Study of subcutaneous Ofatumumab Injections for Pemphigus Vulgaris

• Register: EUCTR
• Last refreshed on: 3 July 2017
• Main ID: EUCTR2013-001370-20-HR
• Date of registration: 02/12/2014
• Prospective Registration: No
• Primary sponsor: Novartis Pharma AG
• Public title: Study of subcutaneous Ofatumumab Injections for Pemphigus Vulgaris
• Scientific title: OPV116910: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Investigate the Efficacy and Safety of Ofatumumab Injection for Subcutaneous Use in Subjects with Pemphigus Vulgaris
• Date of first enrolment: 17/11/2014
• Target sample size: 136
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-001370-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, China, Croatia, France, Greece, Israel, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Ukraine, United States

Contacts

• Name: Project Manager, Peggy Niana
• Affiliation: PPD

• Name: Project Manager, Peggy Niana
• Affiliation: PPD

Key inclusion & exclusion criteria

Inclusion criteria:
To be eligible for enrollment in the study, subjects must meet all of the following criteria:

All Subjects
1. Adults (18 through 70 years of age) with clinically-documented diagnosis of PV for >2 months and <10 years.
2. History of biopsy consistent with PV (H and E staining and direct immunofluorescence). If no history, a biopsy may be performed during the Screening Period.
3. At least 1 previous episode of a failed steroid taper (ie, disease flare/relapse) at a prednisone/prednisolone dose >10 mg/day, with a Pemphigus Severity of Clinical Disease score of moderate (2) or severe (3) (may be historical/retrospective assessment (see Appendix 6 and SPM for guidance), where severity of disease at flare/relapse necessitated an increase of >20 mg/day. Note: prednisone/prednisolone dose should not be increased for the sole purpose of entry into this study.

Additional Criteria Prior to Randomization
4. Screening anti-Dsg antibodies consistent with a diagnosis of PV (ie, elevated anti-Dsg3 antibodies).
5. Has initiated and received a stable dose of prednisone/prednisolone from a minimum of 20 mg/day (eg, 0.25 mg/kg/day for an 80-kg person) up to a maximum of 120 mg/day or 1.5 mg/kg/day (whichever is higher) for >= 2 weeks prior to
randomization. (Note: subjects who are on every-other-day dosing regimens need to change to a daily dosing regimen for >= 2 weeks during the Screening Period in order to qualify.)
6. Has exhibited PV disease control, defined as no new lesions for >= 2 weeks.

Additional Criteria for Female Subjects

7. A female subject is eligible to enter the study if she:
a. Is of nonchildbearing potential, who is documented as either surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or post-hysterectomy) or is postmenopausal without menses for >2 years. Women who are <2 years postmenopausal are required to have menopausal status confirmed by folliclestimulating hormone (FSH) and estradiol levels at the screening evaluation. If FSH and estradiol levels do not provide confirmation of menopause, subject will be considered to be of childbearing potential.
b. Is of childbearing potential, defined as a woman who has functional ovaries, ducts, and a uterus with no documented impairment that would cause sterility. This includes women with oligomenorrhea (even severe), women who are perimenopausal, and women who have just begun to menstruate. Subject must:
- Have a negative serum pregnancy test at screening
- Agree to the consistent and correct use of acceptable methods of contraception during heterosexual intercourse, beginning when the subject provides informed consent and lasting until 12 months after last dose of investigational product. Acceptable methods of contraception are limited to the following:
-Oral contraceptives (either combined or progesterone only)
-Injectable progesterone
-Levonorgestrel implants
-Estrogenic vaginal ring
-Percutaneous contraceptive patches
-Intrauterine device or intrauterine system with a documented failure rate of <1% per year
-Male partner sterilization (vasectomy with documentation of
azoospermia) prior to the female subject’s entry into the study; this male must be the subject’s sole partner
-Double-barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository)
-Complete abstinence from heterosexual intercourse, when this is in line with the preferred and usual life
Exclusion criteria:
Subjects meeting any of the following criteria will not be enrolled:

1. Diagnosis of pemphigus foliaceus, paraneoplastic pemphigus, or other autoimmune blistering disease (other than pemphigus vulgaris).
2. Past or current history of hypersensitivity to components of the investigational product or medically significant adverse effects (including allergic reactions) from cetirizine (or antihistamine equivalent) or paracetamol/acetaminophen.
3. Prior treatment with rituximab without achieving disease control within 6 months of initiating rituximab dosing.
4. Prior treatment with any of the following within the specified periods (refer to protocol, table page 38)
5. Confirmed PML, or neurological findings potentially consistent with PML.
6. Evidence or history of clinically significant infection including:
-Chronic or ongoing active infectious disease requiring long-term systemic treatment, including, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C.
-Positive test for hepatitis B surface antigen (HBsAg). For HBsAg negative, but hepatitis B core antibody (anti-HBc/HBcAb) positive (regardless of hepatitis B surface antibody [HbsAb] status), an HBV DNA test will be performed and the subject will be excluded if results are positive. Consult with a physician experienced in the care and management of subjects with hepatitis B to manage/treat subjects who are anti-HBc positive.
-History of positive serology for human immunodeficiency virus.
-Previous serious opportunistic or atypical infections.
-Prior history, or suspicion, of tuberculosis (TB).
7. Past or current malignancy, except for:
-Cervical carcinoma Stage 1B or less.
-Noninvasive basal cell and squamous cell skin carcinoma.
-Cancer diagnoses with a duration of complete response (remission) >5 years.
Note: A history of hematologic malignancy excludes a subject from
participation, regardless of response.
8. Significant concurrent, uncontrolled medical condition that could affect the subject’s safety, impair the subject’s reliable participation in the study, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol.
9. Any of the following screening laboratory values:
-White blood cells (WBC) <3.8 GI/L (<3800/mm3).
-Neutrophils <2 GI/L (<2000/mm3).
-Platelets <130 GI/L (<130,000/mm3).
-Circulating IgG, IgA, or IgM levels <10% of the LLN and requiring treatment in the opinion of the investigator.
-Alanine aminotransferase (ALT) >2.0 times the upper limit of normal (ULN).
-Aspartate aminotransferase (AST) >2.0 x ULN.
-Alkaline phosphatase (ALP) >1.5 x ULN.
-Bilirubin >1.5 x ULN (except in cases of isolated predominantly indirect hyperbilirubinemia due to Gilbert’s syndrome).
10. Use of an investigational drug or other experimental therapy within 4 weeks, 5 pharmacokinetic half-lives, or the duration of biological effect (whichever is longer) prior to Screening.
11. Electrocardiogram (ECG) showing a clinically significant abnormality or showing a QTc interval =450 msec (=480 msec for subjects with a bundle branch block) (ECG to be obtained during Screening/prior to receiving the first dose of study drug).
12. Woman who is breastfeeding.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Pemphigus Vulgaris
MedDRA version: 20.0 Level: LLT Classification code 10052802 Term: Pemphigus vulgaris System Organ Class: 100000004858

Intervention(s)

Product Name: ofatumumab
Product Code: GSK1841157
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: OFATUMUMAB
CAS Number: 679818-59-8
Current Sponsor code: GSK1841157
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: ofatumumab
Product Code: GSK1841157
Pharmaceutical Form: Solution for injection
INN or Proposed INN: OFATUMUMAB
CAS Number: 679818-59-8
Current Sponsor code: GSK1841157
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: -To evaluate the safety and tolerability of ofatumumab SC.
-To evaluate disease flare/relapse during treatment with ofatumumab SC.
-To evaluate reductions in steroid dose while maintaining disease control.
-To assess population pharmacodynamics and the extent of B-cell depletion and repletion following ofatumumab SC
-To evaluate the immunogenicity of ofatumumab SC.
-To assess the population pharmacokinetics of ofatumumab SC.

Primary end point(s): Two co-primary efficacy endpoints will be evaluated:
-Time to SR on minimal steroid therapy (defined as time from randomization to the time the subject initially tapered his/her oral prednisone/prednisolone dose to =10 mg/day and maintained =10 mg/day of oral prednisone/prednisolone with no new or nonhealing lesions for =8 weeks AND maintained that status until Week 60).
-Duration of remission on minimal steroid therapy (defined as total time [sum] of all periods of remission while on minimal steroid therapy [oral prednisone/prednisolone dose of =10 mg/day] up to Week 60).

Main Objective: To determine the efficacy, based on disease remission, of ofatumumab SC at a dose of 20 mg administered every 4 weeks (with an additional 20-mg loading dose [ie, 40 mg total] at both Week 0 and Week 4) in subjects with PV.

Timepoint(s) of evaluation of this end point: week 60

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: week 60

Secondary end point(s): Proportion of subjects achieving remission on minimal steroid therapy (defined as subjects who had an absence of new or nonhealing lesions while on an oral prednisone/prednisolone dose of =10 mg/day for=8 weeks) at Week 60.
-Time to remission while on minimal steroid therapy (defined as time from randomization to the time the subject initially tapered his/her oral prednisone/prednisolone dose to =10 mg/day and maintained =10 mg/day of oral prednisone/prednisolone with no new or nonhealing lesions for =8 weeks) by
Week 60.
-Time to initial flare/relapse (defined as the time from randomization to the time that =3 new lesions within 1 month appear and do not heal spontaneously within 1 week, or to the time when there is an extension of lesions that were present at the randomization visit) by Week 60.
-Proportion of subjects who did not flare/relapse (defined as subjects who achieved remission on minimal steroid therapy and did not subsequently have a flare of disease) by Week 60. A flare/relapse is defined as new lesions that do not heal spontaneously within 1 week, or when there is an extension of lesions that were present at the randomization visit.
-Time to remission off steroid therapy by Week 60 (defined as the time from randomization to the time the subject initially tapered off all steroids for =8 weeks with an absence of new or nonhealing lesions).
-Proportion of subjects achieving remission while off steroid therapy by Week 60.
-Number of days a subject maintained minimal steroid therapy (an oral prednisone/prednisolone dose of =10 mg/day in the absence of new or nonhealing lesions) by Week 60.
-Cumulative dose of corticosteroids.

Secondary ID(s)

2013-001370-20-IT

OPV116910

Source(s) of Monetary Support

Novartis Pharma AG