafsa Sultan Hospital	Manisa		Turkey	45040
66	Karadeniz Teknik Üniversitesi Tıp Fakültesi Farabi Hastanesi	Trabzon		Turkey
67	Dnipropetrovsk State Medical Academy	Dnipropterovsk		Ukraine
68	Territorial Medical Association "Dermatovenerologia"	Kyiv		Ukraine	01032

Sponsors and Collaborators

• Hoffmann-La Roche
• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Dec 19, 2017
• Statistical Analysis Plan - Oct 18, 2019

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02383589
• Other Study ID Numbers: WA29330; 2014-000382-41
• First Posted: Mar 9, 2015
• Last Update Posted: Nov 10, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Pemphigus; Mycophenolic Acid; Rituximab

Study Results

Participant Flow

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants who withdrew from the treatment period or who completed the total 52-week treatment period entered the safety follow up (SFU) period, and they were observed for 1 year and did not receive any further study treatment.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants who withdrew from the treatment period or who completed the total 52-week treatment period entered the safety follow up (SFU) period, and they were observed for 1 year and did not receive any further study treatment.
Period Title: Treatment Period
STARTED	67	68
COMPLETED	66	58
NOT COMPLETED	1	10
Period Title: Treatment Period
STARTED	66	58
COMPLETED	59	53
NOT COMPLETED	7	5

Baseline Characteristics

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)	Total
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants who withdrew from the treatment period or who completed the total 52-week treatment period entered the safety follow up (SFU) period, and they were observed for 1 year and did not receive any further study treatment.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants who withdrew from the treatment period or who completed the total 52-week treatment period entered the safety follow up (SFU) period, and they were observed for 1 year and did not receive any further study treatment.	Total of all reporting groups
Overall Participants	67	68	135
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.66 (12.98)	46.34 (13.08)	48.48 (13.16)
Sex: Female, Male (Count of Participants)
Female	35 52.2%	38 55.9%	73 54.1%
Male	32 47.8%	30 44.1%	62 45.9%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	13 19.4%	21 30.9%	34 25.2%
Not Hispanic or Latino	45 67.2%	41 60.3%	86 63.7%
Not Stated	8 11.9%	5 7.4%	13 9.6%
Unknown	1 1.5%	1 1.5%	2 1.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.5%	1 0.7%
Asian	3 4.5%	1 1.5%	4 3%
Black or African American	1 1.5%	2 2.9%	3 2.2%
White	49 73.1%	51 75%	100 74.1%
Unknown	14 20.9%	13 19.1%	27 20%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants (Excluding Telemedicine [TM] Participants) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score
Time Frame	From Baseline up to 52 Weeks (up to clinical cut-off date (CCOD) of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included participants in the ITT population (all randomized participants who received any part of an infusion of study drug or oral administration of study drug), excluding the 10 telemedicine (TM) participants. This population was used in the analyses of efficacy outcomes.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	62	63
Number [Percentage of Participants]	40.3 60.1%	9.5 14%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab (RTX), Mycophenolate Mofetil (MMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The analysis was stratified by the stratification factors applied at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion
	Estimated Value	30.80
	Confidence Interval	(2-Sided) 95%; 14.70 to 45.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Cumulative Oral Corticosteroid Dose
Time Frame	From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The mITT population included participants in the ITT population (all randomized participants who received any part of an infusion of study drug or oral administration of study drug), excluding the 10 TM participants. This population was used in the analyses of efficacy outcomes.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	62	63
Median (Inter-Quartile Range) [milligram (mg)]	2775.00	4005.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab (RTX), Mycophenolate Mofetil (MMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Total Number of Protocol Defined Disease Flares
Description	Disease flare is defined as appearance of three or more new lesions a month that do not heal spontaneously within 1 week, or by the extension of established lesions, in a participant who has achieved disease control.
Time Frame	From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The mITT population included participants in the ITT population (all randomized participants who received any part of an infusion of study drug or oral administration of study drug), excluding the 10 TM participants. This population was used in the analyses of efficacy outcomes.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	62	63
Number [Number of Flares]	6	44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab (RTX), Mycophenolate Mofetil (MMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The model was adjusted for the following covariates in addition to log (each participant's duration in study) as an offset: treatment, region, duration of illness, baseline PDAI activity score, and baseline prednisone dose.
	Method	Negative Binominal Regression
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to Initial Sustained Complete Remission
Time Frame	From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The mITT population included participants in the ITT population (all randomized participants who received any part of an infusion of study drug or oral administration of study drug), excluding the 10 TM participants. This population was used in the analyses of efficacy outcomes.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	62	63
Median (95% Confidence Interval) [Weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab (RTX), Mycophenolate Mofetil (MMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	P-value is from a stratified log-rank test used to test the time to first disease flare between the RTX and MMF treatment arms over the 52-week treatment period, adjusting for the stratification factors applied at randomization
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	4.83
	Confidence Interval	(2-Sided) 95%; 1.97 to 11.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time to Protocol Defined Disease Flare
Description	Disease flare is defined as the appearance of three or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a participant who has achieved disease control.
Time Frame	From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The mITT population included participants in the ITT population (all randomized participants who received any part of an infusion of study drug or oral administration of study drug), excluding the 10 TM participants. This population was used in the analyses of efficacy outcomes.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	62	63
Median (95% Confidence Interval) [Weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab (RTX), Mycophenolate Mofetil (MMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is from a stratified log-rank test used to test the time to first disease flare between the RTX and MMF treatment arms over the 52-week treatment period, adjusting for the stratification factors applied at randomization
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score
Description	Total DLQI scores range from 0 to 30 with higher DLQI scores reflecting greater impairment in a participant's health-related quality of life. The DLQI score is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. The measure type mean is the estimated mean from adjusted MMRM.
Time Frame	From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The mITT population included participants in the ITT population (all randomized participants who received any part of an infusion of study drug or oral administration of study drug), excluding the 10 TM participants. This population was used in the analyses of efficacy outcomes. Only participants for whom data were collected are included in the analysis.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	62	63
Baseline	10.14 (7.89)	11.09 (8.52)
Week 52	-8.874 (0.532)	-6.002 (0.662)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab (RTX), Mycophenolate Mofetil (MMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments	P-value is from Mixed Model Repeated Measures (MMRM) with unstructured covariance matrix, adjusting for treatment, region, duration of illness, baseline DLQI score, visit, and an interaction terms for visit × baseline DLQI score and visit × treatment
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Difference in Estimated Means
	Estimated Value	-2.872
	Confidence Interval	(2-Sided) 95%; -4.577 to -1.167
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants With Adverse Events, Serious Adverse Events, and Corticosteroid-Related Adverse Events
Description	An adverse event is any untoward medical occurrence in a participant to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment. A serious adverse event is an adverse event that results in death or is life-threatening or requires/prolongs hospitalization or results in persistent/significant disability/incapacity or congenital abnormality/birth defect. Adverse events of Grade 3 of higher are severe and life-threatening adverse events CS-related adverse events - causality as determined by the investigator.
Time Frame	Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who were randomized and received any part of an infusion of study drug or oral administration of study drug.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	67	68
Participants with AE	85.1 127%	88.2 129.7%
Participants with SAE	22.4 33.4%	14.7 21.6%
Participants with Corticosteroid (CS)-Related AE	34.3 51.2%	38.2 56.2%
Participants with CS-Related AE Grade 3 or higher	1.5 2.2%	7.4 10.9%

8. Secondary Outcome

Title	Percentage of Participants With Anti-Drug Antibodies (ADA)
Description	Participants with treatment-induced and treatment-enhanced anti-drug antibodies. The clinical relevance of anti-rituximab antibody formation in RITUXAN treated pemphigus vulgaris (PV) participants is unclear.
Time Frame	Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The safety population (all participants who were randomized and received any part of an infusion of study drug), only participants for whom data were collected are included in the analysis.

Arm/Group Title	Rituximab (RTX)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.
Measure Participants	67
Number [Percentage of Participants]	31.7 47.3%

9. Secondary Outcome

Title	Percentage of Participants With Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN)
Time Frame	Baseline; Weeks 16, 24, 40 and 52; (end of treatment: up to Week 52) (up to CCOD of 28 November 2018)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who were randomized and received any part of an infusion of study drug or oral administration of study drug.

Arm/Group Title	Rituximab (RTX)	Mycophenolate Mofetil (MMF)
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.	Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
Measure Participants	67	68
Baseline (IgA)	0 0%	0 0%
Week 16 (IgA)	0 0%	1.8 2.6%
Week 24 (IgA)	1.7 2.5%	2.2 3.2%
Week 40 (IgA)	0 0%	2.7 4%
Week 52 (IgA)	0 0%	3.6 5.3%
Baseline (IgG)	6.1 9.1%	6.0 8.8%
Week 16 (IgG)	9.8 14.6%	1.8 2.6%
Week 24 (IgG)	3.4 5.1%	2.2 3.2%
Week 40 (IgG)	3.5 5.2%	0 0%
Week 52 (IgG)	4.3 6.4%	0 0%
Baseline (IgM)	7.6 11.3%	11.9 17.5%
Week 16 (IgM)	24.6 36.7%	23.2 34.1%
Week 24 (IgM)	27.1 40.4%	28.3 41.6%
Week 40 (IgM)	29.8 44.5%	24.3 35.7%
Week 52 (IgM)	29.8 44.5%	28.6 42.1%

Adverse Events

Time Frame	Treatment Period: From Baseline up to Week 52 (up to CCOD of 28 November 2018) Safety Follow-up Period: Approximately 1 year (up to CCOD of 29 October 2019)
Adverse Event Reporting Description	The safety population included all participants who were randomized and received any part of an infusion of study drug or oral administration of study drug. Participants who received the incorrect therapy from that assigned were summarized according to the therapy actually received. This population was used for the analyses of safety outcomes. Only serious adverse events and all infectious adverse events, irrespective of causality, were reported in the SFU period.
Arm/Group Title	Rituximab (RTX)		Mycophenolate Mofetil (MMF)		RTX Safety Follow-up		MMF Safety Follow-up
Arm/Group Description	Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52.		Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.		Participants, who received RTX in the treatment period, and either withdrew from the treatment period or completed the total 52-week treatment period, entered the SFU period. Participants were observed for 1 year and did not receive any further study treatment.		Participants, who received MMF in the treatment period, and either withdrew from the treatment period or completed the total 52-week treatment period, entered the SFU period. Participants were observed for 1 year and did not receive any further study treatment.
All Cause Mortality
	Rituximab (RTX)		Mycophenolate Mofetil (MMF)		RTX Safety Follow-up		MMF Safety Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0%)		1/68 (1.5%)		0/66 (0%)		0/58 (0%)
Serious Adverse Events
	Rituximab (RTX)		Mycophenolate Mofetil (MMF)		RTX Safety Follow-up		MMF Safety Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/67 (22.4%)		10/68 (14.7%)		4/66 (6.1%)		1/58 (1.7%)
Cardiac disorders
MYOCARDIAL INFARCTION	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
Gastrointestinal disorders
ABDOMINAL PAIN	1/67 (1.5%)	2	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
HAEMATEMESIS	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
ILEUS	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
INCARCERATED UMBILICAL HERNIA	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
Immune system disorders
Haemophagocytic lymphohistiocytosis	0/67 (0%)	0	0/68 (0%)	0	1/66 (1.5%)	1	0/58 (0%)	0
Infections and infestations
BURSITIS INFECTIVE	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
CELLULITIS	1/67 (1.5%)	1	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
HERPES ZOSTER	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
INFLUENZA	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
PNEUMONIA	1/67 (1.5%)	1	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
PNEUMONIA VIRAL	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
PYELONEPHRITIS	1/67 (1.5%)	1	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
PYELONEPHRITIS ACUTE	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
SEPSIS	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
SKIN INFECTION	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
UPPER RESPIRATORY TRACT INFECTION	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
Septic shock	0/67 (0%)	0	0/68 (0%)	0	1/66 (1.5%)	1	0/58 (0%)	0
Injury, poisoning and procedural complications
INFUSION RELATED REACTION	3/67 (4.5%)	3	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
LUMBAR VERTEBRAL FRACTURE	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
PELVIC FRACTURE	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
Road traffic accident	0/67 (0%)	0	0/68 (0%)	0	1/66 (1.5%)	1	0/58 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
SMALL CELL LUNG CANCER	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
Nervous system disorders
PARAESTHESIA	1/67 (1.5%)	1	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
Cerebrovascular accident	0/67 (0%)	0	0/68 (0%)	0	1/66 (1.5%)	1	0/58 (0%)	0
Syncope	0/67 (0%)	0	0/68 (0%)	0	1/66 (1.5%)	1	0/58 (0%)	0
Renal and urinary disorders
URINARY RETENTION	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
DYSPNOEA	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
PULMONARY EMBOLISM	1/67 (1.5%)	1	2/68 (2.9%)	2	0/66 (0%)	0	0/58 (0%)	0
Skin and subcutaneous tissue disorders
SKIN ULCER	0/67 (0%)	0	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
Neutrophilic dermatosis	0/67 (0%)	0	0/68 (0%)	0	0/66 (0%)	0	1/58 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Rituximab (RTX)		Mycophenolate Mofetil (MMF)		RTX Safety Follow-up		MMF Safety Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/67 (62.7%)		41/68 (60.3%)		2/66 (3%)		3/58 (5.2%)
Blood and lymphatic system disorders
LYMPHOPENIA	8/67 (11.9%)	14	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
Gastrointestinal disorders
DIARRHOEA	3/67 (4.5%)	5	10/68 (14.7%)	11	0/66 (0%)	0	0/58 (0%)	0
NAUSEA	2/67 (3%)	4	4/68 (5.9%)	4	0/66 (0%)	0	0/58 (0%)	0
General disorders
ASTHENIA	4/67 (6%)	5	4/68 (5.9%)	4	0/66 (0%)	0	0/58 (0%)	0
FATIGUE	5/67 (7.5%)	8	3/68 (4.4%)	3	0/66 (0%)	0	0/58 (0%)	0
OEDEMA PERIPHERAL	2/67 (3%)	2	6/68 (8.8%)	8	0/66 (0%)	0	0/58 (0%)	0
Infections and infestations
NASOPHARYNGITIS	6/67 (9%)	8	8/68 (11.8%)	12	0/66 (0%)	0	0/58 (0%)	0
ORAL CANDIDIASIS	6/67 (9%)	8	6/68 (8.8%)	6	0/66 (0%)	0	0/58 (0%)	0
UPPER RESPIRATORY TRACT INFECTION	6/67 (9%)	9	5/68 (7.4%)	6	2/66 (3%)	2	3/58 (5.2%)	3
URINARY TRACT INFECTION	5/67 (7.5%)	6	2/68 (2.9%)	2	0/66 (0%)	0	0/58 (0%)	0
Injury, poisoning and procedural complications
INFUSION RELATED REACTION	12/67 (17.9%)	19	5/68 (7.4%)	6	0/66 (0%)	0	0/58 (0%)	0
Metabolism and nutrition disorders
HYPOPHOSPHATAEMIA	5/67 (7.5%)	5	0/68 (0%)	0	0/66 (0%)	0	0/58 (0%)	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA	6/67 (9%)	6	2/68 (2.9%)	2	0/66 (0%)	0	0/58 (0%)	0
BACK PAIN	6/67 (9%)	6	1/68 (1.5%)	1	0/66 (0%)	0	0/58 (0%)	0
Nervous system disorders
DIZZINESS	4/67 (6%)	4	2/68 (2.9%)	2	0/66 (0%)	0	0/58 (0%)	0
HEADACHE	10/67 (14.9%)	17	6/68 (8.8%)	7	0/66 (0%)	0	0/58 (0%)	0
Psychiatric disorders
INSOMNIA	1/67 (1.5%)	1	6/68 (8.8%)	6	0/66 (0%)	0	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
COUGH	6/67 (9%)	6	2/68 (2.9%)	2	0/66 (0%)	0	0/58 (0%)	0
OROPHARYNGEAL PAIN	4/67 (6%)	4	3/68 (4.4%)	3	0/66 (0%)	0	0/58 (0%)	0
Skin and subcutaneous tissue disorders
ALOPECIA	2/67 (3%)	2	5/68 (7.4%)	5	0/66 (0%)	0	0/58 (0%)	0
Vascular disorders
HYPERTENSION	2/67 (3%)	2	4/68 (5.9%)	4	0/66 (0%)	0	0/58 (0%)	0

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 only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.