E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pemphigus Vulgaris |
Vulgarni pemfigus |
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E.1.1.1 | Medical condition in easily understood language |
Pemphigus Vulgaris |
Vulgarni pemfigus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052802 |
E.1.2 | Term | Pemphigus vulgaris |
E.1.2 | System Organ Class | 100000004858 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
Na temelju remisije bolesti u ispitanika s pemfigus vulgarisom utvrditi učinkovitost supkutanog ofatumumaba u dozi od 20 mg svaka 4 tjedna (uz dodatnu udarnu dozu od 20 mg [odnosno ukupno 40 mg] u 0. i 4. tjednu). |
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E.2.2 | Secondary objectives of the trial |
-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. |
Procijeniti sigurnost i podnošljivost supkutanog ofatumumaba.
• Procijeniti pogoršanje/povrat bolesti tijekom liječenja sa supkutanim ofatumumabom.
• Procijeniti smanjenja doza steroida tijekom održavanja kontrole bolesti.
• Procijeniti farmakodinamiku te umnažanje B-stanica nakon primjene supkutanog ofatumumaba.
• Procijeniti imunogeničnost supkutanog ofatumumaba.
• Procijeniti populacijsku farmakokinetiku supkutanog ofatumumaba.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 lifestyle of the subject
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated with, or beneficary of, a social security category. |
Svi bolesnici
1. Odrasle osobe (od 18 do 70 godina) s klinički dokumentiranom dijagnozom pemphigus vulgarisa u trajanju > 2 mjeseca i < 10 godine.
2. Prethodno napravljena biopsija kojom je potvrđen pemphigus vulgaris (bojanjem hematoksilinom i eozinom te izravnom imunofluorescencijom). Ako biopsija nije napravljena, može se napraviti u razdoblju probira.
3. Najmanje 1 prethodna epizoda neuspješnog liječenja steroidima (odnosno pogoršanje bolesti ili relaps na dozi prednizona/prednizolona od > 10 mg/dan).
Dodatni kriteriji prije randomizacije
4. Potvrđena antitijela protiv dezmogleina u skladu s dijagnozom pemphigus vulgarisa (odnosno povišena antitijela protiv Dsg3).
5. Počelo je dobivanje stabilne doze prednizona/prednizolona od najmanje 20 mg/dan (na primjer, 0,25 mg/kg/dan za osobu težine 80 kg) do najviše 120 mg/dan ili 1,5 mg/kg/dan (što god od toga bilo više) u 2 tjedna prije randomizacije. (Napomena: da bi bili podobni, bolesnici koji lijek dobivaju svaki drugi dan moraju prijeći na svakodnevno dobivanje lijeka u 2 tjedna tijekom razdoblja probira.)
6. Pokazalo se da je pemphigus vulgaris pod kontrolom, definiran kao nepostojanje novih lezija u 2 tjedna.
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E.4 | Principal 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.
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Kriteriji za neuključivanje
1. Dijagnoza pemphigus foliaceusa, paraneoplastičnog pemfigusa ili druge autoimune bolesti koja izaziva plikove (osim pemphigus vulgarisa).
2. Prošla ili trenutačna anamneza preosjetljivosti na sastojke ispitivanog lijeka ili medicinski značajne nuspojave (uključujući i alergijske reakcije) od cetirizina (ili antihistaminskog ekvivalenta) ili paracetamola/acetaminofena.
3. Prethodno liječenje rituksimabom bez uspješne kontrole bolesti u 6 mjeseci od početka primanja lijeka.
Prethodno liječenje sljedećim lijekovima u navedenim razdobljima:
Ograničenja lijekova i drugih načina liječenja prije randomizacije
Bilo kad 6 tjedana 8 tjedana 6 mjeseci 18 mjeseci
Ofatumumab, potpuno ozračivanje tijela, transplantacija koštane srži, anti CD4 Žive vakcine Ostali lijekovi za pemfigus uključujući:
– azatioprin
– ciklosporin
– dapson
– mikofenolat
– metotreksat Ciklofosfamid, plazmafereza, liječenje imunoapsorpcijom ili imunoglobulinom, kladribin Rituksimab
Potvrđena progresivna multifokalna leukoencefalopatija ili neurobiološki nalazi koji mogu odgovarati progresivnoj multifokalnoj leukoencefalopatiji (vidjeti priloge 4 i 5).
Dokazana povijest klinički značajne infekcije uključujući:
- kroničnu ili trenutačnu aktivnu infektivnu bolest koja zahtijeva dugotrajno sistemsko liječenje, uključujući, ali se ne ograničavajući samo na kroničnu infekciju bubrega, kroničnu upalnu bolest pluća s bronhiektazom, tuberkulozu ili aktivni hepatitis C;
- pozitivan test na HBsAg. Za HBsAg negativne, ali anti-HBc pozitivne (bez obzira na status HBsAb) napravit će se test HBV DNK, a u slučaju pozitivnih rezultata bolesnik se neće uključiti. Za liječenje ispitanika koji su pozitivni na anti HBc potrebno je konzultirati se s liječnikom koji ima iskustvo u liječenju i zbrinjavanju bolesnika s hepatitisom B.
- anamnezu pozitivnih seroloških nalaza na HIV;
- prethodne ozbiljne oportunističke ili atipične infekcije.
- anamnezu ili sumnju na tuberkulozu.
Prošle ili tekuće maligne bolesti, osim:
- karcinoma vrata maternice stadija 1B ili nižeg;
- neinvazivnog karcinoma bazalnih stanica ili karcinoma skvamoznih stanica kože;
- dijagnoze karcinoma s trajanjem potpunog odgovora (remisije) > 5 godina. Napomena: anamneza hematoloških malignih bolesti isključuje bolesnika iz sudjelovanja, bez obzira na odgovor.
Značajno popratno nekontrolirano zdravstveno stanje koje bi moglo utjecati na sigurnost bolesnika, onemogućiti pouzdano sudjelovanje u ispitivanju i procjenu krajnjih točaka ili zahtijevati primjenu lijekova koji nisu dopušteni planom ispitivanja.
Bilo koja od sljedećih vrijednosti laboratorijskih testova na probiru:
- leukociti < 3,8 GI/l (< 3800/mm3);
- neutrofili < 2 GI/l (< 2000/mm3);
- trombociti < 130 GI/l (< 130.000/mm3);
- razine cirkulirajućeg IgG, IgA ili IgM < 10 % od donje granice normale koje prema mišljenju ispitivača zahtijevaju liječenje;
- alanin aminotransferaza (ALT) > 2,0 puta veća od gornje granice normale;
- aspartat aminotransferaza (AST) > 2,0 puta veća od gornje granice normale;
- alkalna fosfataza (ALP) > 1,5 puta veća od gornje granice normale;
- bilirubin > 1,5 puta veći od gornje granice normale (osim u slučajevima izolirane pretežno indirektne hiperbilirubinemije zbog Gilbertova sindroma).
Dobivanje ispitivanog lijeka ili drugog ispitivanog liječenja u 4 tjedna, 5 farmakokinetičkih vremena poluraspada ili trajanju biološkog djelovanja (što god od toga bilo dulje) prije probira.
Elektrokardiogram (EKG) pokazuje klinički značajnu abnormalnost ili interval QTc ≥ 450 ms (≥ 480 ms za bolesnike s blokom grane) (EKG se mora napraviti na probiru ili prije primanja prve doze ispitivanog lijeka).
Žene koje doje.
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E.5 End points |
E.5.1 | 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). |
1. Vrijeme do održive remisije na minimalnoj dozi steroida.
2. Trajanje remisije na minimalnoj dozi steroida.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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. |
• Omjer ispitanika koji ostvare remisiju na minimalnoj dozi steroida u 60. tjednu.
• Vrijeme do remisije dok su na minimalnoj dozi steroida do 60. tjedna.
• Vrijeme do početnog pogoršanja/povrata bolesti do 60. tjedna.
• Omjer ispitanika kod kojih nije bilo pogoršanja/povrata bolesti do 60. tjedna.
• Vrijeme do remisije nakon prestanka liječenja steroidima do 60. tjedna.
• Omjer ispitanika koji ostvare remisiju nakon prestanka liječenja steroidima do 60. tjedna.
• Broj dana u kojima je ispitanik primao minimalnu dozu steroida do 60. tjedna.
• Kumulativna doza kortikosteroida.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity |
Imunogeničnost |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
China |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS |
Zadnji posjet zadnjeg uključenog ispitanika |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |